| Timothy A. Springer: On A Roll
with Cell Adhesion Molecules |
|
 Back in 1992 there
was a flurry of press reports about the biotech industry taking on cell adhesion
molecules. What sparked the flurry, and has the situation cooled since then?
Springer: Part of what was being followed at that time
was the RGD peptides, which are short peptides that are the key recognition motif for many
integrins. Also, some work on rhinovirus had come out. It turns out that ICAM-1, the cell
adhesion molecule that I've mentioned, is a receptor for rhinovirus. It looked like an
interesting target for blocking replication of the cold virus. And the excitement hasn't
fallen off. There's still a lot of interest in the pharmaceutical industry in developing
these as targets. There's actually one that's a drug now-a monoclonal antibody to a
platelet integrin. It blocks platelets from accumulating at sites of clotting after a
myocardial infarction. It's been approved by the FDA.
High Impact Papers from Timothy
A. Springer
Published Since 1990
(Ranked by average
citations per year)
| Rank |
Paper |
Total
citations |
Average
cites per
year |
| 1 |
A. Springer, "Adhesion
receptors of the immune system," Nature, 346(6283):425-34, 1990. |
3,676 |
490 |
| 2 |
T.A.
Springer, "Traffic signals for lymphocyte recirculation and leukocyte
emigration: The multistep paradigm," Cell, 76(2):301-14, 1994. |
1,088 |
311 |
| 3 |
M.B.
Lawrence, T.A. Springer, "Leukocytes roll on a selectin at physiological flow
rates: Distinction from and prerequisite for adhesion through integrins," Cell,
65(5):859-73, 1991. |
810 |
125 |
| 4 |
M.S. Diamond,
et al., "ICAM-1 (Cd54): A counter-receptor for Mac-1 (Cd11B CD18,"
J. Cell. Biol., 111(6):3129-39, 1990. |
388 |
60 |
| 5 |
T.A.
Springer, "Cell adhesion: Sticky sugars for selectins," Nature,
349(6306):196-7, 1991. |
336 |
52 |
|
| SOURCE: ISI's Science
Indicators Database, 1990-June 1997 |
|
What would you now
consider the most important clinical targets for the research on cell adhesion molecules?
Springer: There are a number
of companies that have antibodies, or even small-molecule antagonists, in clinical trials
now. These include antibodies against integrins, for treatment of graft rejection, and for
prevention of traumatic stroke. Antagonists of selectins have been in clinical trials for
a condition in which clots occur in the lung. A number of companies have been formed
around the idea of adhesion. I founded a company called LeukoSite that has monoclonal
antibodies in clinical trials, and we're developing antagonists for chemoattractants, with
the idea of blocking leukocyte recruitment.
In general, the antibodies against integrins could be used either
acutely-say, to prevent shock or stroke, or to reverse some of the damage in stroke that
is leukocyte-mediated. They might be used in chronic conditions such as graft rejection,
or in diseases where there is a flare-up that needs to be treated promptly. We're also
interested in inflammatory bowel disease. One can certainly think of targeting other kinds
of autoimmune diseases, such as arthritis. The chemokine antagonists could also be used in
diseases like rheumatoid arthritis or asthma-something with a chronic immune component.
And, of course, there was a newspaper article last fall on the first results of a clinical
trial of ICAM-1 for treatment of the common cold.
Why a newspaper
article and not a journal article?
Springer: Because it was
presented as an abstract at a meeting. They gave it to patients who were dosed with
rhinovirus- I guess these were college students. You lock them up and see what happens. So
they gave ICAM-1 either at the same time as the rhinovirus or six hours after giving the
rhinovirus, and it definitely reduced symptoms but didn't completely prevent infection.
The patients reported that they felt better compared to the controls. The researchers used
an objective grading system, called nasal mucus weight, and the ICAM-1 seemed to reduce
nasal mucus weight by 50%.
What do you see as
the big open questions in the field as of early 1998?
Springer: One of the key
questions now is how adhesion molecules function in signaling, and how they must
coordinate with the cytoskeleton in order to do that. Many of the key players in that
interaction are still not known. I'm personally working on the structure of these
molecules, and I'm very interested in what we call inside-out signaling through integrins.
That's when the cell rapidly changes the adhesiveness of the integrin. It's a very rapid,
very dynamic way of regulating the adhesiveness of a cell.
The other way would be to, for example, change the density of the molecule at
the cell surface-obviously a slower and less dynamic way to do it. I'm interested in the
structure of integrins and the conformational changes that regulate this. Another
question: Now that we have really defined how leukocytes leave the vasculature, we have to
figure out what determines whereey go afterward. They take very specific pathways through
tissues, but what signals that? What adhesion molecules do leukocytes use as they migrate
through tissues? What are the guidance cues-are they the chemoattractants and their
receptors? There is a lot of work being done right now on discovering new chemoattractants
and new chemoattractant receptors.
Lately there's been
a lot of interest in cell adhesion molecules and AIDS. Could you explain the connection?
Springer: There is a set of traffic signals that helps
direct white blood cells to the correct place in the body-leaving the blood stream and
proceeding, for example, to the site of an inflammation. Some of these traffic signals are
adhesion molecules; some are chemoattractant receptors. A chemoattractant receptor on T
cells is identical to a receptor known as fusin, and the chemoattractant binding to that
receptor blocks the binding of HIV and blocks infection. That's a real hot target now in
the HIV field. It turns out there's another fusin, called CCR-5, and there are people who
are genetically deficient in CCR-5 who don't get HIV. And now there are pharmaceutical
companies trying to develop antagonists to block HIV infection using the receptor.
Now that the
competition in research on cell adhesion molecules has become so heated, has it changed
the way you work?
Springer: Yes. One way I've changed my approach is to try
to go off and discover some new aspect of this area. That's one reason I started working
on chemoattractants and their receptors recently. The field has lately become very crowded
and competitive.
Science
Watch®, March/April 1998, Vol. 9, No. 2
Citing URL: http://www.sciencewatch.com/march-april98/sw_march-april98_page4.htm |
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