In talking with Dr. Robert Green, one of the handful of leading-edge researchers and thinkers on the promise of genomics in transforming health and healthcare, I have gained some quite interesting insights.
Dr. Green is a physician-scientist at Brigham and Women’s Hospital and the Harvard Medical School and has focused much of his professional life on a subject of great passion to me, patient empowerment. As strange as it may sound, he has had to do a considerable amount of clinical study work to prove to the medical community that the consequences of doctors telling patients that they are at serious risk of a degenerative and currently incurable disease are, on balance, positive. His work in that regard has been done through a series of studies called the REVEAL Study, for which he has been the principal investigator.
Genomics, according to the Wikipedia definition, is “a discipline in genetics concerned with the study of the genomes of organisms. The field includes efforts to determine the entire DNA sequence of organisms and fine-scale genetic mapping.”
When I studied genetics in high school as part of a biology course, all I remember is that brown eyes are dominant and blue eyes are recessive, and that, therefore, the chances of someone being born with blue eyes is 1 in 4. I also learned that certain conditions, like Down Syndrome, resulted from individuals having a third copy of Chromosome 21, with the result that such an individual would experience intellectual disability. Later in the 1960’s, after watching the film Alice’s Restaurant, which starred Arlo Guthrie, the son of the famous folk singer, Woody Guthrie, I learned that Woody Guthrie died from a horrible neurological disease called Huntington’s disease. Wikipedia defines Huntington’s disease as follows:
“Huntington’s disease (HD) is a neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline and psychiatric problems. It typically becomes noticeable in mid-adult life. HD is the most common genetic cause of abnormal involuntary writhing movements called chorea, which is why the disease used to be called Huntington’s chorea.”
As the Wikipedia article goes on to point out,
“The disease is caused by an autosomal dominant mutation in either of an individual’s two copies of a gene called Huntington, which means any child of an affected person typically has a 50% chance of inheriting the disease.”
The way we learned, and have talked about, genetics over the last several decades, has caused us to have a few deep misconceptions about how it works relative to health and the effect genes have on the likelihood of someone having a future medical condition. There are two major conceptual flaws in how people outside the field of genomics think about genomics and the study of genetics:
Genetic influences on most diseases are much more complex in most cases than we would think would be the case, based on genetically driven conditions like Down Syndrome or Huntington’s disease.
A small portion of any population with a particular disease will have a genetic profile that matches with, and predicts the future prevalence of a disease. For example, relative to Alzheimer’s disease, about 5% – 10% of all Alzheimer’s disease cases occur earlier in adult life, often as early as when an individual is in his or her 30’s or 40’s. These cases, according to the medical research literature, occur because of the presence of specific genes. As the Wikipedia entry states:
However, the other 90-95% of Alzheimer’s disease cases probably result from various combinations of genes, which interact with behavioral and environmental factors that we do not yet understand. Dr. Green is doing cutting-edge research on an innovative way of thinking about Alzheimer’s disease, by comparing cases in which individuals deteriorate, because of Alzheimer’s disease, over relatively short time periods (a few years) and those in which others deteriorate over much longer periods (as much as 20 years.) He is trying to isolate genes that are present in the short-cycle deterioration cases, compared with the longer-cycle cases. He is starting to make great progress, but the research is costly and the funding is more limited than it was a few years ago.
The key lesson from his work and the work of other colleagues who do cancer research or research into other diseases is that most medical conditions result from complex interactions of multiple genes, not the single-gene drivers that were believed to be the major causes of disease decades ago when this field was much newer.
There are two separate issues with genes under particular study today: the genetic sequence and epigenetics. Changes in the sequence determine whether someone has a pathogenic variation or mutation in a particular gene, causing a failure of that gene to function. Changes in the expression of that gene, also known as “epigenetics” determines whether gene functions are turned up or down in intensity. Because most diseases are caused by multiple genes having the disease-associated variation in the sequence of a gene does not necessarily mean that and individual will get the disease.
The discipline of epigenetics has demonstrated that, although the regulation of genes makes a difference to our health, there are additional epigenetic factors that cause a gene to be “expressed,” which loosely means that it has been “turned on.” Genetic effects can be turned up or down in function. Thus, there are many situations in which two people with the same gene will have different effects, based on the gene being expressed differently in one person than in the other.
Implications of this research
Why is it important to get our thinking our thinking right on these points?
We are in the midst of a time when great discoveries that will unlock the mysteries of many diseases are not far away from happening. Research needs to be done, and that research requires money. If you are interested in learning more, or even contributing to this effort, please check out Dr. Green’s web site at www.genomes2people.org and contribute to his effort at https://giving.brighamandwomens.org/G2P.