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It
was no more than 20 years ago that biologists believed that cell
adhesion molecules were simply the glue of life, the stuff that served to hold cells and
ligaments and everything else together. Since then, however, understanding of these
molecules has gone through a paradigm shift. It is now known that they play roles in just
about every aspect of human biology-from the embryo, where they are crucial for tissue and
organ development, to the adult, where they act as traffic signals to direct the actions
of immune-system cells in wound-healing, inflammation, cancer, and even AIDS.
"A number
of companies have been formed around the idea of cell adhesion," says
Timothy A. Springer of Harvard Medical School. "There's a lot of interest in
the pharmaceutical industry in developing these molecules as targets." |
Today the study of cell adhesion
molecules has been transformed from a back-water of biology into one of the hottest fields
around. "There are probably more immunologists working on adhesive molecules,"
says Harvard Medical School biologist Timothy A. Springer, "than there are on T cell
receptors." Springer should know. His laboratory is responsible for defining many of
the cell adhesion molecules now known, and Springer himself came in at #12 in last fall's
Science Watch ranking of the highest-impact biomedical scientists between 1990 and 1996
(8[5]:1-2, September/October 1997). Springer published eight "blockbuster"
papers during that period, and has had a total of almost 90 papers with more than 100
citations apiece. Four of his papers published since 1986 have been cited over a thousand
times each, including his ultra-hot Nature paper, "Adhesion receptors of the immune
system," which by last June had been cited over 3,600 times.
Springer, 50, did his undergraduate work at
the University of California at Berkeley, where he majored in biochemistry, and then went
on to get a Ph.D. in 1976 at Harvard University in biochemistry and molecular biology. He
then spent a year at Cambridge University working in the laboratory of the Nobel laureate
Cesar Milstein. It was with Milstein, he says, that he first made monoclonal antibodies
and realized their "enormous potential for dissecting molecules on the cell
surface." In 1977, Springer joined the faculty at Harvard Medical School, where he is
now professor of pathology at the Center for Blood Research.
Springer
spoke to Science Watch
from his office at Harvard.
 Let's begin with
the obvious question. Your 1990 Nature paper has been cited an astronomical number of
times. Why?
Springer: Aside from simply
summarizing work in the field and providing a useful reference, I did synthesize a lot of
information. One aspect was classifying adhesion molecules in different families: the
immunoglobulin family, the integrin family, and the selectin family. I also talked about
their different functional roles-for example, their ability to mediate signaling. And I
discussed the relative sizes of these molecules, and how far apart cells were likely to be
when they interacted through them. Adhesion was very hot in immunology at the time, so the
paper received a lot of attention.
Can you give us an
overview of the different functions and families of cell adhesion molecules?
Springer: They fall into at
least two different classes, and it's not a clean division. There are the signaling
molecules, and the adhesive molecules-and in some cases you have adhesive molecules that
also signal. It's not so simple. Some molecules are certainly very important for mediating
adhesion. Take, for example, leukocyte interactions with endothelial cells in the
bloodstream. There you have leukocytes binding to endothelium, and the flow of the blood
actually exerts a very strong force on the adherent white blood cells, threatening to tear
them away from the adhesive contact with the endothelium. So the molecules must be able to
resist force. I would put the integrins, the selectins and the cadherins in the group that
resists force.
Selectins and integrins can act in the vasculature. Integrins and cadherins
are important throughout the body, probably for maintaining the integrity of
tissues-holding l the tissues together. Then there's another class of molecules that are
important in signaling, like CD2, LFA-3 or CD4 and CD8. And now we know that there's a
much larger group of molecules that are important in the immune system, acting as
receptor-ligand pairs. So you have FAS ligand; you have members of the TNF receptor family
that recognize cell surface ligands. You have multiple immunoglobulin family molecules
like CD28, and B7, which are important in co-stimulation. And you have CD40 on B cells
that binds to a CD40 ligand on T cells, which is also important in co-stimulation. A lot
of these molecules are delivering a signal, telling the cell that they're interacting with
the right kind of other cell. Often that signal doesn't do anything unless it's received
together with some other signals-for example, one coming from the T cell receptor.
Can you give us an
example of how this signaling works in the immune system?
Springer: It had been observed in vivo, for instance,
that leukocytes in the circulation come along to a site of inflammation and bind to the
vessel wall, at which point the first thing they do is roll along the wall in this very
odd kind of transient adhesive interaction. So they have to be bound through adhesion
molecules to the vessel wall. But the funny thing is that the zone of adhesive contact is
translated along the vessel wall. It actually provides a mechanism for the white blood
cell to survey the vessel lining for more signals. Next, the cells develop firm adhesion,
so they stop rolling. If you make a video of this, you can even see them change shape and
flatten out when they stop.
In 1990, Mike Lawrence and I showed in vitro that if we took purified
selectins and put them on the wall of a flow chamber, leukocytes would come in and bind,
and then they would start actually rolling along-just like in vivo. They did not pay
attention to an immunoglobulin superfamily member, ICAM-1, on the wall along with the
selectin. But we showed that if a chemoattractant is added to the solution being pumped
through this chamber, within seconds you can see the cells stop rolling as they bind
firmly to ICAM-1 on the substrate and then spread out. So we were able to recapitulate the
steps in vitro that had been seen in vivo, showing that they were mediated by specific
receptor-ligand pairs.
Is this multistep
signaling conserved with many different cellular signals?
Springer: It turns out that it's also seen in
lymphocytes, eosinophils, and monocytes, and it's been seen in vitro with endothelial
monolayers as well as purified molecules on the substrate. So it seems quite general that
selectins mediate rolling, and integrins can mediate firm adhesion-although certain
integrins can mediate both rolling and firm adhesion, so they're sort of intermediate
between the two.
We and others have extended it further and shown that one selectin molecule,
L-selectin, can mediate binding between leukocytes and the endothelium, or can mediate
leukocyte-leukocyte interactions. Other molecules, such as P-selectin and E-selectin, seem
to mediate slower rolling. And then you have VCAM and MAdCAM, which mediate slower rolling
and can also mediate firm adhesion, and so on.
The steps involved in leukocyte-endothelial binding and trans-endothelial
migration are pretty well worked out. What's currently missing is an appreciation of how
cells go from one location in a tissue to another-say, how T cells know to go to a T cell
zone; and how B cells know to go to a B cell zone in lymphoid tissues.  continued
Science
Watch®, March/April 1998, Vol. 9, No. 2
Citing URL: http://www.sciencewatch.com/march-april98/sw_march-april98_page3.htm |
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