# 115 from R&D
Innovator Volume 3, Number 9
Cerami is president of the Picower Institute for Medical Research,
Manhasset, New York. Previously,
he was professor and dean, Graduate and Postgraduate Studies, The
Rockefeller University. Among
his many honors is the 1994 Abbott Laboratories Award from the
American Society for Microbiology.
Some people solve
problems by diving straight into them.
Iíve been involved in a more round-about investigation of
a tropical protozoan cattle disease which led to the isolation of
a factor that other groups were trying to use for cancer
chemotherapy, which then led to a treatment for massive bacterial
Despite all the
research, we still know very little about biology.
I'm no longer surprised when results in one area solve
problems in fields that seem totally unrelated.
I'd like to start
this story when the first student in Rockefellerís new
M.D./Ph.D. program wanted to work with me.
He seemed intent on doing research on trypanosomes, which
are a type of protozoa that causes parasitic diseases.
Iíd never worked in this area, but knew a little about
these diseases from growing up on a dairy farm in New Jersey and
undergraduate work at Rutgers' College of Agriculture.
disease we tackled was nagana, which prevents cattle from being
raised in most of equatorial Africa.
The first person to describe nagana, Sir David Livingstone,
tried to use oxen to explore the area in central Africa where the
tsetse fly is prevalent, but the draft animals became sickly and
scrawny, soon with their skin just draped over their bones.
They all died within a couple of weeks.
(When these trypanosomes infect humans, African sleeping
Around the turn
of the century, the German chemist, Paul Ehrlich, tested
derivatives of organic arsenicals and found several that could
treat African sleeping sickness; derivatives of these compounds
are still being used today.
Since no one had
shown how these organic arsenicals worked, we started there, by
following up a prediction of Ehrlich's, that the arsenic would
react with certain sulfur compounds.
We eventually discovered a sulfur compound which we called
trypanothione, that is produced uniquely by the trypanosome so it
can live inside its animal host.
This uniqueness made trypanothione an ideal target for
drugs--those which could interfere with the parasite's metabolism,
but not the host's.
This was the
start of what looked like a dedicated program directed towards
nagana. Little did I
realize where the research would ultimately lead.
Was Supposed to Save Them, Not Kill Them
several drugs that inhibited trypanothione synthesis by the
finally went to Kenya in 1979 to evaluate the most promising in
cattle. What an odd
result! It killed
infected cows within several minutes of injection; the healthy
cows just kept on mooing.
The next surprise
was that the infected cattle had very, very few trypanosomes in
their body, whereas infected laboratory rats had huge
concentrations. I had
assumed that animals died because the parasites used up essential
nutrients in the blood, but that clearly wasn't the case with the
Kenya cattle. There
just werenít enough
the accepted wisdom about the cause of weight loss in nagana, it
behooved us to come up with a superior one.
Cows with nagana develop cachexia, or wasting syndrome.
If the wasting symptoms werenít produced by competition
between the parasite and host, it must come from a toxin made by
the parasite. When we
got back to the laboratory, we ratcheted backwards from potential
therapies to more basic work with lab animals, seeking to identify
In 1981, we
identified a factor madeónot by the trypanosomeóbut by the
white blood cells of the animalís immune system.
We called this factor cachectin, because it was involved
with cachexia, the wasting phenomenon.
Since the white cells produced cachectin in response to
parasites and, we later found out, bacteria as well, we deduced
that it must play an important role in the normal immune system,
not just in rats but also in humans.
It seemed that we
had made an important basic research discovery.
I figured no one else had taken my roundabout research
route and also discovered cachectin.
We were pretty excited, and also a little smug.
We isolated the
protein cachectin and determined its sequence of amino acids.
We searched the computer database for proteins with similar
sequences and were surprised to find that another group, led by
Lloyd Olds, had reported the same
protein just two months previously.
That group called it tumor necrosis factor (TNF), and was
testing it as an antitumor compound.
What was even more coincidental was that the group was
right across the street at Sloan Kettering Cancer Center!
it Kills Cattle
At this time,
researchers thought TNF would be a useful cancer treatment since
it killed tumor cells in test tubes.
Our findings, however, predicted severe toxicity; but at
that time several biotech companies were using TNF in human
trials. The findings
from my lab were not exactly well-received by many individuals in
these companies. Cancer
patients going through those experimental therapies with TNF
suffered terribly dangerous side effects such as blood-vessel
leakage and heart failure. It
was just too toxic, and generally has been abandoned as a therapy.
Thus, TNF (a term
we now also use) seems to have a general function in helping white
blood cells ward off invading microorganisms (including
trypanosomes and bacteria) as well as cancer cells.
But if too much TNF is present, it does awful things to the
body. These symptoms
also resemble what happens during massive bacterial infections, or
sepsis. Itís then called septic shock.
produced in response to such an infection, actually intensify the
we produced antibodies in the laboratory that would bind to TNF
and inactivate it. When we injected baboons, first with these anti-TNF
antibodies, and then with a lethal dose of pathogenic bacteria,
the animals didnít go into shockóand they survived what would
have been a fatal infection.
As a result of
these exciting experiments, we performed Phase 2 clinical trials
with antibody against TNF and reduced death rates for septic shock
by approximately 50 percent. The antibody is now in larger Phase 3
clinical trials across the U.S. and Europe.
companies are looking to inactivate
TNF to treat septic shock as well as other diseases such as
rheumatoid arthritis. Among
the many curious sidelights to this story:
some of the teams who are now trying to inactivate
TNF were previously proposing to use TNF as a treatment.
successes with TNF, I planned to go back and look at trypanothione
synthesis for another attack against nagana.
Unfortunately, it seem that neither government nor industry
are willing to support a major effort for this tropical disease.
not sitting around. My
general approach has been to try to get at the basic mechanisms of
a health problem. Our
group is involved with diverse programs, including aging and
diabetes. I donít know how that research will end up.
But Iíll bet weíll find many surprises.
And Iíll also bet some of those surprises will lead to
important medical advances.