Here at Front Line Genomics, we are particularly fond of a great story. David Stone is a Senior Principal Scientist at Merck. He’s responsible for some pretty impressive feats in his career, so it was fascinating to hear that it very nearly didn’t happen at all. Ahead of the Festival of Genomics in Boston, we caught up with David to find out a little more about what makes him tick and some of his most memorable times working in genomics.

FLG: Most people working in genomics seem to be working towards a common goal of improving the lives of patients. That being said, people have found their way into the field in a variety of different ways. What first attracted you to a life of research and the commitment of undertaking a PhD way back in the early 90’s at University of Pittsburgh?

DS: Oddly enough, it was light traffic on a Thursday afternoon. I was teaching high school biology a couple of years after completing college, and working on a master’s degree in education. I had left a little early, and with no traffic I ended up at the university about half an hour before class began. I wandered into the anthropology department and struck up a conversation with a couple people, one of whom would later be my PhD advisor.

I have to give a lot of the credit for my success and drive to work on human health to my postdoc advisor, Caleb Finch. My dissertation work was very much on the theoretical side of things, and I’m still not certain what made him take a chance on me for a postdoc in molecular neuroscience. We hit it off famously; he is a guy who never allows himself to be pigeon-holed, and follows the questions wherever they lead, always with the end goal of improving human health. I decided that was the kind of scientist I wanted to be, and I try to let that guide what I do.

FLG: As part of your impressive journey to Merck and Co, you were at Harvard Medical School in the late 90’s where you set up the first molecular biology lab at the Harvard Brain Tissue Resource Center. How did the opportunity come about?

DS: Again, I was unbelievably lucky. The head of the HBTRC (Francine Benes, also I believe the first woman to make full professor at Harvard Medical School) recognized that they needed to bring the current techniques in-house to stay on the front edge of research; I was fortunate enough to have the right skills at the right time. I was extremely close with the people from my postdoc, but they practically threw me out when they heard I had a shot at a Jr. faculty role at Harvard Medical School. They said most people never get a chance like that, and I had to take it.

FLG: Harvard Medical School comes with a very big reputation. How does it feel to be part of that history?

DS: People do notice that on your resume, and without question there are a lot of great minds there. I’m certainly happy to have been there, but I have to say I’ve met brilliant people from almost every university, country, and walk of life.

FLG: The next step was what took you into the world of drug development. You moved to CuraGen where you co-led the team that demonstrated for the first time that drug efficacy could be predicted from gene-expression profiling. Were you ever in any doubt that you were going to be able to do it?

DS: I’ll admit it was a very pleasant surprise when it worked the first time! I had suspected it was possible in one way or another, but had never thought of attempting it. Then I was talking with a co-worker, Erik Gunther, and found out he had put a huge amount of thought into this problem, and finding a “kindred spirit” was enough for us to try to prove it in the wet lab. But we knew the devil was in the details- even if it would work in theory there were dozens of things that could go wrong in practice- so there was a LOT of thought and planning that went into the experiments. After we had published the work it was picked up as an “Editor’s Choice” in both Nature and Science- which again was nice considering how many people told us it would never work!

FLG: You’ve been at Merck and Co now for over ten years. With the explosion in genomic technology in that time, it must be an exciting time for you. One of the highlights was completing the first genome-wide siRNA screen for a neurological indication. Your focus these days is on using genetics and genomics to enable drug discovery. How different is the ‘Big Pharma’ environment to academia?

DS: In some ways the research environment is better in big pharma; in other ways it’s better in academia. I think the scientific rigor is far greater in industry than most people realize, and I suppose this makes sense considering the risks. In academia if your research is wrong you risk having your paper refuted by a colleague; but in industry if you are wrong you risk literally millions of dollars on a failed trial, or worse yet harming a patient.   This isn’t to say there aren’t careful researchers in academia as well, of course, but I do think most people are surprised when they find out how carefully research is done in big pharma, and how critically results are reviewed.

On the other hand, big pharma is corporate America. I’ve seen good projects get derailed because of site closures and layoffs. Obviously academic research is affected by economic forces as well (e.g. government funding) but I think to a lesser extent than for industry. And academia has an unparalleled level of intellectual freedom- one of the great things about science.

FLG: What projects are you working on at the moment?

DS: I’m using a lot of the newer sequencing technologies to look at neurodegenerative diseases.

FLG: Despite having accomplished so much already, you’re showing no sign of letting up. Is there anything in particular that keeps you motivated to keep innovating?

DS: It always comes back to improving human health. As long as you keep that as your primary goal, there’s never a question as to why you are doing this.

FLG: Have there been any moments in particular that you think you will always remember?

DS: An unfortunate incidence an AD/PD conference in Europe several years ago. I was given the honor of choosing the bar we would attend after dinner, and led about a dozen researchers into a hole-in-the-wall establishment in an old building (I chose this place on the strict criteria that I thought the name sounded funny and it was close by). As we sat there drinking beer with the locals, I noticed the young man I was sitting next to had some racist tattoos- it turns out I had quite unwittingly led everyone into a pub that was frequented by a neo-Nazi group. For some reason I decided it was a good idea to explain to him that the genetic evidence refuted his world view, and as you can imagine this conversation got heated and loud rather quickly. Long story short we got out of there without injury or anyone spending the night in prison, but I was told I was not allowed to choose the bar the team would go to at the Society for Neuroscience meeting that year.

FLG: You’ll be taking to the stage at the Festival of Genomics this summer. For the crowd at the Pharmacogenomics stage, you’ll be presenting ‘Connecting opposite ends of the pipeline – how clinical trial pharmacogenetics can enable target ID in drug discovery’. That’s quite a lot to pack into 30 minutes. What are they main points you’re hoping to get across to people?

DS: I think most scientists are beginning to realize that the information generated at each end of the pipeline can, in many instances, be of great use to the other end- especially in the case of genetic information. But not all opportunities are equal. If we are going to try to reduce this to practice at this time we have to focus on the right areas. I’m hoping to give people a view into how Merck is trying to do this.

FLG: It looks like pharmaceutical companies are starting to increase their investment in genetics and incorporating genomic information into drug discovery and development. Improving success rate and making clinical trials much more efficient should help reduce the cost of drug development significantly. This is something that is already starting to take place, but there is still a long way to go before it is a consistent reality. From a drug development perspective, what would you say is the biggest challenge facing those who are looking to use a genomic approach?

DS: On a practical level, dealing with the sheer volume of information is a major concern. If you want to have a well-powered genetic study you need thousands of individuals, and whole genome sequencing data on that many people dwarfs what we could imagine even a few years ago. But big data are here to stay, and I think we are already getting a handle on this. On another level, the question of where to focus internal research and what to leave to the academic world isn’t quite clear. What will have the biggest payoff- PheWAS? Mendelian Randomization? WGS of large populations? Family studies on extreme phenotypes? We all have opinions on this, but we really don’t know which will result in the most therapeutics in the coming years.

FLG: As more and more ethics studies come out, it’s becoming clearer that patients support the use of their genotypic data for research purposes. Which is great, but there still seem to be some misgivings around allowing commercial organisations access. What can drug developers do to try help patients feel more comfortable in supporting their research?

DS: I think we have to make it clear that the end goal of the pharmaceutical industry is the same of that of the practitioners and patients: to develop therapeutics and get them to the people who need them. The more we understand the genetic factors in disease, the more we can focus our research on that area. In some ways this gets at the idea of personalized medicine; not everyone with a given disorder has exactly the same for of the disease, and they will not all respond to the same treatment. The best way to ensure that we are working on your form us the disease is to make sure you are in the genetic studies. And of course we need to let people know that they are anonymous in these studies- we are very strict about being compliant with all patient secrecy laws.

FLG: One of the comments I hear a lot in relation to the use of genetics and genomics from non-scientists is “If there was anything to it, drug companies would already be doing it”. It’s infuriating, but also shows how little people see beyond the political hype. It also suggests that there is a fundamental lack of understanding of the drug development process out here. Associating a genetic variant to a particular indication takes a lot of work to produce a lot of data. There is also no guarantee that it will be drugable. To help all of us who deal with this kind of question, what should we be telling people about how pharmaceutical companies are putting genetic and genomic data to use?

DS: I think we need to be clear about how much evidence there is that genetics can enable drug discovery (for example, the fact that the targets of successful drugs are quite frequently genes which have been associated with human disease or clinical phenotypes). When you pair this with the fact that we still have a vast amount to learn in human genetics and its relationship to disease, I think it is clear that this is the best way forward. Our best hope of finding therapeutics for autism, ALS, schizophrenia, cancer and a host of other diseases really is understand the disease pathophysiology and design treatments that get at the heart of the process.

FLG: The Festival line up was announced a few weeks back for the first time. Who are you most excited to see up on stage in Boston?

DS: Honestly it looks like a great line up. When I read through it I was surprised how many of the talks I wanted to go to!

FLG:Thank you very much for sharing your thoughts with us!

 

David will be speaking at this summer’s Festival of Genomics in Boston. 

More on these topics