Sunday, February 23, 2014

Reductionism! Determinism! Straw-man-ism!

“Reductionism!” is a charge often flung at geneticists, from accusers in the popular press and also, not infrequently, from many fellow scientists. What is it that leads so many people to so fundamentally misunderstand what genetics is about?

Whenever someone presents results showing that variation in such and such a trait is partly influenced by genetic variation, or even showing more specifically that mutations in a particular gene can predispose to a particular outcome, someone is sure to shout: “Reductionism! Single genes can’t cause complex traits – it’s patent nonsense to say that they can! Biological organisms are complex systems interacting in complex ways in an ever-changing environment – particular behaviours can’t be simply determined by genes”.

Of course they are right, but they’re also arguing against something no one is claiming. A couple recent examples illustrate this phenomenon. One is the reaction to coverage of a presentation at the American Association for the Advancement of Science meeting by Dr. Michael Bailey, which described results of a very large twin study, confirming that sexual orientation has a strong genetic component (explaining 30-40% of the variance in this trait).

Nick Cohen, writing in The Observer, quoted geneticist Steve Jones’ reaction to the coverage of this story:

“The idea that they could find a reductionist explanation for a phenomenon as complicated as human sexuality was, well, optimistic. All you could say was genetic inheritance probably influenced it. But then you could say the same about anything.”

Cohen goes on to say:

“Suppose researchers claim to identify gay genes. Their discovery would be pseudo-science. A Gordian knot of environmental, cultural and hormonal influences would be as important in determining sexual preference.”

“To put it another way – if you go along with crude reductionism, you can expect to find yourself at the mercy of crude reductionists.”

In fact, the scientists presenting these findings were quite careful to spell out that their findings do not show that sexual orientation is completely determined by genes in general or any specific genes in particular. They simply show that genetic variation contributes to variation in this trait and that certain locations in the genome may contain some of the genetic variants responsible.

There have been similar reactions to the discussion of the effects of genetic variation on intelligence and educational achievement. Again, the authors of these studies are circumspect about the impact of genetic effects, highlighting the important role of the environment, and emphasising the complexity of the genetic effects.

The main problem, it seems to me, is a fundamental misunderstanding of what genetics as a science studies and how it relates to the function of complex systems. The following statements are not contradictory:

1.     The function of a complex system emerges from the complex and dynamic interactions between all of the components of the system, in a context- and experience-dependent manner.
2.     Variation in single components of the system (or in multiple components) can affect how it functions.

Geneticists investigate the second question. Showing that variation in Gene X affects the behaviour or outcome of a system is not the same as saying that Gene X fully determines that behaviour or fully accounts for the entire system. Gene X is just a piece of DNA sitting in a cell somewhere – it doesn’t do anything by itself. But a difference in Gene X can account for a difference in how the system works.

There’s nothing reductionist about that, except from a methodological point of view, in that scientists often focus on individual components of complex systems, one at a time, in order to get a handle on that complexity and figure out how the whole system works. That has been an extraordinarily successful approach, but does not mean that scientists employing methodological reductionism also ascribe to philosophical reductionism – the idea that the system really can be explained simply from the properties of its lower-level components – that it is no more than the sum of its parts, or that its function can be said to be caused by any one part. a car – the function of this wonderful piece of machinery depends on the integrity of all the components and emerges from their interactions. To say that any one component is somehow responsible for the function of the whole system is nonsense. If you just have a steering wheel, you’re not going to get very far. But it’s also true that if you don’t have a steering wheel, you’re going to have difficulties driving anywhere. A change to one component can drastically affect how even the most complex system functions.

Genetics as an experimental approach studies how a system varies or fails, when individual components are disrupted and uses that information to infer which components are involved in which processes. By contrast, biochemistry or systems biology study how the components of a system are put together and how those interactions mediate its function. These are two complementary experimental approaches to understanding complex systems. (For a very funny analogy along these lines, see here).

As well as inducing mutations in model organisms to learn how various biological processes work, geneticists also study how naturally occurring genetic variation in a population affects various traits. Again, showing that differences in genes contribute to differences in traits is not the same as claiming those genes alone produce or determine everything about the system in question.

Part of the confusion may arise from the two different meanings of the word gene – one based on heredity and the other on molecular biology. In the molecular biology sense, a gene codes for a protein, which carries out some function as a component of some biochemical or cellular system. This is a productive definition of the gene in relation to the system. By contrast, a gene in the heredity sense really means a variant or mutation in the molecular-biology-gene – something that alters its function and thus alters the system. This is a disruptive definition of a gene. Such variants can be passed on and contribute to variation in some trait in the population.

The relationship between a gene (as a piece of DNA coding for a protein) and its function in a biochemical system is thus very different from the relationship between a gene (as a unit of heredity – i.e., a genetic variant) and its effects on some phenotype. For one thing, the effects of a genetic variant can be extremely indirect, cascading across levels from the molecular and biochemical to cellular, physiological and sometimes behavioural. Trying to understand how the phenotypes caused by disrupting a gene relate to the molecular function of the normal gene product is the main enterprise of experimental genetics.

Of course, many geneticists contribute to this confusion (often aided and abetted by journalists and headline writers) by using the egregious “gene for” construct. So, we end up talking about “genes for” schizophrenia or “genes for” intelligence or other traits or conditions – it sounds like these phrases are referring to the productive molecular biology sense of a gene, but really they are using the disruptive heredity sense. What those phrases really refer to is mutations that alter how genes work and that thereby contribute to variation in a particular trait or the likelihood of developing some condition, in the context of the incredibly complex biological system that is a human being, which develops over many years in varying environments. All those qualifiers don’t make for great headlines, I’ll admit, but that’s what the shorthand “gene for” construction really means.

So, claims of genetic influence on various traits are really much more modest than many people seem to think. All they say is that the function of the system in question can vary due to variation in one or more of its components. Hardly the grand threat to civilisation which some people perceive.

While I am at it, here are some other common and equally misplaced arguments against genetic findings:

“I don’t want Trait X to be genetic or innate, so I will simply refuse to believe those data and counter by playing my Reductionist! card”. Political agendas don’t trump scientific facts, thankfully, but this is still a very popular move.

“If genes underlying Trait X are discovered, people will misuse this knowledge”. This may well be true, but it does not speak to the underlying facts of the matter of whether the trait is really influenced by said genes. (More on this in a later post).

“The effects of genetic variation in Gene X are only probabilistic – not everyone with that mutation develops Condition X – how can you therefore say it is causal?” This is akin to saying that because not everyone who smokes gets lung cancer, you can’t really say that smoking causes lung cancer. (Which is true, if you want to be pedantic about the word “causes”, but we can certainly say it causes a much higher probability of developing lung cancer. That is a valid, informative and useful statement and we can make analogous statements about the effects of mutations).

A related one: “The effects of variation in Gene X are only apparent at the statistical level”. Well, the effect of the Y chromosome on height is also only apparent at the statistical level (by comparing the average height of men versus women) but that doesn’t mean it’s not real or useful information. It does mean that this kind of information can’t be reliably applied to make predictions about individuals, which is something some geneticists claim they can do, so this criticism hits the mark in those cases.

“Geneticists have yet to find any specific genes affecting Trait X, therefore it is not really genetic”. This one really gets my goat, especially because people are often referring to negative results from genome-wide association studies (GWAS) or the failure of such studies to explain all the heritability of a trait or disorder and claiming that this implies that it is not really heritable after all. As GWAS only look at one kind of genetic variation (common genetic variants) the only thing such negative results imply is that GWAS may be looking in the wrong place and that heritability is likely to also involve many rare genetic variants.  

I am not suggesting that geneticists never overstep the mark and claim more than they should on the basis of specific findings – this field is no more immune from hype than any other – some might argue it is more susceptible, in fact. That is all the more reason to reserve valid arguments against over-extrapolation of genetic results for when they are needed, rather than levelling the blanket, straw-man charge of reductionism! at the field as a whole.