Building a Bridge from Basic Science to New Therapies:
An Interview with Patrick Griffin
Scripps Florida's Translational Research Institute is an unusual endeavor. While it is part of the nonprofit Scripps Research Institute, the program focuses on translational science—the conversion of basic science discoveries into practical applications—including aspects of drug discovery sometimes found at for-profit pharmaceutical companies. What are the advantages of such an approach? How does it fit with the larger Scripps Florida and Scripps California operations? How has the program evolved over time?
Mika Ono of News&Views speaks with Patrick Griffin, professor and director of the Translational Research Institute, about the effort and his own research at Scripps Florida.
News&Views: To begin, can you give an overview of the Translational Research Institute?
Patrick Griffin: The Translational Research Institute evolved out of our needs. When I came to Scripps Florida, I intended to spend about 50 percent of my time on my research program and, because of my background at Merck and at a small biotech company, the rest of my time starting one of the components within the new drug discovery program, drug metabolism and pharmacokinetics (DMPK). I came to Scripps Florida and set up that component within six or seven months.
But then, in short order, we were faced with making decisions on how to progress compounds further, beyond the initial stages of lead optimization. We realized we needed somebody to coordinate different functional areas within drug discovery, including medicinal chemistry, discovery biology, DMPK, lead identification and high throughput technology, informatics, and pharmacology. I picked the short straw and was nominated to oversee the effort, which we named the Translational Research Institute.
Ideally, the way the process works is that an independent investigator's research program, using proteomic and genomic tools, validates a target for a particular therapeutic area or identifies a new target. We then look at this from the drug discovery standpoint. In most cases, we would run a high throughput screening campaign on that target to look for chemical leads that would be useful for further evaluation and development. Then, the DMPK and the pharmacology components of drug discovery come into play, assuming that hits are found. We would look, for example, at the bioavailability and tissue distribution of a probe compound to see if in fact it is worth doing anything with that molecule. If not, then it has to be modified. The modified compounds are evaluated for efficacy and DMPK properties. We have the ability to apply medicinal chemistry approaches to optimize compounds and hopefully translate these initial findings into compounds that have potential for further preclinical development.
Now, we can only bring compounds so far, basically to the point of preclinical development, where we have interrogated a series of compounds and then picked the best one based on its on-target potency, its off-target profile, its drug metabolism profile, its pharmacokinetic profile, and its in vivo efficacy. At that point we would either look for a partner to further develop the compound or license it out.
News&Views: Are there indications the model is working?
Griffin: Yes. We've been successful despite the fact that we're a relatively small group. We have had several compounds licensed, we have had sponsored research programs around cancer and metabolic targets, and we are a critical component of the Scripps Molecular Library Screening Center. We started working on targets where we thought we had an advantage. Either we had a sense of what the competition was and still felt we could work within that space, for example our early-stage programs in diabetes and cholesterol modulation, or we saw important medical needs, for example Parkinson's, not focused on heavily by the pharmaceutical industry.
News&Views: How do you decide which areas to work on?
Griffin: In the beginning, our first priority was simply to recruit people in all our functional areas in drug discovery. We brought on Layton Smith, who is heading up the pharmacology group, Phil Grasso who is heading up the discovery biology area, and Mike Cameron, who has now taken over the DMPK operation. Bill Roush and Chris Liang lead the effort on recruiting medicinal chemists. Once we had our people in place, we began meeting to nominate drug targets to look at. We had to start somewhere, so we started with targets that people in our group were familiar with and programs that were validated clinically or with genetics that indicated some potential.
We started all the projects from scratch, cloning, protein expression, protein purification, and setting up biochemical and cellular assays. Medicinal chemistry started basically at the same time, working from published structures and developing a plan based on criteria we believed would be important for success.
We monitor the progress of these programs on a weekly basis, reviewing biological and DMPK data, and constantly reevaluating the best compounds in each chemical series we are working with. By doing this we are able to change direction week by week and avoid going down the path of developing compounds that have significant liabilities.
At Scripps Florida, there are still potential licensing opportunities if we stop work on a project because we have collected a lot of information—biochemical data on the target and the target's close family members, cell-based activity, phamacokinetic data, drug metabolism data, in vivo data… It's a pretty impressive package still worthy of a look by potential buyers. These compounds can fill a gap that currently exists in the industry, as shown by several recent early-stage licensing deals.
News&Views: It's the technology transfer people who are doing the business end of saying, "Look at what we have. Do you want it?"
Griffin: Right. We recently hired Peter Policastro as senior director of business development for Scripps Florida, and he's involved in both outreach to potential partners and licensors, and in the process of deciding which compounds to develop and how far to take them. [See article, "Snapshot: Peter Policastro"]
News&Views: The Translational Research Institute seems like an interesting mix because it's right in between the traditional academic and the traditional commercial spaces.
Griffin: Yes, there are academic institutions that venture into some aspects of drug development, but our program is unique in terms of its comprehensiveness, in terms of having all the components in place.
On the other hand, comparing our drug discovery program with big pharmaceutical companies, we work on a much smaller scale and we don't have a large therapeutic area focus. Large companies tend to be silos where they focus all their efforts on one particular target. It's hard to say whether that's good or bad. The Translational Research Institute also can bring in the application of proteomics and genomics to the process. In the pharmaceutical industry, proteomics and genomics efforts vary widely depending on the company.
Small biotech companies usually have only one or two parts needed for a drug discovery effort, rarely all of them. So, they contract out some of the testing, for example DMPK. The problem is that contracting out is often less productive. At Scripps Florida, we look at the majority of the compounds completely, with information on a compound's various properties coming in simultaneously. That's the only way to optimize multiple parameters.
So, a partnership with us could be a tremendous asset to such a small to mid-size company, say, that has focused heavily on protein therapeutics, but without a small molecule arm to its basic research. There is a whole niche of specialty pharma companies focusing in on one or two areas. When they have a compound that's either in late-stage development or on the market, they have to ask: "What are we going to do next?" "What are the next targets we're going to work on?" These firms usually don't have big research arms, and it's difficult to manage different contractors to get needed information. We could be a perfect match.
There's also potential to partner with other academic programs that are spearheading what are essentially drug discovery programs within research groups, for example focused on a Third World disease or another topic away from the mainstream. Again, we're ideal collaborators to add value and hopefully convert some of these exploratory research programs into therapeutic potential.
News&Views: So, one real advantage of being outside of a pharmaceutical company is that you can be more exploratory, and you can do research that isn't necessarily profit-driven.
Griffin: Right. That's why in our target selection we're focusing on things like Parkinson's. Companies are working on PD, but it's not on the radar screen of most large pharmaceutical companies. We can bring forward something that is useful and fills in a missing piece of the puzzle, the next generation products for development.
News&Views: So, not only are you positioned in a space between academics and business, you're also drawing potential samples from all sides.
Griffin: Yes. Scripps Florida is one of the centers in the National Institutes of Health Molecular Libraries Screening Centers Network, so part of our operation is looking at expanding our compound library. There might be a case where we see an available compound and know we can modify it quickly and spin it back out.
We're hoping that as the academic arm grows at Scripps Florida as space becomes available, new researchers will come in with expertise in new therapeutic areas. We have a neurobiology and a cancer focus right now. The opportunities for translational research are going to increase as the site grows.
News&Views: How is your own research?
Griffin: It's coming along really well. I've been lucky to get good people. Within a year of being in this building, we have one paper out, two in press, and several in the works, and we've submitted a RO1 grant application. The work has evolved to a point where it's actually telling a good story, so I'm hopeful we can make an impact.
News&Views: Could you describe your research?
Griffin: By training I am a protein chemist. Coming to Scripps Florida, I took some of the mature research I was familiar with at Merck, looking at target class proteins called nuclear receptors and developing some mass spectrometry-based technologies to look at protein dynamics. We're using these technologies to study ligand interaction and protein-protein interactions.
These targets are activated by ligands. Small molecules come in and induce a change in the dynamics of the protein, and that effects protein-protein interactions. That's essentially the beginning of a signal. We're basically using a chemical biology approach, taking different chemical scaffolds, looking at the effects they have on the receptor, on protein-protein interactions, and then on downstream events. The downstream effects have been studied quite a bit, but the mechanism of activation has not been looked at in great detail and that's where we are focused.
Scripps Florida has helped my research program, in particular sharing an office with John Hogenesch. He suggested using genomic tools to probe a lot of these things we're looking at. That has really strengthened the program. Being around these tools and having people that understand how they work is really key.
News&Views: Do you have much interaction with La Jolla faculty?
Griffin: Yes. I interact with Hugh Rosen, through the Molecular Screening Center. I maintain ties with John Yates, but not on a research basis—John and I were graduate students together at the University of Virginia, then postdocs together at Cal Tech. We have had some interaction with Ben Cravatt on the drug discovery side, taking some compounds he has and looking at them. And the drug discovery group is interacting with Jeff Kelly as well.
In addition, I have given seminars on aspects of the Translational Research Institute, and we have a lot of interest by various groups. We're at various stages of figuring out whether to collaborate and, if so, the best way to do that.
News&Views: It sounds like there's been a lot of flexibility in terms of changing and responding to new input.
Griffin: Yes. We've tried. We've been constantly reevaluating and making sure what we're doing makes sense, modifying when necessary. You don't want to put a square peg in a round hole.
Send comments to: mikaono[at]scripps.edu