Thursday, December 5, 2013

Hang him! Get it over with and worry about 'justice' later!

Buckminster Fuller famously said, “You never change things by fighting the existing reality.  To change something, build a new model that makes the existing model obsolete.”

We hear this all the time in the context of genetics.  Over and over and over, we've written about issues that we think are clear, obvious, certainly not secret; problems with genetics that we think explain why we pretty much can't expect to predict phenotype from genotype, or vice versa.  Many of the same issues apply to identifying environmental causes of disease.  This is the amassed evidence that some defendant (some 'theory' in the case of science) is being wrongly accused (wrongly attributed or applied).

It's more complicated than that, of course.  Mendelian genetics had its day, and the cause of many single gene diseases has been identified, but these are largely rare, often congenital conditions, and while these successes are priceless for families with these diseases, the same kind of success hasn't panned out for common, complex diseases.  And there are even more seriously troubled waters,  if not dangerous rapids, for Mendelian ideas up ahead--as we'll describe in upcoming posts!

The same problems apply to epidemiology -- when infectious diseases were more prevalent in the West, when the field was just coming into its own, infectious agents were readily identified, leading to prevention and cures.  Similarly, tobacco was identified long ago as a cause of disease, as was asbestos in buildings, and other chemical toxins.

Our methods work well when the causal agent has a strong effect, that one could see in a dark room while wearing dark glasses.  Extensive experimental and observational data show that mutations in the CFTR gene seem to cause cystic fibrosis, inhaling coal dust causes black lung disease.  But when multiple genes with small effects, or an interacting network of genes and environmental factors, or a complex diet rather than one component of a single food, or a combination of diet and exercise are the risk factors, identifying cause is harder.  Or impossible.

Courtroom inside Tombstone Courthouse State Historic Park, Photo by Matthew A. Lynn; Wikimedia

We've blogged a number of times in the last month or so about these issues.  About why we think genetics is bogged down with, generally, diminishing returns on ever-larger studies, why its promises of personalized genomic medicine, and the benefits of whole genome sequencing and so on have turned out to be over-promises and won't be attained nearly to their advertised extent. 

We're often told that we're too negative.  And we're told that if we don't have an alternate model, we should not criticize the status quo.  But we believe we've got a positive message, and that is that we've learned a tremendous amount in the last 20 or 30 years about what genes do.  The science wouldn't be where it is if we hadn't that knowledge.  There's still a lot we don't understand, but we think that at this stage, much of that is because we're constrained in our thinking by a prevailing model that doesn't accommodate all observations.  We think new thinking is in order, but, no, we can't personally offer it up.  We think about these things all the time, and work with others to explore the  issues, but the lesson of history is that the field, or some new young thinker will have to do that.

The positive message is that we have tons of what appears to be reliable knowledge, but knowledge that points to the possibility (or, depending on how you view things, high likelihood) that some very fundamental facts of life are missing, and that current methods are not suited to detect.  And the fact that the same sorts of things apply to modern genetics and to evolutionary reconstructions and interpretations, reinforces this:  what the current methods can do, and have done, is to show where the confusing, contrary, perplexing, and sometimes paradoxical issues are. 

So, it's odd to hear that if we can't produce a new model we should shut up.  Or, worse, that by constantly saying these things somebody, like a congressperson, might hear them and wonder if we really need as much money or as many university jobs, as we've been fortunate to have.  But maybe such a threat should exist, and clearly!  What a stimulus to serious thought!

Imagine a 12 person jury evaluating the evidence on a murder case.  Eleven vote to convict, but one juror doesn't, saying that the evidence doesn't add up.  She points out the contradictions and the bits of evidence the others have ignored and so on.  No, she doesn't know who did commit the murder, but she's convinced the defendant didn't.  But the others don't budge.  They tell her that if she can't tell them who did do it, they won't change their vote. Hang the accused!

There are problems in genetics....and to press this point is to do a service, not a disservice, to the elusive truth that confronts us.  Whether or not anybody cares to listen, we will continue to express our message, fallible as we are, as we see it.

But we're also trying, within our poor powers to add or detract (to paraphrase the Gettysburg Address), to find better ideas.

[This post contributed to equally by both Ken and Anne.]


Manoj Samanta said...

Here is what Francis Collins told Congress in 2001 -

"As I recently wrote in the February 2001 issue of the Journal of the American Medical Association, by the year 2010, predictive genetic tests will exist for many common conditions where interventions can alleviate inherited risk; successful gene therapy will be available for a small set of conditions; and primary care providers will be practicing genetic medicine on a daily basis. By the year 2020, gene-based designer drugs are likely to be available for conditions like diabetes, Alzheimer's disease, hypertension, and many other disorders; cancer treatment will precisely target the molecular fingerprints of particular tumors; genetic information will be used routinely to give patients appropriate drug therapy; and the diagnosis and treatment of mental illness will be transformed. By the year 2030, I predict that comprehensive, genomics-based health care will become the norm, with individualized preventive medicine and early detection of illnesses by molecular surveillance; gene therapy and gene-based therapy will be available for many diseases."

Manoj Samanta said...

and that speech to congress ( was backed by this paper.

Do you see how many times Mendel was mentioned?

Anne Buchanan said...

Yep, there's a whole lot of money invested in the prevailing model. Unfortunately, it constrains thinking. More posts on this to come...

Ken Weiss said...

It's far worse (Collins' statements), especially because anyone so brazenly promoting his own interests (the Genome Center not personal interests) should act responsibly especially when the subject is supposed to be 'science'.

In the 90s he was quoted somewhere, perhaps in the now-defunct Journal of NIH Research, promising 'silver bullets' (or some such phrase) against basically all diseases. The bullet being gene-related therapies etc.

Others in similar leadership position were promising life expectancy to reach 400 or more.

Enthusiasm can be phrased responsibly. Bureaucrats who can't express enthusiasm responsibly, aren't responsible and should not be given the powers they have

Manoj Samanta said...

I agree completely. Moreover, when such bold predictions do not come to materialize, it is wrong to not look back and see whether the basic assumptions were wrong. Here is another one from 1999 -

"A hypothetical clinical encounter in 2010 is described here.

John, a 23-year-old college graduate, is referred to his physician because a serum cholesterol level of 255 mg per deciliter was detected in the course of a medical examination required for employment. He is in good health but has smoked one pack of cigarettes per day for six years. Aided by an interactive computer program that takes John's family history, his physician notes that there is a strong paternal history of myocardial infarction and that John's father died at the age of 48 years.

To obtain more precise information about his risks of contracting coronary artery disease and other illnesses in the future, John agrees to consider a battery of genetic tests that are available in 2010. After working through an interactive computer program that explains the benefits and risks of such tests, John agrees (and signs informed consent) to undergo 15 genetic tests that provide risk information for illnesses for which preventive strategies are available. He decides against an additional 10 tests involving disorders for which no clinically validated preventive interventions are yet available.

A cheek-swab DNA specimen is sent off for testing, and the results are returned in one week (Table 1TABLE 1
Results of Genetic Testing in a Hypothetical Patient in 2010.
). John's subsequent counseling session with the physician and a genetic nurse specialist focuses on the conditions for which his risk differs substantially (by a factor of more than two) from that of the general population. Like most patients, John is interested in both his relative risk and his absolute risk.
John is pleased to learn that genetic testing does not always give bad news — his risks of contracting prostate cancer and Alzheimer's disease are reduced, because he carries low-risk variants of the several genes known in 2010 to contribute to these illnesses. But John is sobered by the evidence of his increased risks of contracting coronary artery disease, colon cancer, and lung cancer. Confronted with the reality of his own genetic data, he arrives at that crucial “teachable moment” when a lifelong change in health-related behavior, focused on reducing specific risks, is possible. And there is much to offer. By 2010, the field of pharmacogenomics has blossomed, and a prophylactic drug regimen based on the knowledge of John's personal genetic data can be precisely prescribed to reduce his cholesterol level and the risk of coronary artery disease to normal levels. His risk of colon cancer can be addressed by beginning a program of annual colonoscopy at the age of 45, which in his situation is a very cost-effective way to avoid colon cancer. His substantial risk of contracting lung cancer provides the key motivation for him to join a support group of persons at genetically high risk for serious complications of smoking, and he successfully kicks the habit."

In 2013, 'John' cannot even get a functional website from the government, let alone ultra-personalized genetic testing.