EXCERPT: 'We have a failed or at least an incomplete scientific paradigm called genetic determinism. ... it will be difficult to change direction if for no other reason that it will take a long time to train the next generation of scientists... any change away from the genetic determinist view will also be resisted by corporate socio-economic forces... a resistance that grows stronger as a result of corporate biotech-university alliances....For now the important problem before us is the technological problem defined by genetic engineering of organisms in the light of an imperfect understanding of how the living cell actually works. It must be emphasized that we simply do not understand how living cells will respond over time to their manipulation through genetic engineering and so the error factor here remains large.'

Richard Strohman, Department of Molecular & Cell Biology at UC Berkeley, formerly professor and Chair of the Zoology Department, and Director of the Health and Medical Sciences Program

This is a major part of Strohman's article. Full article available as a pdf: http://www.biotech-info.net/StrohmanMarch09.pdf
---

Human Genome Project in Crisis: Where is the program for life?
Written for the California Monthly 4/2001
Richard Strohman
Department of Molecular & Cell Biology
Stanley Hall
UC Berkeley

The Human Genome Project (HGP) in disarray

Headlines on Sunday morning, February 11, 2001 in San Francisco and elsewhere announced, "Genome Discovery Shocks Scientists". The reference was to the fact that many fewer genes were found (30,000) for the human genome than had been expected (100,000), and discussions focused on the wonder of it all: that a fertile human egg could create such a different organism than a mouse egg with a similar number of genes and where the human had only 300 unique genes not found in the mouse. But we have seen suggestions of 30,000--40,000 for at least a year and we have known for some time that the human and chimpanzee genomes are 98% identical and yet the fertile eggs and embryos of those two species construct from nearly identical genomes two very different creatures. Much was also made of the fact that many genes interacting with one another seemed to be as important in determining human diseases as a few “major” genes; but genetic interaction, known as epistasis, has been part of freshman genetics for at least 30 years. So none of this news, except for the 300 genes unique to humans, should have been a surprise and we are left to wonder why our HGP scientists appear to be shocked.

Perhaps it has to do with something more than just "surprising and challenging new data". To me it suggests nothing less than a breakdown of the major paradigm guiding the entire HGP effort. That is, it was nothing less than the failure of genetic determinism: the biological theory that complex characteristics of human beings may be reduced to genetic information. But after almost a century of life sciences dominated by this theory, and after ten years of the HGP dedicated to finding the genes for human diseases, their diagnosis and cure, and much more; with the human genome finally sequenced and with biotechnologists and drug companies standing by, world wide, to implement those diagnoses and cures ...after all that, to now announce that the entire project was based on an incomplete theory, would have been much more than a shock ... it would be a scandal.

So instead, we have been distracted by press reports of lesser failures having to do with mistakes concerning gene numbers and comparisons of humans with other species, which is not new. Nevertheless, these disclosures are damning enough and led Craig Venter, the president of Celera, the US corporate team, partnered with the US government (NIH) and other national DNA sequencing teams to conclude: "This (the surprising findings) tells me genes can't possibly explain all of what makes us what we are." But having said that, he and the other HGP leaders went on to describe how they would develop new technologies that would enable researchers to read the "book of life" and thereby describe the most complex diseases and behaviors in terms of causal genes. In other words, the HGP leaders were saying that in spite of the surprises, genetic explanations would be found as promised. And nowhere can I find any further mention of what it might be, other than the genome that "makes us what we are".

These contradictions were apparently lost on most of the observers who published comments during the following week... with one exception. Stephen J. Gould, the ex president of The American Association for the Advancement of Science and esteemed professor of biology at Harvard University summed up much of these news reports in an Op-Ed page report of his own (NY Times, Feb. 19th): "The collapse of the one gene for one protein, and one direction for causal flow from basic codes to elaborate totality, marks the failure of (genetic) reductionism for the complex system we call cell biology." (parenthesis added) So, at a minimum, and reading between the lines of the news reports and press conferences with the HGP leadership of Feb. 11 and 12, 2001, we may conclude that the theory behind the technology to be applied to living cells, is flawed.

Where is the program for life?

If Gould and Venter are correct that the genetic determinist theory is wrong and that genes alone do not tell us who we are then, it seems fair to ask, what is correct and what will tell us? If the program for life is not in our genes, then where is it and what is it? Many of us have been saying for years that there is no program in the usual sense of an inherited pre-existing script ready to be read given the right environmental signal. Rather, inside of each cell there are regulatory networks of proteins that function to sense or measure changes in the cellular environment and interpret those signals so that the cell makes an appropriate response. What then is the role of genes? It turns out that some of the protein networks in cells feed back information to DNA so that patterns of gene expression change. Given this finding ... it has been known for about ten years but only recently has a sufficient experimental basis been developed for it ... it now appears that the cell has two informational systems. The first is information stored in DNA (Figure 1) and the second is made up of protein networks that carry out cellular operations including a regulatory function that alters patterns of gene expression (Figure 2).

Figure 1.The genetic determinist view of life.

Phenotype (function) = Genes x Environment

DNA----------------- >>Proteins----------->> Function

The causal pathway is linear: proteins are encoded by DNA and therefore DNA may be said to encode function. Environment acts as a trigger to activate pre-set programs in DNA.

Ever since Watson-Crick and the double helix of DNA (1953) we have been working with the genetic model in Fig.1. Now we realize there is another information processing system in cells.

This second informational system is co extensive with the cell itself, consists of many interconnected signaling pathways and is described here under the heading of “dynamics”; the part of dynamics having to do with control of gene expression is, for historical reasons, called epigenetic regulation.

Figure 2. The epigenetic regulatory view

Phenotype = Genetics x Dynamics x Environment

DNA --------->> Proteins --------->> Function

Protein Control Networks

( Open to Environment)

Note to email readers. Draw arrows from Networks to Function; from Networks to Proteins; from Networks to DNA

Protein networks feedback information from the outside world to DNA, and change patterns of gene expression in a context dependent manner. “Dynamics” refers to regulatory networks of proteins that function partly to connect signals from the environment to DNA where patterns of DNA expression change. The control pathway of gene expression is not closed, one-way and linear as in Fig. 1: it is dynamic and circular (non-linear).

These new findings of epigenetic ... dynamic ... regulatory systems in cells provide the answer to both Venter and Gould. Genetics alone does not tell us who we are, or who we can be, and while the genetic determinist theory has collapsed, as Gould says, the epigenetic or dynamic point of view retains genetics as part of a new theory or paradigm for life; one that has striking implications for the future of life sciences. In this model an incomplete theory of genetic causality is complemented by dynamic protein-based processes. This complementarity is irreducible: that is, DNA does not specify the rules of dynamic networks any more than dynamic networks specify coding sequences for proteins. No theory or technology of modern life can be complete in the absence of either.

Our problem is part science and part philosophy

We must now ask two questions. First, where did the HGP go wrong? That is, where did the mistaken idea originate that complex human diseases could be traced to one or a few major genes? Second, why is the new science of epigenetic-dynamic biology not in the news? The first answer is that, indeed, there are some diseases that are tracable to single genes; these are called monogenic diseases. I worked on one, muscular dystropyhy, for 25 years. This disease is a crippling and life shortening disease in which muscles atrophy over time and affected people die of failure of heart and breathing muscles. We know the cause is in a single defective inherited gene encoding a muscle protein called dystrophin. When the dystrophin protein is defective the muscle cell fails to grow and regenerate normally and ultimately withers away. The key here is that the cell has no back up compensation for the failed gene or protein ... there is no redundancy for the missing information and the disease may then be said to be caused by the defective gene. There are literally thousands of monogenic diseases of this kind... sickle cell anemia, cystic fibrosis for example ... but each is rare and, in total, monogenic diseases account for only two percent of our disease load. Nature does not often invest so much in a single gene but when that happens the result is tragic. And the lesson we learned from studying these monogenic diseases, long before the HGP was born, was that when one irreplacable gene went down and there was no back up, then that gene was easy to detect but it was also impossible to fix - the cell had no answer and neither, so far, does medical gene-based science. The mistake of the HGP was to use the monogenic model to attack common polygenic diseases that involve many genes. But for polygenic traits involving many genes, the effect of each gene is small and loss of function for any one mutation may be compensated by gene interaction and by environmental conditions. HGP scientists thought that they could find a small number of genes that were key in heart disease, cancer, and bio polar disease (manic depression), for example, that account for 70% or more of our disease load. But this strategy is flawed, as the surprising results from HGP now make clear, because the strategy still is centered on genes rather than on genes coupled with dynamics where genetic information alone is insufficient to predict outcome.

The second question is why is the alternative to genetics ... the dynamics of complex diseases not in the news? The answer has as much to do with philosophy and sociology as it does with science. In brief, the dynamic- regulatory- view of life is presently being tested in 4 laboratories around the world and our journals bring weekly news of its progress all of which confirm the general paradigm in Figure 2. However, the full extent of cellular regulatory networks is not understood nor do we have knowledge of how the cell as a whole integrates the output of these systems to produce an adaptive response to a complex set of ever changing external signals. The transition from a genetic determinist paradigm to a new, more complex, regulatory paradigm of [genetics-dynamics] will take much more time. Why? Because, that is the way science works. In the present case the HGP starts as a technology devoted to a determinist gene-based view of life, and spends ten years sequencing the genome. Scientists outside the HGP test various predictions along the way, and the community of science and technology arrives at a much more complex picture of life and of the genome than it started out with. That is called "normal" science and surprises are to be expected. To produce a complete failure of an original theory, or a scientific revolution is rare, but it has happened. Until we have a theory, or view, or paradigm of life that is able to assimilate the contradictions generated by HGP and by the experimental community at large ... that is able to explain what genetics alone cannot ... until then, we will have to move ahead with much caution and with every effort to put the dynamic regulatory science in place alongside the more familiar genetics. We need a new philosophy, or metaphor, or model for life. We thought the program was in the genes and now we see that it is in the cell as a whole and that the cell, through signaling pathways, is connected to larger wholes and to the external world.

Understanding the contradictions coming out of the HGP also requires that we acknowledge the fact that HGP does not exist solely in a world of science. Over the past ten years it has developed strong relationships with corporate social and economic interests and, has, willingly I would say, become a tool of those interests. It has given itself over to a propaganda stream of unprecedented dimension and has made promises that play on the health aspirations of people everywhere. In addition, the corporate world of biotechnology has investments of billions of dollars in the pipeline so that withdrawal from the determinist position is extremely difficult. These are all simple facts to be confirmed in our daily news.

Where do we go from here?

If I face the facts I conclude, along with many other dissident scientists, that we are in the middle of a biological revolution of the kind described by Thomas Kuhn in his influential book The Structure of Scientific Revolutions. We have a failed or at least an incomplete scientific paradigm called genetic determinism. At the same time, we have an alternative paradigm called epigenetic-dynamics, which is extremely interesting but also incomplete. But over the last 50- year we have allowed our research portfolio to become unbalanced, heavily favoring genetics and ignoring dynamics. So it will be difficult to change direction if for no other reason that it will take a long time to train the next generation of scientists who understand both the genetic-biological side of the problem and who also understand the dynamics part which will come from a nexus of biology with physics, chemistry, engineering, and computational sciences. And any change away from the genetic determinist view will also be resisted by corporate socio-economic forces that will need to push current HGP goals through the pipeline and bring to market whatever might emerge: a resistance that grows stronger as a result of corporate biotech-university alliances.

All this is part of a larger issue of paradigm shifts in biology that I am writing about. In the long run the issue of genetic determinism will only be settled when something like epigenesis-dynamics becomes complete enough to challenge the present worldview. For now the important problem before us is the technological problem defined by genetic engineering of organisms in the light of an imperfect understanding of how the living cell actually works. It must be emphasized that we simply do not understand how living cells will respond over time to their manipulation through genetic engineering and so the error factor here remains large.