March 29, 2011
James Mckerrow, MD, PhD is the director of the Sandler Center for Drug Discovery and Vice-Chair for Research Affairs at the University of California, San Francisco (UCSF). His group utilizes techniques from a variety of disciplines to develop new drugs for parasitic neglected diseases to clinic trails. As CDD's first major customer, Dr. McKerrow guided us in our early days and introduced us to the Gates Foundation, making him perfect for our first CDD Spotlight.
"I think the challenge now, which you've hinted at, will be to better coordinate the efforts of the groups around the world."
Interviewed by Barry Bunin, PhD, CEO, Collaborative Drug Discovery, Inc.
Listen to the full audio
[audio src="/wp-content/uploads/2011/03/McKerrow-Spotlight.mp3"]
Edited Interview Transcript
Barry Bunin
My first question is just how someone who's an MD got interested and decided to do research because actually my family is all MDs. My dad's a family physician practicing doctor, my grandpa, all my uncles, and even my brother has a free clinic in LA and they're all seeing patients and you're doing research so…
Jim Mckerrow
Yes.
Barry Bunin
I'm just kind of curious how it came to be for you.
Jim Mckerrow
Sure. Well we can start there and that's an easy answer because there's actually more to the story. Actually I also have a PhD but I'm not an MD-PhD. I went to graduate school first in biochemistry at UCSD to get my PhD after college and my thesis project was on peptide chemistry, so I was really more of a chemist with a biological bent. Following graduate school, I had intended to do a postdoctoral fellowship in x-ray crystallography - but for a variety of reasons, mainly because I was mostly interested in applying biochemistry and structural biology technology to issues of human health and disease, I was talked into going to medical school to get a broader perspective on clinical issues and human disease. So I did the weird thing of instead of doing a postdoc, I went to medical school to get my MD. So I was not really an MD to begin with, I was actually a PhD scientist to begin with. And when I went to medical school, I had all the intention of getting back to a lab as quickly as possible - but after I finished medical school, my medical school advisor said, "Well no, society has just invested all of this money in your medical education, you need to do postgraduate training in medicine," so I did an internship in internal medicine and I did a residency in pathology. I did some elective work during my residency in infectious disease, which is one of the reasons I got interested in that area. And then following my pathology residency, I finally went back and did a postdoc with Zena Werb at UCSF working on protease biochemistry and cell biology. So the answer to why I'm into research is actually pretty easy, that's where I began.
Barry Bunin
Interesting. I read a New York Times interview with you awhile back where it mentioned that you'd done some cancer research and so I’m familiar with your expertise in peptide chemistry and infectious disease. I'm also interested to hear how you initially got tenure at a real respected school like UCSF. Where did your own research start relative to where it is today?
Jim Mckerrow
Well while I was my doing my postdoc with Zena I was working on protease biochemistry. Her lab focus was on the role of proteases in macrophage cell function and innate immunity, how do macrophages move through tissue, how do they grade material they phagocytose, et cetera. And while I was working on those projects, I went to a seminar given by a parasitologist who's very well known in the Bay Area, actually internationally. His name is Don Heyneman. He is an epidemiologist who worked a lot in Africa on parasitic diseases and I was just stunned by his lecture. He was first a really stellar speaker, but he also talked about this organism which goes right through your skin and gets in your bloodstream and then develops, Here I had been looking at how single cells migrate through skin and he was saying, "Well there's this organism that has a thousand cells and it can go right through skin," and I thought: Hmm, sounds like a protease must be involved there, and so that's when I got hooked on the parasite protease side of things. And so when I finished my postdoc, I began working on how the schistosome parasite goes through skin and that was an initial interest, and still is an interest of my lab. That in turn developed into a broader interest in parasitic infections and the pathogenesis of parasitic diseases. And along the way, the cancer side of it was because I had done a lot of work on proteases and because tumor cells, as well as the inflammatory cell response to tumors, generate a lot of proteolytic activity which allows tumors to invade and metastasize. I continued to be part of a program project group at UCSF with Zena, Lisa Coussens, Charlie Craik, Matt Bogyo from Stanford, and Jon Ellman from Berkeley looking at the role of proteases in cancer. There were actually some interesting parallels between the use of proteases by parasitic organisms to invade their host or to acquire nutrients from their host and tumor cell invasion of surrounding tissue and metastasis.
Barry Bunin
So within the - - your current area of focus with the parasitic diseases, what's changed and what's evolved in your own group's research over time and also for the field as a whole perhaps there's some parallels…
Jim Mckerrow
Yeah, taking first the local thing, my initial interest was in the basic biology of parasitic infections - host invasion, residence in the host, acquisition of nutrients, evasion of the host immune response - and my focus, as I said, was primarily on the role of proteases in these activities. But along the way, we began to broaden out from just looking at the schistosome parasite to other major neglected diseases, These would be diseases caused by parasites which effect hundreds of millions of people worldwide but for which there is little if any commercial interest in the pharmaceutical industry because these are diseases of poor people and poor regions of the world. Included in this group be diseases caused by single cell organisms like African trypanosomiasis; Chagas disease in Latin America, leishmaniasis, which is pretty much throughout the tropical world; amoebiasis, the diarrheal disease, malaria. So our focus, our interest was in the role of proteases in these different diseases. But particularly as we began look at Chagas disease, which is caused by a single cell trypanosome, the major protease of that organism looked to be an exploitable drug target. Using my medical background, it was pretty clear that the current therapy for Chagas disease was inadequate, mostly due to the fact that there are severe side effects to current drugs and they have to be taken for 60-120 days! And so a kernel of thought began which was: Hey, maybe we can at least come up with a new direction for drugs to treat Chagas disease by targeting this protease. And so beginning in the late 1980s/early 1990s, I brought together a group of researchers from both UCSF and outside who covered a number of different areas ranging from chemistry with George Kenyon at UCSF and Bill Roush (who at that time was at University of Indiana), computer-based drug design with Fred Cohen and Tack Kuntz (and more recently Brian Shoichet), and protease chemistry with Charlie Craik, and parasitology with Phil Rosenthal. This group began asking the specific question: Can we identify protease inhibitors that might be leads for drugs? This work was supported primarily by the NIH. And then in 2002, as I was presenting some of this work at a local seminar, I was approached Herb and Marion Sandler who had a foundation, and who commented, “we think what you're doing is just the kind of research that we consider important." And to make a long story short, they gave a substantial ongoing gift to the University to start what's now called the Sandler Center for Drug Discovery. The mission of the Center was to expand what we had been doing into a real drug discovery and development pipeline. While it was big research challenge, it was something that we felt we could do and it was the logical evolution of our research. A lot of what we do now is directed towards drug discovery and development. As a result of their gift and also continued support from the NIH (and more recently The Gates Foundation), we've been able to bring in people from industry to UCSF to facilitate the drug development process. Industry was where the expertise was, so the Center at UCSF is now kind of a fusion between academic expertise and industrial expertise.
Barry Bunin
Thank you. So just turning a little toward CDD, how did you work with data and collaborations before CDD, and related why did your lab adopt CDD; what's been the value there?
Jim Mckerrow
Right, initially when we began looking at potential targets for drug discovery and development, our focus was primarily on one type of target, cysteine proteases. At the time, a decade or more ago, the number of inhibitors that were available from any source, whether it be academic or biotech was pretty limited, particularly if we put the criteria on that these have to be inhibitors which don't just hit the enzyme but also can be used in tissue culture, can be used in animal models, have good solubility; reasonable pharmacokinetics and safety, there weren't very many. And so initially the data that we collected was something where anyone of us would remember what we had tested in the last six months. There wasn't a need for database. But over the last decade as our efforts ramped up and we moved into other disease areas, as we developed high throughput screening assays where we could screen compounds in HTS/HCS microtiter format against biochemical targets or the actual parasites, the amount of data that came out of those expanded screens was beyond anything that any individual could remember. It really required a database that was searchable and easy to enter data into, and that's when we began to interface with CDD because you guys had exactly what we needed (italics added). This was part of an evolution as we transitioned from an academic consortium, a program project kind of group, into a more of a biotech fusion where we're working more like a company. We needed an “industrial strength” database.
Barry Bunin
Great. I may come back to CDD a little later. In terms of the research, and it's both within your own lab and with all these collaborators, you mentioned Bill Roush, and I'd worked actually with Jim Palmer at Celera where one of your vinyl sulfones was discovered, but I'm just curious about some of the more things outside the ordinary day-to-day end science where there was interesting discovery or a ah-ha moment or two, I like to call it, in terms of the development of the programs where something was particularly exciting or maybe even just unexpected in terms of a new development that's affected you or your collaborators.
Jim Mckerrow
Early on in our research when we were still primarily interested in the basic science of the enzymes these organisms produced, what role they might play, what function they might have for the organisms, One of the initial “ah-ha” moments that we had was when we began to look at some inhibitors of a protease from Trypanosoma cruzi and asked: Let’s see if we can use these inhibitors as chemical tools to dissect function, so let's expose the organisms themselves to very specific inhibitors and maybe we'll see that they can't eat or they can't process protein or something doesn't go on their surface, and what we found was that the inhibitors actually killed the organisms in fairly low concentrations and we thought: “That’s pretty amazing”. And I think that is what encouraged us to begin to think about targeting this enzyme, not just as a way to understand its role in the parasites' cell biology, but as a target for drug development. The class of enzymes we were looking at were cysteine proteases, which at that time were not of major interest in drug discovery. Serine proteases were of great interest because of their role in hemostasis and complement fixation. A lot of companies were looking at serine proteases and also metalloproteases because of their role in cancer. There were few people working on cysteine proteases, so I think the second surprising discovery that we made was the fact that if you look at invertebrates, cysteine proteases of the clan C1 or papain family actually fulfilled the roles that serine proteases play in vertebrates. The previous perception was that cysteine proteases of this family only had a role in lysosomes and intracellular protein degradation and therefore were pretty boring. But when we began to look at cysteine proteases in these invertebrates, what we found was: wow, they're actually secreted. They actually function at pHs other than acidic. They can function a physiologic pH. They can play a lot of different roles, and I think that that discovery was a major eye opener for us.
Barry Bunin
Sticking with the Chagas disease area, you'd mentioned the treatment is woefully inadequate, 120 days. Are there developments either from the research side or the patient side which suggests that things can or will get better in the future?
Jim Mckerrow
If this was cholesterol or seasonal allergy or Alzheimer's, then there'd be a lot of different companies with a lot of resources trying to come up with something better. For Chagas disease, there isn't. And so the people that are working on it are scattered throughout the world. They have limited resources. There are some people in countries like Brazil who are doing some research or Argentina. There are a few labs in Europe and the United States. There just aren't that many people working in this area and so discoveries/advances don’t come very quickly, and that's one of the reasons we focused on this area because we thought: Here is a place where we could really make an impact. We actually have a protease inhibitor that has now been deemed a drug candidate by the FDA and we have support for GMP synthesis and a way forward towards a phase one trial. So that's something which we're really proud of because it indicates that: Yeah, you can actually get that far outside of the industrial sector. The other groups who are involved in trying to come up with something new for this disease are international virtual agencies. The one that's trying to do the most is called Drugs for Neglected Diseases Initiative, or DNDI. They're out of Geneva, and they're about 60 percent funded by The Gates Foundation, so they also get most of their money from philanthropy. They are trying to take drugs from industrial sources that were used antifungals, particularly a drug called Posaconazole from I believe it's Sanofi-aventis and a drug called Ravuconazole, which is very similar azole derivative from Eisai in Japan and seeing whether those drugs can be effective against Chagas disease in a clinical trials. So that's another major effort that's going on. Our efforts have been more in terms of taking things from discovery, validating the target, and then moving down the pipeline.
Barry Bunin
So you mentioned not too many labs are working in this space and those that are, like yourself, are working virtually with biotechs, with pharmas, with others UCSF or other universities and one of the things that CDD's been focused is also helping to work with virtual groups, work with perhaps more agile organizations and collaborations and some folks may not know it but you're our first real major customer, so you've seen this from the beginning.
Jim Mckerrow
Right.
Barry Bunin
Obviously we're ongoing and evolving continuously, but how has it played out for your own lab and for others as you've seen CDD develop over the years and what do you see as the next challenges for us as well?
Jim Mckerrow
Well I think that the evolution of CDD, particularly for us, is that the organization, the company has been very receptive to developing the types of tools that we need like being able to separate open source data from IP sensitive data. I think the challenge now, which you've hinted at, will be to better coordinate the efforts of the groups around the world that are in this arena because the funding is limited. One can't expect each of these groups to independently do what they want to do. It has to be more cooperative and collaborative and so the challenge is going to be: How do you coordinate efforts when you're dealing with different entities from different academic centers, biotech, industry, and international agencies, each of which may be under regulation and restraint by the funding agencies, venture capital, or stockholders that have supported them so far. That is going to be the next challenge.
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