Last year in the U.S. about 1,500 human hearts were lifted from the chests of clinically dead people and stitched into the chests of transplant recipients. About 1,100 patients received donor livers after complex operations. An additional 9,000 kidneys ended up in abdomens that nature had never meant for them.
The grafted organs, sparked by new nerve connections, immediately set up shop in their new homes. Hearts began beating; livers broke down chemicals into disposable products; kidneys filtered wastes and flushed them away by the gallons-all working steadily to restore health.
Almost simultaneously and with equal determination, the bodies started to reject the good samaritans.
Even as a surgeon had completed a lifesaving transplant procedure, microscopic pieces of the new organ invariably floated off in the bloodstream, perhaps to a neighborhood lymph node where the standing army of white blood cells known as T cells-one group of the body`s infection-fighting agents-spotted the pieces as foreign and began producing antibodies to kill them.
Other circulating T cells, prowling relentlessly throughout the body in search of alien bacteria, stumbled over the new graft itself. These lymphocytes blindly blazed into action, secreting potent substances with odd- sounding names-migration inhibitory factor, interleukin 2, gamma interferon-that activated more defenders to swarm over the new graft and kill it.
Because nature never had envisioned an era when vital organs would be routinely transferred from person to person, the body in such a situation mindlessly takes the side of certain death over life. A kidney will shut down; a liver stops working, causing the brain to lapse into coma; a heart struggles, then ceases beating. Unless something is done, the new organs have no chance at all.
Except for cyclosporine.
Without the miraculous drug, an estimated 150,000 transplant patients worldwide wouldn`t be living today. They wouldn`t be walking around with someone else`s heart, lung, liver, kidney, pancreas, skin, intestine or bone marrow in their bodies.
These lucky survivors may not know of Swiss immunologist Jean-Francois Borel, the discoverer of cyclosporine, but each morning they toast him. They mix their bitter, oily cyclosporine solution with something like orange juice or chocolate milk, and the miracle molecule stops their immune systems from rejecting the foreign body part. It lets them get on with their lives.
”Cyclosporine comes from a fungus, basically, and is found in dirt,”
Borel said in a recent interview in Chicago. The modest, soft-spoken scientist who describes himself as ”only a mouse doctor” had come to the city to receive the ”Gift of Life” award from the National Kidney Foundation of Illinois.
”You can scratch the Earth`s surface, and the fungus that produces cyclosporine is down about an inch deep in the soil,” he explained. ”It may be found anywhere; these fungi are widespread all over the world.”
Yet no other drug has proved so Olympian in its power to challenge perhaps the most fundamental biological system in nature: the body`s determination to reject unwanted intruders.
However, even today, 16 years after a vacationing employee of the Basel-based pharmaceutical house, Sandoz Ltd., serendipitously picked up the mystery microbe in a handful of Norwegian soil above the Arctic circle, no one knows for sure how cyclosporine works.
Not even Borel, 55, now senior scientist in immunology at Sandoz, who at the time was a staff researcher investigating new pharmaceuticals. As a Sandoz employee, Borel has made no money for his discovery. Yet without his fierce determination, the drug would have been doomed to oblivion.
Drug companies sample dirt constantly, Borel said. ”We look for microorganisms because they produce metabolites, interesting compounds that sometimes are chemically novel. Our lab screens as many as 30,000 such compounds a year.”
Placed in petri dishes, the visiting microbes are fed a nourishing broth of agar, a chicken soup for cells. Soon various fungi and molds obligingly appear. The educated eyes of microbiologists study them carefully, looking for something new.
Nobody looks with more eagerness than Borel. But so far, he has seen nothing as remarkable as cyclosporine. An astounding number of research papers have been written about the drug-7,800 so far, and 2,000 more are expected in 1989. But they deal mostly with proper management of patients and possible new uses for cyclosporine, not with the mysteries of how it happened to be.
Despite the laboratory wizardry that brought the synthetic sulfa drugs to humanity, the world`s most interesting pharmaceuticals still come from living creatures: sponges, periwinkles, fungi, bacteria.
The white fungus Tolypocladium inflatum makes cyclosporine.
”It looked like just a white mold,” Borel recalled. ”But it was a new type of white mold. When it was found in 1972, I knew right away it was something special. The drug later gave us a lot of trouble, and many people thought I was a fool for sticking with it.
”But between 1972 and 1976, when the first publication came out, I was very sure of the potential of that molecule.”
Analysis of the molecular structure of cyclosporine revealed a cyclic peptide-11 amino acid molecules, all in a neat little ring. Perhaps one of the amino acids-called C9-ene-holds the key to the mystery. It is new to science. In fact, scientists had thought there were 20 amino acids in nature: That was dogma. Now there are 21. These join together by the hundreds, or thousands, and form links of huge molecular chains that make the tens of thousands of proteins the body needs to exist.
Cyclo, the drug was named, because of the cyclic structure. Sporine because it comes from spores. Nine cyclosporines, labeled A through I, have been discovered so far.
”Some have turned out to be active, and some aren`t,” Borel noted.
”Some work against diseases caused by parasites, like malaria and schistosomiasis, without being immunosuppressive. Some work against chronic inflammation but less well for transplantation.
”The one that really matters is cyclosporin A. That`s active against anything,” he said, laughing like a proud parent.
Once a drug company happens upon an interesting organism, scientists purify it and conduct tests to check for beneficial properties.
At first the Sandoz company had hoped the new compound would prove to be an antibiotic, Borel said. ”We tested for that.”
The test was straightforward. Scientists infected mice with a germ and gave them the new compound to see if could cure them. The Sandoz mice merely dropped dead. Cyclosporine, it turned out, was helpless against germs.
”But we noticed something important,” Borel said. ”The drug was not toxic. The animals tolerated it well. Some microorganisms make compounds that are terribly toxic. We just throw them away. A rule of thumb is that the activity of a drug equals its toxicity-the more potent a drug, the more poisonous. But this wasn`t the case with cyclosporine.”
The benign nature of the chemically interesting cyclosporine intrigued Borel, even after it had flopped as an antibiotic and his bosses had told him nothing good would come of it.
”They ordered me to pour cyclosporine down the drain,” Borel recalled, grinning slyly. ”Several times I was forbidden to work with it. So I worked in secret.”
Indeed Borel later was to risk his life, not to mention his career, for this mysterious ”fungal metabolite,” as he calls it, that utterly transformed transplant surgery.
But what could the fungus do? Could it be a heart drug? A cancer drug? In the course of experimenting, Borel injected cyclosporine into a culture of white blood cells. Remarkably the fungus blocked the ability of the immune cells to grow or function. But they didn`t die. Unlike other immunosuppressive drugs, cyclosporine didn`t kill lymphocytes. It merely muzzled them.
”At the time, rejection was treated with anticancer drugs that killed all rapidly dividing cells,” Borel said. ”Tumor cells grow very fast, but so do the cells that the body summons up to respond to an infection or an alien organ. That`s why anticancer drugs were used.”
But such drugs don`t care what cells they kill. They smash into cells like buckshot and block the synthesis of DNA, destroying blood cells, hair follicles and cells of the stomach lining, as well as cancer.
”You get diarrhea and anemia, or low blood counts. You get nausea,”
Borel said. ”These are good drugs. But they can cause tremendous side effects.”
Still, he adds, there wasn`t much commercial incentive for a drug firm to develop a new immunosuppressant. Transplantation had ground to a halt in the early 1970s. The average one-year survival rate for a transplanted kidney in the U.S. was only 50 percent; for bone marrow transplants, between 20 and 50 percent. Heart transplantation had been virtually abandoned.
”Immunology, my field, was bursting with new discoveries,” Borel said,
”but unfortunately there was nothing for the doctor to use to help patients. This is why I believed so much in this drug. I thought it could have a big effect; that it might even save the idea of organ transplantation, make its practice broaden and give people a chance to stay alive.
”So I found myself assuming the role of a product champion, not just a scientist. I was pushing the drug against the will of company management.”
Quietly testing the drug in animals that had undergone organ transplants, Borel obtained stunning results. Cyclosporine worked entirely differently from other antirejection drugs.
”It doesn`t go after rapidly dividing cells but only the very specific kind of white blood cell (T cells) responsible for the immune defense response,” Borel said.
”Cyclosporine selectively suppresses production of interleukin-2, a chemical needed by the T-cells to proliferate. At least, we think that`s what it does.”
By 1977, however, Borel had a problem. The drug didn`t seem to be water-soluble. ”Unless injected directly into the blood, it just went through an animal`s body. Of course, that would never work for patients. I wanted them to be able to swallow it.”
This problem nearly cost society cyclosporine. Once the company accepted his work, their researchers found that when cyclosporine was given in the form of a gelatin capsule, it was not absorbed in the bloodstream of healthy volunteers, including Borel himself. Maybe the drug worked only in animals but not in humans? Once again Borel was told to shelve cyclosporine.
The pressures on him, he said, were ”tremendous. But I knew from my animals that depending on the solution you put it into you could dramatically increase the absorption rate.”
Again, Borel was virtually a lone voice. He proposed that if cyclosporine were mixed as a kind of cocktail with water, alcohol and a solvent, it would be absorbed by the human body. Other scientists argued that Borel was wrong this time. He had done his best. Let it go.
He demanded that they let him drink such a concoction.
”I told them, `Look, let me try it myself. I want to prove to you that it can be done, that the body will absorb it.`
”The conditions were very controlled. People prepared the substance the way I wanted. Then I drank it, with them all huddled
around me. I took samples of my blood several times. They measured how much of it had gotten in.”
By experimenting on himself before cyclosporine`s toxicity was known, Borel joined the ranks of the most storied medical researchers: He went first and saved one of the most fantastic drugs of all time.
”Oh, it didn`t hurt me,” he stressed. ”I got a little high, that was all. But I proved my point-the drug got into my blood.”
Cyclosporine`s next close call came in 1978, when clinical trials began in England by Dr. David J. G. White of Cambridge University and Dr. Roy Y. Calne of Addenbrooke`s Hospital in Cambridge.
When Calne administered the drug to patients in whom he had transplanted cadaver kidneys, cyclosporine promptly turned around and attacked the very kidneys it was designed to save.
”Calne had used the same dosages he had used in animals,” Borel said.
”He created trouble. For the first time, we learned that cyclosporine in such high doses could cause kidney damage.
”It was a terrible time, a real crisis,” Borel remembered. ”Calne performed biopsies and found what he mistook for the first signs of rejection. So he added more cyclosporine and thereby gave some patients lymph cancer.
”It was really by intuition and genius that he realized how to correct this situation. He decided it was not rejection but kidney poisoning that really was happening. So he drastically lowered the dose of the drug.
”By doing that, he really saved cyclosporine. The kidney function returned, and no more cancer developed. From then on, the results were spectacular.”
In 1983, after tests with more than 2,000 kidney and heart transplant patients, cyclosporine was approved by the Food and Drug Administration.
Transplanted kidneys, which had only a 50 percent chance of surviving the first year with conventional immunosuppressive therapy, now have a better than 90 percent chance with cyclosporine. The success rate for hearts jumped from virtually nil to more than 80 percent. Livers doubled from 35 to 70 percent. Moreover, the drug has shown great promise in preventing graft-versus-host disease in bone marrow recipients, an often deadly complication in which the newly transplanted tissue rejects the patient.
The promise seems limitless, in fact. Doctors recently discovered that cyclosporine seems to induce long-term remissions in insulin-dependent diabetics and may have an effect against systemic lupus erythematosus and collagen disorders ranging from thyroiditis and hemolytic anemia to idiopathic thrombocytopenic purpura. The drug may slow the progress of multiple sclerosis.
But its most dramatic advance was the transformation of organ transplantation into mainstream medicine.
Yet the delicacy of dosage still haunts many doctors. ”There is a tendency to overuse the drug in order to protect the new organs at any cost,” Borel said.
Borel`s dream is to develop drugs with specific organ tolerance. ”By that, I mean you`d give a patient a kidney and a drug that saves that kidney but leaves the rest of the immune system free to fight infection. That way, we probably could stop all medication after a period.
”Cyclosporine certainly can`t do that yet,” Borel said.
But maybe there`s some other mold out there in the dirt somewhere that can.
”Cyclosporine probably was the drug of a lifetime for me,” Borel concluded with a sigh. ”But every day when I go into work, I`m still looking for something better.”
