February 15, 2012
Mike Pollastri, PhD, Associate Professor in the Department of Chemistry and Chemical Biology at Northeastern. Previously he was a medicinal chemist at Pfizer.
"...being able to basically have a one-stop shop for people in my group to go and actually look for their data across multiple projects and also to have my collaborators to be able to just sort of access in an easy way the data that's relevant to their projects without making it a really sort of arduous search to do. I mean basically it's almost like the Project's concept was designed for projects - for labs like mine"
Interviewed by Barry Bunin, PhD, CEO, Collaborative Drug Discovery, Inc.
Listen to the Full Audio
[audio src="/wp-content/uploads/2020/12/Mike-Pollastri-Spotlight.mp3"]
Edited Interview Transcript
Barry Bunin
We're doing the CDS spotlight to give more color to the research done by various interesting collaborators. I also thought you'd be interesting because you worked in industry as well as academia. So maybe just start broadly and tell me about your research both now and a little bit in the past.
Michael Pollastri
Sure. I worked with Pfizer for about nine years working in the area of medicinal chemistry, hit-to-lead and lead optimization, and I left in 2007 to start my academic career. Basically when I was at Pfizer, I worked in areas such as kinase medicinal chemistry, G-protein coupled receptor medicinal chemistry and phosphodiesterases, as well as some chemical technology projects. And then when I left, I wanted to apply these industrial med chem approaches to diseases where that is not frequently applied in the industry, so I work on neglected diseases. I work in medicinal chemistry on targets that are important for diseases like African sleeping sickness and Chagas disease and leishmaniasis. These are basically infectious diseases caused by parasites, and they affect pretty much the poorest parts of the world, and as such, there is no money to be made in selling drugs to folks who have these diseases, and so the industry generally doesn't put any money into it because they could never recoup their R&D costs. So I felt as though going to a not-for-profit environment, such as academia, would be a good place for us to actually do this kind of work where there is no pressure to recover our costs and make a profit. So our research is focused on what we call target repurposing. What we do is we take enzymes that exist in parasites and match them to targets that have been pursued in humans for other indications. So for example, we're funded by the NIH to do a project where we look for inhibitors of phosphodiesterase enzymes in parasites such as Trypanosoma brucei, which causes sleeping sickness, and these enzymes are very similar to the phosphodiesterase enzymes in humans made popular by drugs like Viagra and Levitra that are human PDE5 inhibitors. And so what we're doing is we're taking the historic medicinal chemistry knowledge and repurposing it and directing it towards finding new drugs that will inhibit the parasite enzymes which have been linked to or shown to be essential to the parasites. So if you block these enzymes, it kills them. So that's the idea: it's to basically take all this historical medicinal chemistry knowledge and redirect it towards sort of leapfrogging into optimization projects against parasites.
Barry Bunin
What's the end goal of your research, both the short-term, more modest goals and maybe the long-term, more audacious goals, and how do you plan on getting there most expediently?
Michael Pollastri
Our longest-term goal is to develop a drug for sleeping sickness or Chagas disease or leishmaniasis. Of course, I'm not naive to think that it's going to be easy. In fact, I knew a lot of people at Pfizer who worked their whole careers without actually getting anything into the clinic. It's a difficult process, but nonetheless, that's, of course, our goal. At the very least, the near-term objective is to produce potent compounds that are selective for parasite targets over human targets so that development organizations, such as Drugs for Neglected Disease Initiative, may be interested in picking them up as either late-stage optimization projects or early-stage development projects because organizations like DNDi have the wherewithal and the mandate to take basically compounds or drugs -- potential drugs from the discovery side and bridge the gap into possibly developing new therapeutics. So our goal is to develop chemical matter that can be carried along -- chemical matter that's attractive to others to carry along into development. Our goal is not ourselves to go through the full development process. Our goal is to do the discovery side and then partner with people to get things hopefully to the clinic.
Barry Bunin
Great. So how do you use CDD and why?
Michael Pollastri
Right. So I'm a synthetic chemist, and I am not a biologist. And all the collaborations I have, all these projects are in various aspects of parasitology, and I don't know anything about parasitology. I partner with parasitologists all over the world, Europe, in the U.S., and hopefully some overseas and China as well, and India, trying to basically go where the expertise is. And so we call it our distributed drug discovery model, collaborate with experts and use various areas of parasitology or, I don't know, computational chemistry or wherever our gap happens to be. There are two options to share data as far as I'm concerned. One is by emailing spreadsheets around, which is clearly not tenable, and the other is CDD. And so that's why we use it. We use it for the purpose of registering compounds that we make in our lab and then mapping collaborator's data to those compounds (in our private CDD Vault). Our eventual goal is every time we publish a paper with compounds with data against these parasitic diseases, is to make these structures and the data publicly available through CDD. And because CDD has a track record of this kind of practice (handling private, collaborative, and public data), such as with the TB and malaria sets from Novartis and from Glaxo and others, it seems like the neglected disease community is looking to CDD for this, and so we figured that it makes a lot of sense for us to be putting our data there. That's our end goal also is to share data as much as we can.
Barry Bunin
So one of the things we think about at CDD is how to make what we're doing equally applicable for neglected disease as well as commercial R&D, and so maybe just talk about both, either for CDD or other technologies or even just the process, how much or which aspects are the same for neglected disease and commercial area, and what, if anything, is different in terms of the science and how you would work with those.
Michael Pollastri
We are trying to make it so that there is no difference. I'm of the opinion that the targets in these parasites is no more challenging than the targets in humans, and so while the problems are slightly different with respect to how do we get drugs where they need to go in terms of in the host or getting across the parasite cell membranes or into various tissues in the host where the parasite's living. As far as I'm concerned, there's not a whole lot of difference in how we optimize these from a medicinal chemistry standpoint, so the kinds of data that we would collect routinely, such as in a project at Pfizer, is the kind of data that we would collect here. So I don't see a whole lot of difference between the two. In fact, we're trying to make sure that we're not trying to like strip down the drug discovery process. We're trying to get all the data that we need to get to make good med chem decisions, and so I don't see any difference between what we would need for an industrial, for-profit indication and for this, other than the (selective) data sharing. The data sharing is a key aspect, right, because there have to be a lot of groups working all over the place, not just ours, in trying to find drugs for these bugs. And the more that we can cross share data the better -- the more likely it is that we're going to be successful.
Barry Bunin
Talk about an aha moment in your career in science that was kind of intriguing and perhaps interesting potentially to others as well, but at least something that was an aha moment or interesting to you.
Michael Pollastri
For me, one thing that was sort of a moment for me was when I first decided I was going to leave Pfizer. I was starting to think about these other kinds of projects was just amazed with how wide open the area of neglected disease or parasitic disease drug discovery was because I was coming across potential targets and potential projects that seemed really obvious to tackle. And because of no one really focusing on it at all, the field was wide open, and there aren't that many people who are focused on this area, and for me, what this meant for me was it's not so much a scientific "aha" moment, but more of a personal focus kind of moment which is I sort of view what we're doing as a, I don't know, sort of a moral directive. I feel like we're working on the kinds of diseases that affect the poorest in the world that have no one fighting for them, and here we are with all these targets laid out that seem like really obvious drug discovery approaches that nobody's, or very few people, are working on. And so it seems to me to be sort of a moral imperative, and that's really what turned me onto this and has gotten me to be really passionate about it because like I say, it's basically taking the tools that we already know how to use and refocusing them in a direction where they aren't -- haven't been focused before. That was a very exciting moment. I remember that moment sitting at my dining room table realizing I can't believe that no one's done this. This is just so clear.
Barry Bunin
I mean that's the emotion that drives people in their own research. And then thinking about it… Obviously, people are most focused on their own research, as they should be, but just outside of your own research, is there any other fascinating development or study that you've seen that may be of a broad interest to others in the research community?
Michael Pollastri
I just read an article in, it was either in Science or Nature, about the pros and cons of different approaches to drug discovery. There's the diversity-oriented synthesis approaches and the fragment based approaches. It was almost like a point/counterpoint kind of discussion. It was diversity-oriented synthesis which is more in line with really historical kind of traditional drug discovery of high throughput screening and follow-up, comparing and contrasting that with fragment screening, and which one is the best new ways to go forward. I feel like the high throughput screening paradigm it's come and it's moved along, and it's certainly evolved quite a bit. And the fragment screening paradigm is now sort of coming to fruition, and now we're able to start comparing between the two technologies as ways to start new projects. And I'm really interested actually to see where the thinking in this direction is going to go. I think that that paper is going to sort of start some discussions about whether… Everyone has been looking at fragment screening as sort of a niche, like it's a specialized skill set and it's not really applicable to everybody, but I'm not so sure that's the case. So I was interested in that in that particular article.
Barry Bunin
One of the things we do at CDD is user testing to ensure that the investment and the technology meets the needs of researchers, at least as much as possible, and we were doing this with you, I recall, recently around the new collaborative capabilities. We're calling it Projects within CDD Vaults, and we asked you a question: "How would you use Projects?" And I remember the quote because we wrote it on our whiteboard afterwards, which was, "How wouldn't I use Projects." Maybe talk a little bit about how you envision the new collaborative capabilities being used for your collaborations around the world over time.
Michael Pollastri
Well for me, it became very clear that while the original Vault concept was really a good start, that I had multiple collaborations against multiple parasites with multiple collaborators. And I certainly wasn't ready to necessarily share all my data between all of them. And so as a result it was really clunky to move data around and get stuff. So to get compounds registered and then get data uploaded and this and that, we had to do searches in multiple Vaults, and it was just a total pain. And so what I meant was in terms of how wouldn't I use it, the idea of being able to basically have a one-stop shop for people in my group to go and actually look for their data across multiple projects and also to have my collaborators to be able to just sort of access in an easy way the data that's relevant to their projects without making it a really sort of arduous search to do. I mean basically it's almost like the Project's concept was designed for projects - for labs like mine which is sort of like the hub of the hub-and-spoke kind of model, which is really what we are, right? We have a synthesis hub or a med chem hub, and we sort of link out on spokes on the wheel to different parasites and different targets, and that's exactly what this enables. I was really fired up when that came out.
Barry Bunin
Great. Before you were using CDD, how did you manage your data or collaborations, either internally or externally?
Michael Pollastri
I'm ashamed to say that it was by a combination of spreadsheets and PowerPoint slides. We would have evergreen files that we would basically email back and forth, so I would send the latest version of an Excel file that had screening data, and biologists would add the data to that file and email it back, and we'd both have a copy of it. It was totally clunky, and the worst thing was that it was really hard to link up structures with that data. ChemDraw for Excel sometimes isn't the most reliable and that's the way we would do it. It was killing me because having come from Pfizer, which has this incredible database infrastructure, it was hard to go back to this idea of sharing stuff back and forth by file iterations. It just wore me out. I had used the IDBS system in a previous life, and occasionally I would get access to look at data, but it was really very clunky, and I didn't have any interest in working on something that was big and clunky, nor did I want to set up a database where I had to manage my database in terms of infrastructure. I didn't want to have to have a server that I would have to maintain, and as a result, basically every IT solution I have in my lab, my electronic notebooks, my chemical inventory system and my database for chemical structures and data, they're all Cloud-based. So I'm all about this software is a service kind of model because again, this sort of goes with my whole mentality of let the experts do what they're expert at, so that I can focus on what I'm expert at. So whether it be biology versus comp chem versus chemistry, for me to not have to think about managing a database and knowing anything about Oracle except how to spell it, that's, for me, exactly what I need.
Barry Bunin
I think that's the perfect note to end this on, so we're going to wrap it up, and thank you for the profile.
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