if we genotyped everyone and separated out those individuals with the most significant variant, DR2, we would immediately be able to recognize two different landscapes.
Why would this be an important experiment? Our hope was that if a patient had an MS skyline that contained a genetic variant, this might mean they were better served by one drug therapy versus another. Biotech and pharma companies might specifically design clinical studies for therapies targeted at those skylines. Or even better, novel gene associations might reveal themselves when the “noise” of the architecture was reduced. We might find new associations, and these findings would provide novel targets for drug discovery.
However what was found was that no additional gene associations were revealed. No existing associations were stronger in one population compared to the other. In short, the skylines were pretty un-interpretable, with the exception of that previously known variation, DR2.
Most of the team was undaunted by this finding and excited to dig deeper into the genome to understand every additional peak and valley of genetic risk. However, I was devastated. For me, the disease hit very close to home and I was disappointed that there would not be actionable data for some time. So I headed into drug discovery project management, all the while hoping I was wrong and that additional time and hard work by my colleagues would prove me so.
In truth, I didn’t think much about the genome until 2010 at Thanksgiving, when 23andMe offered a $99 deal for a 500K SNP map of my genome. Perhaps surprisingly, even with my family history, I was pretty certain I wouldn’t find anything that might upset me. Why? I was 37 years old, so nearly past the window of onset for many autoimmune diseases. Moreover, my husband and I currently don’t plan on having children, so any untoward variant would be unlikely to inspire worry for the next generation.
I couldn’t have been more wrong. My genome did upset me. Not because I found a variant that is certain to become a major health burden for me in the next 60 years, but rather because I realized there was very little actionable information in the data. In short, I realized that my genome for the most part revealed nothing about my past, current or future health.
I’m not the first person to realize this. Many folks have probably felt the same way when they view their own profiles. I believe my greater frustration is directly related to the insights I’ve gained from my time at the front lines of drug discovery and human genetics. With this special vantage point, I’m now not sure that the architecture of the genome will ever provide guidance for treatment of most diseases (Mendelian genetic disease and oncology aside).
Finding a drug that provides a therapeutic benefit at doses that are much lower than those that cause toxic side effects is probably one of the most challenging jobs on earth. For many years, drug researchers have all been hopeful that the genome would reveal its secrets for some of the tough diseases like MS, and that they’d find drug targets that allowed them to
