Tuesday, March 30, 2010

Reductionism, part II -- The Tunnel of Love

Choosing to wear blinkers
Yesterday, we suggested that even the early geneticists were well aware of the multifactorial causation of traits, and asked how the 'gene for' thinking that has driven so much recent research, largely without satisfying results, came to predominate as it does currently. Today we suggest that science restricts its view intentionally, as a pragmatic way of discovering the nature of aspects of Nature. Indeed, the early geneticists did the same. And we point out that the price we pay is the way scientific methods restrict the degree to which we understand things more broadly.

'Gene-for' thinking is pragmatic -- understanding the molecular basis of genes and how they work is easier than understanding, say, polygenic interaction or the effect of the environment on development.  And of course great progress was made in molecular genetics throughout the 20th century, which only reinforced the view that the molecule was the thing. This, coupled with formal population genetics, gave researchers rules (how genes segregate, how DNA codes for proteins, and so forth) for cataloging how genes work, giving the field a theoretical framework within which to plan, execute and interpret experiments.

Discoveries in other fields sometimes reinforced the determinist view as well. Following not long after the 'one gene one enzyme' dictum was hypothesized by Beadle and Tatum in 1941, e.g., the coming of the computer age underscored the view of genes as the program or blueprint for life, an appealing and seductive idea that is yet to die. Even if a blueprint needs an architect, and a foreman to supervise the building.

In fact, the idea that the early geneticists had a broader view is only partially true. That they did is well-documented, as we wrote yesterday, but it wasn't ever really put into practice. Then as now, experiments were conducted in a way that enabled these guys to find single genes that 'caused' the traits they were interested in; environment was controlled, and fruit fly lines homozygous for a trait known to be due to the effects of a single gene were crossed so that the effect of a given gene could be assessed, just as Mendel had done with his pea plants.

This is how Morgan mapped genes. And, why those genes were given names like 'hairy wing', 'small eye', 'small-wing', 'vermilion', as though they were the single cause of or were 'for' these traits, even though Morgan knew full well that wing characteristics or eye color were due to many genes. Indeed, he wrote in The Theory of the Gene, "... it may appear the one gene alone has produced this effect. In a strictly causal sense this is true, but the effect is produced only in conjunction with all the other genes."

The question thus becomes a philosophical one about causation. Philosopher of science Ken Waters has written a nice paper about this*, discussing the difference between 'potential' and 'actual difference makers' and how experimental method determines which is found, while prior assumptions determine which are sought. Although Morgan knew that it took many genes to change eye color in flies -- potential difference makers, in Waters' terminology -- the gene that actually changed eye color in his experiments, a direct consequence of the way he conducted them, was the 'vermilion' gene. The actual difference maker. The foundation for gene-for thinking was well-established right from the beginning, and reinforced all along the way.

And, of course, the idea that some of the early eugenicists may have understood that environmental influences could be important in development didn't prevent the Nazis from making life and death decisions based on heredity.

'Gene-for' fervor takes off -- and people actually believe it
After the discovery of the gene for cystic fibrosis in the late 1980s, genes for more than 6000 single-gene disorders were quickly identified. These are largely rare, pediatric diseases, but even so there seemed to be little reason to assume that geneticists wouldn't continue finding genes for disease, and then even for behavior and other kinds of 'normal' traits, even if an important aspect of pediatric disorders is that they occur near birth and hence are relatively less susceptible to environmental effects (not entirely, of course, because even the uterine environment can vary).

This kind of success at finding genes associated with traits was seductive, and the commitment to strong genetic determinism is now found not only among geneticists, but among epidemiologists, psychologists, economists, political scientists, and even further afield. Epidemiology, e.g., had its own history of success finding the cause of infectious diseases, as well as the effects of environment risk factors like asbestos or smoking. But, as with single-gene disorders, when the effect of a risk factor is large, it's a lot easier to find than when there are many cumulative risk factors, some genetic and some environmental. When epidemiology turned to common chronic conditions like heart disease, asthma or diabetes, which generally don't have a single strong cause, they ran into the same kinds of epistemological and methodological difficulties that geneticists were having with these same complex diseases.

Ironically, out of frustration with the difficulty of finding environmental causes for many chronic diseases, epidemiology turned to genetics, and the field of genetic epidemiology quickly grew. Only to be as stymied in terms of the fraction of cases explainable by known genes. The 'strictly numerical basis' upon which Morgan had identified so many putative genes was no longer good enough. Because the counts don't come out in Mendelian terms unless fudge factors (called 'incomplete penetrance', a determinist idea itself, as it imbues the gene with a mystical ability to be more or less expressed) are added to account for other causes relative to a gene under study, usually meaning the gene accounts for only a small fraction of cases and doesn't have nearly Mendelian ratios among siblings, etc.

And it becomes institutionalized
Then of course when the Human Genome Project was finished, the sequencing factories had to be kept running, so yet more promises were made about what we were going to be able to do with genes, more billions were spent on more classically reductionist 'count only' genetics -- and yet the same problems remain unsolved. We still can't enumerate the genes that are responsible for height, and for exactly the reasons Morgan spelled out in 1926, as we noted yesterday.

In fact, the scientific methods that we use identify genes that, when mutated in some ways, cause serious stature problems (Marfan's syndrome makes you very tall, many genes make you very short), but when we look at the normal range as seen in a sample of healthy people, these genes do not generate mapping 'hits' (as in GWAS association studies). And this is probably true of most traits -- it's easier to explain the extremes of their distribution than it is to explain the normal range.

It's not that genes are unimportant. It's that we are only taking into account part of the truth. This is driven essentially by methodological considerations -- we've got well-developed formal theory for genes and how they segregate in families, and what that means about how to find them. But it is more of a struggle to account in useful ways for complex causation -- useful, at least, in terms of dreams of miracle drugs or genetically focused personalized predictions.

Tunneling through the truth
An important reason for the combination of great success in discovery in genetics, and the relatively great failure to account for complex traits has to do with methodology rather than the state of Nature. As we said yesterday, the focus on fixed, chromosomally localized causal elements -- 'genes' in the classical sense -- was driven by Mendel's careful choice of experimental material, followed by similar constraints employed by Morgan and the other classical geneticists of the early 20th century.

The very same logic and approaches have been followed to this day. Genes are identified as localized causal elements in DNA and we study and manipulate them through variation that is studied, as much as possible, by removing all other sources of variation. Traits are narrowly defined, transgenic experiments use inbred animals manipulated one gene (or one nucleotide) at a time, and so on. This is done because it generates a cause-effect situation that is tractable.

That approach, or research program, led to the steady discovery of the nature of DNA, of genes as protein codes, and so on, up to the mapping of entire genomes of a rapidly growing number of species.

Yet at the same time, when it comes to complex traits, we know that we are not discovering the whole truth -- and we know why. It is the same control of variation that led to discovery, that leads to obscuring the whole nature of Nature.

In a sense, what science does is to 'tunnel' through reality. Like any other tunnel, the walls are reinforced to keep things outside the tunnel out, and to make a clear path within. The path is a particular gene we are interested in, and we manipulate that gene, and its variation, treating it as a cause, to see what effects it has. We know it really interacts with the world outside, but we standardize that world as much as we can, to reveal only the effect of variation in the single cause.

This is perhaps a tunnel of love of experimental design, but not so much of the nature of Nature, because by particularizing findings, even on a large scale, we systematically isolate components from each other whose true essence, and origins, are intimately dependent on their interactions.

Maybe tunneling through truth is the only way science can understand the world. From the point of view of garnering facts, and manipulating the world by manipulating the same facts, science is a huge success. But in terms of understanding Nature, maybe we need a different way. If so, as long as the reductionist legacy of the 300 year old Enlightenment period in human history lasts, we will remain the Tunneling species.

Tomorrow we'll discuss how the same kind of thinking has worked in developmental genetics and the EvoDevo world of research.

*The Journal of Philosophy is only available online to members, but the reference is Waters, "Causes That Make a Difference", The Journal of Philosophy, 104:551-579, (2007).

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