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                                                                                MEDICINE, Page 62

The Glue of Life


By manipulating the adhesiveness of cells, scientists hope to
stop the spread of cancer, cure arthritis and develop a new
class of therapies

By DICK THOMPSON/LA JOLLA


    If living cells didn't have a fondness for sticking
together, we would all be colorful gobs of jelly oozing all over
the floor. Fortunately, cells hold to a basic biological premise
that stickiness is desirable for form and essential for
function. They violate this premise at our peril. When cells
become either too sticky or too slippery, arteries can get
clogged, cancer cells can skate around the body, and
inflammation can turn subversive. Researchers have long believed
that if they could somehow manipulate stickiness, they would
have a formidable new set of tools for healing.

    Now, after decades of frustration and obscurity, the world
of adhesion science is beginning to fulfill its promise.
Researchers who look at many diseases as a failure of stickiness
are designing both antisticky drugs and Super Glue-like drugs
to treat a range of disorders, including heart disease,
transplant rejection, stroke, arthritis, shock and cancer.
Michael Gimbrone Jr., head of vascular research at Harvard
Medical School, predicts "a whole new generation of therapeutic
interventions." Several drugs are now being tried on humans, and
early next year the first of them -- a gel that spurs wound
healing -- will enter the final U.S. government approval
process.

    Stickiness is central to almost all biological processes.
Cells are able to form organs and function as a unit thanks to
a fascinating category of complex glues they secrete known as
extracellular matrix. Securing cells in their matrix are
Velcro-like patches called cellular-adhesion molecules (CAMs),
which are present on every cell except red blood cells. These
cellular glues not only hold things together but also play a
vital role in growth, fetal development, repair of damaged
tissue and elimination of noxious invaders.

    But when cellular glues become too sticky or fail to hold,
the outcome is often disastrous. In cancer, for instance,
advancing tumors often secrete an enzyme that chews up their
matrix, freeing malignant cells to leak into the bloodstream.
Some inevitably stick and pro liferate at sites elsewhere in the
body. Thus the lethal process of metastasis may be viewed as a
breakdown in stickiness.

    At the opposite end of the spectrum are inflammatory
diseases like arthritis and multiple sclerosis, in which things
have got a bit too sticky. Normally, inflammation is part of
the healing process. At a wound site, for example, chemical
signals prompt the cells of nearby blood vessels to produce more
CAMs, turning the vessels into a kind of biological flypaper
that attracts platelets, leukocytes and other repair cells to
the scene of destruction. Once healing is under way, the
signals subside so the vessels lose their stickiness and
inflammation recedes. But in a disease like arthritis, the
chemical signal is always present. Vessels remain sticky, and
repair cells pile up, causing pain, swelling and other symptoms
of chronic inflammation.

    Still, too much inflammation is probably better than none
at all. The latter is the peculiar plight of Brooke Blanton, a
13-year-old Dallas girl who has taught researchers much of what
they know about cell adhesion and wound healing. Brooke first
came to doctors' attention as an infant, when her umbilicus and
teething sores failed to close and became infected. Strangely,
Brooke's lesions contained no pus -- the carcasses of millions
of white cells that pile up at infection sites -- even though
her bloodstream was teeming with infection-fighting white
cells, or leukocytes.

    Mystified, Baylor University physician Donald Anderson and
Harvard pathologist Timothy Springer decided to test the child's
white cells to see how sticky they were. "There was absolutely
no binding at all," says Anderson. A new disease had been
discovered: leukocyte-adhesion deficiency. Unable to produce the
CAMs that enable leukocytes to stick where they are needed,
these rescue cells were sliding past Brooke's wounds like a
convoy of ambulances with no brakes. "This child can't heal a
paper cut," says Brooke's mother Bonnie. For now, her daughter's
life remains a continuous battle against infection, though gene
therapists at Baylor hope to cure Brooke by inserting into her
white cells a gene for the missing CAM.

    Researchers have similar dreams of manipulating stickiness
in more commonplace ailments, including cancer.
"Cellular-adhesion research isn't going to cure cancer, but it
might stop metastasis," says Massachusetts Institute of
Technology scientist Richard Hynes. At the La Jolla Cancer
Research Foundation in California, genetic scientists have
succeeded in inserting a CAM gene inside a tumor cell. Once the
cell starts manufacturing patches of biological Velcro, it is
essentially "glued in place. It becomes incapable of
metastasizing," says Erkki Ruoslahti, president of the
foundation. A second approach to controlling cancer is known as
"walking on ice." Here the goal is to deny tumor cells traction
so they can't grip the walls of blood vessels to implant
elsewhere in the body. This may be accomplished by using drugs
to block certain CAMs on malignant cells.

    While such therapies remain theoretical, reducing
stickiness is already proving useful in heart disease,
specifically in combatting a dangerous side effect of
clot-busting drugs like streptokinase or TPA. Doctors have found
that after such drugs are used, lingering pieces of broken-up
clots (consisting mainly of platelets) look to surveillance
cells like a flood of damaged tissue. Instantly, the
inflammation process kicks in: the affected region of the heart
becomes sticky and therefore prone to further clotting. Adhesion
research has produced a drug now being tested on heart patients
that keeps the scattering clot fragments from sticking.

    Another antiadhesion drug is being developed for the
treatment of traumatic shock. Here too the goal is to prevent
the body's own healing process from going awry. Traumatic shock
can occur when accident victims lose large quantities of blood,
causing cells in vital organs to starve for oxygen. The starving
tissues trigger a distress signal that summons leukocytes and
other members of the body's damage-control team, which begin to
destroy distressed cells. Alas, if the signal stays on too long,
cells are killed at a phenomenal rate and major organs begin to
die even while hospital trauma teams are rushing to the rescue.
Each year 25% of the shock victims who make it to the emergency
room are revived only to die later. "It seems evolution never
intended for someone to be resuscitated after shock," says John
Harlan, head of hematology at the University of Washington in
Seattle. Harlan and his colleagues hope to outfox evolution with
a CAM-blocking drug that keeps white cells from sticking after
shock. In a series of animal studies, the drug saved 75% from
certain death.

    Furthest along of the new adhesion drugs is an "artificial
matrix" designed to promote wound healing. Normally, a wound
site looks like the Grand Canyon to arriving rescue cells. But
this biodegradable gel, produced by Telios Pharmaceuticals, is
peppered with synthesized CAM molecules so that cells arriving
at a wound site will have plenty of places to get a grip. With
the new gel filling in the gap, repairing wounds, including
severe burns or skin ulcers, takes 30% less time and leaves less
of a scar, claims company scientific director Michael
Pierschbacher.

    All this is coming from a science that nearly became
extinct. Following some excitement during the war on cancer in
the early 1970s, many scientists abandoned the field in
frustration for the more glamorous search for the genes of
disease. Yet a handful pressed on, captives of their own
curiosity. Many, like Harvard's Martin Hemler, had their
research proposals regularly sent back from the U.S. National
Institutes of Health stamped IRRELEVANT. Without a group to call
their own, with no papers circulating, with no annual meetings,
sticky cellsters worked in isolation, unaware that anyone else
was keeping the faith.

    Two events saved the field. The first, in 1976, was the
discovery of hybridoma technology. This allowed scientists to
build exquisitely precise probes to explore cell surfaces and
search for CAMs. The second boost came in the mid-1980s, when
M.I.T.'s Hynes noticed a resemblance between research coming
from obscure labs working on cancer, immunology, developmental
biology and hematology. Hynes began to see that these
researchers were all exploring aspects of cell adhesion. In 1987
he drew together these separate lines of research and published
a landmark paper in the journal Cell that finally connected the
dots. "All of a sudden, these fields fused; they were one," says
Hynes.

    Since then the pace has swiftly accelerated. Biotech
companies are scrambling to capitalize on sticky science.
"Thousands of papers are coming out. It's crazy, absolutely
crazy," exults Jean Paul Thiery, director of research for the
French National Center of Scientific Research. The excitement
serves as a reminder that the best guidepost for research may
be what it has always been: the persistent pull of curiosity and
the tenacity of scientists who ignore fashion and stick with it.