This was not the most worrying sign of a health problem, just a nosebleed that would not stop. So, in February 2017, Michael Schaffer, 60, who lives near Pittsburgh, first went to an emergency room and then to a hospital where a doctor finally managed to cauterize a small cut in the nostril.
Then the doctor told Mr. Schaffer something that he had never expected to hear: "You need a liver transplant."
Mr. Schaffer did not know that his liver was failing. He had never heard of the diagnosis: Nash, for nonalcoholic steatohepatitis, a fatty liver not related to alcoholism or infections.
The disease may not have obvious symptoms even if it destroys the organ. This nosebleed was a sign that Mr. Schaffer's liver was not producing the proteins needed for blood clotting. He had serious problems.
The news was soon revealed: the doctors asked Dr. Schaffer to become the first patient of an experiment to try something that transplant surgeons have been dreaming of for more than 65 years.
If it worked, he would receive a donated liver without needing to take powerful drugs to prevent the immune system from rejecting it.
Before the discovery of anti-rejection drugs, organ transplants were simply impossible. The only way to convince the body to accept a given organ is to reduce its immune response. But the drugs themselves are dangerous, increasing the risks of infection, cancer, high cholesterol, accelerated heart disease, diabetes and kidney failure.
Within five years of a liver transplant, an average of 25% of patients died. In 10 years, 35 to 40% have died.
"Even if the liver works, patients can die from a heart attack, stroke, or kidney failure," said Dr. Abhinav Humar, transplant surgeon at the Center. University of Pittsburgh, who is leading the study in which Mr. Schaffer participated. "It may not be entirely due to anti-rejection drugs, but anti-rejection drugs help."
The kidneys in particular can be damaged. "It's not uncommon to end up with a kidney transplant in patients who have had a lung, liver or heart transplant," says Dr. Humar.
Patients are generally aware of the risks associated with drugs, but the alternative is worse: the death of those who need the liver, heart or lungs; or, for kidney patients, a life in dialysis, resulting in a life expectancy and quality of life even worse than that of a kidney graft.
A glimmer of hope
In 1953, Dr. Peter Medawar and his British colleagues had an experience with such a staggering result that he shared the Nobel Prize. He showed that it was possible to "train" the immune system of mice so that they do not reject transplanted tissues from other mice.
His method was not really practical. It was to inject newborn or fetal mice white blood cells from unrelated mice. When the mice were adults, the researchers placed unrelated mouse skin grafts on the backs of those who had received the blood cells.
The mice accepted the transplants as if they were their own skin, suggesting that the immune system can be modified. The study culminated in a scientific quest to find a way to train the immune system of adults in need of new organs.
Peter Medawar, circa 1960, when he won the Nobel Prize for studies on the immune system. Credit Bettmann, via Getty Images
This has turned out to be a difficult task. The immune system is already developed in adults, while in baby mice, it always "learns" what is foreign and what is not.
"You are trying to deceive the body's immune system," said Dr. Humar. "It's not easy to do."
Until now, most scientific research has focused on liver and kidney transplant patients for several reasons, said Dr. James Markmann, head of the division of transplant surgery at Massachusetts General Hospital.
These organs can be transplanted from living donors. Donor cells are therefore available to try to train the immune system of the transplanted patient.
Many more people need kidneys than any other organ – there are about 19,500 kidney transplants per year, compared with 8,000 transplanted livers. And these transplanted kidneys rarely last all their life with immunosuppressive drugs.
"If you're 30 or 40 years old and get a kidney transplant, it's not the only kidney you'll need," said Dr. Joseph R. Leventhal, who leads the kidney transplant and kidney transplant programs. pancreas from Northwestern University.
Another reason to focus on the kidneys: "If something goes wrong, it's not the end of the world," said Dr. Markmann. If an attempt at weaning immunosuppressive patients fails, they can get dialysis to purify the blood. The rejection of other transplanted organs can result in death.
The liver intrigues the researchers for different reasons. It is less subject to rejection by the body's immune system. In case of rejection, the organ undergoes less immediate damage.
And sometimes, after people have lived with a transplanted liver for years, their bodies simply accept the organ. Some patients have discovered this by chance in deciding for themselves to dispose of their anti-rejection drugs, usually because of the costs and side effects.
It is estimated that 15 to 20% of liver transplant patients who have tried this risky strategy have succeeded, but only after years of taking the drug.
In an essay, Dr. Alberto Sanchez-Fueyo, Liver Specialist at King's College London, reported that as many like 80% could stop taking anti-rejection drugs. In general, these patients were older – the immune system weakened with age. They had long used immunosuppressive drugs and had normal liver biopsies.
But the damage caused by immunosuppressive drugs is cumulative and irreversible, and their use for more than a decade can cause significant damage. Yet, there is no way to predict who will succeed in withdrawing.
Deceive the immune system
The more researchers learned about the symphony of white blood cells controlling responses to infections and cancers – and transplanted organs – the more they began to hope to change the body's immune system.
Many types of white blood cells work together to create and control immune responses. A number of researchers, including Dr. Markmann and his colleague, Dr. Eva Guinan of the Dana-Farber Cancer Institute, have chosen to focus on cells called regulatory T cells.
These are rare white blood cells that help the body identify its own cells as non-foreign. If these regulatory cells are missing or impaired, people can develop diseases in which the body's immune system attacks its own tissues and organs.
The idea is to isolate regulatory T cells from a patient about to undergo a liver or kidney transplant. Scientists then try to cultivate them in the laboratory with donor cells.
Then, the T cells are reinjected to the patient. Scientists hope that this process will teach the immune system to accept the given organ as an integral part of the patient's body.
"The new T cells signal the rest of the immune system to leave the organ quiet," said Angus Thomson, director of transplant immunology at the University of Pittsburgh Medical Center.
Dr. Markmann, who works with liver transplant patients, and Dr. Leventhal, who works with kidney transplant patients, begin studies using regulatory T cells.
In Pittsburgh, it is planned to modify a different cell of the immune system, called regulatory dendritic cells. Like regulatory T cells, they are rare and allow the rest of the immune system to differ from non-self.
One advantage of regulatory dendritic cells is that researchers should not isolate and grow them in sufficient quantities. Instead, scientists can induce a more abundant type of cells – immature white blood cells – to turn into dendritic cells in Petri dishes.
"It takes a week to generate dendritic cells," said Dr. Thomson. In contrast, the development of a sufficient number of regulatory T cells may take weeks.
Regulatory T cells also need to stay in the bloodstream to control the immune response, while dendritic cells do not have to stay long – they control the immune system during a brief journey into the circulation.
"Each of us takes advantage of a different approach," Dr. Markmann said. "We do not know which one is the best yet. But the terrain is at a fascinating point. "
What about patients who have already undergone an organ transplant? Is it too late for them?
"I am asked this question almost every day when I see patients," said Dr. Leventhal.
For now, the answer is that it is too late. These patients are not candidates for these new strategies to alter the immune system. But researchers hope this situation will change as they learn more.
"Someone must be first"
When Michael Schaffer, the Pittsburgh patient, was informed that he needed a liver and that he could be the first patient of the group's clinical trial, he raised the shoulders. "Someone must be the first," he said.
Schaffer began researching a living donor, a close relative willing to undergo a major operation to remove a lobe of liver – or a stranger whose cells were compatible and who was willing to donate.
The Pittsburgh scientists told him how to proceed. Ask your immediate family, then your family, friends and colleagues. If that fails, he should start advertising with leaflets and Facebook posts.
Mr. Schaffer is one of eight brothers. Four were over 55 years old, too old to have some of their liver removed. The three younger brothers were in poor health.
He went to nieces and nephews. Three agreed to donate and one, Deidre Cannon, 34, who was a good match, continued the operation.
That happened on September 28, 2017. Later, Dr. Schaffer took 40 tablets a day to prevent infections and suppress his immune system as his body learned to accept the new organ.
But now he has reduced his consumption to one pill, a low dose of one of the three anti-rejection drugs he's initiated. And doctors even hope to wean him off.
His case may be intriguing, but he is only one patient. Scientists plan to try the procedure on 12 additional patients and, if successful, extend the study to other patients at multiple test sites.
For Schaffer, it's all worth it. He is active and works with a teenage grandson to replace the floor tiles in his kitchen. He shovels snow and mows the lawn as a favor to his neighbors and helps take care of his grandchildren after school.
"My goal is to live up to 100 years and get shot in bed by a jealous husband," Schaffer said.