Popular culture references, including Homer’s Greek mythological

creature that is part lion, goat, and snake as well as an ape species with human
intelligence in Planet of the Apes, have fantasized the possibilities for human-
animal chimeras. Nevertheless, a study published in January of this year reported
the creation of the first human-animal chimeras using the embryos of higher order
animal species and human induced pluripotent stem cells (Wu et al. 2017). The
therapeutic potential for this research is promising, especially given the
theoretical possibility of generating new human organs for transplantation.
Although current technology is far from realizing this outcome, ethical debates
surrounding this type of research have emerged, demonstrating the public’s
financial, religious, and moral concerns. Notably, human-animal chimeras
question our definition of a species, and some may argue that they are an affront
to human dignity. As such, in 2015, the NIH issued a funding moratorium, yet has
since made its stance more lenient, permitting funding on a case by case basis for
studies that would introduce human stem cells into post-gastrulation mammals.
Regardless, the ethical controversies must be thoroughly deliberated and
guidelines proposed before research intended to produce new substances of both
human and animal origins for clinical translation is actively pursued. Scientists
must first work to better understand the technological capacity and limitations of
human-animal chimera systems. Thus, although human-animal chimeras may
possess therapeutic promise in the distant future, they should primarily serve as
basic research models to study fundamental biological mechanisms within the
scope of embryogenesis, evolution, and human disease and to establish proofs of
principle for testing experimental interventions.
A human-animal chimera is an organism that contains two genetically
distinct cell types derived from more than one zygote. It is sometimes confused
with a hybrid, or an organism containing a single cell type that within itself
possesses the genetic information from two species. A chimera is most commonly
created by implanting human stem cells into the embryo of a different animal
species via a process called embryo complementation. However, a human-animal
chimera may be produced by a variety of other methods. Fetal or adult tissue of
one species may be transplanted as a graft onto an individual of a different species
(Behringer 2007). An aggregation chimera may be created by mixing embryonic
stem cells from two individuals of different species. Finally, human genes may be
inserted into the genome of a different animal species. The last of these methods
of generating human-animal chimeras presents additional complications since
what is being implanted is not a discrete entity, like a cell or tissue graft, and
instead integrates as a foreign gene into the host genome. It is even more difficult
to control the precise development of the chimeric organism via this method.
Through these protocols, and perhaps lesser known to the public, human-animal
chimeras have persisted in research studies for decades, resulting in many
successful human biological studies and therapeutic strategies for disease.

MICHAEL: TECHNICAL EXPLANATION OF EARLY CHIMERA

EXPERIMENTS USING EXAMPLES FROM SLIDE ABOUT STUDYING
HUMAN DISEASES

In the apparent future, the primary goal of human-animal chimera research

must still be to produce human cellular characters in animals, without the
additional intention of generating new tissue for transplantation. The chimeric
animal containing human tissue should be studied or treated as a more realistic
model of human physiology than the native animal model. In this way, scientists
would first work to more fully understand the extent to which these chimeras are
genetically and phenotypically human. After identifying the remaining technical
barriers to achieving model human likeness and developing further studies to
lessen these barriers, scientists may then consider the possibility of creating new
tissue via this system that would eventually end up in a human. As per ethical
standards, research guidelines must first set limitations on research with the far-
reaching scope of creating new tissue for transplantation in humans.
First, research involving human-animal chimeras should work to recreate
human physiology in health or disease states to enable further exploration of
human developmental processes. For instance, human neural stem cells (hNSCs)
should continue to be studied in other host species to more generally understand
how brain size and neural networks are regulated during development. Ourednik
et al. sought to determine how different populations of hNSCs in the adult brain
emerge during embryogenesis (Ourednik et al. 2001). Using the brain of an Old-
World monkey, the researchers found that the hNSCs distributed into two
subpopulations: one that contributed to organogenesis and the other that remained
undifferentiated for future use for homeostasis and repair. These findings
expanded upon knowledge of human developmental biology by determining the
genetic origins of some nervous system plasticity and the migration patterns of
hNSCs through the cerebrum of a higher order species (Price 2001). The authors’
conclusions did not exaggerate or significantly allude to the therapeutic potential
of human-animal chimera systems. Rather, it laid the groundwork for future
studies that would examine neural aspects of human embryogenesis.

MICHAEL: TECHNICAL EXPLANATION AND SPECIFIC EXAMPLES OF

CHIMERA TECHNOLOGY FOR STUDYING HUMAN
DEVELOPMENT/EMBRYOGENESIS, WITH EMPHASIS ON OUREDNIK ET
AL. PAPER
 Simulating human physiology via chimera systems aids in the
development and testing of experimental therapies. With a more clinically
relevant model, researchers can more accurately predict the human response to a
new drug. This procedure establishes a proof of principle that the intervention can
contribute to tissue formation or repair of damaged human tissue in a nonhuman
animal. Moreover, many clinical trials enrolling large numbers of human subjects
fail because new treatments appear to be effective in animal trials yet elicit
unexpected and dangerous effects in humans. The use of human-animal chimeras
as research subjects would not only prevent harm to countless human subjects of
clinical trials but also reduce the amount of wasted money and other resources,
since Phases I-III of clinical trials for a new drug typically cost between $30-40
million (Sertkava et al. 2016). Thus, human-animal chimeras may be both life-
saving and cost-effective in their roles limited to research models and subjects.

MICHAEL: TECHNICAL EXPLANATION AND SPECIFIC EXAMPLES OF

CHIMERA TECHNOLOGY FOR THERAPEUTIC DRUG SCREENING

The most exciting yet controversial aspect of developing human-animal

chimeras is the prospect of generating new human organs for transplantation. The
donor organ shortage crisis affects approximately 120,000 Americans each year,
and 22 die each day waiting on any given transplant list (UNOS 2017). While the
average wait time for a kidney is currently three years, that for a custom-made
kidney via a human-animal chimera would be as little as five months (Robson
2017). In principle, researchers could knock out the target organ in an adult
nonhuman animal with human-like anatomical structure and implant human stem
cells in the void, making sure that the foreign human cells comprise the dominant
cell type of the new organ and are not immunologically rejected by the nonhuman
host during development. The human tissue would ideally be limited to specific
organs within the chimera system. Moreover, the human tissue would be derived
from autologous stem cells to reduce the risk of rejection by the organ recipient as
well as the need for dangerously high doses of anti-rejection drugs. However,
aside from the ethical implications of endowing higher order species with
additional human-like parts and functions, there are nonetheless many significant
technical hurdles that require extensive consideration before expanding the role of
a human-animal chimera beyond that of a biomedical research paradigm.

MICHAEL: TECHNICAL EXPLANATION AND SPECIFIC EXAMPLES OF

CHIMERA TECHNOLOGY FOR GENERATING NEW HUMAN ORGANS,
INCLUDING WU ET AL. 2017 PAPER
MICHAEL: TECHNICAL LIMITATIONS OF CHIMERA RESEARCH,
INCLUDING THOSE FROM OUREDNIK ET AL.

Principally, two technical aspects of the chimera development process

have the greatest ethical implications: the type of implanted human stem cells and
the time point of implantation. Pluripotent stem cells migrate and multiply
throughout the developing fetus, uniquely specializing into all three germ layers.
If human pluripotent stem cells are implanted prior to gastrulation, which marks
the beginning of distinct cell lineages, they could theoretically end up anywhere
and create a chimera with an unintended greater proportion of human-like
anatomy and function than intended. Implanting hNSCs would be even more
worrisome given their potential to develop into brain parts with human cognitive
capacities, since it is known that transplanted neural cells can transfer behavior
characteristics in birds (Batini et al. 1996). However, Ourednik et al. prevented
the uncertainty of this outcome by implanting hNSCs in monkey embryos at 12-
13 weeks into development (Ourednik et al. 2001). First studying biological
mechanisms of neurogenesis in chimeras models would avoid unwanted human
neural development in the process of generating new tissues and organs.

References

Batini, Cesira, Marie-Aimée Teillet, Robert Naquet, and Nicole M. Le Douarin.

"Brain chimeras in birds: application to the study of a genetic form of reflex
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Behringer, Richard R. "Human-animal chimeras in biomedical research." Cell

stem cell 1, no. 3 (2007): 259-262.

Ourednik, Václav, Jitka Ourednik, Jonathan D. Flax, W. Michael Zawada,

Cynthia Hutt, Chunhua Yang, Kook I. Park et al. "Segregation of human
neural stem cells in the developing primate forebrain." Science 293, no. 5536
(2001): 1820-1824.

Price, Jack. "Neural stem cells--Where are you?." Nature medicine 7, no. 9
(2001): 998-1000.

Robson, David. "The birth of half-human, half-animal chimeras." BBC, January 5,

2017. http://www.bbc.com/earth/story/20170104-the-birth-of-the-human-
animal-chimeras.
Sertkaya, Aylin, Hui-Hsing Wong, Amber Jessup, and Trinidad Beleche. "Key
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United Network for Organ Sharing (UNOS). "Data." April 20, 2017.
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Wu, Jun, Aida Platero-Luengo, Masahiro Sakurai, Atsushi Sugawara, Maria

Antonia Gil, Takayoshi Yamauchi, Keiichiro Suzuki et al. "Interspecies
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