Everyone knows that drugs cause side effects. While doctors and pharmacists counsel patients according to their personal medical histories, sometimes severe and even fatal side effects do result―and the problem is that they are usually unpredictable.
Termed idiosyncratic drug reactions, they are often completely unrelated to the primary action of the drug. Clinicians cannot caution patients about these adverse effects, due to their unpredictable nature .
Dr. Jack Uetrecht, professor of pharmacy and medicine at U of T, is conducting research on this very property of idiosyncratic drug reactions. Research in this field will help better characterize these reactions to caution against the use of specific medications among “at risk” populations. The Varsity sat down with Uetrecht and discussed his research and academic background.
The Varsity: Can you tell us a bit about your research?
Dr. Uetretcht: We’re trying to understand the mechanism of idiosyncratic drug reactions. For the pharmaceutical industry, this problem drives them nuts because these reactions are totally unpredictable. For patients, these types of reactions are extremely rare but often fatal. Drug companies don’t know that this will be a problem, at least until tens of thousands of patients have taken the drug. The problem is that you can’t study patients prospectively to see if they’ll have a reaction because they’re so rare. Also, if the patient already had a reaction, you can’t really study the events leading up to it.
TV: What kinds of studies are being conducted to investigate these reactions?
DU: You really need animal models to better understand this, but in order for this to be applicable, the mechanism of the drug reaction in animals must be the same as that in humans. One approach is to take lessons from immunologists who work on cancer. The problem is overcoming immune tolerance and I think that’s the same problem in idiosyncratic drug reactions. We’re trying to find out mechanisms of immunity and also develop mouse models of idiosyncratic drug reactions. As of yet, we have been challenged the most on the mouse model aspect but we have a few tricks up our sleeve.
TV: What is the specific mechanism by which these reactions occur?
DU: There’s a lot of controversy over what the basic mechanisms are, especially drug-induced liver toxicity. It may be [mediated by the immune system, but] others believe that it may involve mitochondrial mechanisms.
I think that these are immune-mediated. Even reactions which don’t have typical features of immune-mediated reactions, or don’t develop on rechallenge [when the medication is given a second time] still may be immune-mediated.
TV: Why did you decide to pursue a career in research?
DU: I’ve always been curious. I just like to figure out how things work. I went to university during the Vietnam era and I really did not want to go to Vietnam. I always wanted to be a chemist and so I went to grad school and got a PhD in chemistry. I really liked chemistry, but I wanted to use it to study biological systems. Towards the end of my graduate degree, I took a course in pharmacology and thought—this is pretty neat. I then wanted to apply my research to people and animals, and applied to medical school and veterinary school. I wanted to understand diseases in a better way. Med school was fun, but it was always research that I wanted to do.
TV: In medical school, did you like the undergraduate part better or your residency?
DU: I went to Ohio State and there we had the option of self-study or going to class. Let’s just say I’ve never played so much tennis in my life. It was a hoot. If you talk to medical school students now and ask them, “Are you having fun?” they would say, “What are you talking about?” You had to be disciplined because there was nobody making you do anything. It was fun. I didn’t enjoy my first-year residency. You got no sleep. We would work 36 hours straight and I don’t do well without sleep.
TV: Who was your mentor growing up?
DU: I didn’t really have one. My brothers were quite a bit older than I was. I grew up on a dairy farm in Ohio and I just sort of played around and discovered early on that I was not going to be a farmer. My brothers had trophies from taking animals to the fair—but you had to keep records of the feeding, etc. When I would compete, I would come in 11th out of 12 and that funny experience from when I was 10 or 12 years old really shifted everything, and I knew I did not want to be a farmer.
TV: What advice would you give to a student who is interested in research?
DU: Research is definitely not for everyone. I always tell people that research is the opposite of medicine. Medicine is very high-energy, learning a lot very quickly, but then with time, you find yourself seeing the same thing over and over again. There is a satisfaction in dealing with people, but it’s certainly not like House. Research [on the other hand] is slow. You can spend years and you may not make much progress, but you will not repeat the same mistakes. In research, you’re getting interesting information all the time. I think it’s more interesting, but you have to have an awful lot of patience in the beginning.
TV: How do you define a successful researcher?
DU: One of the nice things about research is that it takes all kinds. You can have someone who focuses on a very narrow technique and be very good at it or you could be like me and have a specific problem to work on and use any method to help solve that problem. The students [in my lab] are doing techniques I have never even done before. As a successful scientist, you should pick a problem that’s doable and be interested and curious enough about it and spend enough time thinking about it. It’s not a 9-to-5 [workday]—it sort of becomes a part of you. If you spend long enough at it, you will pick the right problem.
TV: What’s your biggest success?
DU: I hope that I’ve had some success in my family life, teaching and research, and I would be sad without any of those three.
TV: What do you do for fun?
DU: I enjoy my work—and that is part of it. I spend too much time doing it. I love to play tennis, stargaze, hike, canoe, eat, and drink nice wine.
TV: What’s your favourite food?
DU: That’s hard. I guess I shouldn’t eat this anymore because it’s almost endangered, but Chilean sea bass. It’s a very rich tasting fish. If you look at the analysis, it doesn’t have much fat in it and I don’t know what’s in it that gives it so much flavour.
TV: If you could have any profession outside of science, what would it be?
DU: That’s tough. As I said earlier, I really wanted to get out of going to Vietnam. I would’ve been a coastguard and been involved in the shipment of hazardous materials. I would also be some sort of teacher. I like teaching, but it did not come naturally to me.
TV: What’s your favourite place to travel?
DU: I really liked New Zealand. I wish the whole world had a population density like New Zealand. It’s a beautiful country.
TV: What do you to relax?
DU: Go up to the cottage and go canoeing or look at stars or go out in the woods or sit and watch the fire. I really like the outdoors but I also like to cook inside on the wood-burning stove.
