Commentary Magazine


DNA

To the Editor:

I enjoyed Arthur B. Cody’s article [“Messages from the Genome,” June], but I was a little puzzled by its tone. Although he seemed to agree with my book Genome in every particular, he nonetheless conveyed an impression of fairly strong criticism. So let me simply comment that my book is very much not one that claims “we now know” everything or that “ignorance is rapidly evaporating.” Far from it: I believe that the more we discover in the genome, the more we realize we do not know. Science is the process of discovering new mysteries, and the genome is a fertile source of those mysteries.

Matt Ridley
Newcastle Upon Tyne
England

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To the Editor:

Arthur B. Cody decries genetic engineering because we will not know the results until it is too late. I sympathize with his plea for caution, but I cannot endorse the adoption of his all-or-nothing argument. Just as ether has been used successfully for decades as an anesthetic even though we do not know how it works, so it is possible to use our knowledge of the effects of a particular regulatory gene or molecule on the cascade of protein-signaling between genes without understanding the entire genetic process.

Consider, for example, the Rx gene, one of several identified as necessary for mammalian eye development. If this particular gene is not active (that is, functionally dominant), eyes and bony sockets do not develop. Were this a widespread human malady, we would not need to know every bit of the signal-transduction pathway that produces these structures in order to attempt to reverse eye loss through Rx gene manipulation.

Mr. Cody maintains that, since the number of genes involved in the development of an organism is enormous, the number of possible developmental end-products is virtually limitless—another reason that genetic manipulation can be dangerous, especially if done at the gametic level. This sounds reasonable, but a survey of multicellular life demonstrates that repetition of form, not unabated novelty, is the rule. Even though an organism may have a vast number of identifiable genes, only 200 or fewer are indispensable in embryonic development.

Nevertheless, Mr. Cody defends his position by asserting that, because the genome “operates in an environment of such freedom . . . at every point, its alternative viable courses are virtually infinite.” This might appear to make sense when talking, as he does, about differences among individuals in the proximity of stomach to sternum. But it is not relevant at the level of development that creates novel morphologies or behaviors: that is, the stuff of new species.

Novelty derives from changes in the activation, timing, and spatial relationships of regulatory genes and their products—which, contrary to Mr. Cody’s assertion, do interact across cell boundaries. Variability in stomach-to-sternum positioning is not the same as having a stomach and a sternum. Too often, variability is seen as a requisite of evolution. It is not. Variation of a feature is only manifest after the novelty has become established and slight differences in structural gene expression emerge among individuals.

We may never know how the genome works in every minute detail, but if discoveries in developmental genetics are to have broader application than the satisfaction of intellectual curiosity, their judicious use in helping to ameliorate the human condition is mandatory.

Jeffrey H. Schwartz
University of Pittsburgh
Pittsburgh, Pennsylvania

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To the Editor:

I found Arthur B. Cody’s “Messages from the Genome” very interesting. He does a good job of describing what is known in a way that can be understood by the intelligent layperson, and he poses some important and provocative questions.

My view differs from Mr. Cody’s in several respects, however. It is quite easy for me to imagine where the genome derives its—and our—complexity. First, our different genomes do not simply contain 100,000 identical sets of genes, encoding 100,000 identical proteins. Instead, each of us can inherit one of several sequence varieties at each gene site, and those varieties change the code just enough to direct the synthesis of proteins with significantly altered functions. Changes in a single nucleotide of a single gene can lead to devastating inherited illnesses like cystic fibrosis and affect such traits as one’s susceptibility to cancer or propensity for addictive behavior. To make matters even more complex, many genes give rise to several different proteins; in the most striking example, one gene is known to encode 1,000 different protein entities.

Nor do our genes function simply in an “on” or “off” state. Each cell regulates the levels of all 100,000 genes individually, according to cell-fate decisions made early in the process of development, but also in rapid-fire, real time, enabling us to respond to a changing environment. Nutrition, stress, DNA damage, injury, hormonal fluctuations, and many other factors influence gene expression and protein levels in our cells. The levels at which each gene is expressed—on, off, higher, slightly lower—are controlled by regulatory DNA sequences, and we can carry different functional versions of those sequences, too. The unique selection of different choices or combinations of choices among 100,000 genes provides plenty of opportunity for complexity.

At present, the protein-coding sequences are all that we understand (and even those, just partially), so that is the subject everyone talks about. But it is the gene-regulation machinery, and the self-regulatory/interactive mechanisms built into RNA’s and proteins, that turn this one-dimensional code into an infinitely complex, multidimensional, living network. Information to regulate genes and proteins and to direct their complex interactions is also encoded in our genomes, but we barely understand it at all.

I agree entirely with Mr. Cody’s rejection of the “blueprint” metaphor for the genetic code, which, though it can be useful, misses the real point. Our genomes do contain the plans from which each cell in our body is constructed. But this particular code also directs the creation of its own construction crew, janitorial staff, repairmen, and every piece of necessary machinery. No real scientist would tell you that this first decoding of the human genome is anywhere near the end of the story. Rather, we understand that the genome sequence is like the bare frame of a ship that can take us to the New World, which so far we have seen only in a fog and from a distance. We know all too well that the really huge and humbling tasks still lie before us.

Lisa Stubbs
Lawrence Livermore
National Laboratory
Livermore, California

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To the Editor:

Arthur B. Cody provides a valuable summary of the current state of the Human Genome Project and some of its limitations. I particularly appreciate his acknowledgement of Walter Elsasser, the eminent theoretical physicist, for an understanding of the fundamental difference between physical and biological science arising from the intrinsic complexity of the organism. Elsasser was the first to analyze that complexity in quantitative terms, long preceding the current wave of interest in complexity theory.

But Mr. Cody shows he has not pursued Elsasser’s biological thought far enough when he asserts the need for a “profound new idea, some tremendous leap in human understanding” before we can comprehend the essential nature of the living state. In his last book, Elsasser proposed three basic principles for moving toward a theory of organisms. The third of these principles postulates that the information transfer in organisms is dualistic, consisting of both the familiar engraving in a molecule (DNA) and a kind of holistic memory involving the entire apparatus of the cell. He described the latter as memory without storage in macromolecules, and applied it to the transmission of information over time in the brain as well as to the reproduction of cells and organisms. Memory without an intervening storage device surely meets Mr. Cody’s demand for a “profound new idea.”

The formal and abstract nature of Elsasser’s biological principles accounts for their being largely ignored by the community of biological researchers. Modern biologists consider themselves hard-nosed pragmatists interested only in experimental results that, for the most part, can be reduced to the molecular level. This form of realism contributes to the dearth of biological theory with the broad organizing power that quantum mechanics and relativity have given to physics.

The problem in biology is to find a way of bridging the gap between the technologically powerful experiments of molecular biology and the abstractions of biological theory, in order to make both more meaningful. Elsasser suggested that verification of the holistic properties of organisms requires a new methodology, one that would supplement conventional molecular reductionism with studies of the dynamics of change among intact living cells. An example that has emerged lately is the mathematical modeling which shows that the driving force in tumor development is selection of altered cells rather than their genetic destabilization.

Further interaction between theory and experiment should lead to a deeper understanding of organisms in general and ourselves in particular. Without it, genomic research risks becoming a sterile exercise.

Harry Rubin
University of California
Berkeley, California

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To the Editor:

Arthur B. Cody’s article on the current state of molecular biology was fascinating and clarifying, if too pessimistic for my taste. I believe, however, that he has confused one fundamental concept with another. Mr. Cody writes, “In molecular biology there is something called the central dogma: one gene, one protein.” But the central dogma, as first formulated by Francis Crick in 1957, says something different: that the “information” in the gene passes from DNA to RNA to protein. What Mr. Cody is referring to, I believe, is the “sequence hypothesis,” which simply states that the sequence of bases in a segment of nucleic acid suffices to determine the sequence of amino acids in the corresponding protein.

As for Mr. Cody’s general viewpoint—he feels that the genome is asked to do too much for its perceived capacity—maybe that is the case. But 50 years ago, the entire field was a muddle. It was clear to only a handful of researchers that the genetic material was even contained in the cell nucleus. Compared, say, to physics, molecular biology is still in its infancy. The work accomplished so far may be characterized in the words of Einstein in connection with Louis Victor de Broglie’s thesis on electron waves: “He has lifted a corner of the great veil.”

Leslie Klein
Lexington, Massachusetts

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To the Editor:

In warning of the dangers involved in gene therapy, Arthur B. Cody writes that it “is premised on the idea that . . . by locating and replacing a faulty or missing gene in an organism we can thereby effect a cure.” This suggests that the new gene can be introduced at the site of the faulty or missing gene. The actual procedure, however, is much more haphazard than this, for it introduces the missing gene at random sites throughout the organism, where it may or may not be expressed. This haphazard distribution may also introduce unforeseen morbidities.

Marco Rabinovitz
Bethesda, Maryland

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To the Editor:

I was intrigued by Arthur B. Cody’s “Messages from the Genome.” The number of different cells that theoretically can be compounded out of four fixed elements, as Mr. Cody theorizes, is extravagantly large, almost infinite. And yet, this wonderful organism keeps running. We can and do predict with great accuracy how organisms will function, just as we can predict atomic actions and the effects of gravity. But we cannot control these biological and physical phenomena. The reason we have no control, of course, is that something else does. That something can be called Natural Law or the Great Programmer. Acknowledgement of this is exactly what is missing from Mr. Cody’s conclusions.

Edward Kaplan
West Palm Beach, Florida

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To the Editor:

Arthur B. Cody’s article provides a very thoughtful caution against the excessive claims being made for the Human Genome Project. In the past few months I have heard the heads of distinguished university genetics departments list the understanding and control of human behavior among the accomplishments that will follow from this project. When I challenge them, they acknowledge that there is indeed a great difference between our understanding of the genes that control physical somatic features like eye color and our vague and primitive speculations about the role of genetics in determining human behavior.

Mr. Cody’s reminder that what makes us human and individual is far more complex than some narrow-thinking scientists imply is very welcome.

Joseph Berger, M.D.
Toronto, Ontario, Canada

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Arthur B. Cody writes:

I am pleased to have received thoughtful letters from such distinguished individuals. A few observations are nevertheless in order.

It is very agreeable to learn that Matt Ridley concurs with me that science is, as he puts it, “the process of discovering new mysteries.” This is nowhere truer than in molecular biology, where each new discovery opens up a thousand new such mysteries. In line with this, Mr. Ridley now declares that, contrary to my stated impression, his book is “Very much not one that claims . . . ‘ignorance is rapidly evaporating.’ ” I must have been misled. Somehow, from passages like this one—“In just a few short years we will have moved from knowing almost nothing about our genes to knowing everything”—I got the wrong idea.

Jeffrey H. Schwartz takes me to task for an all-or-nothing argument I did not advance. Rather than suggesting that gene therapy should never, ever, be done, I caution against undertaking it without a greater understanding than the one we possess now of the way the genome works. The reason is to be seen in the universal concession that many genes must work together in building an organism. It follows that if one, even the Rx, is altered, there may be far-reaching and unpredictable effects, some of them deleterious.

Limited to a single volunteer, and assuming full disclosure in advance, experimentation of this kind might be morally tolerable; but if our knowledge of what we are doing is no greater than the knowledge we command of ether, manipulating at the gametic level is surely wrong. Ether’s effects, after all, are not inherited.

As for Mr. Schwartz’s citation of the number 200 in connection with embryological development, I fail to see its relevance; surely he is not suggesting that we can fiddle with the other 99,800 genes as much as we like so long as we leave the 200 alone. Although he grants that we may never know how the genome works in every minute detail, he understates our ignorance. We know practically nothing of how the genome works; minute details are a very long way off. Finally, I am of course in accord with the view that the application of developmental genetics should include “their judicious use in helping to ameliorate the human condition.” The question is what judiciousness requires, and what ameliorating is.

Like Lisa Stubbs, I am aware that a single nucleotide of a single gene can produce a serious or fatal disease, and that, by “alternate splicing,” a single gene can produce many different proteins. I did not know that one gene can encode as many as 1,000 different proteins, but I would have thought that this fact reinforces rather than undercuts the position I advanced. The question remains: what is the agency that selects which protein to express at any given time? Surely it cannot be another gene-protein, and so on ad infinitum. Certain factors external to the cell prompt the selection but do not cause it; something responds to the prompting and then selects which way the gene is to go; what that something is, we know not.

A similar observation may be made concerning the point about how cells regulate gene levels. An encoding gene makes a protein or it does not; on or off. It is the level of proteins—that is, the number activated at a given time—that varies according to the factors Lisa Stubbs enumerates, but the technique by which these factors hold sway is simply mysterious. “We know all too well,” she writes, “that the really huge and humbling tasks still lie before us,” but the really huge and humbling task, the task that is first in importance, is to figure out how the damned thing works.

Though I share Harry Rubin’s admiration for Walter Elsasser, and agree that he should be more widely read, I cannot agree that he has managed to come up with the profound new idea we are waiting for. Elsasser, as Rubin reports, speaks of “holistic memory,” or memory without storage. It is a curious idea, suggesting that what in physics is impossible and makes no sense is commonplace in biology. Although the genome is informationally impoverished, the organism regains all the information required for its development, enormously more than what is available from the little piece of its parent that is passed down.

But there is nothing more to Elsasser’s idea than this: no elaboration, no mathematics, no formulas, no crucial experiments. However much one agrees with his analysis, or sympathizes with his willingness to see the presence of unique principles at work, he has not discovered such a principle. Incidentally, Harry Rubin, long a sound and knowledgeable critic of complacency in biology, is himself a no less salutary voice than Elsasser’s.

I confess I cannot see the source of Leslie Klein’s confusion, or of what he calls my confusion. Originally it was thought that each gene produced an enzyme. Subsequently it was found that genes express not only those proteins that are enzymes but all of the body’s proteins. Perfect accuracy would demand certain qualifications: the route from DNA to RNA to organelles to transportation is an elaborate one; there are some genes that do not code for proteins; in some cases one gene codes for only a part of a protein while another codes for another part and the parts get put together later; and some code for several different proteins. But it still remains true that what we do not know about all this is what we want to know most, namely, how genes construct anything belonging to an organism. That they do so we cannot doubt, but it is not in any way like the way they make proteins. The corner of this biological curtain has been lifted, to be sure, but it is a very much bigger curtain—though microscopic in itself—than the one de Broglie and Einstein peeked under.

I thank Edward Kaplan and Joseph Berger for their comments.

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