Toward a new paradigm for life
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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.
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Figure 2. The epigenetic regulatory view Phenotype = Genetics x Dynamics x Environment DNA --------->> Proteins --------->> Function Protein Control Networks 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). |
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 HGP scientists but for many other biologists DNA is not a book but simply a collection of words from which a meaningful story of life may be 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.
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 management-epigenetic-dynamic 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 the 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 HGP 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 disease 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 interatcting 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 - is 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 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.
But HGP 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 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 predicting 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 the historical details to make predictions. Finally, the strategy is flawed because it takes all causality back 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.
Our second question is: 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 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.
The transition from a genetic determinist paradigm to a new, more complex regulatory paradigm will take much more time. Why? Because that is the way science works. In the case we have been considering, the Human Genome Project starts as a technology devoted to a determinist, gene-based view of life, and spends ten years sequencing the genome. But 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 that it started out with. That is called "normal science," and surprises are to be expected.
Until we have a theory, or a paradigm, of life that is able to assimilate the contradictions generated by the HGP 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. But moving ahead with caution, and with an incomplete theory of life, is not exactly newsworthy in today's atmosphere of certainty and instant rewards.
We must further understand that the HGP 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-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 withdrawal from the determinist position is extremely difficult. These are all clear facts, confirmed in our daily news.
If I face the facts, I conclude, along with many other scientists, that 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. 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. 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.
It seems to me that we must move ahead at several levels. The first as 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 HGP tell us anything, they tell us that we do not now 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 [here I think I know what this means! The wider surround.] so necessary for the healthy expression of genes now present in all of us.
But for the universities and the national science laboratories, none of this is inevitable. In pursuit of a technology of genetic immortality, the HGP 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 provided with 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 ththe 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, as already mentioned, 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?
The University of California (Cal), may have a profound impact in the resolution of this question. Cal is designing a new program in graduate biology that is following a more complex view of life than is embraced by a genocentric biology and that appears, from its design nexus with the physical sciences, to have anticipated some of the deficiencies in genetic determinism discussed here.
The academic plan for Cal's new biology program, while still on the drawing board, apparently creates the correct interdisciplinary structure for the analysis of biological dynamic systems. However, the program appears to remain focused on developing an individual-oriented medical technology centered on molecular and other mechanical devices and on genome informatics. And no one can argue with that.
But the University can also exercise a choice to expand its new program to include the science and technology of nature we have discussed. It is within this perspective that we will be able to define the larger issues of context-dependent individual development, growth, and aging, as well as the evolution of populations, all of which remain at the periphery of future plans for a post-genomic science, not only at Berkeley but at most other universities eager to embrace the opportunities opened by the declining power of a genocentric world view.
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.
| Richard Strohman, Professor Emeritus of Molecular and Cell Biology at University of California, Berkeley. He is among the working retired Cal faculty, teaching freshman seminars and writing a book dealing with the issues in this article. He has been at Berkeley since 1959, serving as chair of the nation's top-ranked zoology department and director of the Health and Medical Sciences Program. In 1992, while on leave, he was research director for the Muscular Dystrophy Association's fight against neuromuscular disease. He is a frequent contributor to Nature Biotechnology, a leading journals in the biotech industry. |
Published here on March 22, 2001 with the permission of the author.
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