Of Translation and Basic Research:
An Interview with Hugh Rosen

Professor Hugh Rosen, who arrived at The Scripps Research Institute (TSRI) about six months ago, recently spoke with News&Views staff Mika Ono and Jason Socrates Bardi. Rosen shares his thoughts on translational science—the application of basic science discoveries to the measurable enhancement of therapy—and describes his research program.


NEWS&VIEWS: We'd like to ask you both about translational science at TSRI and about the research of your lab. Let's start with the translational science.

ROSEN: The institutional approach to translational medicine is essentially in its infancy. One of the objects of my coming here was to augment the expertise so that we could have an informed institutional discussion on this topic and define a strategy.

A translational science program needs to be rigorously approached. It needs to be done in a way that builds on the unique strengths of TSRI and that adds measurable value to the institution while avoiding added risk. Scripps is a basic biomedical research institution and, as such, has a high standard to apply—pushing the boundaries of the scientific and medical fields.

NEWS&VIEWS: So, any translational science program here has to be compatible with the mission of the institution?

ROSEN: That's exactly right. We need to look at where and when it truly adds value to the institution. So I think we have to be responsible in how and where we use the resources in our labs in order to sustain them and also how we access resources within the institution.

There are a number of components of translational research that already exist within the institute. There is expertise within the Department of Molecular and Experimental Medicine. There is the General Clinical Research Center. What is less well developed is access to preclinical translational expertise.

In an institution like TSRI, the first thing that you look at is where the science is. If you don't get that right, you're not going to have any useful impact on the discussion about therapeutics. After you build a foundation, namely the fundamental science program, then over and above that, you can have self-sustaining scientists with the bandwidth to be able to contribute beyond the science program, to help the institution explore therapeutic possibilities.

NEWS&VIEWS: What role can a translational science program play in an academic institution?

ROSEN: Translational science can do a number of things for an institution. It can provide a forum in which modalities that may have an impact in therapeutics can be flagged and certain key high-value experiments, particularly preclinical experiments, can be done to strengthen the intellectual property surrounding those discoveries.

Some of these discoveries flowing out of Scripps may be mechanisms that can be tested in a proof-of-concept way by using agents or biologicals that already have a body of human safety data. Under those circumstances, a path to translation is direct and appropriate for an institution like Scripps.

There are other discoveries [that will require] introducing a novel molecule of unknown toxicity into humans, requiring a large body of preclinical data. This includes data on its pharmacology, its mechanism of action, its long-term safety and toxicities in a variety of preclinical animal tests. All of these are difficult studies to do. They can be tremendously time- and resource-consuming, and therefore very expensive.

NEWS&VIEWS: And I assume that other institutions are already set up to do this.

ROSEN: Those costs are generally associated with pharmaceutical or biotech research and development. These challenges are capital intensive and human resource intensive and I personally believe that they should not be done within the context of an academic institution, which should instead focus on its mission to further cutting-edge knowledge and understanding of science and the medicine.

In the past, TSRI discovered major therapeutic modalities affecting the lives of patients. The classic example is 2-Chloro-deoxyadenosine and the treatment of hematologic malignancies. However, the world in which that happened was different than today. We now live in an environment which is significantly—and I would argue justifiably—more tightly regulated so any clinical experiments involving an introduction of a new compound or biological into man falls under the direct review of the FDA [Food and Drug Administration]. This is an essential protection for patients, researchers, institutions, and the public at large. The burden of evidence needed to be able to achieve a safe introduction to man is very much higher than it was perhaps 20 years ago.

NEWS&VIEWS: Especially in light of several recent high-profile cases...

ROSEN: Exactly. So the philosophy behind an introduction into normal human volunteers or patients is "Thou shalt do no harm." The ethical boundaries are clearly the most important ones. You can't compromise on them.

NEWS&VIEWS: Given rigorous FDA and NIH [National Institutes of Health] guidelines in both clinical and preclinical studies, institutional review boards, and other safeguards, what is the role of the researcher in communicating the benefits of translational science?

ROSEN: I would argue that the most effective way to get our message across in the long run is by being able to convince the public at large that [translational science] is reasonable, safe, and beneficial to the goals of society. When mishaps have occurred, they have generated a tremendous suspicion about the motives of scientists and physician-scientists in the pursuit of these data. I would argue to you, therefore, that translational experimentation has to have a zero-tolerance approach to patient risk because even a single deleterious outcome to a patient or a volunteer is unacceptable and damaging. That is our goal and we take it seriously. Ultimately, we have to convince the public that translational science is worthwhile. Members of the lay public are not only the beneficiaries of our translation, but also are the taxpayers who, through the NIH and the various other federal funding agencies, are the source of most of the funding that drives our scientific experimentation in the United States.

NEWS&VIEWS: Let's talk about the research that you are doing at TSRI. You have been here for just over six months now. Did you bring a group with you?

ROSEN: One of the interesting things about moving from industry as I did is that you move alone. I didn't bring a group. In fact, I didn't even bring any cell lines or reagents. I have essentially started the program from scratch. On the first of July, I sat in this office on a borrowed chair with a borrowed little table and my lab footprint was empty, with the Michael McHeyzer-Williams lab way at the other end. It was absolutely empty. It was an interesting moment.

The focus of the lab is on understanding a novel mechanism of immunosuppression that I discovered in my previous lab, work that we published last year in Science. In this case, we used an approach that I call reverse pharmacology, where there was a compound with a biological effect through an unknown mechanism. Based on some of the structural homologies within the compound, we were able to generate a hypothesis that was predictive of its physiological mechanism of action.


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Professor Hugh Rosen is investigating a mechanism of immunosuppression and is contributing to a discussion of translational science at TSRI. Photo by Kevin Fung.