There is an interesting set of commentaries in the current issue of The New England Journal of Medicine in which scientists reflect on why genetic screening strategies have had such limited value, for explaining the risks of onset of the great human diseases and disorders. There has been a longstanding presumption (most strongly held by deterministic geneticists) that it is ‘genetics uber alles’. All we have to do to establish your own weaknesses for falling victim to the great ‘diseases’ of humankind is to screen your personal DNA. From this screen, “Voila!”. We define a risk profile for you that informs us about your medical fate — and what drugs you should take or what different life strategies you should adopt to at least slow it down.
It turns out that reading the tea leaves of your DNA is not quite so simple. For most of the great human maladies, we CAN find genetic loci that do definitely confer risk for the onset of this or that neurological or psychiatric or somatic disease. However, most of those factors merely define a small, statistically significant increase in risk; most people who have the disease DON’T have the fault; and there is a very strong probability that even while you have the inherited fault, you’ll never succumb to the disease. Moreover, in disease after disease, a bewildering array of MULTIPLE genetic faults have been described that largely degrade the accuracy for validly weighing risk.
I was particularly intrigued by one interesting argument by David Goldstein, a prominent Duke University geneticist, who I identify as one of the leading advocates, in his earlier career, of “genome association studies” (in which you associate the genetic faults that distinguish individuals suffering from a particular disease to define how it arises from their bad genetics, analyzed by contrasting their genetic profiles with all of those ‘control’ individuals who do NOT have the disease]. Goldstein now argues that there may be hundreds or thousands of uncommon genetic variations that can contribute, in a myriad of combinations that may (or may not) overlap to a highly variable degree, to the emergence of a disease like schizophrenia. Given this complexity, this brilliant scientist has apparently become skeptical about the ability of genetic profiling to provide reliable risks assessments for many of the most-common neurological, psychiatric and somatic diseases.
Other geneticists contributing to the NEJM discussions took a more deterministic stance, arguing that to define risk to a substantially higher level of certainty we simply have to document all of those combinations of the hundreds or possible thousands of rarely-occuring mutations. The right combinations, they conclude, shall explain disease onset.
In the words of my sainted grandmother, “Poppycock!” Real bodies and brains operate with very complex processes that alter them as a function of how they’re used, from the cradle to the grave. Those processes are PLASTIC. Most of the great illnesses of human bodies and brains reflect a wonderfully complex dance between these incredibly complex, multifactorial homeostatic and change processes and your genetics that — over and over again — shall richly frustrate and simple genetic-hits analysis.
Let me cite a specific case in the scientific literature as an example. Scientists have put ‘gene chips’ into the brains of schizophrenics, to determine which genes have altered expressions of activity in patients vs non-patients. They find that 150-250 genes are statistically more active in sick than in the normal individuals; another 150-250 genes are less active. The recorded signature of ‘up-regulation’ and ‘down-regulation’ = the genetic expressions of schizophrenia.
300 processes abnormally strengthening or abnormally weakening provides an incredibly complex basis of explaining the functional differences between SZ vs normal brains. Let’s say that I fix one of these weaknesses. How does that impact the other 299? In any event, most of these changes in genetic expression are NOT specific to SZ. They merely reflect the well-known fact that brains are PLASTIC, and when I’m schizophrenic, that plasticity has moved me to a different operating state that has several hundred expressions. [Of course LOTS of OTHER diseases, bumps on the head, brain infections, et alia will similarly alter my operating state via several hundred expressions.] I examine the brain in schizophrenics in a hundred behaviors. How it responds, how it is engaged locationally, how it controls the patients actions are abnormal in every instance. Dozens if not hundreds of significantly powered process variables are in play Getting from a DNA profile to an accounting for these altered variable is bewilderingly complex!
Genetics research continues to richly inform us about biological principles and process. It has revealed to us that most of our great human illnesses arise from ‘common failure modes’ for our regulated brain and body processes that can arise from the accumulated weaknesses from many, many, many combinations of genetic faults. Understanding disease origin requires that we understand those PROCESSES, and why and how they fail catastrophically — as much or more than does our understanding of the remarkably complex underlying genetics.
The bad news is that not too many world scientists actually study these biological processes. Numbers and money spent are certainly small, in comparison to our investment in modern genetics. More bad (and some perhaps-good) news is that the commercial drive to provide each of us with a risk profile that can explain how likely we are to run into trouble in life by contracting this or that serious illness has been slowed down considerably by the complexity of the human biology that is us.
