Beyond Genetic Determinism:
Toward a New Paradigm for Life 

RICHARD STROHMAN, PH.D. / Pressing Times Spring02

Editor's Note: As anyone who has experienced the world of scientific research and post-graduate academia knows, what is pursued is what gets fielded, and what gets funded is what makes money.

Recently, the pharmaceutical industry and the "high tech" industry have played a key role. Those two industries came together as in the 1990's, as the "human genome project" swallowed up billions in funding and became the basis of an entire "biotech" industry which used academia as its R&D machine. And it was not simply a matter of academia: the media enthusiastically advertised the project of' "mapping the human genome. " Hardly a week passed without a news story about the latest ''gene'' being discovered—"the fat gene, " "the snarl gene, " etc. And private corporations registered their °rights " to the "code" contained in the gene.

The media plays un important role because who makes the decisions on what is to be funded and not to be funded are not, in the final analysis, biologists and researchers but politicians and corporate executives, since foundations and universities obtain their fielding from politicians and corporations and run under the same principles.

To believe The New York Times, which has used its credibility to regularly tout the discovery of the '''genes" for various functions (intelligence, obesity, etc.) joined by Time magazine, the evening news, etc., knowledge of this science of the average politician or bean-counting decision-maker the "human genome project" was the greatest boon to mankind. Yet its completion in February, 2001, according to Professor Strohman, is unlikely to Yield the sort of magical results predicted.

In this article, Professor Strohman explains why genetic determinism -the theory of a one-to-one correlation of gene to function, that could change the human product by genetic manipulation—is wrong.

When the highly anticipated sequencing of the human genome was completed in February, 2001, a headline in The San Francisco Chronicle announced: "Genome Discovery Shocks Scientists." The discovery was that many fewer genes were found (30,000) for the human genome than had been expected (100,000), and discussion focused on the wonder of it all: that a fertile human egg could create such a different organism than a mouse egg, where the human egg had only 300 unique genes not found in the mouse.

HUMAN GENOME SCIENTISTS SHOCKED
... BUT WHY?

News articles also made much of the fact that many genes interacting with one another seemed to he as important in determining human diseases as a few "major" genes. Another hit of news was that there are more proteins than genes and this was a surprise because of the accepted idea that each gene encodes a single protein.

But on all of these matters, except for the 300 unique human genes, the "discoveries" were not new, nor were they shocking. We have seen suggestions of 30,000 to 40,000 genes for at least a year: we have known for some time that different species have highly similar genomes—humans and chimps for example: and genetic interaction has been part of freshman genetics for at least 30 years. Finally, we have known for years that DNA sequences within one gene may he used in coding many proteins.

In short, many biologists, worldwide, have known for decades that genetics alone is not sufficient to explain life's complex outcomes, and that another kind of information management system must he present. For them, none of this news was a surprise and we must ask why our Human Genome Project scientists appeared to he so shocked.

Perhaps it has to do with something more than just "surprising and challenging new data.

THE FAILURE OF GENETIC DETERMINISM

To me, it suggests nothing less than the failure of genetic determinism: the biological theory that complex characteristics of' human beings are caused by specific genes.

But after almost a century of life sciences dominated by this theory, and after ten years of the Human Genome Project dedicated to finding the genes for human diseases, their diagnosis and cure, and with the human genome finally sequenced, and biotechnologists and drug companies standing by around the world to implement these diagnoses and cures—after all that, to announce that the entire project was based on an incomplete and flawed theory would have been much more than "shocking." It would have been a scandal.

So, instead of being apprised of deeper problems with the Human Genome Project, we have been distracted by press reports of lesser failures having to do with mistakes concerning gene numbers and comparisons of human beings with other species (neither of which is new). Nevertheless, these disclosures are damning enough and led Craig Venter, the president of Celera, the U.S. corporate group partnered with the U.S. government and other national DNA sequencing teams, to conclude: "This tells me genes can't possibly explain all of' what makes us what we are."

But, having said that, he and the other Human Genome Project 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 Human Genome Project leaders were saying that, in spite of the "surprises," genetic explanations would be found as promised.

After their shock and surprise, most of the observers who published comments following the February, 2001, announcement of the sequencing of the human genome, fell back to genetic determinism. One exception was the distinguished Harvard biologist Stephen J. Gould, who wrote this in The New York Times: "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."

So, at a minimum, and reading between the lines of the news reports and press conferences with the Human Genome Project leadership last February, we may conclude that the theory behind the technology to be applied to living cells is flawed. While it does tell us much about our genome, it tells us little about who we are and how we got that way.

WHERE IS THE PROGRAM FOR LIFE?

If Gould and Venter are correct in saying that genes alone cannot tell us who we are, then what will they 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 sense of an inherited, pre-existing script ready to be read. Rather, inside 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.

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 and Crick proved the double-helical structure of DNA (1953) we have been working with the genetic mode. 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 (function) = Genetics x Dynamics x Environment
            DNA ——>>Proteins ——>> Function
Protein Control Networks (Open to Environment)

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. I: it is dynamic and circular (non-linear).

What, then, is the role of genes? Genes specify information necessary to make proteins and the genome provides a collective informational source. However, by itself a genome is passive: DNA, for example cannot make itself, and cannot construct a protein never mind an actual cellular function. DNA has been called the "book of life" by Human Genome Project scientists but for many other biologists DNA is not a hook but simply a collection of words (like a dictionary) from which a meaningful story of life may he assembled.

In order to assemble a meaningful activity or story, a living cell uses a second informational system. Let me give an example. We know that at least 100 genes are related to a heart disease. These genes code for at least 100 proteins, some of which are enzymes. So you have a dynamic/epigenetic network of 100 proteins, many biochemical reactions, and many reaction products. It is dynamic because it regulates changes in products over time, and it is epigenetic because it is above genetics in level of organization. The output from these networks change in response to signals from the body and from the environment. And some of these changes feed back to DNA to regulate gene expression. The key concept here is that dynamic/epigenetic networks have a life of their own: they have network rules not specified by DNA, and we do not understand these rules.

In short, genetics alone does not tell us who we are, or who we can or will be. The new findings of epigenetic or dynamic regulatory systems in cells describe an information management system that we have known about for quite a while but are only now beginning to understand. While, as Gould says, the genetic reductionist theory has collapsed, 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 the life sciences.

THE PROBLEM IS PART SCIENCE
AND PART PHILOSOPHY

We must now ask two questions: First, where did the Human Genome Project 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 gene biology not in the news?

In response to the first question, there are indeed some diseases that are traceable to single genes. I worked on one, muscular dystrophy, for 25 years. This group of diseases has provided a simple model for molecular medical genetics seeking answer in terms of a simplified formula: one gene leads to one disease.

But that model is wrong because it has limited application, muscular dystrophy being one of the few clear cases where it works. In these relatively simple diseases, a single defective gene finds no redundancy, or back-up information, in the cell, and therefore the gene may be said to be the single cause changing environments or behavior and interactions with other genes are often of no consequence. But these diseases are rare; in fact they account for only 2 percent of our disease load.

The mistake of the Human Genome Project was to use that simplified model to attack all diseases, including the common (sporadic) diseases such as most cancer, heart disease, and bipolar disease (manic depression). Together, those diseases account for over 70 percent of our disease load. For the vast majority of cases, human diseases are multifactorial: They are influenced by many genes interacting with one another and by a vast array of signals forming the cellular environment (nutrient supply, hormones, electrical signals from other cells, etc.), and all of these will reflect the external world of the organism as a whole. Thus, mutations in specific genes in one human body, given its genetic background (all other interacting genes), might produce a disease; but in any other human body there might be little or no disease. And each human being has a genetic background that is unique.

In addition, many diseases will be altered when the conditions of life—the environment are altered, especially in early life. Why`? Because, for those diseases 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. Environmental change coupled with gene interaction can reverse some, but not all, simple diseases. For common diseases, lung cancer is the most obvious example of ing the disease outcome unless one also knew the "initial conditions" surrounding the developmental history of the individual. In addition, most multifactorial diseases, like cancer, take many years, even lifetimes, to develop, and one would have to know all environmental impact where, even for long-term smokers, the impact on life expectancy is vastly improved for those who give up the habit. Even more telling is Spina bifida; long thought to be a multifactorial genetic disease, it is now actually known to be due to a vitamin (folic acid) deficiency. Spina bifida is one of several potentially fatal neural tube diseases in which there is failure of spinal cord or brain to close or to develop. In 1992, a large population study concluded that 75% of some of these diseases could be eliminated by giving small doses of folic acid, one of the B vitamins. If the 70 million women capable of becoming pregnant were to take folic acid one month prior to conception many of these neural tube diseases would disappear.

Human Genome Project scientists thought, and still do, that they could find a small number of genes that were the key to these diseases. However, this strategy is flawed because:

(1) For most multifactorial diseases affected by many genes, those genes have small, not large effects. And genes with small effects are very hard to find. Even when found, one would have no way of predict the historical details to make predictions.

(2) It takes all causality hack to genes rather than to genes coupled with dynamics: the duration of exposure to changing environments. Here again lung cancer is instructive since the disease is dependent on the dose (number of cigarettes) and the duration (number of years) of exposure.

POLITICS DEFINES
THE SCIENTIFIC ISSUE

Why is the alternative to genetics—the dynamic-genetic management of complex diseases—not in the news? The answer has as much to do with philosophy and sociology as it does with science.

The Human Genome Project started as a technology devoted to a determinist, gene-based view of life, and spent ten years sequencing the genome. It was tailored to meet with approval in today's atmosphere of instant rewards and emphasis on capital-intensive solutions requiring advanced technological innovations implemented through private corporations supported by taxpayer subsidies.

In short, the Human Genome Project does not exist solely in the world of science. Over the past ten years, it has developed strong relationships with corporate, social, and economic interests, and has 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 withdrawal from the determinist position is extremely difficult. These are all clear facts, confirmed in our daily news.

At the same time, the dynamic-regulatory view of life is right now being tested in laboratories around the world, and scientific journals bring weekly news of its progress. 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.

Until we have a theory, or a paradigm, of life that is able to assimilate the contradictions generated by the Human Genome Project and by the experimental community at large—one that is able to explain what genetics alone cannot—we will have to move ahead with caution and with every effort to put the dynamic regulatory science in place alongside the more familiar genetics.

WHERE DO WE GO FROM HERE?

We are in the middle of a biological revolution. We have a failed or, at the 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. Unfortunately, over the last 50 years 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 than it will take a long time to train the next generation of scientists who understand both the genetic-biological side of the problem and the dynamics part—which will come from a nexus of biology with physics, chemistry, engineering, and computational sciences. Any change away from the genetic-determinist view will also be resisted by corporate socio-economic forces that will need to push current Human Genome Project goals through the pipeline and bring to market whatever might emerge. This resistance grows stronger as a result of corporate-biotech and university alliances.

All this is part of a larger issue of paradigm shifts in biology. 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 world view. 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 respond over time to their manipulation through genetic engineering, and thus the error factor here remains large.

We must move ahead at several levels. The first is at the level of the social science of biology, and the second is at the level of biological science itself. By social science I mean the construction and imposition of scientific standards that should constrain present and future attempts to genetically engineer or clone ourselves, our children, other animals, and the plants that constitute the basis of our agriculture and much more. If the announcements from the Human Genome Project tell us anything, they tell us that we do not know how organisms make themselves. We are still, as many developmental biologists have said, in the dark ages about how organisms regulate their genomes to produce adults. The obvious ethical problem is thus framed by the science of what we do not know and by the logical constraint that, while the scientific inquiry must go on, the inevitable technological applications, whether in medical centers or in corn fields, must stop until the science assures us that we may proceed while doing no harm.

At the level of science itself, we must now ask what we want our life scientists to do next. The technology already developed is superb: It can measure and show us things far beyond our expectations of only a few years ago. But now we are reminded, once again, that wider environment and complex cellular processes—and not just genes—all play important roles in shaping our lives. The work of corporate biotechnology will go on; as the Wall Street Journal reminds us, it is inevitable, as is human cloning, as is a future gene-based medicine for the wealthy few who will then immunize themselves against premature diseases and death. But that will be a false hope. Premature disease and death will surely come if we allow a continued degradation of the very environment so necessary for the healthy expression of genes now present in all of us.

For the universities and the national science laboratories, none of this is inevitable. In pursuit of a technology of genetic immortality, the Human Genome Project may be said to have put us on the road to finding technological improvements for the genomes of a few, using resources that could bring substantial benefits to all, if applied as preventive measures to the general population. Emphasis on gene technology causes us to forget that a technology called public health has already provided a model for the future. Public health technology has given us nearly forty years of increased life expectancy in just the past 100 years—without genetic engineering of any kind, proving that the genomes we all have are already competent to provide us with a life expectancy at birth of 85 years: providing, of course, that we are given a world reflective of our conserved and adapted genomes.

The university and national (public) laboratories may now choose to take up the quest for new rules of complex adaptive systems we call life. We can choose to support work that would allow us to discover constraints at the level of multi-cellular organisms, populations, and ecological settings that could be violated only with great risk to individual health, to stable ecosystems, to renewable resources, and to sustainable agriculture. We might call the implementation of this science a "technology of nature."

We thought the program was in the genes, and then in the proteins encoded by genes. But knowing all the individual proteins would not reveal a program: for that you need to know the rules of protein networks that are coextensive with the cell itself. The program location is the cell as a whole, and the cell, through signaling pathways, is connected to larger wholes and to the external world. If we could find the financial and other necessary inspiration, and the will to implement the additional research, we would have a science and a technology—a university-industrial complex—that everyone could invest in. The real question is: Who is the we who chooses, and who is the we who decides the future of life'?

It seems relatively easy to obtain funding for the individual-oriented medical model, but funding is much more difficult for the broader view of a context-bound model in which the organisms of the world—plants and animals—grow and develop in a natural world of lawful constraints, only one of which is genetic. The discovery and understanding of those laws is the real next challenge beyond the genome. That is a long-range challenge, and the important questions are: Who will lay down the challenge and who will pay for the research and development needed to meet it? For the university it would require requests for funding new research not popular with corporate interests or even with the present leadership of our National Institutes of Health. Such requests could drive a change in the direction of a new complex biology that includes genetics but is "beyond the genome" as the single answer to life's questions.

Editor's Afterword: 

Professor Strohman points out good reasons why it was known all along by scientists working in the area, or should have been, that genes alone could not explain a great many diseases, much less other phenomena, but only a small part. So why were so many billions poured into this theory'?

Thirty years ago, journalist Arthur Koestler wrote a hook which attracted some attention, The Case of the Midwife Toad. In the book, Koestler described the discoveries of Viennese biologist Paul Kammerer, who claimed to have demonstrated experimentally that acquired characteristics could be inherited. After some initial publicity, his results were tainted and sabotaged, and he was subjected to a large-scale international media campaign to discredit him. Shortly after receiving an invitation from the Academy of Sciences in Leningrad in the Soviet Union to be given his own laboratory there, he was found shot in the head in a Viennese park, and adjudged a suicide.

The unsoundness of determinist theory has never been widely promulgated in the U.S. media—and it is the media which speaks to and is used by those who set the funding mechanisms for research into motion.

Genetic determinism is not merely a scientific theory. It is politically and economically attractive to a minority seeking to exploit the majority of working people, playing one grouping of them against another. In the 1920's, in Germany, which had already built a modern universal access health care system, eugenics proved handy for a government facing an economy in depression. It was "scientific" to deny care that was "useless." One German professor Alfred Hoche wrote an essay, which he published as "Permitting the Destruction of Life Not Worthy of Life," that embraced euthanasia as a proper and legal medical procedure to kill the weak and vulnerable so as not to taint the human gene. Adolf Hitler was a fan of Hoche's writing and popularized and propagandized for the idea. Many people fail to realize that prior to the extermination of Jews by Nazi Germany in the so-called "final solution," as many as 350,000 Germans were sterilized because their gene pool was deemed to be unsuitable to the Aryan race, many because of physical disability, mental deficiency or homosexuality.

After World War 11, the genocidal use Hitler gave to eugenics gave eugenics a bad name. In the 1970's, Nobel Prize winning physicist William Shockley of Stanford University could not find an audience when he claimed, on the basis of "genes," the racial inferiority of Blacks. He was shouted down on some campuses and others would not permit him to speak. Yet, in the 1990's, the authors of The Bell Curve, which promulgated similar "genetic evidence" for racial inferiority, found ready audiences in the editorial pages of newspapers, on the evening news, on talk shows and campuses.

Today, most would condemn the "big lie" of racial inferiority promoted by the Nazis through the propaganda machine of his Minister of Propaganda, Joseph Goebbels. Yet, an entire propaganda network has been prepared through broadcasting genetic determinism through the magic of the "human genome project." In that atmosphere, newer versions of Hoche's arguments have been promoted recently under the guise of "managed care" to the advantage of HMO's, including the promotion of euthanasia.

As Professor Strohman points out, so many billions have been invested in the "biotech" sector, based upon this faulty theory and tied to this research, that to promote an alternative is to risk vilification, program cuts and lost of position and status if the truth can be effectively misstated or hidden from view.

The need for a media not beholden to the economic juggernaut of the pharmaceutical companies and HMO's is evident, so that the truth might he told and false syllogisms such as the cause and effect of gene and function laid to rest rather than promoted because science cannot "bite the hand that feeds it."