Michel Morange. The Misunderstood Gene (2001)

     Michel Morange. The Misunderstood Gene (2001) Mendel was lucky: in his experiments, he observed characters of peas governed by a single gene. He didn’t know this, of course, and neither do those who learned of genetics via his story, the standard story told in high school and college biology classes. The result is a profound misunderstanding of what genes do, and of what our manipulation can and cannot achieve. Morange tries to dispel these misunderstandings, and succeeds, but only with people willing to plow through his dense and in places highly technical text. His lycee-learned style is the main culprit, for despite his mastery of English idioms, he does not write with the clarity of an Ian Stewart, for example (who makes many of the same points in his Collapse of Chaos, written with Jack Cohen).
     Nevertheless, this book is worth the effort. I hope it is the first of many books and articles that will demystify the gene. His main point is that the "blue-print" and the "program" metaphors are so misleading as to be wrong. In particular, he makes great efforts to disabuse us of the notion that there is some kind of one-to-one mapping of genes and features, that there is a gene for blue eyes, for example, and a gene for brown eyes, and which eyes you get is decided by the genes you inherit from your parents. This one-to-one mapping of genes and features is extremely rare. Most traits are the result of several genes, whose precise interactions are not well understood. For most traits, the genes involved are not yet known. Hence genetic determinism is a mistaken concept. One consequence of this is that most “genetic engineering” is doomed to a priori failure. In developing this thesis. Morange makes several main points:
     1) Genes code for proteins, not for features or characteristics of organisms. It’s the interactions of proteins that determine how an organism develops and functions. But the same protein will have different functions at different times in the organism’s lifespan, and similar proteins will have different functions in different organisms. And some proteins are made only during a specific (and usually short) period in the organism’s development. For example, sexual maturation depends on various hormones whose production is modulated partly by a molecular clock, and partly by such things as the organism’s rate of metabolism, its food intake, its physical growth, and even external factors such as the time of year, and so on.
     2) Most features of organisms are determined by a suite of genes acting at different times during its development. For example, we normally have five fingers. But the embryo starts with a flipper-like appendage. To make fingers, certain cells must die: genes determine which cells will die, but there is no “gene for five fingers,” since the same genes, activated in different organs at different times in the embryo’s development, also control the growth of other organs and features of the human organism. How do the genes “know” when to activate the death process, and when not to? Well, that depends on signalling between and within cells, in other words, the cells’ environment, which is determined by still other genes that code for the proteins that make up, act as, or set up these signalling systems.
     3) The vast majority of features of an organism are the result of a complex interplay of proteins coded by many different genes at different times, as well as external factors such acidity, temperature, and so on. A mutation in any one of these genes can be and almost always is offset by the buffering action of the many other proteins involved. The system as whole tends towards a stable form regardless of the actual mutations in the genes. There are also repair mechanisms, which prevent mutations in the DNA of any one cell from destroying it, and also ensure that the daughter cells function properly.
     4) Although it’s possible (at least in principle) to trace backwards from effects to genetic causes, it’s not possible to predict what any given combination of genes will cause to happen. The reason is, again, the complexity of the protein interactions, and more importantly, the self-organising properties of biological systems.
     5) The value of a gene is determined by the environment in which the organism finds itself. What’s good in one time and place may be bad in another. This explains why sickle-cell anaemia, for example, persists in the human gene pool: it confers some resistance to malaria, and that resistance outweighs it deleterious effects where malaria is endemic. Malaria will kill many victims before they reproduce; while sickle cell anaemia usually doesn’t kill until later in life, after reproduction. The same mathematics accounts for Huntington’s and other late-onset diseases (including the diseases of old age): these strike a decade or more after the prime reproductive years.
     What I take from Morange’s book is that genetic engineering is to a large extent a fantasy. It will have at best very limited success. For one thing, so few features are controlled by a single gene that it’s just a matter of luck that features such as resistance to Roundup can be engineered at all. There was no a priori reason to suppose that such resistance would be governed by a single gene. On the other hand, the fact that Huntington’s is caused by a single mutation on a single gene means we can eliminate it.
     Secondly, the effect of a protein depends on its environment. A protein will not necessarily have the same effect in the host organism as it had in the donor. Again, it’s pure dumb luck that the protein for Roundup resistance has the same effect in the host plant as in the original donor plants. Also, the gene may be recessive, or the mutation we are interested in may act differently when paired with the unmutated allele.
     Thirdly, the odds are enormous that any given gene transferred to another organism will have unpredictable effects in addition to or in place of the effect(s) it had in the donor. Proteins initiate or intervene with many biochemical pathways. There is no guarantee that a given protein will act the same in the host as it did in the donor. Some of the end results may not show up in the host organism, but in the ones that eat it.
     Morange also points out that a clone made with current techniques is in fact less like the donor than identical twins are to each other. The current techniques involve harvesting a cell from the early embryo (of few dozen cells in size), removing the nucleus, and inserting the nucleus taken from the donor cell. The clone shares the nuclear DNA with the donor, but has the mitochondrial DNA of the host oocyte, which was determined by the maternal genes. Identical twins share both nuclear and mitochondrial DNA. Only if we can develop techniques that in effect convert a donated cell into a zygote will the clone be an identical copy of the donor. Of course, even then, the clone will be an independent individual subject to all the vagaries of an unpredictable environment, and so when fully developed will not be identical copy of the donor, any more than twins are identical copies of each other.
     Morange does see good things coming out of our increasing understanding of the effects of genes. How a gene affects its carrier depends hugely on the environment, and humans are able to control that, so they are also able to influence the effects of their own genetic heritage.
     Morange thinks that knowing one’s genetic heritage and its biological meaning will enable us to counteract otherwise damaging effects, and he thinks this a far easier mode of “genetic engineering” than attempts to change the genome itself. Changing the genome of the cells in some organs does hold great promise for individuals, but will not be passed on to their offspring. Changing the germ line itself is far more problematic. Apart from a few diseases like Huntington’s, most diseases and disabilities result from such a complex interplay of so many genes that changing one or even a few of them will not have any observable effect for several generations, if then. Lifestyle changes for the individual have a much greater payoff.
     Morange’s book, or rather its message, is important and deserves a wide audience. It also deserves interpretation to the general public, which still thinks of the genome as some sort of master plan that we are fated to follow. The truth is both more complex and more liberating. *** (2003)