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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