# 115 from R&D Innovator Volume 3, Number 9          September 1994

This Treatmentís Deadly!
by Anthony Cerami, Ph.D.

Dr. 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 infection--toxic shock. 

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.

The trypanosome 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 sickness results.) 

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.

It Was Supposed to Save Them, Not Kill Them

We developed several drugs that inhibited trypanothione synthesis by the trypanosome.  I 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 trypanosomes!

Having overturned 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 this substance.

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!

Remember, 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.

Could TNF, produced in response to such an infection, actually intensify the disease?  Intrigued, 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. 

Several biotech 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.

After our 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. 

However, Iím 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.  

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