THE EMERGENCE OF MEANING IN

BIOLOGICAL SYSTEMS

THESIS SUBMITTED FOR THE DEGREE OF

“DOCTOR OF PHILOSOPHY”

BY

URI HERSHBERG

SUBMITTED TO THE SENATE OF THE HEBREW UNIVERSITY

OCTOBER 2003
 THE EMERGANCE OF MEANING IN
BIOLOGICAL SYSTEMS

THESIS SUBMITTED FOR THE DEGREE OF

“DOCTOR OF PHILOSOPHY”

BY

URI HERSHBERG

SUBMITTED TO THE SENATE OF THE HEBREW UNIVERSITY

OCTOBER 2003
This work was carried out under the supervision of
Prof. Sorin Solomon of the Hebrew University and
Prof. Irun R. Cohen of the Weizmann institute.
I would like to dedicate this thesis to my parents Dov and Aia
Hershebrg and to the person I always look for, who keeps the world
at bay when I cannot - Shira Ninio.

“…. I love her and that's the beginning of everything.”

~F. Scott Fitzgerald~
 Acknowledgments

Every word in this thesis is a collaboration and so I have a long list of people
to thank. I was aided and abetted, both scientifically and in finding the proper
elegant turn of phrase, by Shira, by my family – Dubi, Aia and Ruthi, and by
more good and wise friends than I deserve: Prof. Anat Ninio, Prof. Evelyne
Andryewsky, Dr. Yoram Louzoun, Mr. Sol Efroni and Mr. Eldad Betelheim, to
name but those that top the list. I was also extremely fortunate to have a
committee of open minded and far seeing professors. I would thus like to also
thank Prof. Henri Atlan, Prof. Lee Segal and Prof. Stefan Brocke for being kind
enough to listen to my thoughts and give advice and insights from their wide
and varied experience.

Lastly and most importantly I would like to take this opportunity to thank my
supervisors Prof. Irun R. Cohen and Prof. Sorin Solomon for all the vistas and
opportunities they have opened before me. It has been a great joy to travel in
science with them.
 Summary

'The time has come,' the Walrus said,

'To talk of many things:’
The Walrus and the Carpenter in Alice in Wonderland by Lewis Carroll.

This is a work of interdisciplinary research. It contains concepts form biology,

physics and cognitive science. We take principles from cognition and show
how attempts to see immune reactions as cognitive reactions radically change
our view of how immunity works and what its functions are. Likewise we
study the immune system as an example of cognitive perception and find new
basic principles of cognitive development and of the environments in which
they can develop. In this thesis we present the results of simulations of the T
cell repertoire and of HIV dynamics and discuss theoretical insights into
cognitive systems in general and the immune system in particular.

The theory of Useful Examples: - We built a theory of cognitive systems and

the common strategies of interaction which are at the basis of their
capabilities. At the heart of this theory is the concept of Useful Examples.
Cognitive systems must learn to be cognitive systems. We present a view of
the system's mode of learning which we describe as a direct result of
unsupervised interactions with concrete examples of the environment. Such a
simple form of learning is sufficient to allow the system an understanding of
its environment because the environment is ordered. There are a few
examples which are encountered with high frequency while most other
examples are encountered less frequently. The high frequency examples are
not ubiquitous by chance. Their prevalence reflects a multiplicity of use within
the interaction of system and environment. We call such examples of the
environment Useful Examples because they are useful for learning the most
relevant general properties of the environment.

In a sense we have built up a theory for the common form of environments

that cognitive systems interact with. Our theory suggests a new model of
research for cognitive systems. The focus, in studying cognitive systems and
their capabilities of interaction in their environment, shifts from attempting to
decipher a system’s function to finding the natural distribution of examples in
the environment and the identification of the Useful Examples.

Models of immune cognition: The theoretical conclusions regarding cognitive

systems are utilized to build models of immune dynamics interacting correctly
with their environment (T cell repertoire) and when the immune system is
fooled by disease (HIV).

Our method is to study how the manipulation of relationships between

receptors and the examples that excite them educates the immune system.
To do so we employ Microscopic Simulations of immune dynamics and the
relations in shape space1 between immune receptors and the antigens that
excite them. Presented here are two models:

− A model of T cell repertoire dynamics in health, and following a

primary infection.

− A model of HIV short-term and long-term progression.

A functioning (cognitive) immune system: - By considering the distribution of

examples encountered naturally by the immune system, we can identify the
Useful Examples of immune interaction. We described how the study of the
natural distribution of examples encountered by the immune system in our
body enhances our understanding of the immune system and its capabilities.

We did this with a model of a functioning T cell repertoire in health and

following a primary infection. Our simulation was that of a generic scenario
of the T cell repertoire that replicates the time course of a response to a
primary infection and the return to steady state. Our model closely followed

1
Shape space is an imaginary space in which entities represent receptors /
ligands. Receptors and ligands at nearby points on shape space, to each
other, are at high affinity and those at distant points are at low affinity.
the dynamics and shape distribution of T cells and the self and non self
antigens in the shape space of T cell and antigen forms. Our ability to
replicate known T cell repertoire dynamics shows the need for a reevaluation
of several basic principles of immunology. In particular, by suggesting how
the immune system treats the self as the background signal of its reactions,
we change the place of self-reactivity in immune function. Such a change
causes a paradigm shift towards a cognitive view of the immune system.

Self-reactivity is now the basis not the nemesis of immune reaction. More
importantly immune function is focused not merely on foreign exclusion but
rather on self maintenance in general. These conceptual shifts have one
major conclusion for immune research. The immune system is always active
and its activity (and reactivity) in disease is based on its activity in health.
Therefore the focus of immune research must shift from studying the body in
state of distress (i.e. disease). Instead we should study the immune system
under conditions of health so as to understand its function in conditions of
disease.

HIV - A (cognitive) immune system’s conceptual mistake: - As we have said, a

cognitive system is tested by the way it interacts with its environment. The
interaction is with the system’s conceptual picture of reality and not just
directly with the individual signals that form this picture. This dual form of
interaction leads to the abilities of a cognitive system but also implies that we
should find the system makes conceptual mistakes in the way it interprets its
environment. Our model of HIV progression illustrates how a misconception in
the immune system’s conceptual picture of its viral invader leads to the long
term latency of HIV ending in AIDS. We show how HIV hyper-mutation (i.e.
diffusion in shape space) allows HIV to hide form the repeated successes of
the immune system against it. The AIDS virus manipulates the immune
system into thinking it is dealing with more and more ‘new’ diseases until it is
tired out and collapses.
We thus further strengthen the cognitive outlook of immune dynamics in our
model of the shape space interaction of the immune system and the AIDS
virus. The cognitive outlook not only enables us to describe the working
immune system but also works in the case of a duped immune system, as we
succeed in connecting between the known progression of normal viral
infection and the long-term latency and progression of HIV.

Coda: - Our final conclusions have to do with the study of cognitive systems
in general. Our interest in shape space raises new questions as to the kinds of
environment in which cognitive systems develop. It also leads us to some
novel conclusions, namely that for a naïve cognitive system to develop its
capabilities, the environment it encounters needs to have some internal order.
This order is naturally existent for our cognitive systems because we have
evolved to certain niches. We are blinkered by our history from the infinite
possibilities of creation towards specific parts of reality. However, in these
limitations lie our abilities to reach cognitive perception.

We have shown how this concept of Useful Examples is central to the study of
cognitive systems, and suggest that it especially pertains to the design of
artificial systems. We offer a new formulation of the design question for
building artificial cognitive systems. Rather than asking how to create artificial
systems that function as cognitive systems, we ask how to define Useful
Examples in the environment so that through interaction with them the
system creates itself. This is especially pertinent in complex environments
where no natural cognitive system exists, such as for instance the information
space of the Internet. Following the theory of Useful Examples, we are no
longer aiming to create agents which function intelligently in the net. Rather,
we ask how can we divide the net into niches in which different agents, by
their interaction with these niches, will find Useful Examples. The new
question is an improvement since it acknowledges the interconnectedness of
the system, its development and its environment.
Contents
1.Introduction ..........................................................................................6
Emergence of immune meaning and cognition .........................................6
Meaning and information........................................................................6
Autopoesis ............................................................................................7
The cognitive paradigm of immune dynamics...........................................8
The immune system ..............................................................................8
The clonal selection theory .....................................................................9
A cognitive view of the immune system ...................................................9
Shape space ....................................................................................... 10
Microscopic Simulations of shape space................................................. 11
2. Methods ............................................................................................. 13
Microscopic Simulations of the immune system ...................................... 15
3. Results............................................................................................... 18
The theory of Useful Examples and optimal exemplar learning in cognitive
systems .............................................................................................. 18
Paper 1: The Immune system and other cognitive systems.................. 19
Paper 2: Optimal exemplar learning in cognitive systems ..................... 27
Self affinity is the basis not the nemesis of immune reaction ................... 36
Paper 1: What is the basis of the immune system's specificity? ............ 38
Paper 2: Useful Examples and a new model of the immune system ...... 45
HIV time hierarchy - Winning the war while loosing all the battles ........... 56
4. Discussion .......................................................................................... 70
HIV .................................................................................................... 70
The place of self affinity in immune capabilities...................................... 71
The shape space of cognitive systems ................................................... 72
References ............................................................................................. 75

5
1.Introduction

Not everything that can be counted counts,

and not everything that counts can be counted.
Albert Einstein

Emergence of immune meaning and cognition

We suggest a novel theoretical framework to study immune dynamics. In this

framework the interaction of chemical signals to which the immune system
reacts builds a conceptual picture of the immune environment. The immune
system like other cognitive perceptual systems reacts to the overall picture
and not to any one of the individual signals from which it is built.

We built several computer simulations showing how the conceptual picture is

built and how it is sometimes subverted by disease.

In building these models we use the immune system as a specific example of

the general mechanisms that allow meaning to emerge from the natural
interaction of biological systems and their environment. The immune system
is a very interesting system to study in this context. This is true not only
because of the general dividends to our survival that understanding of
immunity gives us, but also because the immune system is a system whose
definition of self is a cognitive one (Cohen 2000).

Meaning and information

To explain this point let us start by differentiating between meaning and

information. Biological systems and the immune system among them deal
with meanings, not with information (Atlan & Cohen 1999). For a definition of
information we go back to Shannon’s theory of information. This model is
extremely robust since it holds true regardless of the form of the information
borne by the message or its eventual result. Whether we analyze the
transference of a phone message or the transcription of DNA to mRNA we can

6
find the loss of ‘Shannon’ information due to noise. However, this very
impartiality to the ‘form’ of the message is a weakness when dealing with
biological and cognitive systems. In such systems practically all signals are
context dependent. For instance, two sentences may have the exact same
amount of Shannon information but, through differences in order, convey
completely different meaning. Information, as discussed above, is a property
of the intrinsic organization of the message in the form of a frequency
distribution of its elements. The meaning of the message, in contrast, is the
relationship of the message to some reference point outside of the
information borne by the message. Meaning is referential and contingent.

A further point lacking in Shannon’s theory is the neglect of the creation of

new information. Self-organizing systems like the brain, the immune system
and even uni-cellular organisms create new information and are not merely
transmitters of pre existing information. To solve this second problem H. Atlan
developed a formal theory to resolve the paradoxical loss of information
which is necessary for diversification or ‘ Complexity from noise’ (Atlan 1983).

In principle this theory states that the effect of noise in a channel is different
when appreciated at the output of a channel or on a system which contains
the channel as one of its parts. For example, a mutation in an antibody gene,
which disorganizes the gene’s original string of nucleic acids, could produce a
new gene encoding a new antibody that could add information to the
organism as a whole. In order that this diversification does not come at the
expense of prior information, there is a need of redundancy. However,
successful diversification reduces the initial redundancy. Systems that want to
continue to diversify must replenish their redundancy. For instance the
existence of set learning periods in development is a function of the inability
of the brain to replenish its redundancy of neurons.

Autopoesis

This outlook on meaning fits in well with the definition of living entities as
autopoetic machines (Maturana and Varela 1980). This definition demands an

7
auto-catalytic capacity along with a clear differentiation between the entity
and its outside world. In other words every living thing has its own point of
view and sense of self, even if this is just mechanically defined by a
membrane. In the case of second order autopoetic entities such as ourselves,
which are themselves built of multiple auotopoetic machines, the sense of self
- the differentiation from the world, can never be defined in a purely
mechanistic way.

This is obviously true in the case of our consciousness and the cognitive
modalities that form it. The personal point of view does not have strictly
physical constraints and can only be defined in terms of the general working
of the system in its environment and the context of its interactions. In a
sense the autopoetic nature of life implies the emergence of cognition
(Stewart 1996).

The cognitive paradigm of immune dynamics

The cognitive view of immune dynamics is less widely accepted. It is that, as

stated above for other cognitive systems, the self is not defined by molecular-
structural properties. It is defined by a protocol of behavior, whose
observance by the agents of the immune system (cells, antibodies, etc.)
defines a normal mode of communication between these agents and the rest
of the body, encompassing the immune system as a whole. This
communication is based on a string of signals that accompany the
presentation of antigens to the immune system (Cohen 2000).

The immune system

Like the brain the immune system is a dispersed system that has many types
of cells as well as effector and signaling substances. The main populations of
cells, which constitute the immune system, are known as lymphocytes. The
two most important groups of lymphocytes are called B cells and T cells.
Both of these cell families have a unique ability to create receptors which use
different combinations of the same genetic material to create an immense

8
variety in their final form. The shape of the receptor, which like all proteins is
based on the DNA sequence of a certain gene, implies the shape and type of
molecule that will activate the receptor. The genetic variability gives the
immune system the potential ability to have receptors that can identify an
astronomical number of molecular shapes. The molecules which immune
receptors identify are commonly known as antigens. The immune system’s
identification of and reaction to a pathogen, or other immune events, is
dependent on mutual reaction by both T cells and B cells to that event
(Langman & Cohn 2000).

The clonal selection theory

Despite this receptor diversity and the essential need for cooperative
receptivity, as far as the immune system is concerned, the common view of
researchers has been a mechanistic non-cognitive one. Most theories of
immune dynamics are still based on the clonal selection paradigm, which
claims that the immune system relies on the existence of a receptor that can
preferentially select between our chemical self and the outside world (Burrnet
1957, Langman & Cohn 2000).

However when we look at the actual interaction of immune receptors and

their molecular environments we encounter two major problems. First, due to
our common ancestry and eons of co-evolution there exists an essential
similarity between our cellular biology and that of our ‘invaders’ (Gupta 1998).
Second, the existence of a necessary benign level of self affinity exists in
healthy immune receptor repertoires (Lacroix-Desmazes et al 1998, Goldrath
and Bevan 1999). These problems have created doubts as to the validity of
the clonal view, and led to the cognitive paradigm of immune reaction (Varela
1994, Cohen 2000).

A cognitive view of the immune system

The major difference between the cognitive paradigm and other paradigms
of immune research lies in its view of how the immune system reaches its

9
specificity of reaction. Other paradigms put the emphasis on single receptors
and the process that allow the system to acquire highly tuned specific
receptors of a given type (Cohn and Langman 2000). This causes several
internal problems as immune receptors are actually very widely tuned in their
reactivity and highly cross reactive (Borras et al. 2002). The Cognitive
paradigm solves this problem by viewing immune decisions as being on a
level above the single cell, at the level of the system. The immune system is
reacting not to any one signal, but to the overall pattern of signals (Atlan &
Cohen 1999). When viewed in such a fashion the degeneracy and cross
reactivity stop being a hindrance. The immune system, like other cognitive
systems such as vision, is building a very precise picture from very imprecisely
tuned receptors. We suggest that Immune reaction is to the overall concepts
which are built of many separate but interacting signals. Immune cells and
receptors may react very widely, however the overall reaction of the immune
system from the pattern of these reactions will be specific.

Shape space

In our study of the forming of patterns that influence immune dynamics we

decided that more informative representations could be found by studying the
shape space of such dynamics.

Shape space is an imaginary space in which every point represents the

shapes of receptor/ ligands that are reactive to each other (Perelson & Oster
1979). Entities which are close in shape space are similar and those that are
distant are dissimilar. This makes modeling and measuring reactions in shape
space a useful representation of the relationship between different patterns
and their reactions. The dimensionality of the space and the connectivity of
the points depend on the specificity, redundancy and degeneracy of reaction
between receptors and ligands of the given system.

The representation of the hypothetical space of examples and the receptors

that react to them is a very powerful tool for the study of the general
principles of the emergence of meaning common to various cognitive

10
systems. The dimensionality and connectivity of a given shape space
represent aspects of degeneracy and redundancy of the receptive capabilities.
We can now focus on these factors and their relationship in cognitive systems
without having to deal with their different physiological and physical
underpinnings in each system.

Models of the shape space of different receptor systems have been used to
study various systems such as the olfactory system (Lancet, Sadovsky &
Seidemann 1993) and also the diversity and size of the immune receptor
repertoire (Perelson & Wesibuch 1997). However, in most previous instances
the models of shape pace were essentially static in their representation of the
population of entities in shape space. The element studied where overall
levels of cross reactivity or, at best, the strength of points in shape space
were seen as weights in an immune network (Burns & Ruskin 2002). This
outlook misses two aspects of importance to modeling of biological
phenomena. First, the importance of discrete occurrences (Shnerb et al.
2000, Louzoun et al. 2003) and second, the ability of the receptor repertoire
to change. The shape space of a young visual system is not the same as the
shape space of an old visual system. As vaccines tell us this is also true for
the immune system.

Microscopic Simulations of shape space

Our simulations of immune dynamics in shape space, using Microscopic

Simulation techniques, have dealt with the two points mentioned above. In
our shape space model we take into consideration the specific clone
population sizes at specific times and the existence of diffusion (mutation) in
shape space. This dynamical outlook on the evolution of receptor/ ligand
populations in shape space allows us to ask questions about the development
of the immune system and cognitive systems in general:

− What are the population dynamics of the (immune) receptor repertoire

in terms of their types of affinities?

11
 − How are these dynamics influenced by the types of naturally occurring
examples (antigens) in the (immune) environment (our body)?

In the results we will start by presenting our theory of Useful Examples, in

which we have made a general theoretical suggestion as to the distribution in
shape space of examples (ligands) that enables naïve systems to acquire
cognitive capabilities. We will show the relevance of this theory to the way
cognitive systems in general, and the immune system in particular develop
and maintain their capabilities. In section two, we show the ramification of
this theory to immunology explicitly, with the aid of a computer model. We
show a new model of T cell repertoire dynamics at rest and following a
primary infection. With this model we will show how self antigens create for
the T cell repertoire a conceptual image of self. In the last section of the
results we will present our model of HIV proliferation. With a simpler model of
shape space we modeled HIV’s capability of fooling the immune system by
changing its conceptual image in the immune system’s ‘eyes’: Appearing
again and again as a new invader.

12
2. Methods

What’s a beast without an algorithm?

The Cyberiad by Stanislaw Lem
This thesis describes a theoretical study of biological dynamics and
interactions with the environment. We have used computer simulations to
elucidate the various theoretical suggestions this work makes.

During the last decade Professor Solomon's group has developed techniques
through which one can systematically follow the birth of complex macroscopic
phenomenology out of simple fundamental microscopic laws (Solomon 1995).
In the field of fundamental physics such understanding was obtained for a
wide range of phenomena, using theories based on Microscopic
Representation and Universal Dynamics paradigms.

These paradigms deduce the macroscopic objects (Macros) and their

phenomenological complex ad-hoc laws in terms of a multitude of elementary
microscopic objects (Micros) interacting by simple fundamental laws. The
Macros and their laws then emerge naturally from the collective dynamics of
the Micros as their effective global large-scale features. However, the mere
microscopic representation of a system cannot lead to satisfactory and
complete understanding of the macroscopic phenomena.

Indeed, the mere copying on the computer of a real-life system with all its
problems does not, by itself, constitute a solution to those problems.

It is clear that a satisfactory representation of complex systems, like the

immune system, has to recognize the relevant objects and laws, which
describe effectively the system at each scale, and to establish the relations
between the different scales. Therefore, our approach is not to try to
substitute the study of one scale for the study of another scale (a strategy of
"reduction"); rather we attempt to unify into a coherent picture the
complementary descriptions of one and the same reality. The main goal is to
build the intermediate stages between the meaning we observe in the global
network and the microscopic molecular interactions.

13
We describe the state of the system using an ad-hoc top-down description to
find out which are the components taking an important part in the system's
evolution. We then try to define the interactions between the components,
using the bottom-up description, starting at the molecular level. The size and
complexity of the immune system prevents us from building a direct link
between the two scales, so that we have to build intermediate levels. These
levels should contain rules that are based upon the 'lower' level applications,
but their results should be in agreement with the global description. Despite
the fact that the fundamental interactions act locally between individual
neighbors, the resulting dynamics of the system are such that the effects of
acting on the system at a particular point are significantly felt globally.

The emergence of this sort of a multi-scale operational way of acquiring and

expressing knowledge has a very far-reaching methodological potential. This
is even more evident when coupled with modern computer simulation,
visualization and animation capabilities.

The following research routine has been the basis for previous experiments
that were conducted in other domains:

1. Modeling the system as a composite of many Micros.

2. Computer simulation and visualization of the resulting model.

3. Identification of the Macros.

4. Modeling the system at the macroscopic level using the macros as

building stones.

5. Predictions based on the 'Macro'-scopic behavior of the model.

6. Return to microscopic level to tune the type and amplitude of the

local interactions.

7. Comparison with experimental macroscopic behavior.

14
 8. Confirming or correcting the microscopic model in view of the
comparison.

9. Starting new experiments based on the results both in the micro and
macro level.

The use of this dialogue, inside an artificial system created in the computer in
order to understand natural properties, extends to systems away from
equilibrium and to complex systems such as the immune system which are
not characterized by energy functionals or by asymptotic probability
distributions.

Microscopic Simulations of the immune system

Generally accepted knowledge about the Immune System can be summarized

by specifying:

1. The Microscopic Elementary Objects (Molecules) which compose the

Immune System (e.g. B-cells, antibodies, T-cells, cytokines, NK cells,
macrophages etc.)

2. Microscopic interactions between these objects (e.g. macrophages may

swallow molecules or cells that are covered by antibodies, killer-T-cells
may kill cells when presented with certain molecular complexes etc.)

3. The Emergent Macroscopic Objects and Processes composing the

Immune System: FUNCTIONS, (e.g. foreign invaders are identified and
attacked.) MALFUNCTIONS, (e.g. sometimes the Immune System attacks
the self), KINETICS, (e.g. It takes seven days to heal a bout of the flu.)

The form of Microscopic Simulation we have used in the work presented

here is a hybrid of the two major methods hitherto used to simulate biological
dynamics. These are differential equations and Monte-Carlo simulations:

(1) Ordinary differential equations - The results of such equations simulate

the evolution of the average population under the assumption of spatial

15
 homogeneity. With partial differential equations we divide the population
into points in space. At each point we consider the population to be
homogenous

(2) Monte-Carlo simulations - Work in our group has previously shown the
importance of using microscopic Monte-Carlo simulations to describe the
dynamics of auto catalytic entities.( Shnerb et al. 2000, Louzoun et al.
2003, Solomon 1995). The importance lies in the discretization of the
population levels on the one hand while treating time as a continuous
parameter on the other. This auto-catalytic situation is almost universally
prevalent when simulating biological and especially immune dynamics.
These types of simulations can be divided into two types: asynchronous
and synchronous.

(2a) Asynchronous simulations

An asynchronous simulation is built over a lattice of a given

dimensionality. Each lattice point contains a potentially unlimited
number of reactants. In asynchronous simulations at every time
step one and only one reaction between a number of individual
entities will happen. The reaction, which may include diffusion,
and the entities are selected at random, at a rate proportional to
their rates of reaction and concentrations. The size of the time-
step which passes after every reaction is not constant. It is also
proportional to the chance of the reactions occurrence. This in a
sense turns time into a continuous parameter of the simulation.

(2b) Synchronous simulations

The main difference between the two Monte-Carlo simulation

types is that in synchronous simulations more than one reaction
can happen at every time step. In this type of simulation each
time step (dt) is constant. We computed the probability of each
reaction at each spot. We then chose the number of reactions

16
 taking place according to a Poisson random generator with the
appropriate mean. The Poisson random generator was used as
we supposed that each reaction was independent of the others.

If simulating interactions between large amounts of entities of the same

type the differences in results between a-synchronous simulations and
synchronous simulations become negligible.

When there are big differences in the population levels of entities, over short
periods of time, or in different regions in space, Monte-Carlo simulations are
very costly in computer run time, we have therefore used in the works shown
here:

(3) Hybrid models (Microscopic Simulation) - These computer simulations

move fluidly from using synchronous Monte-Carlo simulation to
differential equation based cellular automata. Which system is used
depends on the population levels at a given point on the lattice. As
shape space need not be constrained to real space dimensionality we
built lattice structures of N-dimensionality or of random connections,
depending on the kinds of similarity in shape we were trying to model.
At each point in shape space the reactions were computed by ordinary
differential equations when concentration was high and by synchronous
Monte-Carlo simulation when concentrations where low. Diffusion was
treated as another reaction which removed entities from one point and
randomly distributed them to its neighbors. As with the other reactions
the amount of diffusion was calculated either by synchronous Monte-
Carlo or by ordinary differential equations, depending on the
concentrations at the point from which the diffusion started. Note that
the use of hybrid models is justified when the average local density is
relatively low, and the average number of reactions per time step is
limited.

17
3. Results
Ask me a riddle and I reply – coddelstone, coddelstone, coddelstone pie
Winnie the Pooh by A.A. Milne
The theory of Useful Examples and optimal exemplar
learning in cognitive systems

Hershberg U. and Efroni S. (2001) The immune system and other

cognitive systems. Complexity, Vol.6 issue 5 pp.14-21.

Hershberg U. and Ninio A. (in press) Optimal exemplar learning in

cognitive systems, Cognitive Systems. To be published in a
special issue on the Multidisciplinary Aspects of Learning.

The two papers in this section deal with a theory we built which shows a
common criterion of all cognitive systems. This criterion is the essential
adaptive stage in the formation of the capabilities of any cognitive system.
We further suggested that the adaptive strategy used by naïve cognitive
systems has similar general principles among different systems and that
the outward representation of these principles can be seen in the
distribution of examples in the environment. Certain examples are at a
relatively high frequency in the environment, furthermore these high
frequency examples are generic of the rules of interaction of the system in
the environment. In other words, the shape space of cognitive systems is
not regular. A few nodes will be highly populated and will also be highly
connected compared to the rest of the shape space which will be relatively
empty. We called the important nodes – Useful Examples as they are very
useful for the cognitive system in its attempt to learn the rules of
interaction with the various signals in the shape space. The first paper
describes, in general, the theory of Useful Examples using vision, language
and immunity as examples. The second paper explicitly deals with the
adaptive method used by naïve cognitive systems, which we called optimal
exemplar learning, and its relation to the form of their environments. In
this paper only the acquisition of syntax and the forming of immune
specificity are used as examples.

18
 The Immune System and Other
Cognitive Systems
URI HERSHBERG AND SOL EFRONI
Uri Hershberg is at the
Interdisciplinary Center for Neuronal
Computation, at the Hebrew
University, Jerusalem, Israel. Sol Efroni
is at the Computer Science and Applied
Math Department and at the
Immunology Department at the
Weizmann Institute of Science,
Rehovot, Israel.
E-mail for communication:
uriher@cc.huji.ac.il.
14 COMPLEXITY
In the following pages we propose a theory on cognitive systems and the
common strategies of perception, which are at the basis of their
function. We demonstrate that these strategies are easily seen to be in
place in known cognitive systems such as vision and language.
Furthermore we show that taking these strategies into consideration
implies a new outlook on immune function calling for a new appraisal of
the immune system as a cognitive system.
I
t is becoming clear that the field of immunology is approaching a paradigm shift.
It is agreed by most researchers that the immune system is a complex system
both in its composition and its behavior. However, the most popular ideas of
immune function treat the immune system in a mechanistic and reductionist man-
ner. According to the clonal selection theory the immune system’s function is to
defeat pathogens. The immune system identifies foreign antigens and destroys
them. The identification of the foreign is made possible by removing, in the immune
system’s prenatal development, all receptors that recognize self. Anything that an
immune receptor identifies “must be the enemy” [1]. Countering this mainstream
view are a growing number of voices that state the need to change the clonal
selection theory or discard it, claiming that such a simplistic appraisal of the im-
mune system’s function and mode of action is untenable because, at the molecular
level, we are closely related to the pathogens that invade us. There is a need to
consider the immune system as a integrative system with the ability to see patterns
and understand context [2,3]. It is in the context of this argument about the immune
system that we present our theory of cognitive systems and claim that the immune
system should be seen as such a cognitive system.
The phrase “cognitive system” is used in many fields to describe the various
faculties that we and other organisms use to perceive and interact with the world.
Despite its widespread use, the phrase “cognitive systems” has not yet been defined
in a way that can be applied to all of the cases in which it is used.
We suggest the following criterion to differ between cognitive and noncognitive
systems: In cognitive systems the perceptual sensitivities of the system are not
preordained only by the plan of the system but need an interaction with their
environment to define the system’s exact sensitivities.
© 2001 John Wiley & Sons, Inc., Vol. 6, No. 5
19
 We propose a theory of the general
FIGURE 1
underlying principles of cognitive sys-
tems, their perception regarding the en-
vironment, and the way in which they
deal with the complex patterns their en-
vironments present. This is essentially
divided into two phases—a phase of
priming (top of Figure 1), in which the
system defines the general properties of
its environment that it knows and a
phase of specific interaction (bottom of
Figure 1), in which the cognitive system
utilizes its knowledge of the general
properties to interact with specific en-
counters with its environment. These
phases are not necessarily chronologi-
cal by nature and happen with each in-
teraction of the cognitive system with
its environment.

C
ognitive systems are innately built
with a tendency toward perceiv-
ing certain aspects of the environ-
ment. These tendencies are such that
they cause the cognitive systems to be
receptive toward seeing certain general
properties of the environment and ex-
amples that embody them. However,
the cognitive system will only acquire
general properties that are corroborated
in its initial interactions with the envi-
ronment. The definition of general
properties by cognitive systems is
something that is not completely prede-
termined but rather defined through in-
teraction with the environment; the en-
vironment’s reinforcement is what de-
fines the final set of general properties
that the cognitive system uses to know
its environment. The general properties
are an important aspect of the shape
space,1 and so they are encountered of-
ten in meaningful interactions with the
shape space. Examples of such proper-
ties which are both generic for and

1
Protein shape space is an analogy com-
monly used to describe a vector space, in
which every point describes a configura- In the above figure we explain our theory on cognitive systems, utilizing for this purpose
tion of the protein [4]. We will use this in examples from vision, language and the immune system. The figure shows the two phases
a more general way to describe the vector encompassing cognitive perception.
space of the various cognitive modalities.

© 2001 John Wiley & Sons, Inc. COMPLEXITY 15

20
ubiquitous to the relevant environment,
are extremely beneficial in learning the
environment. As such we will call them
“useful examples.”
Through specific interactions and
based on the previous tendencies of the
system certain general properties are
corroborated by “useful examples” of
these properties appearing in the envi-
ronment. This corroboration leads to
the formation of an achieved set of rep-
resentations in the system. Specific en-
counters with the environment start
with a deconstruction via a detection of
similarities to the useful examples, em-
bodied in the achieved set. After this de-
tection there is a refitting and fine tun-
ing to the specific elements of the event.
Having identified the specific elements
of the event, there is now a reconstruc-
tion of the event together with an asso-
ciation to other contextual factors to a
functional/meaningful event that can be
appropriately reacted to and added to
the memory of the system. [The two
phase are chronologically mingled;
both happen simultaneously. Every en-
counter is a specific encounter even
while the cognitive system is still build-
ing its understanding of the general
properties. Also in many cognitive sys-
tems it is not clear if the process of de-
fining new general properties ever
comes to a complete stop. “Young” cog-
nitive systems are less fluent in working
with the general properties, and it is
harder to teach an “old” cognitive sys-
tem new tricks, but all interactions with
the environment have elements of both
phases.]
I
n this discussion of cognitive sys-
tems, we will start with the visual
system. Visual systems are built ac-
cording to the niche in which they are
used. A bee’s view of flowers is different
from ours. The limits of sensitivity to
wavelength and contrast are to a great
extent built in. However, seeing is not
merely a matter of light sensitivity. We
see because we have learned how to do
so; we know what things to “look” for
and what they mean. This knowledge is
an understanding of the natural context
of vision and the general properties of
the visual stimulus that we encounter.
16 COMPLEXITY
As an example, take a look at Figure 2
where our knowledge will not help us.
A painting from the brush of Salva-
dor Dali, this picture shows how com-
plicated it is to know what we are look-
ing at when we do not have the natural
context to tell us what we should look
for. The title may give you a hint, “Ap-
parition of a Face and Fruit Dish on a
Beach.” Once we reveal that the “appa-
rition” hides the figure of a dog, it is
doubtful if you could ever again look at
this picture without seeing man’s best
friend. Our preknowledge is not of spe-
cific aspects of every stimulus but
rather of their general properties. The
knowledge of the general properties of
visual stimuli is not something that we
are born with; rather, it is acquired
through the natural exposure to the en-
vironment. The process starts with the
natural visual tendencies of the visual
apparatus and the innate bias that we
are born with toward certain things,
such as complex stimuli and move-
ment; however, these innate aspects are
not enough. Given this tendency, the vi-
sual system, in its first stages of devel-
opment, builds up the tools that later
will allow the act of vision.
The need for this priming stage and
the existence of a critical period for its
occurrence is easily seen in people who
have had blocked corneas from infancy.
FIGURE 2
“Apparition of a Face and Fruit Dish on a Beach”: Salvador Dali (1970).
21
Such people, if their cornea is removed
too late, will remain functionally blind;
for although they can react to light, they
cannot resolve the images they see [5]
(much like living in a painting by Dali).
In those of us free to see the world, the
process of learning the general proper-
ties is unsupervised and is based on the
existence of useful examples for the
general properties of naturally encoun-
tered visual stimuli.
The general properties are those
things that are both ubiquitous to the
different stimuli and appear in many
different meaningful contexts. In vision
these would be things such as edges or
regularities of scale [6]. Their high fre-
quency and usefulness very naturally
cause their corroboration, until eventu-
ally we have a visual system with an
achieved set of representations based
on the “useful examples” (stage 1 in Fig-
ure 1). This “achieved set” is what en-
ables, from then on, the resolution of
visual stimuli: the deconstruction and
reconstruction of the second stage,
which allows the acquiring of the
proper functional understanding of the
image and memory.
Vision starts with the general prop-
erties of the image rather than its par-
ticulars. In our representation this is the
phase of detection (second half of Figure
1). Sight, as opposed to taking a picture,
© 2001 John Wiley & Sons, Inc.
is done while knowing what the impor-
tant things in the image are. Edges,
movement, and other “eye catching”
things tell the visual system where to
look. Once this phase of detection and
deconstruction is done, the visual sys-
tem can refit to the particular image it is
dealing with and can associate it to the
current context. This gives the stimulus
meaning and achieves a functional im-
age, while widening the knowledge of
the visual world via memory.
The fact that our visual ability is
based on and inseparable from our per-
ception of the general properties of vi-
sual stimuli can easily be seen in the
kinds of illusions that fool us. Movies,
animation, and paintings are all only
good copies of natural images in the
sense that they capture the general
properties of the visual world.
Note the different scales involved in
the two phases that we have discussed
so far regarding vision. The first stage,
the stage of priming and obtaining the
achieved set, is a stage that responds to
some external input, but does so in a
duration orders of magnitude longer
than the time needed to process new
input once the system is fully func-
tional. Moreover, the second stage, spe-
cific interaction, is a continuous pro-
cess going on all the time, whereas the
first stage is a once in a lifetime oppor-
tunity. It takes a long time to put to-
gether an organism, but, once it exists,
the organism has to use its mechanisms
immediately.
O
ne cognitive system where this
separation in time is clearly seen
is in the development of language
in children. As infants and children, we
learn to speak, and it is a long and la-
borious process. However, once lan-
guage is acquired, when we add new
words to our vocabulary, learning them
and their correct use is something that
we can do almost instantaneously. We
will deal with only one aspect of the ac-
quisition of language—the learning of
correct syntactic combinations—how
we know the correct order of words that
make a meaningful sentence. This step
is made possible by the previous stages
of auditory and cognitive development,
© 2001 John Wiley & Sons, Inc.
which are influenced by various innate
and learned biases. The exact amount
of learned and innate influence is the
scene of many an argument in the cog-
nitive sciences that we will not go into
[7]. In any case, it is obvious that at the
stage of syntactic development the lan-
guage system already has a “tendency”
that sets the stage for the learning of
syntactic combination. This can be seen
in the fact that the learning of sentence
formation is always preceded, in chil-
dren, by a stage of rapid growth in vo-
cabulary or “vocabulary explosion,”
that brings about the creation of the vo-
cabulary necessary for syntactic combi-
nations [8].
In studies concerning the use of in-
transitive and transitive verbs in syntac-
tic combinations, in parents’ conversa-
tions with their children, it was seen
that parents use a very small subset of
verbs at a very high frequency when
talking to their children. Words such as
want, come, go, and make account for
a high fraction of the verbs used in
parental conversation. All these high-
frequency verbs are very general, have
uses that are almost empty semanti-
cally, and can be said to be generic of
FIGURE 3
Figure 3. Cumulative number of different verbs in VO and SVO word combinations produced by
a subject as a function of age [9].
22
the verb subcategories to which they
belong. In return, all the first verbs used
by children are drawn from this group
of verbs (though individually each
child’s first verb need not be the most
commonly said word of his parent).
Further, once the first verbs are learned
in a certain syntactic construction, the
speed of learning other verbs in the
same syntactic construction, but not
necessarily in other constructions, is
greatly enhanced. This could be indica-
tive of a scenario where the child learns
the first 2 or 3 examples, after which the
others are greatly facilitated (Reference
9 and Figure 3).
In effect, because of the shape space
of languages, in the course of normal
conversation, children are exposed to
the useful example of the different types
of syntactic combinations and the cor-
rect use of language. The first words are
very common and have many uses (they
embody various ideas). In this fashion
the useful examples of language are cor-
roborated, bringing about the forma-
tion of an achieved set of representa-
tions that greatly facilitates the latter
identification of similarities to the use-
COMPLEXITY 17
ful examples and the formation of cor-
rect functional syntactic combinations.
The studies mentioned above deal
with the learning of intransitive verb-
dependent combinations and of transi-
tive verbs in verb–object (VO) and sub-
ject–verb–object (SVO) relations. The
view of the first examples as useful ex-
amples is further strengthened by the
fact that the first words learned are eas-
ily seen to be generic of some relation of
the speaker to the world. In learning in-
transitive verbs children deal with ani-
mate objects, and the first few verbs
spoken in word combinations (i.e.,
learned) always cover categories both of
active (come, go) and passive/static
(fall, sleep) relations [9]. VO syntactic
combinations are learned before SVO.
The improvement in one syntactic com-
bination is separate from the improve-
ment in the other. In 13 of 16 children,
the Hebrew verb “raza” (want) was one
of the first VO verbs (and if not, it was
generally the first SVO verb). In VO,
84.4% of first utterances were requests,
whereas in SVO 25.9% were requests
and 44.4% were descriptions of creation
or consumption of objects. In learning
both syntactic combinations what is be-
ing learned, along with the correct use
of VO and SVO, are useful examples of
the child’s relation to alienable objects
(things that can be part of me or not
part of me). The child is learning to add,
remove, or maintain objects in his “per-
sonal space” [10] and in essence is ac-
quiring an achieved set of representa-
tions to deal with objects and their ab-
stract reflections.
The statistical shape of language is
such that when speaking to those who
do not speak, we will use those words
that are useful examples and enable the
cognitive task of learning. Languages
are “built” so that when talking in
simple language to children, we will
corroborate the general properties of
correct speech and sentence formation,
thus enabling the acquisition of lan-
guage. Possibly, we have here also evi-
dence for the priming phase of the most
cognitive of modalities: our ability to
exercise abstract thoughts. Together
with the general properties of language,
we see here that children learn useful
18 COMPLEXITY
examples of the mental interaction with
alienable objects and define some of the
general properties of abstract thought.
H
aving shown how our theory
works in systems, commonly
agreed upon to be cognitive, we
come now, finally, to the immune sys-
tem. It is in treating the immune system
as cognitive that we believe that our
theory is most controversial and also of
the greatest benefit compared with the
present paradigm, the clonal selection
theory. We hope to show, citing various
sources of contemporary research, that
present knowledge of the immune sys-
tem and its interaction with the anti-
genic/molecular patterns of our body
calls for the treatment of the immune
system as a cognitive system.
The immune system has an ability to
identify specific events and changes in
the body. The immune system’s envi-
ronment is the body. It interacts on the
cellular/molecular level. To do this, it
has many types of cells as well as effec-
tor and signaling substances, many of
which are yet to be identified and un-
derstood. However, in general the
population of cells that make the im-
mune system can be characterized as
the populations of cells known as lym-
phocytes. The two most important
groups of lymphocytes are called B cells
and T cells.
Both of these cell families have a
unique ability the create receptors,
which, though they all originate from the
same genetic material, use different com-
binations of this material to create an im-
mense variability in their final form. The
shape of the receptor, which like all pro-
teins is based on the sequence of a cer-
tain gene, implies the shape and type of
molecule that will activate the receptor.
Therefore, this genetic variability gives
the immune system the potential ability
to have receptors that can identify a near
infinite number of molecular shapes. The
molecules that immune receptors iden-
tify are commonly known as antigens.
The region within the antigen to which
they attach is known as an epitope. A
single antigen may have several different
epitopes.
23
The receptors of B cells identify ex-
tracellular substances. The receptors of
T cells identify intracellular substances
by interacting with specialized antigen-
presenting proteins known as major
histocompatability complex (MHC) re-
ceptors [11], which are expressed on the
surface of every one of the body’s cells.
MHCs present fragments of intracellu-
lar proteins, in effect mirroring the in-
ternal state of the cell. Together, T cells
and B cells can identify most intra- and
extracellular substances. The immune
system’s identification and reaction to a
pathogen or other immune events is de-
pendent on mutual reaction by both T
cells and B cells to that event [12].
In trying to fit the immune system to
our theory of cognitive systems, we are
making a remark on the kind of recep-
tor repertoire that the immune system
forms out of its potential variability.
The potential repertoire of receptors
is immense, between 1011 for B cells
and 1016 for T cells [4]. Because (in
mice) the immune system contains only
about 108 of each of the types of cells
and every single cell has only one type
of receptor, it is obvious that the actual
repertoire is smaller. If the immune
system were to have a repertoire built
of every potential receptor it can gener-
ate, then in a rat, for example, this
would necessitate having a spleen 70
times the size of the rat’s entire body
[13]. What kind of repertoire actually ex-
ists, and what factors are important in
its formation?
As we mentioned above, immunol-
ogy is in the midst of a paradigm shift.
There is an especially widespread de-
bate on the way in which the immune
system differentiates between the mo-
lecular patterns of the body and foreign
pathogens [3]. We will not go into all
aspects of this discussion. In plain
words, the current textbook outlook on
immunity, the clonal selection theory,
states that anything that an immune
cell receptor identifies is a foreign
pathogen. According to the clonal selec-
tion theory, this state of affairs is
brought about in the following way:
During embryonic development im-
mune cells are created randomly, each
reactive to a different antigen. Those
© 2001 John Wiley & Sons, Inc.
cells bearing receptors that bind to self-
antigens at a certain level of affinity or
above are eliminated. This is known as
negative selection. At the end of this
process any receptors that remain can
only be activated by foreign pathogens
[1,14].
This is a classical reductionist theory
that is extremely elegant and simple. It
explains how we create a repertoire,
which on the one hand can identify
pathogens and yet does not react falsely
with our body’s molecular patterns. It is
also a very mechanistic way of viewing
the workings of the immune system.
One major implication of this theory is
that autoimmunity—the reaction of im-
mune receptors to self antigens—is
something that exists only as a pathol-
ogy and never in a properly functioning
immune system or a healthy body. Even
if we were not about to show that the
immune system works like a cognitive
system, there is a major problem with
this theory. The elimination of self-
repertoire completely ignores other
functions of the immune system that
are essentially involved with self, such
as wound healing and combating
cancer [2,15].
Several generally known aspects of
immune detection, agreed on even by
the most ardent supporters of the clonal
selection theory, seem to imply that the
immune system is working as a cogni-
tive system: First, the need for costimu-
lation of B cells and T cells for immune
reaction [12], and second, the fact that
B cells are reacting to extracellular in-
formation, whereas T cells react to in-
tracellular information. Together these
appear to imply an immune reaction to
patterns and context.
Treating the immune system as a
cognitive system, the idea of building a
repertoire in the way suggested by the
clonal selection theory becomes less
plausible. The immune system’s envi-
ronment is built completely of cells
both endogenous and exogenous,
which at the time of encounter are re-
siding in the body. Also, all of this cel-
lular and viral life is built of similar
building blocks. There is no intrinsic
molecular signal that differentiates be-
tween the organic substances of our
© 2001 John Wiley & Sons, Inc.
body and those of other organisms. Re-
moving all receptors to self amounts to
removing all receptors to all of the
things that are common to all cellular
life. Building a system that needs to rec-
ognize the important aspects of this en-
vironment but is blind to the general
properties (which are those things that
are ubiquitous in the environment) is
like building a human visual system
that can not become aware of edges.
We are suggesting a model of the im-
mune system as a cognitive system.
This implies several things about the
way the immune system is primed and
how it detects its environment (see Fig-
ure 1). As we showed for vision and lan-
guage, the priming of the system and
building of the achieved set of represen-
tations starts by fulfilling innate sys-
temic biases or tendency. In this case,
this would probably be a genetically
transferred tendency to present certain
protein examples that are used to build
the receptor repertoires. These useful
examples would, as in vision and lan-
guage, be examples of the general prop-
erties of the living molecular environ-
ment. They should, therefore, be ex-
amples of self that cause a positive
selection of receptors with at least some
minimal affinity to these examples.
We would, therefore, expect to find
that, from the first randomly generated
stock of receptors, the adult repertoire
of immune receptors are created by a
combination of positive and negative
selection using specific molecular ex-
amples of self.
Part of the reason that the clonal se-
lection theory is being forced to change
is that positive selection is apparently
important for the creation of the mature
repertoires in both B cells and T cells
[16,17]. This is especially evident in T
cells. One form of positive selection is
agreed on for T cells, even by the clonal
selection theory. T cells must have a
minimal affinity for at least one self an-
tigen—MHC receptors—if they are to
function. However it appears that the
recognition of self-MHCs is not the only
kind of self-recognition that is neces-
sary for proper T-cell development, in
fact the proteins nested in the MHCs,
while selection is in process, affect the
24
positive selections outcome [18]. Fur-
ther, it has been shown, using genetic
engineering techniques, that an im-
mune system built with fewer kinds of
fragments presented by MHCs, within
the context of positive selection, will
have a less diverse T-cell repertoire [18].
The selection of T cells within certain
boundaries of affinity to MHC receptors
and the fact that MHC receptors only
present the fragments of certain pro-
teins [11], together show a possible
mechanism by which the immune sys-
tem creates an important bias toward a
certain population of examples while
creating the repertoire of receptors.
What are the “useful examples” pre-
sented by the MHCs bias? The exact
types of proteins, fragments of which
are presented by MHC, have not yet
been characterized. However, let us
consider, given a tendency, what would
constitute the useful examples that are
corroborated, and what is the environ-
ment for which they create an achieved
set? As we mentioned before, the envi-
ronment of the immune system is the
body’s cellular life. Candidates for “use-
ful examples” would have to have the
following properties: they would have
to be part of every cell; they would have
to have been there all through the his-
tory of the development of the immune
system for them to be such a major part
of its function; they should be relevant
in times of stress (or otherwise they
cannot serve extreme conditions usu-
ally common in immune response).
Indeed, it is possible to find such a
set. The set corresponds to a group of
antigens Cohen has named “homuncu-
lar antigens” [2], and all belong to a
group called housekeeping or mainte-
nance proteins. Housekeeping proteins
are essential in all cells, because they
are responsible for ongoing energy me-
tabolism, protein construction, and ba-
sic genetic manipulations.
One group of housekeeping proteins
of special interest is called heat shock
proteins (HSPs). HSPs are part of a
larger group of proteins called chaper-
ones, which are essential in correct pro-
tein construction and folding. HSPs
help cells maintain the proper form
(and function) of proteins in various
COMPLEXITY 19
states of emergency and stress. The
situations when HSPs are most ex-
pressed, emergency and stress, are also
the ones where you may usually find
immune response. That alone suffices
to mark HSPs as useful examples to the
immune system, but more than that,
because states of emergency abound in
all environments, HSPs are essential
and are expressed in all cells. In fact,
these proteins are ubiquitous in cells in
times of stress and are highly preserved
throughout evolution, from prokaryotes
to multicellular organisms [19]. All this
suggests HSPs to be part of the useful
examples that build the achieved set
through which detection is carried out.
Now that we have proposed this pos-
sible achieved set (the homuncular an-
tigens), we can go on to the mechanism
of detection. If the immune system be-
haves according to our suggested
theory, we would expect several points
of immune behavior. We have just
shown that housekeeping genes in gen-
eral and HSPs in particular would be
good candidates as “useful examples,”
which would imply that the immune
system and its receptors would have a
bias in its reaction to these proteins
when reacting to the environment and
performing immune functions. At least
in HSPs this appears to be the case. Re-
ceptors to different types of endog-
enous and exogenous HSPs have been
shown to be important to immune re-
action. In Cohen and Young’s review of
the immunological reaction to HSPs,
they show that during almost any reac-
tion to bacteria and parasites, the rec-
ognized antigen detected is a type of
HSP [20]. In other immune activities, T
cells reactive to specific self-proteins,
for example, HSP60 and MBP (an essen-
tial factor in nervous tissue), have been
shown to enhance the regeneration of
skin and nerve tissue [21–24].
If the immune system is indeed
working as a cognitive system, as we
have described it, then the immune
mechanisms of detection should in-
clude a means for the detection of the
general properties of the environment
along with a mechanism for refitting to-
ward specific encounters. This should
allow for the deconstruction and recon-
20 COMPLEXITY
struction of the immune “image.”
Therefore, we are expecting an adult
repertoire of receptors built to react de-
generately, at a median level of affinity,
to a few self-antigens. This repertoire
will not change much during our life-
time. Along side this, we expect a rep-
ertoire of non-self-reactive receptors,
which changes and evolves over time as
the immune system encounters patho-
gens and evolves throughout our life.
Both T cells and B cells have adult
receptor repertoires that are highly
cross-reactive and react degenerately to
self-antigens. These repertoires remain
at a steady level throughout life [13,25].
B cells have an added ability: when ac-
tivated by the innate immune reper-
toire, they start a process of fine tuning,
known as affinity maturation [26], by
which they create highly specific and
accurate receptors that react to a spe-
cific antigens. In B cells we find a sharp
distinction between a self-reactive rep-
ertoire, which remains permanent
throughout life, and a changing popu-
lation of receptors that is a result of the
immune system’s interactions with dif-
ferent immune events [25]. B cells,
while acquiring a growing repertoire
toward specific pathogens, during the
lifetime of the organism, maintain a
permanent repertoire of cross-reactive
receptors, possibly through inter-
action with the less changeable T-cell
repertoire.
The stability of T-cell repertoires and
fluidity of B-cell repertoires could very
well be a way to allow the process of
detection and refitting, while keeping
focused on the achieved set of molecular
life (homuncular antigens).
The existence of self-reactive recep-
tors does not mean that an autoim-
mune reaction of the immune system
is something that happens in health.
It means that such an occurrence
is avoided, not through the lack of
self-reactive immune receptors, but
rather through their heavily controlled
existence.
Although we have not described ex-
act cellular mechanisms of detection
and interaction, we feel that we have
given enough of an argument to justify
25
treating the immune system as a cogni-
tive system.
The immune system’s ability to
function is dependent on its under-
standing the environment in a cognitive
manner and its ability to discern the
complex patterns it encounters. The
world of immune function is the body
in which it resides. This is the source of
the examples it uses to see the generali-
ties of cellular life. These points imply a
new outlook at the receptor repertoire
of the immune system, which enables it
to react to changing and unexpected
patterns.
Our self is the source of examples,
and yet in the end the immune system
knows not to react to the patterns of
self. This could be because the immune
system has no receptors for self and so
the immune system can not “see” it. We
would suggest that this is not so, but
rather the immune system has many re-
ceptors with a sensitivity for self; how-
ever, their interaction is such that it rec-
ognizes the patterns of self as what they
are—the background on which the pic-
ture of immune events are painted. Self-
immunity is the basis not the nemesis
of immune function.
I
n closing, although we have used vi-
sion and language as examples to ex-
plain something about the immune
system, still in doing so we have also
put together principles that are at the
base of all cognitive systems. These
three systems are all different in their
particular components and in the spe-
cific fashion in which they interact with
their part of the environment. Still they
all share the common traits of dealing
with the specifics of their environment
through an acquired sensitivity to the
general properties of their environment.
We would say that this is what makes
them all cognitive systems.
Cognitive systems have the common
trait of functioning in an existing envi-
ronment constantly on the brink of
change. Noncognitive systems are built
with a limited hardwired perceptual
ability capable of reacting to certain
stimulants and no others. In cognitive
systems, the existence of a built in (ge-
netic) tendency promises the acquisi-
© 2001 John Wiley & Sons, Inc.
tion of generalities proven to be impor-
tant over several evolutionary steps.
However, because of the need for cor-
roboration, the cognitive system retains
an ability to change, over time, the defi-
nition of the generalities with the
changing of the environment. The abil-
ity to modify the innate tendencies and
the need to build the understanding of
general properties relative to the envi-
ronment for every generation is what
sets apart the function of cognitive and
noncognitive systems.
Cognitive understanding deals with
specific things and the ability to recog-
nize a great amount of the specific as-
pects of its environment. However, the
ability to deal with all of the varying and
changing aspects of the environment
starts not from the specifics of the world
but from generalities. First are learned
the general metaphors, the useful ex-
amples of general properties, which are
applicable in many different ways to the
world. Once they are grasped, it is easy
to apply them in many different ways to
the world around us. The fact that gen-
eralities take on many different aspects
is not a drawback to learning them. It is
one of the main reasons they are
learned first. We have dealt here with
only three systems and only in a super-
ficial manner; still, we are sure that
studying other cognitive systems will
show similar patterns. Furthermore, we
believe that in studying cognitive sys-
tems discovering the nature of their
useful examples and the general prop-
erties they represent will tell us much as
to those systems basic function and
abilities.
ACKNOWLEDGMENTS
We thank Professor Irun Cohen, of the
Immunology Department at the Weiz-
mann Institute in Rehovot, and Profes-
sor Anat Ninio, of the Psychology De-
partment at the Hebrew University in
Jerusalem. Without their insights and
help, none of these ideas would have
started forming, nor could they have
reached their final shape. This research
was supported by a grant from the Min-
istry of Science, Israel.

REFERENCES
1. Burrnet, F.M. A modification of Jerne’s theory of antibody production using the concept of clonal selection. Aust J Sci 20, 1957, 67–69.
2. Cohen, I.R. Tending Adam’s garden. Academic Press, San Diego, CA, 2000.
3. Seminars In Immunology. Vol. 12, No. 3, (June 2000, R.E. Langman, M. Cohn, eds.).
4. A.S. Perelson, and G. Weisbuch. Immunology for physicists. Rev. Mod. Phys. 69/4, 1997, pp. 1219–1267.
5. Clyde, W.O. The human eye. Sinauer, Sunderland, MA, 1999.
6. Cutting, J.E. Perception with an eye for motion. MIT, 1986.
7. Ingram, D. Child Language Acquisition: Method, description, and explanation. Cambridge University Press, 1989.
8. Bates, E., Bretherton, I., Snyder, L., and Beeghly, M. From first words to grammar: individual differences and dissociable mechanisms. Cambridge
University Press, 1988.
9. Ninio, A. Model learning in syntactic development: Intransitive verbs. International Journal of Bilingualism, 3, 111–131. (Invited article for a special
issue on Cross-linguistic Studies of Early Grammar, edited by M.M. Vihman, 1999).
10. Ninio, A. Pathbreaking verbs in syntactic development and the question of prototypical transitivity. Journal of Child Language. 26/3, 1999, pp.
619–653.
11. Germain, R.N., Stefanova, I. The dynamics of T cell receptor signaling: complex orchestration and the key roles of tempo and cooperation. Annu Rev
Immunol 17: 1999, pp. 467–522.
12. Langman, R.E., and Cohn, M. A minimal model for the self/non-self discrimination: a return to the basics. Seminars in Immunology 12(3): 2000, pp.
189–195.
13. Mason, D. A very high level of crossreactivity is an essential feature of the T-cell receptor. Immunology Today 19(9): 1998, 395–404.
14. Janeway, C.A., Travers, P., Walport, M., and Capra, J.D. Basic concepts in immunology. Immuno-biology: the immune system in health and disease.
Chapter 1, especially Figure 1.13. (4th ed., 1999).
15. Paul, W.E. Tumor immunology: effector mechanisms in cancer immunity. Fundamental Immunology Chapter 37 (4th ed., 1998).
16. Hayakawa, K., Asano, M., Shinton, S.A., Gui, M., Allman, D., Stewart, C.L., Silver, J., Hardy, R.R. Positive selection of natural autoreactive B cells.
Science 285(5424): 1999, 113–116.
17. Sebzda et al. Selection of the T cell repertoire. Annu Rev Immunol 17, 1999, 829.
18. Barton, G.M., Rudensky, A.Y. Requirement for diverse, low-abundance peptides in positive selection of T cells. Science 283(5398): 1999, 67–70.
19. Gupta Redhay, S. Protein phylogenies and signature sequences: a reappraisal of evolutionary relationships among archaebacteria, eubacteria, and
eukaryotes. Microbiol Mol Biol Rev 62(4): 1998, 1435–1491.
20. Cohen, I.R., Young, D.B. Autoimmunity, microbial immunity and the immunological homunculus. Immunol Today 12(4): 1991, 105–110.
21. Moalem, G., Yoles, E., Leibowitz-Amit, R., Muller-Gilor, S., Mor, F., Cohen, I.R., Schwartz, M. Autoimmune T cells retard the loss of function in injured
rat optic nerves. J Neuroimmunol 106(1–2): 2000, 189–197.
22. Schwartz, M., Cohen, I.R. Autoimmunity can benefit self-maintenance. Immunol Today 21(6): 2000, 265–268.
23. Abulafia-Lapid, R., Elias, D., Raz, I., Keren-Zur, Y., Atlan, H., Cohen, I.R. T cell proliferative responses of type 1 diabetes patients and healthy
individuals to human hsp60 and its peptides. J Autoimmun 12(2): 1999, 121–129.
24. Kipnis, J., Yoles, E., Porat, Z., Cohen, A., Mor, F., Sela, M., Cohen, I.R., Schwartz, M. T cell immunity to copolymer 1 confers neuroprotection on
the damaged optic nerve: possible therapy for optic neuropathies. Proc Natl Acad Sci USA 97(13): 2000, 7446–7451.
25. Lacroix-Desmazes, S., Kaveri, S.V., Mouthon, L., Ayouba, A., Malanchere, E., Coutinho, A., Kazatchkine, M.D. Self-reactive antibodies (natural
autoantibodies) in healthy individuals. J Immunol Methods 216(1–2): 1998, 117–137.
26. Paul, W.E. Affinity maturation. Fundam Immunol Chapter 25. (4th ed., 1998).

© 2001 John Wiley & Sons, Inc. COMPLEXITY 21

26
 1

Optimal exemplar learning in cognitive systems

Uri Hershberg* and Anat Ninio +
*Interdisciplinary Center for Neuronal Computation, Hebrew University,
Jerusalem Israel. Email:- uriher@cc.huji.ac.il
+Department of Psychology, Hebrew University, Jerusalem Israel.

Abstract

The following paper is the fruit of an interdisciplinary discourse between the

study of the learning of syntax in infants and the study of the development of
immunity. Showing specific examples from these fields, we propose a form of
optimal exemplar learning. We suggest that this form of learning is how all
cognitive systems reach the "rules" or general properties of their environment.

In such learning, the specific interaction of the system with any example is
identical. However, not all examples of the environment are equally encountered
in natural interactions with the environment. There is a class of examples that
are ubiquitously encountered and generic of the general properties of the
environment. This ensures that they will be the first noticed and learned by
the system. The very ubiquity of the useful examples also ensures their rapid
reinforcement and facilitates the learning of other examples of the same
property.

In talking to infants, parents use with high frequency a set of verbs that
are almost empty semantically, being generic to the subcategory to which they
belong. The first verbs used by the infants in learning syntax belong to the
same group of verbs. Once these first examples of a given syntactic combination
are learned, the ability to learn further examples is greatly facilitated.

In living cells those proteins that the cells need most in trauma that are
most highly conserved throughout evolution. These proteins are ubiquitous in
both humans and microbes. The immune system creates the major antibody clones
precisely to these proteins when combating diseases.

In summary, we have discovered an underlying similarity between the learning

processes of two a priory unrelated systems. This leads us to believe that
optimal exemplar learning may be operative in all cognitive systems. This is a
strong hypothesis that should now be investigated in other cognitive systems.

27
 2

1. Introduction.

There are many different cognitive systems, and there exist many
descriptions of their characteristics and functioning. In terms of general
system theory one trait that is quite clearly common to all such system
regardless of their definition, is their self organization through interaction.
In all cognitive systems the final capabilities of the system are not fully
determined by the plan of the system. To reach these capabilities the system
must interact with its environment (Hershberg & Efroni, 2001). In the following
pages we present a theory of the common traits and learning strategies of
cognitive systems. Specifically we would like to suggest a form of exemplar
learning, called Optimal Exemplar Learning, that enables a cognitive system to
learn to be a cognitive system. These common strategies do not reflect a
similarity between the specific building blocks of each system. They are a
result of a common relationship between cognitive systems and their
environments. To demonstrate this point we will use two very disparate systems,
language and immunity. It is very clear that both systems are very different
both in their biological substrate, neurons and lymphocytes, and in their
environments, the abstract information space of language and the molecular
jungle of our bodies.

However, as we will see in the following pages, both share a common

strategy in the manner by which they interact with their diverse environments
and acquire their capabilities.

2. Optimal Exemplar Learning: How does a cognitive system learn to

be a cognitive system?

The mode of learning by which a cognitive system acquires its capabilities

and understanding of the general properties of the environment is by interacting
with concrete exemplars of the environment. Learning is the result of
unsupervised interactions with exemplars; all interactions with the environment
are of the same type.

We think that this mode of learning is extremely efficient in cognitive

systems because the environment itself is ordered, and because examples of the
general properties of the environment are ubiquitous. We call these optimal
exemplars of the environment "useful examples", because they are useful for
learning the environment and its relevant general properties by the relevant
cognitive systems.

Learning of examples of the general properties of the system does not change
the types of interactions with new examples. However, due to the centrality of

28
 3

Useful Examples in the environment, learning them facilitates the acquiring of,
or the correct reaction to, new examples. Useful Examples make for optimal
exemplar learning.

The environment is ordered in a specific way which is especially pertinent

to a naive unformed system. This order is not a chance occurrence; it is a
reflection of the fact that cognitive systems are fitted to certain niches.
Based on genetic inheritance and previous development, a cognitive system has
certain tendencies, which give it the framework of its environment. This
reflects the previous environments in which this system has developed / evolved
and not the final capabilities of the system, which are dependent on future
interactions with the environment.

It is tempting to speculate that if there were no statistical disparities

among the exemplars of the environment, making the central exemplars easiest to
assimilate by the learner, learning would be much more difficult, drawn-out and
error-ridden than it is in fact. This is why we call exemplar leaning based on
Useful Examples of the environment, Optimal Exemplar Learning.

Having given a general description of Optimal Exemplar learning we would

like to show how two cognitive systems, language and the immune system fit in
with these principles. We will start our examples with language, a more
accepted cognitive system, and show how it works within the framework of optimal
exemplar learning.

3. Language: The role of central examples in the acquisition of

syntax.

We will deal with only one aspect of the acquisition of language – the
learning of correct syntactic combinations, namely, how to construct a
meaningful sentence from more than one word. However, our points should hold
for other stages of language acquisition as well. Learning syntax is made
possible by various innate and learned biases whose exact amount of influence is
the scene of many an argument in the cognitive sciences which we will not go
into. In any case, it is obvious that at the stage of syntactic development the
language system already has a "tendency" which sets the stage for the learning
of syntactic combination. This can be seen in the fact that the learning of
sentence formation is usually preceded in children by a stage of rapid growth in
vocabulary or "vocabulary explosion", that brings about the creation of the
vocabulary necessary for syntactic combinations (Bates, Bretherton, Snyder &
Beeghly, 1988).

29
 4

It is a fact of long standing that, in general, the statistical shape of

language is such that a relatively small subset of words are highly frequent
while the rest are used at a lower frequency (Zipf, 1965). According to
hypothesis, the highly frequent words have a special role in syntactic
development (Ninio 1999a, 1999b).

The studies on the basis of which this hypothesis was formed, compared the
order in which children learned to form syntactic combinations with intransitive
and transitive verbs, with parents' use of verbs in syntactic combinations in
conversations with their children. It was observed that parents use a small
subset of verbs with very high frequency when talking to their children. Words
like want, come, go and make account for a high fraction of the verbs used in
parental conversation. All these high frequency verbs are very general, have
uses that are almost empty semantically and can be said to be generic of the
verb sub-categories to which they belong, defined by their following a certain
set of syntactic rules. In other words, children are presented with high
frequency exemplars that have very few irrelevant features as far as their
syntactic behavior is concerned. In return, all the first verbs used by
children in combination are usually drawn from this group of verbs.

Fig. 1. Cumulative number of different verbs in VO and SVO word- combinations

produced by a child acquiring English, as a function of age. Source: Ninio
(1999a).

30
 5

Once the first verbs are learned in a certain syntactic construction, the
speed of learning other verbs in the same syntactic construction, but not
necessarily in other constructions, is greatly enhanced. This could be
indicative of a scenario where the child learns the first examples with a great
deal of investment of effort, after which the ability to learn new verbs in the
same syntactic combination is greatly facilitated. Figure 1 presents as an
example two graphs documenting the development of verb-object and subject-verb-
object word-combinations in a child, as a function of age. The dependent
measure is the cumulative number of different verbs participating in each type
of construction as observed in recorded interaction sessions of child and
caregiver. Each verb is counted at the age when it is first produced in the
relevant syntactic construction.

It is evident that these graphs have the characteristic shape of typical

gradually accelerating learning curves: The time it takes to apply the new rule
to yet another verb is much longer at the beginning of acquisition of that rule,
and it gets shorter the more verbs the child has already learned to produce in
the relevant pattern. Accelerated learning has also been observed with regard to
other aspects of language acquisition such as the growth of vocabulary(Dromi
1987, Van Geert & van Dijk, 2002).

The conclusion is that languages are statistically shaped so that when we

talk simply to those who are just learning to talk, we are accentuating the
general properties of language. The statistical structure is a means of
ascertaining that language can be learned through meeting with the concrete
exemplars of the linguistic environment. The statistical structure of language,
in other words, allows Optimal Exemplar Learning.

4. The Immune System: Learning from similarities.

The definition of the behavior of the immune system as a cognitive system is

not new; it has been put forward by Cohen (2000), Varel (1994) and others
(Hershberg & Efroni, 2001).

The immune system starts with a large random collection of receptors from
which only a subset survives. The receptors of the immune system are selected
according to a certain level of affinity to antigen examples from the body,
through a process of negative and positive selection in which all receptors of
too high or too low an affinity to these antigen examples are killed (along with
the cells that produce them). These examples reflect the expression of proteins
in the various cells of our bodies. As in other perceptual systems the
selection of receptors is competitive. If a receptor spends a long time

31
 6

inactive, it will be pushed aside by more active receptors (Goldrath & Bevan,
1999). The immune system is left with a repertoire of cells that all share this
level of affinity to the antigen examples of the body.

Let us look how this fits in to the principles of optimal exemplar learning.
It seems bizarre to emphasize that all examples are concrete in the immune
system. Compared to other, more obvious, cognitive systems, where it is
apparent that abstraction and general concepts may exist as objects, in the
immune system the receptors are all dealing with specific concrete molecular
patterns. However, as in the other systems, the environment is ordered, and to
reflect this order the receptor repertoire is better served by learning form
certain examples and not others. All accumulation of knowledge from previously
presented examples is by transference. Cells of the immune system react
differently to an antigen or other chemical signals depending on previous
experience and reaction to examples. This is true in the thymus where a previous
reaction may cause cell death but also in the periphery where activation can
cause differentiation of naive immune cells to active and to memory cell
subsets.

To show how the immune system fits to the form of Optimal Exemplar Learning,
let us start with the statistical distribution of examples. As in language the
environment is ordered, the antigens, which select the cells, have a
distribution which is similar in shape to that of words in language. In an

Antigen Presenting Cell 50% of all antigens presented will belong to 200 of a
possible 10^14 antigens (Barton & Rudensky, 1999).

In an attempt not to use too many names and other forms of biological jargon
we have left out what exactly are the Useful Examples in the immune system and
what are the general properties they embody. The general properties the immune
system notices are based on the fact that as cells, both our selves and the
pathogens that invade us are not far distant from each other. We all stem from
the same evolutionary chain and share many biological mechanisms. Possible
candidates as Useful Examples that reflect this fact could be housekeeping
proteins (Cohen, 2000). This group of proteins have, as their name implies,
essential cellular housekeeping functions that are expressed in times of
cellular stress to help the cell maintain its viability in hard conditions.
These are good candidates for Useful Examples of cellular status for three
reasons first they are expressed in times of stress which is a good signal to
raise the interest of the immune system, second they are necessary in all cells
and so are expressed in all the cells of our body and outside it. Third and not
least they are so important that they have changed very little over the
evolution of life on earth and so are extremely similar in us and in the

32
 7

bacterial pathogens that invade us (11). Therefore a receptor repertoire built

around such examples would have to change little to become efficient identifiers
of foreign proteins and their derivatives. Beyond these theoretical
considerations such housekeeping proteins and the immune receptors that are
sensitive to them have been found to be important for good immune reactions to
both foreign invaders, and to other immune functions, such as combating caner
and the repair of damaged tissue (Cohen & Young, 1991; Moalem, Yoles, Leibowitz-
Amit, Muller-Gilorr, Mor, Cohen, Schwartz, 2000 Schwartz & Cohen, 2000).

Much like in learning language, when the immune system interacts with its
environment it will often encounter the Useful Examples causing the repertoire
of receptors to be built around them. A repertoire built around other examples,
not ubiquitous to all cells would have receptors that could be irrelevant to
some pathogens, or even some cells of our bodies. As it is possible that some
cells do not even express these proteins or any proteins similar to them. Even
should some of the repertoire be built around other antigens these receptors
will be less versatile in dealing with immune events and so over time should die
out relative to the repertoire built around the Useful Examples which better
reflect the common ground of cellular life and the factors essential to its
viability.

5. Conclusions: Differences and unifying principles

Although we have dealt here only with two system, we believe that what we
have said here may hold true for other cognitive systems as well. Cognitive
systems and their environments differ in their interactions and in their
building blocks. General properties and the examples that represent them have
different reason for being signaled out by the perceptual tendencies of
different cognitive systems. In the immune system it is the co-evolution of
pathogens and hosts that defines the general properties. In language it is the
fact that language is a cultural artifact, which needs to be passed on between
users. For each cognitive system the reason for the singling out of specific
Useful Examples is different. It depends on the specific environment and the
specific types of interactions that the cognitive system undergoes with its
environment. This reflects the fact that cognitive systems are fitted by
evolution to specific niches. Therefore this difference basically represents the
differences of environment and strengthens the feeling that in many disparate
environments different cognitive systems are using the same rules to learn to be
cognitive system.

33
 8

Optimal Exemplar Learning allocates great importance to the statistical

structure of the natural environment and in particular, to the identity of its
most frequent exemplars. In attempts to study and simulate cognitive systems we
must retain the statistical shape of the natural environments in which they
develop, as this appears to be one of the essential features in their
development. Even before we consider other aspects of cognitive learning
implied by the principles of Optimal Exemplar Learning, for example the
embodiment of examples in their natural environment; the importance of the
behavioral and perceptual tendencies of the system; and so forth, we must
consider the statistical distribution of the environments. This distribution by
itself may direct us to the essential pieces of information that the systems use
to learn their capabilities.

When studying a specific cognitive system and its environment or, for that
matter, when trying to create an artificial system with the traits of a
cognitive system, we should try and understand what are the Useful Examples they
use to learn to be cognitive systems, as knowing what the Useful Examples are,
gives a great amount of information about the cognitive system, its environment
and the nature of the interactions between them.

References:
Barton, G. M. & Rudensky, A. Y. (1999). Evaluating peptide repertoires within the
context of thymocyte development. Seminars in Immunology,11, 417-422.

Bates, E., Bretherton, I., Snyder, L. & Beeghly, M. (1988). From first words to grammar:
Individual differences and dissociable mechanisms. Cambridge University Press.

Cohen, I. R. (2000). Tending Adam's garden. San Diego, CA: Academic Press.

Cohen, I. R. & Young, D. B. (1991). Autoimmunity, microbial immunity and the

immunological homunculus. Immunology Today, 12, 105-110.

Dromi, E. (1987). Early lexical development. New York: Cambridge University Press.

Goldrath, A. W. & Bevan, M. J. (1999). Selecting and maintaining a diverse T cell

repertoire. Nature, 402, 255-262.

Gupta, Redhay S. (1998). Protein Phylogenies and Signature Sequences: A Reappraisal of

Evolutionary Relationships among Archaebacteria, Eubacteria, and Eukaryotes.
Microbiology and Molecular Biology Reviews, 62, 1435-1491.

Hershberg. U. & Efroni, S. (2001). The cognitive immune system: reaching the general
properties. Complexity, 6, 14-21.

Moalem, G., Yoles, E., Leibowitz-Amit, R., Muller-Gilor, S., Mor, F., Cohen, I.R. &
Schwartz, M. (2000). Autoimmune T cells retard the loss of function in injured rat
optic nerves. Journal of Neuroimmunology, 106, 189-197.

34
 9

Ninio, A. (1999a). Pathbreaking verbs in syntactic development and the question of

prototypical transitivity. Journal of Child Language, 26, 619-653.

Ninio, A. (1999b). Model learning in syntactic development: Intransitive verbs. Invited

article for a special issue on Cross-linguistic Studies of Early Grammar, edited by
M. M. Vihman. International Journal of Bilingualism, 3,111-131.

Schwartz, M. & Cohen, I. R. (2000). Autoimmunity can benefit self- maintenance.

Immunology Today, 21, 265-268.

Van Geert, P.L.C. & van Dijk, M. (2002), Focus on variability: New tools to study intra-
individual variability in developmental data. Infant Behavior and
Development,25,340-374

Varela, F. (1994). A cognitive view of the immune system. World Futures, 42,31-40.

Zipf, G. K. (1935/1965). Psycho-biology of languages. Cambridge, MA: MIT Press. (first

published by Houghton Mifflin).

35
Self affinity is the basis not the nemesis of immune
reaction

Hershberg U., Solomon S. and Cohen, IR. (2003) What is the basis
of the immune system's specificity? Mathematical
Modelling & Computing in Biology and Medicine,
(V.Capasso Ed.), pp. 377-384 The MIRIAM Project Series,
Progetto Leonardo, ESCULAPIO Pub. Co., Bologna, Italy.

Hershberg U. ( in press) Useful Examples and a new model of the

immune system, Revue d'Intelligence Artificielle (11
manuscript pages).

The papers in this section present two versions of a model of T cell and
antigen populations in the immune periphery. The various clone types are
represented as populations at points in shape space. T cells can react to
antigens at the same points as themselves in shape space and also (at
less affinity) to those on adjacent points in shape space. The use of this
shape space representation allows us to embody the degeneracy and
cross-reactivity of T cell receptors along with their essential level of self-
affinity. We succeeded in building a stable (i.e. benign) T cell repertoire,
around a small set of self-antigens, which reacts to a foreign antigen and
returns to its resting state once the foreign antigen is destroyed.

The success of this model radically changes the view of immunity as it

shifts the place of self-immunity and degeneracy from being possible
faults to being essential assets.

The first paper in this section and its concepts are obviously influenced by
the papers in the previous section. However, our wish to emphasize the
biological / immunological aspects of our results led us to leave out the
more general ideas relevant to cognitive systems. The final paper can be
considered to be a summary of the three papers before it. It explicitly
connects between the theory of Useful Examples, optimal exemplar

36
learning, our simulation, and the new view of immunology it entails. The
simulation presented in it is similar to the one in the paper before it but it
utilizes multiple foreign antigens to represent the pathogen while reaching
similar results.

The reason for inserting both papers on the T cell repertoire simulation
into the thesis is because it is only through understanding the reasoning
and results from both a cognitive science and an immunological point of
view, that we gain its full interdisciplinary import.

37

 

 
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44
Useful Examples and a New Model of the
Immune System

Uri Hershberg

Interdisciplinary Centre for Neuronal Computation

Hebrew University of Jerusalem,
Israel.
uriher@cc.huji.ac.il

ABSTRACT: It is central to the development of cognitive systems that they have in their
environment certain examples that are both high frequency and generic to some general
property of their interaction with the environment. We have called such examples Useful
Examples and suggested that in order to understand cognitive systems and their capabilities
we must study these examples. In the following pages I will use a model of immune cell
repertoire dynamics in the immune response to pathogens as an illustration of this point. This
model is based on the application to immunology of the theory of Useful Examples and on
existing knowledge of immune dynamics. Its conclusions place self-reactivity at the basis of
immune specificity of reaction, causing a paradigm shift in existing conceptions about
immune functions and sensitivities. In closing I will go over conclusions about the general
importance of Useful Examples in the study of cognitive systems.

KEY WORDS: complex systems, immunology, cognitive systems, learning, development, self
organization .

Revue d'Intelligence Artificielle. Volume X – No. X/2001, pages 1 to n

45
2 Revue d'Intelligence Artificielle. Volume X – No. X/2001

1. Introduction

When talking of analogies and their use in the behaviour and development of
cognitive systems we focus mostly on how much the two ‘ends’ of the analogy are
the same. We ask how this sameness is used by cognitive systems to relate and learn
about the world. This ignores a basic facet of analogies, which is that by finding
things similar we are implicitly saying that they are not the same. What we learn
form the analogy are the differences. The similarities are used as framework /
scaffold to teach us about the new and the different.
We have previously suggested that cognitive systems share a common strategy
of interaction with their environment to acquire their capabilities (Hershberg &
Efroni 2001). Cognitive systems must learn to be cognitive systems. We have
presented a view of the system's mode of learning in which we described it as a
direct result of unsupervised interactions with concrete examples of the environment
(see fig. 1 and Hershberg & Ninio 2003).
Such a simple form of learning is sufficient to allow the system an
understanding of its environment because the environment is ordered. There are a
few examples which are encountered with high frequency while most
other examples are encountered less frequently. The high frequency examples are
not ubiquitous by chance. Their prevalence reflects a multiplicity of usages for these
examples within the interaction of system and environment. Viewed as separate
instances, the variety of contexts in which such examples exist appears a deterrent to
learning. However, when examined in the light of the complete set of interactions
between system and environment, this variety becomes an asset. In effect, these
examples embody important properties of the environment for the cognitive system.
These examples are constantly encountered; once acquired, they can greatly
enhance the ability to learn new less generic examples by similarity-matching; and
finally, both in their own right and due to their similarity to other examples, they
will be consistently reinforced by the system's interaction with its environment. We
call such ubiquitous and generic examples of the environment Useful Examples
because they are useful to the system for learning the environment, and its relevant
general properties. The distribution of examples in the environment is not arrived at
by chance. For each cognitive system the reason for signalling out of specific Useful
Examples is different. It depends on the specific types of interactions which the
cognitive system undergoes with its environment. This reflects the fact that
cognitive systems are fitted by evolution to specific niches. Based on genetic
inheritance and previous cognitive development a cognitive system has certain
tendencies, which give it the framework of its environment.
As an example of the application of this theory of Useful Examples to the study
of cognitive systems I will in the rest of this paper, deal mostly with the immune
system. I will show how studying the Useful Examples, used by a given system to
acquire its capabilities, can influence our scientific understanding of that cognitive

46
 Useful Examples and a New Model of the Immune System 3

system and its function. I will explain how by leading from the theory of Useful
Examples we reach a new model of immune reaction and the importance of self
reactivity to the proper maintenance of immune capability.

Figure 1. The two phases encompassing cognitive action/perception: Through

specific interactions, and based on the previous (innate) tendencies of the system,
certain general properties are corroborated by Useful Examples of these properties
appearing in the environment. This corroboration leads to the formation of an
achieved set of representations in the system. Specific interactions with the
environment start with the deconstruction of the specific patterns encountered via
the detection of similarities to the Useful Examples embodied in the achieved set.
After detection there is a refitting and fine-tuning of the perception to the specific
elements of the event. Having identified the specific elements of the event there is
now a reconstruction of the raw event, accompanied by association to contextual
factors into a functional or meaningful event, which can be appropriately reacted
to and added to the memory of the system. The two phases are chronologically
mingled. Every interaction is a specific interaction even while the cognitive system
is still building its understanding of the general properties. In addition in many
cognitive systems it is not clear if the process of defining new general properties
ever comes to a complete stop. 'Young' cognitive systems are less fluent in working
with the general properties and it is harder to teach an 'Old' cognitive system new
tricks, but all interactions with the environment have elements of both phases.
(Adapted from Hershebrg and Efroni 2001).

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4 Revue d'Intelligence Artificielle. Volume X – No. X/2001

2. Paradigms of immune specificity.

To show how the theory of Useful Examples changes our view of the immune
systems sensitivities we must first go over the existing view. The immune system
starts with a large random collection of receptors from which only a subset survives.
The receptors of the immune system are selected according to a certain level of
affinity to certain molecular shapes from the body, called antigens. The receptors are
selected through a process of negative and positive selection in which all receptors
of too high or too low affinities to these antigens are killed (along with the cells that
produce them).
The resulting immune system is unique among the systems in our body in having
an amazingly diverse variety of receptors. This great variance is used to identify a
near infinite number of different antigens. The high sensitivity of different antigen
receptors is however highly regimented allowing the immune system to react to one
type of antigen in a given context while ignoring other antigens. It is as yet an open
question how the immune system maintains the specificity of reaction. - The
possible answers lie in two camps: Receptor specificity and systemic response
specificity. By receptor specificity we mean that antigen receptors themselves are
each highly focused and specific. Thus the specificities of an immune response is
based on a repertoire built only of certain kinds of receptors. By systemic specificity
we mean a mechanism that does not rely on the specificity of the receptors, but
rather on some global behaviour of the system.
The mainstream paradigms of immunology answer this question by various
mechanisms of receptor specificity (Langman et al 2000) based to some extent on
Jerne’s clonal selection theory: The immune systems function is to defeat
pathogens. The immune system identifies foreign antigens and destroys them. The
identification of the foreign is made possible by removing, in the immune systems
prenatal development, all receptors that recognize self. Anything that an immune
receptor identifies “must be the enemy” (Burrnet 1957).
The fact that we can find receptors sensitive to practically any substance and the
importance of negative selection in the building of the immune system’s naïve
repertoire have supported this paradigm based on receptor specificity. However, a
closer look at the way immune cells are selected in the bone marrow and the thymus
indicates that this interpretation is problematic:
− Immune cells are not completely specific; they are degenerate and cross-
reactive.
− A certain level of benign affinity to self-antigens exists in all receptors.
These points hold true for all cells of the adaptive immune system, and weaken the
claims that the immune system’s specificity is based on any type of receptor
specificity. The adaptive immune system is usually divided into two main groups of

48
 Useful Examples and a New Model of the Immune System 5

cells, humoral immunity (B cells) and cellular immunity (T cells). We present a

model of T cells, focusing on the theoretical problems relevant to T cells.
All T cells are highly cross-reactive, each T cell can react to 3*10^7 different
antigen types (Borras et al 2002). Furthermore, although T cells of a high affinity to
self antigens are culled by negative selection, all T cells must have some level of
affinity to self or they will not pass the positive selection phase and die of neglect
(Goldrath and Bevan 1999). Positive selection appears to be especially important as
it is now found to be an essential factor in the maintenance of the T-cell repertoire in
the periphery. Low level affinity to self is not only essential as a maintaining signal
of T cells but is also prolifirative in its effect (Ernst et al. 1999). We thus find a
situation where the actual T cell repertoire is not, as is commonly suggested by
immune theory, built of specific receptors reactive to foreign antigens. The
repertoire is, in point of fact, built of highly cross-reactive receptors that all share
some minimal common affinity to self antigens.

3. Looking at the order of the immune environment.

The answer rests in replacing the mechanistic view of the immune system with a
view of the immune system that considers it to be comparable to other cognitive
perceptual systems (Varela 1994, Cohen 2001, Hershberg and Efroni 2001). This
view leads us, as we suggest from the study of other cognitive systems (Hershberg
and Ninio 2003), to study the distribution of examples that are naturally encountered
by the immune system. When we do this we see that not all antigens are equally
encountered. Much as has been seen in language (Zipf 1935) the distribution is such
that a few antigens are highly frequent while most potential antigen types are rare or
non-existent. In fact 200 antigens, out of 1014 potential types, will be presented in
50% of T cell encounters (Barton and Rudensky 1999). This over expression in itself
is not enough for us to apply the theory of Useful Examples as it does not suggest
any generic trait of immune interaction. However if we add that most, if not all, high
frequency antigens are self antigens the picture changes. We would like to suggest
that the above inhomogeniety of presentation reflects the fact that certain families of
proteins are ubiquitously expressed in all cells while others are only sometimes
expressed. The proteins that are most expressed are those which are essential for
cellular life, such as chaperones and other housekeeping proteins. Such
housekeeping proteins have been suggested as important to immune function and
they are expressed in all cells and at high levels (Cohen 2000). Because they are so
important these proteins are also the most highly conserved (Gupta 1998).
We share a common heritage with the pathogens that invade us. The points of
similarity between invader and host represent the essential factors of cellular life –
the manipulation of genetic material and energy production. Those molecules that
we share with our pathogens are essential to them and to us. It should therefore be
no surprise that antigens derived from such proteins make effective immune signals.

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6 Revue d'Intelligence Artificielle. Volume X – No. X/2001

They are older than the immune system, can be counted on to exist in all immune
environments and cell types, and are over-expressed in times of stress. In fact, it has
been found that antigens derived from certain foreign housekeeping proteins are
very immunogenic, and induce better activation of the immune system the more they
are similar to self proteins (Cohen & Young, 1991; Schwartz & Cohen, 2000).
Considering the wealth of information regarding points of similarity between the
self and its pathogen invaders, building an immune system that ignores the self is
like constructing an eye without a fovea. In the immune system the general
properties of interaction are based on the co-evolution of cellular life. The Useful
Examples of such an environment are those proteins essential to cellular viability.
Such proteins, due to their importance to all cells, are ubiquitous and highly
conserved throughout evolution. Their derivatives are therefore ideal as base signals
of cellular stress and change.

4. A model of primary immune reaction based on affinity to self.

We have presented the following model to show how a repertoire of cross

reactive T cell receptors with a common affinity to self antigens could function
effectively against a foreign pathogen (Hershberg et al 2003). In this model, we
focus on the relationship between similar antigens (be they foreign or self) and the T
cells that react to them. To do so, we ignore the physical space of immune
interaction and look at the multi dimensional shape space of T cells and antigens (for
illustration figure 2 shows a two dimensional representation of shape space). Every
point in shape space represents the various similar antigen shapes that a single clone
of T-cell is reactive to with high affinity (figure 2 (iii)); high affinity is that affinity
which leads to negative selection in the thymus (A). First neighbours in shape space
are those antigens and T cells that have enough of an affinity to be affected by the
positive selection of protein antigens (A’).1
We present a generic scenario that models the immune reaction in terms of the
following observed mechanisms (Goldrath et al. 1999):
− A steady feeding of T cells from the thymus to the periphery regardless of
immune activity (figure 2 (ii)). The T cells will only arrive into points in shape space
that are close enough to the high frequency self antigens ((A)) so that they where
positively selected in the thymus.
− T cells proliferate at a rate relative to the level of antigen they encounter
and to their level of affinity to each other (figure 2 (iii)), regardless of the source of
the antigen (self or non self).

1
This supposes the existence of a relatively permanent group of self- antigens, similar in the
thymus and the periphery.

50
 Useful Examples and a New Model of the Immune System 7

Figure 2. Reactions in shape space – shape space is an imaginary space in which

every point represents the shapes of receptor/ligands that are reactive to each other
As represent antigens and Ts represent T cells . (i) If a T cell and an antigen are at
the same point (AT) they have high affinity to each other. If they are far away (T a)
they have a low affinity to each other.
− To represent the homeostatic competition between T cell clone types the T
cells die at a rate proportional to the total population of T cells.
To these three reactions of T cell repertoire maintenance we add an effector
mechanism to kill pathogens. Based on existing ideas suggesting that the effector
mechanism may be activated not merely by antigen activation but rather by changes
in T cell activity (Grossman et al 2001), we have built in the model an effector
mechanism which is activated against antigens that change the level of T cell
activity. In this model only positive changes in activity are considered.

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8 Revue d'Intelligence Artificielle. Volume X – No. X/2001

5. Results and conclusions for immunity.

Figure 3. Results of the simulation: Upper panel: Snapshots at progressive days

post infection until the height of T cell reaction at approximately eight days post
infection. Changes in T cell repertoire activity [a-c] Changes in the antigen
repertoire [d-f] of self antigens (blue) and non-self antigens (red). Lower panel: T
cell repertoire three days [g] and three weeks [h] after the foreign antigens are
cleared.
Built around a permanent set of antigens, representing the high frequency (self)
antigens, the above reactions result in a steady homeostatic population of T cells
(fig. 3 [a]), without reactivity of the effector mechanism, as long as no pathogen is
evident. We therefore add a primary infection in the form of new antigen
populations in shape space (fig. 2 (iv) - A’). We place them so that no T cell will
have a higher reactivity to them than to the self antigens that maintain them.
Therefore there is no possibility of receptor specificity.
The foreign antigens differ in two traits. They are in a new place in shape space
causing an imbalance in the T cell competition over antigens; and they have
different dynamics from self antigens – they are proliferating rapidly.

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 Useful Examples and a New Model of the Immune System 9

Figure 3 shows the effect of a primary infection on the T cell repertoire. In these
“snapshots”’ we see the change of the T cell repertoire [a-c] until the clearance of
foreign antigen, and the relative types of antigens [d-f] of self (blue) and non self
(red) that push this change. At first when the level of the foreign antigens is low [d]
the repertoire is at its stable resting state [a]. The rapid proliferation of pathogens [e]
causes the immune system to turn its attention and resources towards the change in
the pattern of antigens in shape space [b]. This change in T cell activity activates the
effector mechanism, which rapidly decimates the pathogens and the antigens they
exhibit [f]. Much as in reality the highest point of T cell activation is shortly after
the height of the disease [c]. Those T cell types that are most highly expressed at
this stage become the memory cells that allow more rapid reaction to secondary
infections. The entire time course of the simulation, from infection to the height of
immune reaction takes eight days2, much as is seen in actual infections. Once the
foreign pathogens are cleared the two final snapshots show the return of the
repertoire to its resting state. Within a few days without the drive of foreign antigens
the overall level of T cells is close to normal, however some T cell types are still
over expressed [g]. Approximately three weeks later [h] the repertoire is once more
at its resting state shaped around the self antigens of the body.
Thus without ignoring T cell cross-reactivity we have built a model that uses a
small set of self antigens to educate the T cell repertoire. In doing so the simulation
successfully recaptures the dynamics of a primary infection without the need for T
cell specificity. We have shown a way that the immune system could react to foreign
pathogens without the need for a special affinity to non self antigens. This success
strengthens the plausibility of the paradigm of cognitive immunity and of systemic
specificity in immune reactions. Most importantly it causes a complete revaluation
of the place of self immunity in immune function. Self immunity is no longer
viewed as the bane of an over reactive immune system, instead it is seen to be the
basis of immune specificity. The ability to detect novel antigens and maintain a
stable repertoire is based on a background signal built of the affinity to self.
The re-evaluation of the place of self immunity does not merely change our
conceptual view of immune dynamics - it calls for an actual change in the way
immunology is studied. Immunology is highly motivated by our wish to combat
disease and by our perception of disease. This has lead to a unique scientific
situation. Usually in science the system studied is compared at rest to its perturbed
states. In immunology the view that when not activated by foreign antigens the
immune system is inactive and in dynamical sense non-existent, has lead to a
skewed scientific research situation. Most, if not all, immune research is done on the
perturbed (disease state) immune system. However, with this new view of self
affinity as a calibrating background signal, we see that the immune system is
constantly active and that to understand immune disease dynamics we must first
study the immune system in healthy states.

2
A day in the simulation is calculated according to the steady rate of T cell arrival form the
Thymus which is known to be ~2% a day of the resting population.

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10 Revue d'Intelligence Artificielle. Volume X – No. X/2001

6. Useful Examples and study of other cognitive systems.

In the last sections I have shown how considering the natural distribution of
examples encountered by the immune system has suggested a model of immune
interaction that radically changed the basic paradigm of immune study. In closing I
would like to stress that this is not unique to the immune system. The immune
system is brought here as a primitive example of cognitive systems in general. The
example is not at the level of the building blocks. There is no claim here that
immune cells and neurons are the same. The similarities rest in the common
strategies of interaction and in the need to create a fit between system and
environment though their natural interaction. This actually strengthens the theories
relevance for the creation of artificial systems. It tells us something about the
general design principles of a cognitive system regardless of its specific building
blocks or function.
If we wish to understand or to recreate cognitive systems we must look at the
initial developmental stages that turn a naïve system into a fully functional cognitive
one. The outward representation of this process is the skewed distribution of
examples in the environment. The networks of analogies are not evenly distributed.
Some nodes are far more central and, once learned, give the system a much easier
access to the rest of the network. We have called these nodes Useful Examples; by
studying them we have an observable handle to study cognitive systems. Such a
handle is essential, as cognitive systems are so intuitively known to us as to make it
very hard for us to study them objectively. This paper has shown, using the
immunes system as an example, that our intuitive view of the function of a cognitive
system is not a good place to start studying them. We should instead, when
attempting to study or emulate a cognitive system, focus on the actual patterns of
interaction with the environment and the Useful Examples that embody them.
This form of research has been shown to be relevant to the development of
several cognitive systems - language (Ninio 1999, Hershberg &Ninio 2003), and as
seen above immunity. Due to its generality we anticipate that it should hold true also
for the study of other cognitive perceptual modalities.

Acknowledgements

I would like to thank Prof. Anat Ninio, Prof. Sorin Solomon and Prof. Irun
Cohen for their guidance; Pierre Bohn, Yoram Louzoun, Eldad Bettelheim and Sol
Efroni for arguing with me, and Shira Ninio for helping me make sure it was
convincing.
Uri Hershberg is a recipient of The Levi Eshkol fellowship given by the Israeli
MOS.

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 Useful Examples and a New Model of the Immune System 11

7. References

Barton, G. M. & Rudensky, A. Y. Evaluating peptide repertoires within the context of

thymocyte development. Seminars in Immunology, 11, (1999) pp.417-422.
Borras E., Martin R., Judkowski V., Shukaliak J., Zhao Y., Rubio-Godoy V., Valmori D.,
Wilson D., Simon R., Houghten R. and Pinilla C. Findings on T cell specificity revealed by
synthetic combinatorial libraries, Journal of Immunological methods 267 (2002) pp.79-97.
Burrnet FM, A Modification of Jerne’s Theory of antibody Production Using the Concept of
Clonal Selection. Aust J. Sci. 20:67-69. (1957).
Cohen, I. R. Tending Adam's garden. (2000) San Diego, CA: Academic Press.
Cohen, I. R. & Young, D. B Autoimmunity, microbial immunity and the immunological
homunculus. Immunology Today, 12 . (1991) pp. 105-110.
Ernst B., Dong-Sup Lee, Chang, J.M., Sprent J., and Surh C.D. The Peptide Ligands
Mediating Positive Selection in the Thymus Control T Cell Survival and Homeostatic
Proliferation in the Periphery Immunity, Vol. 11 (1999) pp.173–181.
Goldrath, A. W. & Bevan, M. J. Selecting and maintaining a diverse T cell repertoire. Nature,
402, (1999) pp. 255-262.
Grossman Z. and Paul W.E. Autoreactivity, dynamic tuning and selectivity Current Opinion
in Immunology, 13 (2001) pp. 687–698
Gupta, Redhay S. Protein Phylogenies and Signature Sequences: A Reappraisal of
Evolutionary Relationships among Archaebacteria, Eubacteria, and Eukaryotes. Microbiology
and Molecular Biology Reviews, 62, (1998) pp. 1435-1491.
Hershberg. U. & Efroni, S. The cognitive immune system: reaching the general properties.
Complexity, 6 (2001) pp.14-21.
Hershberg U. & Ninio A. Optimal Exemplar Learning Cognitive Systems Special issue on
multidisciplinary approaches to leaning in cognitive systems( to appear 2003)
Hershberg U., Solomon S. and Cohen, IR. What is the basis of the immune system’s
specificity? , special issue of MIRIAM devoted to papers from the 5th international
conference of the European society for Mathematical and theoretical Biology (to appear
2003).
Langman RE and Cohn M, A minimal model for the self-nonself discrimination: a return to
the basics Seminars in Immunology Vol. 12, No.3 (June 2000) pp. 189-195.
Ninio, A. Pathbreaking verbs in syntactic development and the question of prototypical
transitivity. Journal of Child Language, 26, (1999) pp. 619-53.

Schwartz, M. & Cohen, I. R. Autoimmunity can benefit self- maintenance. Immunology

Today, 21, (2000) pp. 265-268.
Varela, F. A cognitive view of the immune system. World Futures, 42,(1994) 31-40.
Zipf, G. K. Psycho-biology of languages. Cambridge, MA: MIT Press (1935/1965 first
published by Houghton Mifflin).

55
HIV time hierarchy - Winning the war while loosing all the
battles

Hershberg U., Louzoun, Y., Atlan H. and Solomon, S. (2001) HIV time
hierarchy - Winning the war while loosing all the
battles. Physica A: 289 (1-2) pp.178-190, also placed on
the net at xxx.lanl.gov (Nonlinear Sciences-Adaptation
and Self Organizing Systems).

Chronologically this was our first attempt to use a model of dynamics in

shape space to model the immune system. The actual view of immunity is
very simple and mechanistic. Measuring the changes in relations between
populations of immune cell types and populations of virus types resulted in
a simple explanation connecting between normal virus dynamics and the
special dynamics of HIV. In the wider view of this thesis we see here how
the immune system makes a conceptual mistake in identifying the escape
mutants of HIV as novel invaders. The use of shape space shows us a
potential hiding place for HIV which de-mystifies the diseases insidious
dynamics. The virus’s high mutation rate is modeled as diffusion in shape
space which allows HIV escape mutants to propagate. Thus, after every
immune victory, in which both immune system and virus behave much as
in the case of a normal virus, a few strains of HIV are created and escape
to adjacent points in shape space where no immune reaction is as yet
ready. These grow and are duly identified and destroyed by the immune
system, except for a few more escape strains. At every stage the immune
system triumphs over a specific strain but the overall number of strain
types and the overall population of HIV continues to rise. At some point,
the immune system, which is being decimated by global levels of HIV
without the need for identification in shape space, is overwhelmed and the
HIV population explodes.

56
 Physica A 289 (2001) 178–190
www.elsevier.com/locate/physa

HIV time hierarchy: winning the war while,

loosing all the battles
Uri Hershberga , Yoram Louzouna , Henri Atlanb , Sorin Solomonc; ∗
a Interdisciplinary Center for Neural Computation, Hebrew University, Jerusalem, Israel
b Human Biology Research Center Hadassah Hebrew University Hospital, Jerusalem, Israel
c Racah Institute for Physics, Hebrew University, 91904 Jerusalem, Israel

Received 15 June 2000

Abstract
AIDS is the pandemic of our era. A disease that scares us not only because it is fatal but
also because its insidious time course makes us all potential carriers long before it hands us our
heads in a basket. The strange three stage dynamics of aids is also one of the major puzzles
while describing the disease theoretically (Pantaleo et al., N. Engl. J. Med. 328 (1993) 327).
Aids starts, like most diseases, in a peak of virus expression [R.M. Zorzenon dos Santos, Immune
responses: Getting close to experimental results with cellular automata models, in: D. Stauer
(Ed.), Annual Review of Computational Physics VI, 1999, pp. 159–202; R.M. Zorzenon dos
Santos, S.C. Coutinho, On the dynamics of the evolution of HIV infection, cond-mat=0008081],
which is practically wiped out by the immune system. However it then remains in the body
at a low level of expression until later (some time years later) when there is an outbreak of
the disease which terminally cripples the immune system causing death from various common
pathogens. In this paper we show, using a microscopic simulation, that the time course of AIDS
is determined by the interactions of the virus and the immune cells in the shape space of antigens
and that it is the virus’s ability to move more rapidly in this space (its high mutability) that
causes the time course and eventual “victory” of the disease. These results open the way for
further experimental and therapeutic conclusions in the ongoing battle with the HIV epidemic.
c 2001 Elsevier Science B.V. All rights reserved.

PACS: 87.22.As

Keywords: Multi scale; Monte Carlo simulation; Evolution; Immunology; HIV; Hybrid models

∗Corresponding author. Tel.:/fax: ++972-2-6585761.

E-mail address: sorin@cc.huji.ac.il (S. Solomon).

0378-4371/01/$ - see front matter c 2001 Elsevier Science B.V. All rights reserved.
PII: S 0 3 7 8 - 4 3 7 1 ( 0 0 ) 0 0 4 6 6 - 0
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1. Introduction

The natural progression of the human immuno-deciency virus (HIV) infection varies
between individuals, however a general pattern of the progression has been observed
(Fig. 1).
• Within weeks of infection, a short transient jump of plasma virema (virion concen-
tration in plasma) is seen together with a marked decrease in immune cell counts
(CD4 T helper cells).
• Partial control of the disease by the immune system ensues, causing variable periods
of practically, asymptomatic clinical latency, which can last for several years. During
this period the immune cell population continues to slowly decline until the immune
system is so crippled that it can no longer contain the disease.
• A renewed outbreak of the virus which, together with constitutional symptoms and
the onslaught by opportunistic diseases, cause death [1].
The dynamics of HIV was traditionally described using simple homogeneous ODEs
[5] (for a review see Perelson [6]). This method was enlarged to models considering
the spatial structure mainly by Zorzenon dos Santos and Coutinho [2,3]. Such models
consider the importance of the localization of the interactions between the HIV virions

Fig. 1. The typical three-stage evolution of the HIV illness: according to the experimental data, the HIV
illness presents three distinct phases. During the rst months after infection, there is an acute phase with a
very large increase in the virus population and a corresponding destruction of the immune cells. This ends
with the reprise of the immune system to the invasion and the decrease of the virus population to very
low values. After the immune systems reprise, comes a long period of slowly increasing virus population
and slowly decreasing immune cells population. At some stage, the virus population explodes and the
immune system collapses (the AIDS phase) resulting in an onslaught of opportunistic diseases and death.
(Addapted from picture, Copyright Dr. R.E. Hurlbert, from the Washington State University Fundamentals
of Microbiology 101 course home page: http://www.wsu.edu:8080/ ˜hurlbert/pages/Chap16.html#STD intro)
[4].

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and immune cells. Taking into consideration the global features of immune response
and the high mutation rate of HIV they described the spatial and temporal interactions
of infected and healthy cells in lymphoid tissue in the body.
The methodology used in spatially extended models was limited up to now mainly
to cellular automata [2,3], or to compartmental models [7]. The main advantage of
cellular automata is their capacity to emphasize the emergence and the importance of
spatial structures. For example the propagation of waves of infection in the lymph
nodes, or the creation of immune cell aggregations [2,3]. Consequently Zorzenon dos
Santos and Coutinho, in contradiction with most ODE models, succeeded to reproduce
all the stages of HIV evolution, using a single set of rules (see Ref. [3], and Fig. 13
in Ref. [2]).
The present model is inspired by the observed interesting features in the spatially
extended model [2,3]. Our model acts in the shape space rather than in the physical
space and exploits the dynamical implications of the HIV virus ‘propagation’ in the
molecular shape space: The immune system’s need to identify the virus’s form correctly
in the shape space of possible viral and immune receptor shapes. The main ingredients
in our model are the mutations (represented by propagation of the multiplying virions
in the structure-less innite dimensional shape space) and the confrontation with the
immune system cells (resulting in the disappearance of the both cells and virions).
Our model does not display any geometrical patterns in either space or shape space.
In this model we assume that we can average the spatially distributed reactions (as in
the ODE approach).
The model presented in the following pages relies on the basic known facts on the
immune defense system. The viruses (antigens) have various characteristic geometrical
shapes. In order to act against them, the immune system has to ‘identify’ them by
producing cells which contain shapes complementary to the geometry of (parts of) these
antigens. Since the immune system does not know a priori what is the characteristic
shape of every new invading virus, the immune system generates randomly cells with
various shapes. If a cell encounters (by chance) an antigen (virion) with complementary
shape, then more cells with characteristic shapes identical to it are produced and a
mechanism is triggered for the destruction of all the individuals (virions) belonging to
this virus strain (and sharing the same shape) [8].
Usually the destruction mechanism is quite ecient and once a virion is “identi-
ed” by the above random search in the shape space, its fate and the fate of all the
virions in the same strain is sealed: they are wiped out by the immune system within
days.
With HIV however, the issue is more complicated [2,3]: Since the virus’s replication
mechanism is relatively imprecise, as it multiplies, it undergoes a large amount of mu-
tations/changes in shape compared to those found in other kinds of virus [9 –11]. Based
on empirical and theoretical results in the research of HIV we propose the following
scenario. The immune system cells that are complementary to the old shape are ineec-
tive in dealing with the new mutant virus strain. The virions belonging to the strain with
the new shape can multiply with impunity until a strain of immune cells which ts the

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Fig. 2. The HIV strains in the primary infection are detected and annihilated by the immune system. However
some virions escape the immune system by mutating. While the new population which they engender is also
eventually discovered and destroyed by the immune system, their mutating descendants will escape again.
These phases of escape and destruction enable the intermittent proliferation of HIV after the immune systems
primary response and with it the idiosyncratic time course of HIV infection. (Picture, Copyright Dr. R.E.
Hurlbert, taken from the Washington State University Fundamentals of Microbiology 101 course home page:
http://www.wsu.edu:8080/ ˜hurlbert/pages/Chap16.html#STD intro [4]).

new shape is generated by the immune system. Once the immune system’s shape gen-
eration process succeeds to produce by chance a immune cell carrying a complementary
shape to the new virus strain and this cell encounters (by chance) a virion belonging
to the new strain, the new strain is wiped out too (with the exception of the eventual
new mutants that again can multiply freely until their new shape is detected by the
immune system). The process continues indenitely with the virus loosing every battle
but succeeding to produce increasingly many small populations of new shapes (Fig. 2)
[8,12–16].
The process is compounded by the additional fact that virions can kill directly and
indirectly immune cells (whether or not they are of complementary shape) [17].
The immune system continues to win every battle until the increase in production
of immune cells with shape complementary to a virus strain is overcome by the rate
at which the immune cells are destroyed by various other HIV strains. At this point
the immune system has eectively lost the war.
In the rest of the paper we provide a detailed microscopic simulation model [18–21]
which supports this scenario and that ts quite well the known phenomenological data
on HIV in terms of the following basic mechanisms:
• The local (in shape space) destruction of HIV by the immune system [15].
• The fast mobility of HIV in shape space (high mutation rate) [9,10].
• The global destruction of immune system cells by HIV [17].

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2. The model

We represent the shape space of the virus by a random lattice in which each site
(i) has a xed number of neighbors. Neighboring sites represent shapes that can be
reached from one to the other by a single base mutation of the virus. The occupation
number on each site (NVi ) represents the number of virions existing with that shape in
the organism. The immune system cells that recognize that shape are also represented
through an occupation number on the same site (NCi ). Note that the existence of a virus
and an immune cell on same lattice site does not imply their proximity in real space:
Quite to the contrary they might be located in very distant locations in the organism.
However, there is a small probability that the virus and the corresponding cell might
meet and react in real space. Therefore, each pair of virion and immune cell located
on the same lattice site has a small, but nite probability to react (according to the
rules described in detail below).
One represents the eventual mutations of the virus and the immune cells by their
rate of diusion in the shape space (DV ; DC ). More precisely both viruses and immune
cells have a certain probability for jumping between neighboring sites. 1
HIV can replicate in and destroy immune cells. This is irrespective of the cell’s char-
acteristic shape. That is, the virus can destroy immune cells located on sites arbitrarily
far away from the site of the virus). In our model we represent this by:
• A virus proliferation rate proportional to the total immune cells population (Ctot ).
• An immune cell death rate proportional to the total viral population (Vtot ).
We list bellow the reactions taking place in the model:
(1) When an HIV virion and an immune cell reside on the same site the immune
cell duplicates with a rate of C . However, following realistic biological data, we limit
the multiplication rate of the immune cells (to a factor of 3 per day).
(2) When an HIV virion and an immune cell reside on the same site the virion is
destroyed with a probability rate of dV .
(3) Each HIV virion replicates with a rate (V Ctot ) proportional to the total number
of immune cells.
(4) Each immune cell is destroyed with a probability rate (dC Vtot ) proportional to
the total number of virions.
(5) New immune cells, with various shapes are created continuously. We represent
this by a probability rate () for an immune cell to appear on a random lattice site.
(6) Both the immune cells and the HIV virus diuse slowly in the shape space with
rates DV and DC .

3. Results
The reactions listed in the previous section lead to the following scenario for the
evolution of the HIV infection. The virus enters the body in a high concentration
1 The diusion rate, and the neighborhood structure implied by the node’s connectivity can be dierent for
the virus and for the immune cells.

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Fig. 3. The acute phase analyzed by strains. The simulation of the acute phase provides an explanation to
the very large peak in the virus population: as opposed to an infection by a single strain, the organism has
to discover a multitude of strains. The height of the virus population peak is dominated not by the average
strain population but by the population of the strain which is discovered last by the immune system (and has
the longest time to exponentiate). The acute phase starts with a constant concentration of HIV distributed
between 20 strains (upper-right drawing). Each one of these strains activates an immune response and is then
destroyed (upper-left drawing). The observed average HIV and immune cell concentration is the average
over all strains (lower drawing).

limited to a restricted number of strains. As long as there is no immune cell in the site
corresponding to a certain strain, the virions located in this strain site proliferate expo-
nentially. The rise in virus concentration is accompanied by a destruction of random T
cells hosting the virus (according to item (4)). These T cells can be located anywhere
in the lattice. Eventually, one of the immune cells generated by the immune system
will fall by chance on the site of this strain (according to item (5)). This immune cell
will proliferate very fast, since, according to item (1), the proliferation rate increases
with the local viral concentration. The resulting high local immune cells concentration
will destroy all the virions of this strain (item (2)). As a result, after a short period
(1–2 month) all the initial strains will be discovered by the immune system and will
be destroyed ending the acute phase of the disease. In the absence of virus diusion
in shape space (i.e., mutations), this would stop the disease (Fig. 3).
It is the diusion rate of the virus in shape space (item (6)) which is responsible for
the continuation of the infection. Before all the initial strains are destroyed, some of
the virions have a chance to mutate and escape to lattice points containing no immune
cells.

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Each of these new lattice points in the shape space will contain a lower concen-
tration of virus than the original infection. Since the probability for the discovery of
a virus strain by the immune cells is proportional to the virus strain concentration
(according to item (1)), the time it will take for the immune system to discover, and
destroy these new strains (item (2)) will be longer than it is in the acute phase. By
the time these new strains are destroyed some virions from these strains will have
diused to neighboring sites (undergo mutations), and constitute the germs for a new
generation of emerging strains. These strains in turn will have the fate of their prede-
cessors in the previous generation. One sees now that one can describe the long-term
evolution of the HIV infection as an iterative process. More precisely, the long-term
evolution will consist of a chain of small infections, each of which is easily defeated
by the organism. However, after each such infection the number of strains will grow.
Therefore, even though the number of virions in each strain is always kept under
control by the organism, the total amount of virions will slowly increase stochasti-
cally. The increase is stochastic, since it depends on the random time it takes the
immune system to discover and destroy each new strain. As the number of virions
increases, the death rate of the immune cells also increases (item (4)). At a cer-
tain stage the death rate will be high enough to impair the capacity of the immune
system to react locally to new strains. This constitutes the last stage of the disease
(Fig. 4).
This typical scenario can vary from person to person:
(1) The typical case observed in most hosts is a disease composed of three stages
(Fig. 4). The rst acute stage is due to the fast proliferation of the original strains before
the appropriate immune response is set. This stage ends when the appropriate immune
response to each and every original strains is completed. This stage takes approximately
 ln (number of original strains) days (see below). This gives an expected number of
virions at the peak, which is much higher than in a usual disease (Appendix A). The
latent stage is the stage in which the number of virion strains is limited, and the
number of virions in each strain is low. This stage will last as long as the number of
strains is much smaller than C =dC (Appendix B). When the number of strains grows
above C =dC the last stage of the disease occurs. This is the regime in which the local
(in shape space) activation of the immune system by the local virus strain (item (2))
becomes lower than the global destruction rate of immune cells by the virions (item
(4)), and the immune system fails to destroy locally (item (4)) the existing strains.
At this stage many old strains that were kept under control during the previous stages
can reappear.
(2) If the ecency of immune reaction to HIV (items (1) and (2)) is high enough,
the immune system will manage to defeat the new virus strains fast enough. Thus, the
average number of strains will stay constant or slowly decrease. In this case, the total
number of virions will vary around a xed number, or slowly decrease to 0. This fate
can be one of the long-time carriers [22,23]. In reality, the total number of virions
never decreases to zero, since there are other sources (macrophages, neuronal cells,
etc.) that contribute a small number of new virions [22,24] (Fig. 5).

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 U. Hershberg et al. / Physica A 289 (2001) 178–190 185

Fig. 4. Typical HIV evolution in our simulation: in the top part of the gure we see that with our simulation,
we capture the dynamics found in the empirical data. By comparing with the Fig. 1, one sees that our model
reproduces correctly the three stages of the disease. The acute phase (A), a phase of chronic latency (B)
and nally a renewed outbreak of HIV coupled with the destruction of the immune system (C). Note that
the rst 100 days are plotted at a dierent scale. In the other two gures we see, over the progression of
the disease, the number of dierent HIV strains (middle) and the average concentration of virions per strain
(bottom). Together these two graphs strengthen our explanation that the time course of HIV is based on the
contradiction in local and globals concentration of HIV – locally the levels of HIV are kept by the immune
system at a minimum far below the level found in the primary infection. Globally, through the rise in the
number of strain types, the virus is spreading stochastically through shape space and increasing its numbers
by avoiding the local immune attacks.

(3) When, on the other hand, the ecency of immune reaction is low a large number
of new strains will be created before the immune cells nish destroying the virions
from the strains of the rst infection. In this case, the acute phase will directly lead to
the death of the host (Fig. 6) [22,25].
The results of our simulations show that although each new strain that emerges is
destroyed within a few weeks (like any ordinary disease), the long-term evolution of the
infection takes several years. The time scale that determines the long-term evolution
scale is the diusion (mutation) rate of the virus. A number of new strains grows
exponentially with time, but the unit of time in this exponential is the time it takes for
a new strain to establish itself i.e., weeks.
One might ask how the scale hierarchy between the cellular interactions (hours)
and the evolution of the infection (years) emerges in this model. The answer is the
following. The single strain lifetime is determined by an exponential rate proportional
to the local interaction rate (h). This exponent rises to macroscopic virus concentration
within weeks. Only when the value of this exponent is high enough does the long-term

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Fig. 5. Merely by raising the eciency of immune cell reaction to HIV at the dierent sites we can bring
about a time course suggesting the progression of HIV in long-term latents [23].

Fig. 6. By decreasing the eciency of immune cells we arrive at a scenario where already in the rst acute
phase we witness a full- edged outbreak of AIDS. This is reminiscent of empirical evidence to the fact that
quick progressors of HIV have a less exible immune system and thus succumb to the disease with less
strains of the virus in their bloodstream [25]. (Note that since death is so rapid the time course is only
measured until the collapse of the immune system around day 400).

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mechanism of virus mutation becomes operative. Thus, the time unit for one interaction
in the shape space is the time needed for a single strain to establish itself. The time
scale of the entire disease is the time necessary for evolving a macroscopic number
of strains. Therefore, we expect that the time scale of the entire disease will relate
to the time scale of new strain creation as the time scale of the strains relate to the
individual virion division time. The actual numbers are indeed (13 years=2 weeks) =
(2 weeks=hours).

4. Conclusions

The main success of the present model is the natural emergence of a hierarchy of
very dierent dynamical time scales. The very long-term decrease in immune (CD4+T)
cells count cannot be explained by a simple dynamic system. The transition from
the microscopic time scales (hours) to the macroscopic time scales (years) requires a
profound explanation. A simple dynamical system would require extreme ne tuning
of its parameters in order to achieve such a transition [2,3]. We propose a mechanism
that can bridge between the microscopic and macroscopic time scales, which does not
need ne tuning. The transition can be expressed best by representing the evolution of
the system in the shape space (the strain of the virus), rather than the real space (the
location of the virus in the organism). The relevant unit of time step for the operations
in shape space is the time it takes for a strain to reach a macroscopic concentration
and therefore have a signicant probability to generate a mutant. This time step is of
the order of weeks and not of hours. The evolution of the disease takes a few hundred
time steps. i.e., a few hundreds of weeks.
The mechanisms operating at the short times and at the long times are completely
dierent. At the microscopic level the mechanism is the recognition and the destruction
of the virions by the immune cells. The short-time scale evolution of the disease is
similar to any other disease. The long-scale evolution of HIV infection is based on the
competition between localized (in shape space) processes and global processes. To be
precise the evolution is due to the spread of the virus strains across the shape space.
In the initial acute phase most of the viral load is distributed between a small number
of localized virus strains. At the last stages of the disease the viral load is distributed
between a large variety of many strains. The immune cells manage to destroy locally
every particular virus strain within a couple of weeks from its emergence. However, as
the number of strains at each given moment increases, the virus succeeds in destroying
an increasing amount of immune cells. Thus, locally the virus looses every battle. Yet
in the end, the shape space is lled with a multitude of small but numerous strain
populations. At that point, the virus wins the war by killing more immune cells than
it activates.
In short, during the latent stage every virus strain looses every battle since it is
activating the cells that can destroy it. Transition to AIDS occurs when the combined
contemporary virus population wins the war by killing in total more immune cells than
the sum of cells it activates.

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Acknowledgements

We acknowledge Prof. Zorzenon dos Santos for sharing with us the content of
Ref. [3] before publication.

Appendix A. Acute phase

Imagine one has a lattice containing V nodes out of which N are occupied by the
strains that constitutes the initial infection. We assume that the population of each
initial infection strain is large enough that if the immune system generates randomly
an immune cell in this site (a cell with a complementary shape to that virus strain) then
that cell will discover this strain with probability 1. The probability rate for generating
in a given lattice site an immune cell is . Therefore, the probability rate for discovering
one of the strains is N. Thus, the average time it takes the immune system to detect
the rst strain in the initial infection is 1=N. Once this strain was discovered the
probability rate to discover one of the remaining (N − 1) strains is (N − 1). This
means that the time it takes to discover a second strain is 1=(N − 1) and so on.
Thus, the average time it will take for the immune system to discover the N strains
is: 1=1N 1=i which is approximately ln(N ). As long as the virus strain is undetected
by the immune system, it can proliferate freely. Therefore, the strain discovered last
had the most time to proliferate. The factor by which it grew more than a single strain
infection is
eln(N )−1=∗V ∗Ctotal ∼
= N V ∗Ctotal = : (A1)

Appendix B. Transition to AIDS

In this appendix we estimate the conditions for the nal collapse of the immune
system, when it fails to react appropriately to local virus strains. The dynamics of the
population of the immune cells in a given site in the shape space is dominated by two
parallel processes:
• Proliferation due to the activation of the immune cells by the interaction with the
local (in shape space) virus strain (C Vi ) (item (1)).
• Random global destruction by arbitrarily shaped virus strains (dC Vtot ) (item (4)).
An immune strain can increase its population if its proliferation rate is higher than its
destruction rate. C Vi ¿ dC Vtot . In other words we need the ratio between local virus
concentration and global virus concentration to be: Vtot =Vi ¡ C =dC . If we have N virus
strains proliferating in the system, we can assume that their population are of the same
order of magnitude, and estimate Vtot =Vi = Nstrains . Thus, in order for an immune strain
to be able to rise its concentration and react appropriately against the corresponding
virus strain, one needs the number of virus strains not to exceed: Nstrains = C =dC . If
one assumes that the virus population is not equally divided between strains then the
inequality is even more stringent.

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Appendix C. Discretization vs. continuous dierential equations

The evolution of a dynamical system can be expressed by two types of models:

(1) Ordinary dierential equations (ODE) that simulate the evolution of the average
population under the assumption of spatial homogeneity.
(2) Microscopic simulation (MS) models, that compute each reaction separately.
The ODEs have the advantage of being cheap in CPU time. They enable us to
simulate precisely the system when its concentration is very high, but fail to describe
the stochastic aspects of the system. The MS takes into account the stochastic eects
and describes precisely the discrete aspects of the agents and of the strains. However,
MS is very inecient if the number of agents and the probability for reaction are high.
In the present model, most of the sites are basically empty. However, there is a
relatively small number of sites occupied by a macroscopic number of virions and
immune cells. This special situation invalidates both the possibility to use continuity
assumption (ODE), and discrete operations (MS).
We solved this problem by using a hybrid model. This model computes the probabil-
ity for interaction between every two agents at every site on the lattice in a given time
interval. If this probability is higher than the threshold (30) then the number of agents
created or destroyed is computed in a deterministic way using an ODE formalism for
this site. If on the other hand the probability for a reaction is lower than the threshold
the number of new agents created or destroyed is computed in a discrete stochastic
way.
This is a particular application of the hybrid models we developed [18–21].

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4. Discussion

…and yet even if this story isn’t true it does have a grain of sense and
instruction to it,…, so is worth the telling.
Thr Cyberiad by Stanislaw Lem
The common theme of this research concerns the kind of shape space in
which living / cognitive systems and their environments interact. We present
our conclusions on this theme from the most specific to the most general

HIV

In our model of HIV dynamics we suggest that HIV escapes the immune
system by changing the immune system’s conceptual view of the virus. By
creating escape mutants that move to different points in shape space HIV
convinces the immune system that it is dealing with a new virus. Since the
immune system fails to see the various HIV strains as one conceptual whole,
the virus can continue to attack and weaken the global immune cell
population. The addition of an explicit relationship in shape space between
different virus strains and immune cell types allows us to show the connection
between normal immune system / virus dynamics and the special long term
latency of HIV. Since the publication of the paper presented here the results
of this model where vindicated in various empirical results on HIV and SIV
(Goulder et al. 2001, Allen. et al. 2000 ). They also led to more complex
immune system models of HIV dynamics (Bernaschi & Castiglione 2002). In
this more complex model the genetic type of the HIV strains and their
appropriate phenotypes was explicitly modeled allowing the measurement of
distances in shape space between the original strains and their escape
mutants. This can also be used to model varying mutation rates during
different stages of the disease, dependant on the capabilities of specific
strains. The further development of such models, possibly including models of
the various cell types that HIV infects, should give us an even more precise
idea of how the HIV dynamics develop and maybe how we can stop them.

70
The place of self affinity in immune capabilities

The model of general T cell repertoire dynamics presented in section three of

the results led to several important conclusions regarding the basic paradigm
of study in immunology. At a theoretical level we have changed the place of
self-affinity and degeneracy in immune reactions. Where previously these two
traits of all immune receptors were considered liabilities, we see them now as
essential properties in the maintenance of the repertoire flexibility. In the
shape space of the immune system self-antigens and non self-antigens are
closely related and relevant to each other. The immune system needs to
perceive important shifts in populations in this shape space. It uses affinity to
self as a background signal upon which to base its reaction to changes. The
existence of self-affinity and cross reactivity in immune receptors now
becomes the basis and not the nemesis of proper immune reactivity.

In this view we do not deny autoimmune disease. In fact we point out that
hitherto immunology has been looking for the wrong suspect. Autoimmune
disease is not the result of a problem with any single, overly self reactive,
receptor. All receptors have some level of self-affinity. We therefore suggest
that there is a need to look at the systemic level of immune interactions to
find the misstep that turns, the usually beneficial signals of self-affinity into
the false reactions of auto-immune disease.

These theoretical conclusions on immunity lead more or less automatically to

a shift in our functional view of adaptive immunity. Once self-affinity becomes
an asset it is much simpler to see that the kinds of signals that interest the
immune system need not necessarily be foreign. The maintenance of a
functioning multi cellular unity of a level of complexity found in vertebrates,
which incidentally are the first to have adaptive immune systems, calls on the
immune system to have further immune functions. These include tissue
repair, destroying cancerous tissue and combating foreign intrusions. Once
we realize that the signals the immune system reacts to have self affinity at

71
their base it becomes much easier to see that the function of an adaptive
immune system is not merely to guard against the foreign, but in general, to
maintain in health the continuation of a molecular and (multi) cellular self.

These shifts in our view of the relevance of self affinity and of immune
function lead to a change in the way that we practice immunology. Previously,
the immune system was viewed as mostly active when we are in disease and so
its reactivity has been studied in such situations. Following the work
presented here we now realize that the immune system is always active and
reactive. Therefore if we wish to understand the ‘language’ of our immune
system, we must study and learn its reactive capabilities when our bodies are
healthy, as this is the background on which all disease state reactivity is
based.

The shape space of cognitive systems

The final and most general conclusions from this work are about the form of
shape space which is common to all cognitive systems. By this we mean the
relationship between different examples in the environment that a given
cognitive system can manipulate. To what extent are these examples
degenerate and redundant, and are certain examples more central than
others i.e. do some examples have many neighbors in shape space while
others are more isolated.

When we think of cognitive systems one of their primary traits appears to be

their nigh infinite capabilities. We can construct any sentence, and identify as
correct or incorrect combinations of words we have never seen. Our visual
and auditory capabilities also have no apparent limit. We create music we
never heard and visualize worlds and things that never passed our retinas.
The shape space for a cognitive system need therefore also be huge and
intricately interconnected; this is a daunting thing to attempt to model.

However as our results show, the actual environment is not filled with infinite
possibilities. In interactions within the environment certain examples are

72
highly over expressed while most examples are infrequent. When dealing with
a naïve system this skewed nature is even more pronounced. We talk using
mostly a few hundred words and we spend most of our time talking about
food and the weather. Moreover those things we encounter often are usually
more important and therefore connected to more types of interactions.

The shape space of cognitive systems, though huge, is at least at its

beginning largely empty. It can be represented by a few important, highly
populated and interconnected nodes, while leaving most of the rest of the
shape space empty. Cognitive systems do not need to understand a shape
space built of infinite signals to form their rules of interaction. Rather, they
learn a few important nodes and by manipulating their similarities and
differences create cognition’s apparent limitlessness.

The immune system was for us an amazingly good example of these ideas.
On the one hand antibodies can be found to practically any substance, on the
other hand when we look at the actual types of antigens encountered we see
that a few antigens are highly over expressed. In the models we built of the
shape space of immune reaction we did not however deal with the different
connectivity of different points in shape space. For an exact description of the
importance of the Useful Examples in the development of cognitive systems
we will have to add this in the future, especially if we wish to show the
connection between the distribution of examples and their embedded
meanings apropos the system’s interaction in its environment.

Our interest in shape space has raised new questions as to the kinds of
environment in which cognitive systems develop. It was also to lead us to
some novel conclusions, namely that for a naïve cognitive system to develop
its capabilities the environment it encounters needs to have some internal
order. This order is naturally existent for our cognitive systems because we
have evolved to certain niches. We are blinkered by our history from the
infinite possibilities of creation towards specific parts of reality. However in
these limitations lie our abilities to reach cognitive perception.

73
We have shown how this concept of Useful Examples is central to the study of
cognitive systems, and suggest that it especially pertains to the design of
artificial systems. We offer a new formulation of the design question for
building artificial cognitive systems (Hershberg 2002). Rather than asking how
to create artificial systems that function as cognitive systems, we ask how to
define Useful Examples in the environment so that through interaction with
them the system creates itself. This is especially pertinent in complex
environments where no natural cognitive system exists, such as for instance
the information space of the Internet. Following the theory of Useful
Examples, we are no longer aiming to create agents which function
intelligently in the net. Rather, we ask how can we divide the net into niches
in which different agents, by their interaction with these niches, will find
Useful Examples. The new question is an improvement since it acknowledges
the interconnectedness of the system, its development and its environment.

We further believe that the skewed nature of our cognitive environments is

maintained even in our most abstract capabilities - concept formation. Our ability
to create concepts and invent ideas is based on a few core concepts and on
the concrete interactions with reality that created them. This does not mean
that we have some hardwired stable concepts in our mind. Rather it means
that the stable facets of reality cause certain concepts to stand out, from
which we build our internal reality and abstractions. To model such a fluid
network, whose nodes are concepts, we shall have to take our shape space
models beyond population dynamics of receptors and ligands. We will have to
add a mechanism which changes the connectivity of specific nodes depending
on their activity. In this kind of shape space the very geography, the
connectivity of the points, and the identity of their neighbors is fluid form
second to second and depends on the activity of the receptors (concepts) that
populate it. This mapping of the fluid shape space of our imaginations is we
believe the eventual outcome of the above research.

74
 References

Allen, T.M., O'Connor, D. H., Jing, P. et al., 2000, Tat-specific cytotoxic T

lymphocytes select for SIV escape variants during resolution of primary
viraemia Nature, 407:386-390.

Atlan, H., 1983, Information Theory, in: Cybernetics: Theory and Application,
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Atlan, H. & Cohen, I. R., 1999, Immune information, self-organization and

meaning International Immunology, 10: 711-717.

Bernaschi, M. & Castiglione F., 2002, Selection of escape mutants from

immune recognition during HIV infection, Immunol Cell Biol, 80 (3): 307-
313.

Borras E., Martin R., Judkowski V., et al., 2002, Findings on T cell specificity
revealed by synthetic combinatorial libraries, Journal of Immunological
methods 267:79-97.

Burns, J. & Ruskin, H. J., 2002 Modeling the human immune system using the
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Dublin City University –
http://computing.dcu.ie/research/CA_Working_Papers/backup/0402.ps

Burrnet F.M., 1957, A modification of Jerne’s theory of antibody production

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Cohen, I. R., 2000, Tending Adam's garden. San Diego, CA: Academic Press.

Cohn M. & Langman, R. E., (ed.), 2000, Seminars in Immunology, 12(3),

Special issue on the place of self / non-self reactivity in immune function.

Goldrath, A. W. & Bevan, M. J., 1999, Selecting and maintaining a diverse T

cell repertoire, Nature, 402: 255-262.

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Goulder, P. J. R., Brander, C., Tang, Y et al., 2001, Evolution and transmission
of stable CTL escape mutations in HIV infection, Nature, 412:334-338.

Gupta, R. S., 1998, Protein phylogenies and signature sequences: A

reappraisal of evolutionary relationships among Archaebacteria,
Eubacteria, and Eukaryotes, Microbiology and Molecular Biology
Reviews,, 62:1435-1491.

Hershberg U., 2002, Proposing a new focus for the study of natural and
artificial cognitive systems, Proceedings of the 2nd International
conference on Epigenetic Robotics, August, Edinburgh pp: 43-47.

Lacroix-Desmazes, S., Kaveri, S.V., Mouthon, L., Ayouba, A., Malanchere, E.,
Coutinho, A. & Kazatchkine, M.D., 1998, Self-reactive antibodies (natural
autoantibodies) in healthy individuals, J Immunol Methods, 216(1–2):
117–137.

Lancet, D., Sadovsky, E. & Seidemann, E., 1993, Probability Model for
Molecular recognition in biological receptor repertoires: Significance to
the olfactory system, Proc. Natl. Acad. Sci., 90:3715-3719.

Langman, R. E. & Cohn, M., 2000, A minimal model for the self-nonself
discrimination: a return to the basics, Seminars in Immunology,
12(3):189-195.

Louzoun, Y., Atlan, H., Solomon. S. & Cohen, I. R., 2003, Proliferation and
competition in discrete biological systems, Bulletin of mathematical
biology 65(3): 375-396.

Maturana, H. R., & Varela, F. J., 1980, Autopoesis and cognition, Reidel,
Derdecht.

Perelson, S., & Oster, G. F., 1979, Theoretical studies of clonal selection:
minimal antibody repertoire size and reliability of self-non-self
discrimination, J Theor Biol, 81(4):645-670.

76
Perelson, A. S., & Weisbuch, G.,1997 Immunology for physicists. Rev. Mod.
Phys, 69(4):1219–1267.

Shnerb. N., Louzoun. Y., Bettelheim E. & Solomon. S., 2000, The importance
of being discrete - life always wins on the surface, Proc. Natl. Acad. Sci.
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Solomon, S., 1995, The Microscopic Representation of complex macroscopic

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Stewart J., 1996, Cognition = Life: Implications for higher-level cognition.

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Varela, F., 1994, A cognitive view of the immune system, World Futures,
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77
‫ההווצרות של משמעות במערכות ביולוגיות‬

‫חיבור לשם קבלת תואר דוקטור לפילוסופיה מאת‬

‫אורי הרשברג‬

‫הוגש לסינט האוניברסיטה העברית‬

‫אוקטובר ‪2003‬‬
‫ההווצרות של משמעות במערכות ביולוגיות‬

‫חיבור לשם קבלת תואר דוקטור לפילוסופיה מאת‬

‫אורי הרשברג‬

‫הוגש לסינט האוניברסיטה העברית‬

‫אוקטובר ‪2003‬‬
 ‫עבודה זאת נעשתה בהדרכת של‪ :‬פרופ’ סורי סולומו‬
‫מהאוניברסיטה העיברית ופרופ’ ירו כה ממכו וייצמ ‪.‬‬
 ‫תקציר‬

‫מחקר זה הנו מחקר בין תחומי‪ .‬הוא כולל מושגים מן הביולוגיה‪ ,‬הפיזיקה‪ ,‬והמדעים‬
‫הקוגניטיביים‪ .‬אנו לוקחים מושגים מחקר הקוגניציה ומדגימים כיצד ניסיון לראות תגובות‬
‫חיסוניות כסוג של תגובה קוגניטיבית משנה מן הקצה אל הקצה את האופן בו אנו מגדירים‬
‫את הפעולה החיסונית ואת הפונקציה של מערכת החיסון‪ .‬במקביל אנו חוקרים את מערכת‬
‫החיסון כדוגמא לתפיסה קוגניטיבית‪ .‬בעזרת דוגמא זאת מצאנו עקרונות חדשים העומדים‬
‫בבסיס של התפתחות קוגניטיבית ובקשר בינה לבין הסביבות שבהן היא אפשרית‪ .‬בתזה זו‬
‫אנו מציגים את התוצאות של סימולציות של הדינמיקה של רפרטואר תאי ה‪ T -‬ושל מחלת ה‪-‬‬
‫‪ . HIV‬תוך כך אנו דנים בתובנות מסימולציות אלה לגבי מערכות קוגניטיביות בכלל ומערכת‬
‫החיסון בפרט‪.‬‬

‫'התיאוריה של הדוגמאות השימושיות' )‪ -:(Useful Examples‬בנינו תיאוריה המתארת‬

‫מערכות קוגניטיביות ואסטרטגיות האינטראקציה המשותפות שלהן עם הסביבה‪ ,‬שהן בבסיס‬
‫יכולתן‪ .‬בלב תיאוריה זו נמצא המושג של 'דוגמאות שימושיות'‪ .‬מערכות קוגניטיביות חיבות‬
‫ללמוד להיות קוגניטיביות‪ .‬אנו מציעים שאופן הלימוד הוא באמצעות אינטראקציות ישירות‬
‫וללא פיקוח‪ ,‬עם דוגמאות מוחשיות של הסביבה‪ .‬דרך פשוטה כזו של למידה מספיקה מכדי‬
‫לאפשר למערכת להבין את סביבתה‪ ,‬כיוון שלסביבה סדר מסוים‪ .‬ישנן מעט דוגמאות שבהן‬
‫נתקלים בתדירות גבוהה‪ ,‬בעוד ששאר הדוגמאות הן רובן ככולן נדירות מאוד‪ .‬הדוגמאות‬
‫המופיעות בתדירות גבוהה אינן כאלה במקרה‪ .‬התבטאותן הרבה מצביעה על ריבוי‬
‫השימושים הנעשה בהן באינטראקציה של המערכת עם סביבתה‪.‬‬

‫במובן מסוים בנינו תיאוריה על התצורה המשותפת של סביבות שבתוכן מערכות קוגניטיביות‬
‫יכולות להתפתח ולפעול‪ .‬התיאוריה שלנו מציעה מודל חדש לחקר מערכות קוגניטיביות‪.‬‬
‫המוקד בחקר מערכות קוגניטיביות ויכולת האינטראקציה שלהן עם סביבתן מוסט מניסיון‬
‫לפענח את התפקיד של המערכת‪ ,‬לניסיון לגלות את ההתפלגות הטבעית של דוגמאות‬
‫בסביבה‪ ,‬וזיהוי ה‪' -‬דוגמאות השימושיות'‪.‬‬

‫מודלים של קוגניציה חיסונית‪ -:‬המסקנות התיאורטית בהקשר של מערכות קוגניטיביות נוצלו‬

‫לצורך בנית מודלים של תהליכים חיסוניים המובילים להתנהגות נכונה בסביבה )רפרטואר‬
‫תאי‪ ,(T -‬ותהליכים שבהן מערכת החיסון נכשלת באינטראקציה עם מחלה )‪ .(HIV‬השיטה‬
‫שלנו היא לחקור כיצד שינוי היחסים בין רצפטורים לבין הדוגמאות המפעילות אותם מחנכים‬
‫את מערכת החיסון‪ .‬בכדי לעשות כן אנו משתמשים בסימולציה מיקרוסקופית של תהליכים‬
 ‫חיסוניים‪ ,‬וביחסים ב‪' -‬מרחב הצורות'‪ 1‬בין רצפטורים אימונוגנים‪ ,‬והאנטיגנים המפעילים‬
‫אותם‪ .‬מוצגים כאן שני מודלים‪:‬‬

‫‪ -‬מודל של הדינמיקה של תאי‪ T -‬בגוף בריא‪ ,‬ולאחר הדבקות ראשונית‪.‬‬

‫‪ -‬מודל של התפתחות קצרת טווח וארוכת טווח של‪.HIV -‬‬

‫מערכת חיסון )קוגניטיבית( מתפקדת‪ -:‬ע"י התייחסות להתפלגות הדוגמאות בסביבה‬

‫הטבעית של מערכת החיסון אנו יכולים לזהות את ה‪' -‬דוגמאות השימושיות' של‬
‫אינטראקציה חיסונית‪ .‬הראינו כיצד החקר של ההתפלגות של הדוגמאות השונות בהן‬
‫נתקלת מערכת החיסון באופן טבעי בגופנו משפר את הבנתנו את מערכת החיסון ויכולותיה‪.‬‬
‫עשינו זאת בעזרת מודל של רפרטואר מתפקד של תאי‪ T -‬בגוף הבריא ובתגובה לזיהום‬
‫ראשוני‪ .‬הסימולציה שלנו הצליחה לשחזר את התהליכים ואת והקצבים של התגובה‬
‫החיסונית לזיהום הראשוני‪ ,‬ואת החזרה למצב מנוחה‪ .‬במודל אנו עוקבים במדויק אחרי‬
‫התהליכים ואחרי התפלגות הצורות של רצפטורי ה‪ T -‬ושל אנטיגנים עצמיים ולא עצמיים‬
‫במרחב הצורות‪ .‬יכולתנו לשחזר את הדינמיקות המוכרות של רפרטואר תאי ה‪ T -‬מראה‬
‫שיש צורך בחשיבה מחודשת לגבי כמה מהעקרונות הבסיסיים של האימונולוגיה‪ .‬אנו‬
‫מדגימים כיצד מערכת החיסון משתמשת ברגישות לעצמי כאות הרקע לתגובותיה‪ ,‬ובכך אנו‬
‫משנים את המקום של התגובה לעצמי בתפקוד החיסוני‪.‬‬

‫התגובה לעצמי הי כעת הבסיס‪ ,‬ולא המכשול לתגובה חיסונית נכונה‪ .‬חשוב מכך‪ ,‬פעולות‬
‫חיסוניות אינן מתמקדות רק בהרחקת הזר‪ ,‬אלא באופן כללי בשימור עצמי של הגוף‪.‬‬
‫לתגובות אלה בתפיסה שלנו את מערכת החיסון ישנה השלכה מרכזית אחת לגבי חקר‬
‫מערכת החיסון‪ .‬מערכת זו פעילה תמיד‪ ,‬ופעולותיה בעת מחלה הן תוצר של פעולתה בזמן‬
‫בריאות‪ .‬לפיכך‪ ,‬יש צורך שחקר מערכת החיסון יתמקד גם בחקר המצב הבריא‪ ,‬ולא רק‬
‫בתפקודים החיסוניים בזמן מחלה‪.‬‬

‫‪ -HIV‬טעות קונספטואלית של מערכת חיסון )קוגניטיבית(‪ -:‬לפי טענתנו‪ ,‬מערכת קוגניטיבית‬

‫ניתנת לזיהוי בדרך שבה היא מתנהגת בסביבתה‪ .‬האינטראקציות הן עם התמונה‬
‫הקונספטואלית הכוללת שהמערכת יוצרת‪ ,‬ולא רק ישירות עם הסיגנלים הבודדים הבונים את‬
‫אותה תמונת עולם‪ .‬האינטראקציה הכפולה הזו מובילה ליכולות של מערכות קוגניטיביות‬
‫ומאפשרת לנו להניח שבהתנהגות של מערכת כזאת נמצא גם שגיאות קונספטואליות‬
‫בתפיסת הסביבה‪ .‬המודל שלנו של התפתחות מחזור החיים של‪ HIV -‬מראה כיצד טעות‬
‫בתמונה הקונספטואלית שמערכת החיסון בונה על הפולש הנגיפי שלה‪ ,‬מובילה לדינמיקה‬

‫‪'1‬מרחב הצורות' הוא מרחב דמיוני שבו כל יחידה מייצגת רצפטור‪/‬ליגנד‪ .‬רצפטור וליגנד בנקודות קרובות במרחב‬
‫הצורות הם באפיניות גבוהה אחד לשני‪ ,‬ואילו הרחוקים באפיניות נמוכה‪.‬‬
‫ארוכת הטווח של‪ ,HIV -‬המסתיימת ב‪ .AIDS -‬אנו מראים כיצד תהליך ההיפר‪ -‬מוטציה של‪-‬‬
‫‪) HIV‬כלומר תהליך הדיפוזיה של הווירוס במרחב הצורות( מאפשר ל‪ HIV -‬להתחבא‬
‫מההצלחות החוזרות ונשנות של מערכת החיסון כנגדו‪ .‬נגיף ה‪ AIDS -‬משטה במערכת‬
‫החיסון כך שהיא חושבת שבכל פעם מדובר בנגיף ובמחלה חדשים‪ ,‬עד שלבסוף היא‬
‫מתמוטטת כליל‪.‬‬

‫כך אנו שוב מחזקים את הפרדיגמה הקוגניטיבית של דינמיקה חיסונית בהוסיפנו את הדוגמא‬
‫של ה‪ .HIV -‬ההסתכלות הקוגניטיבית אינה מתארת רק את מערכת החיסון המתפקדת‪,‬‬
‫אלא גם את המערכת בקלקלתה‪ .‬כך אנו מצליחים לחבר בין הדינמיקה המוכרת של תוקפים‬
‫נגיפיים רגילים‪ ,‬והדינמיקה ארוכת הטווח של ה‪.HIV -‬‬

‫קודה‪ -:‬המסקנה הסופית שלנו קשורה בחקר של מערכות קוגניטיביות בכלל‪ .‬התעסקותנו‬
‫במרחב הצורות מעלה שאלות חדשות לגבי אופיין המשותף של סביבות שבהן מערכות‬
‫קוגניטיביות מתפתחות‪ .‬היא גם מובילה למספר מסקנות חדשות‪ :‬בכדי שמערכת‬
‫קוגניטיבית נאיווית תפתח את יכולותיה‪ ,‬הסביבה שאתה היא באה במגע צריכה להיות בעלת‬
‫סדר פנימי מסוים‪ .‬סדר זה קיים באופן טבעי במערכות שלנו משום שבאבולוציה אנו‬
‫התפתחנו והותאמנו לפלחים מסוימים של הסביבה‪ .‬כמו סוסים רתומים לעגלה עינינו‬
‫מנותבות מאינסוף האפשרויות לחלק מסוים של הבריאה‪ .‬אולם מסתבר שדווקא מגבלות‬
‫אלה הן המאפשרות לנו להגיע לתפיסה קוגניטיבית‪.‬‬

‫אנו הראנו כיצד המושג של 'דוגמאות שימושיות' הנו מרכזי לחקר של מערכות קוגניטיביות‪.‬‬
‫אנו מציעים שמושג זה במיוחד חשוב לצורך תכנון ועיצוב של מערכות מלאכותיות‪ .‬אנו‬
‫מציגים שאלה תכנונית חדשה בניסיון לבנות מערכות קוגניטיביות מלאכותיות‪ .‬במקום‬
‫לשאול כיצד ליצר מערכות מלאכותיות בעלות פונקציות או יכולות קוגניטיביות מסויימות‪ ,‬אנו‬
‫מציעים לנסות לזהות או להגדיר 'דוגמאות שימושיות' בסביבה‪ ,‬אשר בעזרת אינטראקציה‬
‫איתן המערכת תייצר את עצמה‪ .‬זוהי תובנה חשובה במיוחד בסביבות שבהן עד היום לא‬
‫הייתה מערכת קוגניטיבית שניתן לחקותה‪ ,‬כגון האינטרנט‪ .‬בעקבות התיאוריה של 'דוגמאות‬
‫שימושיות' לא ננסה ליצר‪ agents -‬בעלי תפקודים אנטיליגנטים‪ .‬במקום זאת ננסה לשאול‬
‫כיצד ניתן לפרק את המרחב )של האינטרנט( לפלחים שונים שבהם יצורים שונים‪ ,‬ע"י‬
‫אינטראקציה עם אותם פלחים‪ ,‬מגיעים ל‪' -‬דוגמאות השימושיות'‪ .‬שאלה זו מהווה שיפור על‬
‫פני השאלה הקודמת כיוון שהיא מכירה בקשר ההדדי שבין המערכת הקוגניטיבית‪ ,‬תהליך‬
‫ההתפתחות שלה‪ ,‬והסביבה בה כל זה מתרחש‪.‬‬
 ‫תוכן‬
‫‪ .1‬מבוא ‪6..............................................................................................................‬‬
‫היווצרותה של משמעות וקוגניציה במערכת החיסון ‪6..................................................‬‬
‫משמעות ומידע ‪6.................................................................................................‬‬
‫אוטופואזיס ‪7......................................................................................................‬‬
‫הפרדיגמה הקוגניטיבית של דינמיקה חיסונית ‪8.........................................................‬‬
‫מערכת החיסון‪8..................................................................................................‬‬
‫פרדיגמות החיסון המקובלות ‪9................................................................................‬‬
‫מבט קוגניטיבי על מערכת החיסון ‪9.........................................................................‬‬
‫מרחב הצורות ‪10.................................................................................................‬‬
‫סימולציות מיקרוסקופיות במרחב הצורות ‪11.............................................................‬‬
‫‪ .2‬שיטות ‪13........................................................................................................‬‬
‫סימולציות מיקרוסקופיות של מערכת החיסון ‪15........................................................‬‬
‫‪ .3‬תוצאות ‪18.........................................................................................................‬‬
‫התיאוריה של דוגמאות שימושיות ולמידה אופטימלית מדוגמאות במערכות קוגניטיביות ‪18‬‬
‫מאמר מספר ‪19........... The Immune system and other cognitive systems -.1‬‬
‫מאמר מספר ‪27.............. Optimal exemplar learning in cognitive systems -.2‬‬
‫זיהוי עצמי הוא הבסיס ולא המכשול של פעילות חיסונית ‪36.........................................‬‬
‫מאמר מספר ‪38..... What is the basis of the immune system's specificity? -.1‬‬
‫מאמר מספר ‪Useful Examples and a new model of the immune system -.2‬‬
‫‪45................................................................................................................‬‬
‫ההתקדמות בזמן של ‪56.............................................................................. HIV -‬‬
‫‪ .4‬דיון ‪70..............................................................................................................‬‬
‫‪70............................................................................................................. HIV‬‬
‫התפקיד של רגישות לעצמי ביכולות של מערכת החיסון ‪71..........................................‬‬
‫מרחב הצורות של מערכות קוגניטיביות ‪72...............................................................‬‬
‫רשימה ביבליוגרפית ‪75............................................................................................‬‬

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