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Thinking about Life Sciences

http://blog.aesisgroup.com

Monday, June 09, 2008

Where the Action’s at With Secrets of Everyday Life: Proteins or DNA?

There has been much excitement about the promise of molecular genetics and the Human Genome
project, in particular, in curing myriad diseases. Ever since the double-helical structure of DNA was published
by Watson & Crick in 1953, DNA has been billed as the repository of the secrets of life. Within DNA resides the
genetic instructions driving life itself. Countless scientists and billions of dollars expended worldwide to
cracking that secret. The code has, indeed, been cracked and we know now – as announced in 2003, a
half-century after the double helix was first revealed – the complete sequence of a human genome.
Yet progress has been slow to convert that overwhelming volume of information - three billion
base-pairs spread over 46 chromosomes of human DNA - into useful knowledge. The War on Disease
continues and diseases remain uncured, many still incurable. And so, with the continued emphasis on the
genetics of disease, these shall remain largely incurable.
Why is this so? Conventional military strategy holds that decapitation of central targets, the command
and control centers or better yet the highest level leaders of the enemy is the most effective means towards
achieving victory. Surely, a cell’s DNA – a command & control center like none other – would be the ideal
target for therapy. What better than to strike at, or manipulate the very secrets of life. But the secret of life,
embodied in DNA is not the same as the secret to life which resides in the proteins. Proteins are where the
action is.
Prior to 1953, there was still considerable debate as to whether deoxy-ribonucleic acid (DNA) was
actually the genetic material of cells. Many scientists, in fact, believed that only proteins – composed of twenty
different amino acids in all sorts of configurations – had the necessary “information content” and “information
complexity” to store the massive amounts of genetic data that would be required, for example, to build an entire
human being from scratch. Mind boggling as it seemed for mere molecules to give rise to such complexity, in
the absence of religious miracles, molecules it had to be and proteins were a more likely candidate than any other
intracellular substance.
DNA on the other hand was a rather bland molecule. A DNA molecule, when broken down into its
constituents was composed of only four (not twenty as in proteins) subunits. These four substituents - termed
nucleotides - were adenine, thymine, guanine and cytosine. The apparent paucity of information content was
further exacerbated by the fact that in all chromosomal DNA isolated to date, the stoichiometric (that is to say,
numerical) quantity of adenine was absolutely identical to that of thymine and likewise the quantity of guanine
was identical to that of cytosine. It was difficult to imagine such a blandly appearing molecule as being capable
of holding so much information. Many regarded it as biological “filler material” or fulfilling some other obscure
role. Like Aristotle before who had used his brain to theorize that the brain was merely a cooling mechanism for
the blood, many scientists believed that DNA served only a mundane role within the cell.
This view was to change with the famous Hershey-Chase “blender” experiment of 1952 which used
extracts of viruses to demonstrate that genetic traits were propagated through DNA, not proteins. 1953 and the
double helix confirmed that, of course, on a biophysical and mechanistic level. People could see that despite the
blandness of the constituents of DNA, infinite variety would result from a different sequence of nucleotides and
perfect replication would be assured through a double-helical copying mechanism.
The excitement over DNA and the sudden reversal of its fortunes was infectious. Proteins became the
more staid characters on the stage of life. They carried no information and were simply dutiful workhorses,

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produced and dictated by the magical genetic codes emanating from the cell’s nucleus. They did their jobs, no
questions asked. And while the action of life took place at the level of proteins, the action of laboratory biology
took place at the level of genes. For a time, cloning a gene was enough to publish a major paper or earn a PhD.
Elucidating a set of genetic mechanisms or regulatory pathways was a sure step to a Nobel Prize.
This is a simplification, of course. Major work has been done around proteins. Sequencing proteins –
insulin for example – or solving the three-dimensional structure of a protein – myoglobin, for example – have
led to substantial accolades, including Nobel Prizes and, most importantly, significant progress. The point,
however, is two-fold. First, is to emphasize the natural bias in favor of DNA. DNA captures the imagination
and still excites scientists and lay public alike. The combination of utter uniformity and infinite variety makes
DNA both relatively easy to study and impossibly mysterious to fathom. It is a potent, emotional combination.
Proteins on the other hand are both more prosaic and more complex. They do not extend, near infinitely, in a
single double-helical structure but rather manifest in a myriad of shapes, some more or less spherical (like
hemoglobin), others elongated (like myosin), yet others thin as cables (like collagen) and others a mix of the
globular and extended (like antibodies and the other immunoglobulins). To study a single protein molecule
could be a life’s work. To study DNA could be the work of life which explains, in a nutshell, the appeal of
genetic research and its expansive outlook over its more single-minded partner – protein chemistry. To be sure,
proteins are more dynamic creatures than the staid drones that described above.
Whatever the case may be, proteins are truly where the action is. Nearly all drugs act on proteins.
Aspirin binds to a protein (cyclooxygenase). Penicillin binds to a protein (transpeptidase). Morphine binds to a
protein (the μ-opioid receptor). Most congenital diseases result from the presence of abnormal proteins. Cystic
fibrosis results from a mutation in the CFTR protein involved in chloride transport across cell membranes.
Sickle cell anemia results from a mutation in the hemoglobin gene. Hemophilia results from any number of
disrupted coagulation factor proteins. While it is the DNA of these patients that harbor (and transmit) the
mutations, it is the resultant proteins that create disease and hence represent the potential targets for
intervention.
If one can fix the CFTR protein, one has fixed cystic fibrosis even without addressing the fundamental
mutation at the genetic level. This therapy, moreover, would not simply be a palliative treatment but would, in
fact, be truly curative. One does not need to completely fix the DNA to cure the disease. It is like making
concrete. One does not have to apply nanotechnology techniques in moving about the constituents of concrete
molecule-by-molecule in order to attain the desired strength and weight. The Romans did it in ways that match
– in terms of the result – the sophistication of modern methods. The Pantheon, still standing in Rome after
nearly 2,000 years, is simple evidence of that.
While not perhaps as fundamental as DNA, nor as glamorously simple, aiming at proteins, however, is
likely to be the most fruitful approach to winning the war on disease. This has been the case, after all, for many
millenia as medicines using salicylic acid (the core ingredient of aspirin) have been used since antiquity. In the
long run, then, the heyday of genetics will likely be a sideshow to where the real action lies. The study of DNA,
ironically, will be but a supplement to the main feature, an important one to be sure, providing further insight
into proteins and a richer and deeper list of the products of these genes, namely the proteins that have for the
longest time past and future been the targets of our Promethean desire to manipulate life and death.
Proteins are also the target for more sinister applications. Other than applying massive physical
destruction (e.g. overwhelming flames, a large explosion or a bullet through the head for example), there are
limited ways in which a life can be rapidly extinguished. It is virtually impossible to do this through DNA.
DNA, after all, is just sitting there waiting for its information to be decoded and translated into proteins. The
victims of Hiroshima and Nagasaki who survived the initial blast (e.g. the massive physical destruction noted
above) died days and weeks, even after the gamma radiation flowing about them caused catastrophic damage to
their DNA. Many died, but it was not at all quick. Plutonium is considered the most toxic substance – weight
for weight – known. Its effects, however, take days and weeks to exert.
Apart from physical destruction – which is obvious – other methods of rapid killing involve the
pharmacological manipulation of proteins, specifically those involved in critical functions such as breathing and
circulation and the neurologic circuits that support these functions. Curare, for example, relaxes muscle and

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hence makes breathing impossible by binding to and blocking the nicotinic acetylcholine receptor. This protein
transmits the signal for muscle cells to contract. No signal, no contraction. The rapidity of paralysis depends on
the mode of administration. Intravenous injection (as used by anesthesiologists) results in paralysis within half a
minute. If breathing is not artificially supported, death will occur a few minutes afterwards. Of course, medical
anesthesia combines muscle paralysis with artificial ventilation along with agents that induce sedation and
unconsciousness. Whether one saves a life or kills one, the target is the same – the nicotinic acetylcholine
receptor. The end result all depends, in a technical sense, on how that target is attacked and, in a moral sense, on
the intentions of the attacker.
Botulinum toxin is another example – and a protein itself. It is one of the most toxic naturally occurring
substances though, as is well known (Botox) it is used in near homeopathic concentrations for wrinkle effacing,
cosmetic treatments. The botulinum toxin (of which there are several subtypes) is a multi-chain protein that
binds to a protein at the neuromuscular junction. The neuromuscular junction is the nexus between nerve and
muscle in which the signal for the muscle to contract is transmitted via acetylcholine molecules that flow from
one side (the nerve side) to the other, muscle side of the junction. The botulinum toxin binds to a fusion
protein, a protein that would otherwise allow acetylcholine containing vesicles on the nerve side to fuse with the
membrane releasing their contents into the cleft between nerve and muscle. With botulinum toxin in the mix,
there is no fusion of these vesicles. No fusion, no acetylcholine released. No acetylcholine, no signal and hence
no contraction. The end result is similar to that of curare though somewhat slower in effect.
One might think that interfering directly with the muscle proteins – for example the myosin-binding
protein in cardiac muscle might be a good target. In terms of conventional pharmaceutical approaches, there are
two problems with this strategy. First, the intracellular location of such proteins limits the possibilities for drugs
to reach these targets quickly and efficiently. Among other functions, the cell membrane is protective and allows
foreign elements to enter only sparingly. Second, interfering with only a fraction of muscle proteins is likely to
have only an attenuated effect. An absolute flood of drugs need to wash over nearly all of the muscle
constituents and this, too, is neither practical nor quick. Neuromuscular junction elements, therefore, represent
effective drug targets. They are extracellular and the binding to just a few targets amplifies the effect by virtue of
the signaling function at such junctions.
Electromagnetic radiation, however, is not constrained by the same limits as pharmaceutical methods
face. Many forms of radiation pass through the body (and into cells) fairly easily. Certainly ionizing radiation
such as gamma rays and x-rays do and even much lower energy electromagnetic radiation such as radio waves
likewise traverse easily into cells. Finally a ray of electromagnetic energy can easily wash over all the constituents
of a cell and, of course, an organ. If such radiation could incapacitate critical protein functions then potent
medical (and military) applications could easily be conceived. Whether the technology is used for life or death
depends on the mode of application as well as the intentions and moral constitution of the operator.
Ogan Gurel, MD MPhil
gurel@aesisgroup.com
http://blog.aesisgroup.com/

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