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Sunday, June 13, 2010

"A Decade Later, Genetic Map Yields Few New Cures": I Disagree

In a June 12, 2010 New York Times article entitled "A Decade Later, Genetic Map Yields Few New Cures" by Nicholas Wade (, we are told that "the primary goal of the $3 billion Human Genome Project — to ferret out the genetic roots of common diseases like cancer and Alzheimer’s and then generate treatments — remains largely elusive." Mr. Wade further writes:

"The pharmaceutical industry has spent billions of dollars to reap genomic secrets and is starting to bring several genome-guided drugs to market. While drug companies continue to pour huge amounts of money into genome research, it has become clear that the genetics of most diseases are more complex than anticipated and that it will take many more years before new treatments may be able to transform medicine.

'Genomics is a way to do science, not medicine,' said Harold Varmus, president of the Memorial Sloan-Kettering Cancer Center in New York, who in July will become the director of the National Cancer Institute."

I disagree. Although the Human Genome Project in and of itself hasn't yet provided revolutionary therapeutics, and the genetics of most diseases are indeed more complex than originally anticipated, apparently not taken into account is the decade-long work of a small Israeli biotech company named Compugen, which has established itself as the world leader in predictive biology.

Mapping the human genome was no small feat, but it provided the equivalent of a basic alphabet, hardly enough in and of itself to begin redacting the complex manuscripts of disease, but nevertheless a beginning.

Example: It is well known that the manner in which certain proteins fold or interact with other proteins gives rise to specific diseases; however, a map of the human genome does not provide the ability to prevent proteins from folding into disease associated conformations or from binding to one another and inducing intracellular events which cause disease. Additional years of fundamental research were necessary to bridge this gap, and tiny Compugen appears to have paid its dues.

Compugen realized early on that there could be no shortcuts, and it initiated a pioneering study of alternative splicing, which helped provide a map of the human transcriptome. The human transcriptome in turn yielded the human proteome (the map of human proteins), which in turn provided the human peptidome (the map of human peptides, i.e. protein fragments), which could not have been achieved without first discovering the correct cleavage sites of proteins.

Can drug discovery be premised upon theoretical predictive discovery? Building on both theoretical success and failure as validated in the laboratory, Compugen has until now created 12 discovery platforms. Inaccuracy at any stage in the process would have rendered these platforms useless. However, evidence of their viability came already in 2007 when Compugen's GPCR peptide ligand discovery platform was put to the test. As disclosed by Compugen:

"GPCRs are membrane protein receptors that are involved in signal transduction of numerous physiologic processes. GPCRs are by far the largest family of known drug targets. There are approximately 370 GPCRs relevant for drug discovery and development and at least 40% of drugs in the market are thought to act on GPCRs. It is estimated that at least 40 novel endogenous GPCR peptide ligands have yet to be discovered, and there are ample precedents that indicate the high value associated with GPCR peptide ligands. In particular, GPCR peptide ligands have a high probability of being developed into new drugs.

* * * *

Applying a machine-learning related technology to our peptidome resulted in a collection of novel peptides likely to activate GPCRs. Thirty three peptides, all novel, were synthesized and screened in a functional assay against a panel of 152 GPCRs. Eight peptides were shown to activate six different GPCRs in a concentration-dependent manner, including some for which there are no known endogenous ligands."

Had Compugen's maps of the transcriptome, proteome and peptidome proven false, the GPCR Peptide Ligand Discovery Platform would have crashed and burned. Instead, the results met with resounding praise from the scientific community (see, e.g.,

But the GPCR Peptide Ligand Discovery Platform was only the beginning. More recently, for example, Compugen revealed a discovery platform to predict cell penetrating peptides for drug delivery, which, according to Compugen, can create "new therapeutic opportunities for many indications" (

Compugen has also disclosed two additional discovery platforms, its Protein-Protein Interaction Blockers (PPI Blockers) Discovery Platform for the prediction of peptides to block disease associated protein-protein interactions (, and its Blockers of Disease-Associated Conformation (DAC Blockers) Platform for the identification of peptides that block proteins from adopting their disease-associated conformations ( Without knowledge of the genome, transcriptome and proteome, facilitating a map of the peptidome, together with a detailed study of evolutionary mutation, these discovery platforms would not have been possible.

And with the preliminary use of Compugen's discovery platforms, primarily designed to validate the platforms, have come new therapeutic candidates for diseases desperately requiring new medicines, e.g., pulmonary fibrosis, multiple sclerosis, inflammatory bowel disease.

This is not to say that all of Compugen's candidates will succeed (the majority will not) or that they will reach the market anytime soon. However, Compugen is responsible for a revolution in drug discovery, which is constantly improving upon itself, resulting in an ever expanding inventory of new drug candidates and providing hope where Big Pharma has hit the wall. I have no doubt that predictive biology will prove itself indispensable to future drug discovery and the basis for treating heretofore "incurable" diseases in the years ahead.

[As noted in prior blog entries, I am a Compugen shareholder, this blog entry is not a recommendation to buy or sell Compugen shares, and in mid-September 2009 I began work as a part-time external consultant to Compugen. The opinions expressed herein are mine and are based on publicly available information. This blog entry has not been authorized or approved by Compugen.]


  1. Thank you Jeffrey for a lucid exegesis of the achievements of the most exciting company in the world of pharma today.

    We are close to the pivotal-point when the true scale and scope of Compugen's science is realized in multiple agreements.

    Until comparatively recently it seemed the leading pharma companies were in relative denial. They could admit their methods were not yielding new drugs. Reluctant to axe their R+D divisions in whom they had invested hundred of millions of dollars to so little avail they nevertheless continued to pour money away- no doubt at the urging of their own scientists, anxious to save their own jobs. And those scientists were partially or completely failing to provide new drugs. But that is all changing with R&D staff being axed and generic competitors devouring their profits at the other end.

    The situation had to change. And now Pfizer has woken to the fact that it needs the scientific edge provided by Compugen’s steady mapping of the transcriptome, proteome and peptodome. Their research is not complete, but with every achievement Compugen announces, their task is further facilitated, to the point where Compugen became the first company ever to undertake to discover molecules on a predictive basis. This is no less than extraordinary and when the skeptical market and pharma world sees delivery and milestone payments, it will be unignorable.

  2. When life science and medicine become less distinguishable, medicine may become more efficacious, being more compatible with organic processes. I'm no doctor or even a scientist, but my understanding is that what CGEN does could prompt not just more ways to create wellness but new ways. Reminds me of nonbiological physics. The way to warp drive isn't with fuel, but by bending space. The way to attack disease is not with toxins but will a deeper understanding of what causes disease on a molecular level so manipulating processes becomes more therapeutic.

    I welcome critique of my analysis.

  3. Thanks, Happyminyan.

    As you know, several of Compugen's platforms focus on peptide therapeutics, whose advantages include: lower toxicity, higher specificity, low immunogenicity, smaller size (facilitating improved penetration and potency), and lower likelihood of drug-drug interactions.

    Compugen's therapeutic efforts, of course, extend well beyond peptides, e.g., mAb targets.

    I agree: These discovery platforms strive for a specificity that could not be attained without Compugen's modeling of biological phenomena on the molecular level.

  4. I've heard a theory that diseases as cancer are caused by violation of an internal ecological balance within an individual. The bad strands of cells get some advantage and spread. The traditional approach to healing is to kill bad cells or to try to modify their behavior. Another approach would be to modify the internal environment back in favor of the good strands, so they can prosper again. I do not know if somebody is working on it yet.