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.
NEWS&VIEWS: What's the particular physiological condition?
ROSEN: We focused on a family of receptors for a lipid that is produced
by platelets and by a variety of tissue cells called sphingosine 1-phosphate.
Sphingosine 1-phosphate acts on a family of receptors called the S1P receptors
or the "edg receptors," originally defined as endothelial differentiation
genes. They activate these receptors and regulate a range of physiological
functions that include cardiovascular function and blood pressure. We
showed that they control the recirculation of lymphocytes—which was
never understood before.
We found that these sphingosine 1-phosphate lipids or synthetic chemical
agonists of the S1P receptors are able to alter the trafficking of lymphocytes
in a reversible way. These are very potent. They act on receptors in the
low nanomolar and sub-nanomolar range. They lead to the misdirection of
lymphocytes.
Lymphocytes circulate around the body in order to mediate immunity and
mediate the bystander damage of tissues—whether it's a transplanted
tissue as in a rejection or damage to normal tissue as in autoimmunity.
This mechanism regulates the egress of lymphocytes from lymph nodes and,
as we show in a paper that we've just submitted for review, the egress
from thymus into the blood.
Lymphocytes normally come from two organs, the bone marrow and thymus,
then enter the bloodstream. They circulate through the blood to secondary
lymphoid organs—lymph nodes, Peyer's patch, the spleen. If they encounter
antigen in the secondary lymphoid organ, they begin to proliferate and
to undergo clonal expansion, producing various effector cells. These effector
cells leave the lymphoid organs and return to the blood, having acquired
the ability to enter the tissue spaces and remove what they recognize
as non-self. This could be a transplanted organ, a viral or a bacterial
antigen, or, in the case of autoimmune disease, normal tissue that has
broken tolerance and has become recognized as non-self.
We've discovered a couple of key steps are regulated by these sphingosine
1-phosphate receptors. There is a biological toggle switch—an on-off
switch—that is regulated as you activate these receptors. You essentially
shut off a switch and, as you activate these receptors, the lymphocytes
disappear in a reversible way from peripheral blood and you can protect
an animal or a person from transplant rejection and from autoimmune-mediated
tissue damage.
NEWS&VIEWS: At the same time, though, you are suppressing the immune
system.
ROSEN: In fact, you are. One of the reasons we are particularly interested
in this research topic is that it represents a mechanism of immunosuppression
that has the potential to be significantly less dangerous than other mechanisms
of immunosuppression.
Why do I say this? What are the other modalities of immunosuppression?
Corticosteroids not only suppress lymphocytes, but also lead to significant
reductions in function and number of myelomonocytic cells, neutrophils,
and monocytes. So a patient's ability to withstand bacterial or fungal
infection is compromised. In addition, corticosteroids cause significant
changes in metabolism. They are diabetogenic and cause significant loss
of bone mass, which can lead to osteoporosis and bone fractures.
Calcineurin inhibitors, like cyclosporin, are used for serious autoimmune
disease and for treatment of transplant rejection. They have a number
of mechanism-based toxicities including causing dose-dependent renal dysfunction
and hypertension.
Rapamycin and the TOR kinase inhibitors cause significant alternations
in blood lipids, some of which can cause acute heart attacks.
What we have here is a mechanism that can spare the use of these other
drugs that are potentially very toxic. Secondly, it impairs lymphocyte
recirculation, but doesn't impact on myelomonocytic cell function. So,
it should not cause enhanced bacterial and fungal infections, which would
be an advantage to patients. There are no metabolic consequences that
one knows of associated with this mechanism. It should, therefore, not
produce osteoporosis, pathologic fractures, or diabetes, nor should it
promote renal dysfunction or blood pressure changes.
NEWS&VIEWS: What would you guess the potential side effects to be?
ROSEN: One could guess that potential side effects would be those associated
with, for instance, the inability to clear a localized viral infection.
There is data in the literature showing that the systemic response to
a viremic delivery of antigen, in this case of LCMV in mice, is quantitatively
normal, but distributed differently. In other words, you get T-cells,
but the effector CD8 cells are largely restricted to the lymph nodes and
don't get into the periphery. We see the same thing for CD4 effector cells
in a paper that we've got coming out in the April 1 issue of Journal
of Immunology. You can mount responses to systemic infection, but
not necessarily in the right place.
One should always bear in mind that one would generally only use immunosuppressive
strategy in somebody who was seriously ill. It's not something one would
use for a disease that is self-limiting and non-disabling.
NEWS&VIEWS: What happens to the lymphocytes themselves? Are they
sequestered in the lymph nodes, and, if so, what happens to them there—do
they eventually go back into circulation?
ROSEN: Let's take it in two steps. What do we know? We know that cells
will accumulate acutely in lymph nodes. Lymph nodes in the mouse for instance
might increase in size by about 20 percent over the first two to three
days. By 14 days, these nodes have returned to normal size and appear
to maintain that normal size, so it doesn't seem to directly affect cell
fate in that sort of timeframe. In the long-run, we don't know what happens
to the fate of lymphocytes.
As you sequester cells in lymph nodes, you actually stop egress from
the thymus. In fact, in a paper that we have currently sent out for review,
we can actually stop export of cells from thymus by about 95% within two
hours. We can switch this mechanism on and off and the cells arrest in
the thymus.
Over time, the thymic cortex will thin and the medulla will become more
cellular as more mature T cells are behind the barrier blocking their
egress into blood. Do we understand the homeostatic mechanisms that come
into play to regulate thymic size and the feedback loops? I would argue
to you that we don't.
That becomes one of the future approaches that we would take. How do
you use evoked responses to small molecules to unlock or understand homeostatic
pathways that are very hard to discern in the steady state? By small molecules,
I mean chemical probes, small organic molecular probes of protein function
that allow one to measure and perturb the physiology in measurable ways—in
other words, chemical biology. That is one of the general approaches that
we like to take within the lab.
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