2010-06-13

Genetic mapping and diseases

Today the New York Times ran this article:

A Decade Later, Gene Map Yeilds Few New Cures

This article talks about the fact that scientists have largely been unable to "ferret out the genetic roots of common diseases like cancer and Alzheimer's" using the map of the human genome. Here is a typical example of what has been happening:
A medical team . . . collected 101 genetic variants that had been statistically linked to heart disease in various genome-scanning studies. But the variants turned out to have no value in forecasting disease among 19,000 women who had been followed for 12 years.
This news was not very surprising to me because I have been skeptical about theories linking diseases to genetics for a long time.

There are some diseases that are obviously genetic in origin because they follow straight Mendelian rules (Huntington's Disease, Tay-Sachs, etc.) in being passed from parents to children.  However, it never made sense to me to assume a genetic component to a diseases that didn't strictly follow Mendelian rules.  For example, to my way of thinking if heart disease had a significant genetic component we would expect to see clear statistically patterns of heart disease among the children of two parents who have heart disease, just like we do with Huntington's disease (and we would also expect identical twins to always both get the disease).  Also, I have never heard an evidence-based explanation for why would should expect common diseases to have a genetic link.  Most of the explanations I have heard have been basically "just-so" stories, along the lines of "we don't know what causes this disease so it must have a genetic origin" and/or "children of people with this disease have an increased risk for it, so it must be genetic."  Neither of these arguments have ever seemed very compelling to me.  Maybe diseases just happen.  Maybe children are exposed to the same environmental factors as parents.  Maybe there is a behavioral causes that gets passed down by parents teaching their children.

What seems odd to me is that scientists seem to be doubling down on the genetic theory of disease rather than using the recent failures of gene mapping as a wake up call that they need to be investigating new theories for the causes of these diseases:
But with most diseases, the common [genetic] variants have turned out to explain just a fraction of the genetic risk. It now seems more likely that each common disease is mostly caused by large numbers of rare variants, ones too rare to have been cataloged by the HapMap.
The underlying assumption here is that diseases must have a genetic cause, so when studies fail to find a few genetic variants causing the diseases then the theory automatically becomes that each disease must be caused by a large number of different genetic variations. But what about the possibility that these common diseases are not linked to any flavor of genetic variation? What if these diseases are exclusively caused by environmental or behavioral factors? Why discount that possibility?

I think two factors favor researchers pursuing genetic theories of disease. One is pretty obvious: if a disease is caused by genetics then it increases the probability that it can be treated with a drug, and drugs are very profitable.  The other factor is that a genetic origin of disease relieves people of guilt and/or pressure to change their behavior.  If a disease is caused by behavior then people with the disease tend to feel guilty about inflicting the disease on themselves, and they feel pressure to change their habits, neither of which is emotionally comfortable.  The same emotional discomfort holds for diseases with environmental causes (avoiding environmental factors requires changes in behavior).  Finding a genetic cause for a disease takes the social and emotional pressure off people.

Another quote from the article that I think illustrates narrow-mindedness in the scientific community:
At this point, some 850 sites on the genome, most of them near genes, have been implicated in common diseases, said Eric S. Lander, director of the Broad Institute in Cambridge, Mass., and a leader of the HapMap project. “So I feel strongly that the hypothesis has been vindicated,” he said. But most of the sites linked with diseases are not in genes — the stretches of DNA that tell the cell to make proteins — and have no known biological function, leading some geneticists to suspect that the associations are spurious.
 What about the possibility that these stretches of DNA with no known biological function are controlling stuff using mechanisms we haven't even conceived of yet?  What if the protein coding genes are just one small part of a vastly more complex biological control system that we haven't even imagined yet?

Towards the end the article provides support of my theory that there are complex things going on in the genome, and biology, that we haven't even begun to imagine:
But while 10 years of the genome may have produced little for medicine, the story for basic science has been quite different. Research on the genome has transformed biology, producing a steady string of surprises. First was the discovery that the number of human genes is astonishingly small compared with those of lower animals like the laboratory roundworm and fruit fly. The barely visible roundworm needs 20,000 genes that make proteins, the working parts of cells, whereas humans, apparently so much higher on the evolutionary scale, seem to have only 21,000 protein-coding genes.
The slowly emerging explanation is that humans and other animals have much the same set of protein-coding genes, but the human set is regulated in a much more complicated way, through elaborate use of DNA’s companion molecule, RNA.
If roundworms and humans have approximately the same number of genes doesn't that scream that genes are not where the interesting stuff is happening? Is anyone looking to find out what that something else is that makes the difference between humans and roundworms?

I have no idea what the answers are, but it seems to me that there are all kinds of red flags that our basic paradigm about genes, the genome, biology, and diseases are fundamentally unsound on some level and a major paradigm shifting discovery is out there waiting to be made.

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