Photograph by Brandon Dill
St. Jude director and CEO Dr. William Evans with 3-year-old patient Kylie Overton.
When Dr. William Evans thinks back on the formative years of the hospital he now directs, he raises some interesting questions: If you were looking for a disease to cure during the late 1950s and early ’60s, why would you pick childhood cancer, which was almost totally fatal? If you were considering, during that same era, a headquarters to study a disease that required biomedical research scientists and facilities, why would you pick Memphis? And if you’d devised a business model providing the best medical care possible, why would you give it away to those who couldn’t pay? “None of it made any sense,” Evans says with a smile, “but they did it anyway. And it worked.”
It worked in large part because a young physician named Dr. Donald Pinkel had a concept he felt bound to try. Trained in pediatric cancer at Harvard, Pinkel was working at Roswell Park Memorial Institute in Buffalo when a fledgling institution in Memphis contacted him about a job. “Don hadn’t been the search committee’s first choice,” says Evans, adding that cofounders of St. Jude Children’s Research Hospital were looking for someone older and more experienced. Having no success with other candidates, however, the committee gave the 34-year-old Pinkel a call. Though he was planning a visit to Colorado for another interview at the time, he told them he’d stop in Memphis. While serving as a medical officer in the Army, Pinkel had contracted polio, and his physician in Buffalo advised him to move to a milder climate.
Though Memphis’ climate held appeal, its racism did not. Like Danny Thomas, Pinkel believed in equality of care for all children, and he doubted this could be achieved in the South. But he met with Ed Barry, a local lawyer, philanthropist, and founding chairman of St. Jude, and Mike Tamer, who directed fundraising for the new hospital — both strong supporters of civil rights who insisted St. Jude would serve every child with cancer, regardless of race, religion, or ability to pay. Pinkel still hesitated, thinking he was too young to take on such a demanding job. But senior colleagues in Buffalo, stressing the opportunity that lay before him, urged him to seize the challenge.
In July 1961, Pinkel accepted the position of medical director, and on October 18th — which happened to be the Feast Day of St. Jude — he moved here with his wife and seven children (he eventually was father of 10). He went to work on November 1st in a building that had one finished room: his office. From there he started recruiting “to create an institution out of nothing,” says Evans. “He had nurses from St. Joseph Hospital [which later merged with Baptist Memorial Hospital] and that was about it.”
Though convincing research scientists and pediatric physicians to relocate to the South in the early ’60s posed a challenge, Pinkel was able to hire enough qualified personnel to open the hospital on February 1, 1962. By the end of that year — during which 126 patients were admitted to St. Jude, girls and boys, black and white, Catholic, Protestant, and Jewish — Pinkel had assembled a staff of 100. He believed in clinicians and researchers working together daily, and the star-shaped building encouraged that collaboration. “In the same corridor you had biomedical research scientists and an inpatient hospital and a clinic in the middle,” says Evans. “Everyone was expected to work together sharing information to develop new protocols. That was unheard of at the time. Now everybody wants to do it.”
“He broke the back of acute lymphoblastic leukemia . . .”
Also unheard of then was the concept Pinkel gradually made reality. Top physicians at major institutions administered only one chemotherapy drug at a time — which prolonged a child’s life by about a year and a half at best. Pinkel asked, “Why not use multiple drugs at once?” After all, clinicians had seen some responses to each drug but nobody had logically combined them.
“There were five or six drugs available and by the time doctors decided to try a second one, it was almost too late,” says Evans. “Don wanted to use our best drugs in their full doses up front, to win the war as early as possible.” Given free rein at St. Jude, and with a sense of urgency to save more lives, Pinkel developed the Total Therapy concept aimed at acute lymphoblastic leukemia (ALL), the most common form of childhood cancer. He wrote up a protocol using prednisone, vincristine, and asparaginase, then moved on to high doses of methotrexate, mercaptopurine, and cyclophosphamide to fight residual cancer cells.
At first, it was hard to tell if the new multiple-modality treatment was working, “because nobody stayed in remission but a few months,” says Evans. Then doctors began to notice remissions lasting longer — six months, a year. As part of Total Therapy, Pinkel tried yet another weapon considered radical. Because cancer cells could hide out in children’s brains and spinal cords, Pinkel aimed radiation at these areas. “He started in low doses and worked from there,” says Evans.
Though several years of research were required to test Pinkel’s theory, the final results were conclusive. The study titled Total Therapy V 1965-68 recorded an astonishing 50 percent survival rate. As Danny Thomas at one point declared about Pinkel: “He came, and he stayed, and he broke the back of acute lymphoblastic leukemia.”
“Why didn’t this happen at Harvard?”
So successful against ALL were chemo and radiation combined that Pinkel and his colleagues, realizing the harsh effects of sustained dosages, considered taking some patients off treatment. These children, five in all, had been in remission — with a complete absence of cancer cells — for two years. After discussions with Pinkel and other clinicians, the parents and their children agreed to stop treatment (see “Success Stories,” page 51), marking a major milestone for the young Memphis hospital — which by 1968 was accepting more referrals of children with leukemia than any other U.S. institution.
“Taking patients off therapy was completely unknown territory,” says Evans. “One theory was that we were just keeping the cancer in check with treatment. The other theory was that children were truly cured. We wouldn’t know till we stopped treatment.” Today, three of the initial group of five patients taken off therapy are still alive. “That’s extraordinary.”
As for Total Therapy V, which was published in 1972, Evans says, “That was a breakthrough. It began to put the word ‘cure’ in the conversation and it put St. Jude on the map. This little startup place in its first decade had come out with a new treatment for leukemia that was curing kids. Why didn’t this happen at Harvard? Or Stanford? It was due to Don’s determination and his recruitment of a lot of people who believed, as Don did, that it would work. There he was on crutches, working six days a week, 12 hours a day. At times, the hospital didn’t have money to pay him. Mr. Barry had to write personal checks to cover his salary. But Don exuded confidence and created that same confidence in the people working with him. The success of Total Therapy V told everybody, ‘Yes, he might be right. And if we can do it for leukemia, why can’t we do it for other cancers?’”
“What mattered was the idea . . .”
Evans realized his own passion for research while a student at the University of Tennessee-Memphis and later UT’s College of Pharmacy, from which he received his doctor of pharmacy; he joined St. Jude in 1972 as a student technician. Already impressed with the commitment and enthusiasm of the people at St. Jude, he recalls how Pinkel was open to questions and ideas regardless of an individual’s position or rank. “It didn’t matter that I was a student,” he says, “What mattered was the idea — how well-thought-out it was and if it could be pursued.”
Evans was hired about the time that Total V was published and Pinkel was awarded the Albert Lasker Award for Medical Research, the highest prize given in the U.S. Pinkel shared the honor with scientists in Boston and New York who had told him he couldn’t combine different drugs. “The argument [for that],” says Evans, “was that if he hadn’t had the drugs to work with, he wouldn’t have been able to put them together. But it was his decision to combine them and to try different combinations that started saving lives.”
New directors, new achievements
Pinkel, at 86, now lives in California and still teaches part-time. He left St. Jude in 1973 to return to laboratory research, specifically the study of solid tumors. Hired as director in 1973 was Dr. Alvin Mauer, and during his nine-year tenure, St. Jude doubled in size and opened a $10.5 million research building. Despite growth, Mauer emphasized continued collaboration between clinicians and researchers.
In addition to intensified research in ALL, scientists ramped up studies and treatments for other childhood cancers and diseases; these ranged from acute myeloid leukemia (AML) and lymphomas, to brain tumors, bone cancers, and sickle cell disease. Because chemotherapy and other treatments could wreak havoc on children’s immune systems, one important discovery helped improve their quality of life. In 1977, Dr. Walter Hughes, who directed St. Jude’s infectious diseases division, developed the first preventive therapy for pneumocystiis carinii pneumonia. The drug trimethoprim-sulfamethoxazole (TMP-SMZ) proved almost 100 percent effective against this infectious strain, and today is a standard preventive treatment. Later, when St. Jude started admitting children with pediatric AIDS, the drug was used to help protect these patients from pneumonia.
In 1983, Mauer returned to research and patient care, and Dr. Joseph V. Simone was hired after working 15 years at St. Jude, both as head of hematology and associate director of clinical research. Simone intensified focus on why normal cells turn cancerous and expanded research into gene studies and replacement. One important finding in that period was by pathologist Dorothy Williams. “She did a study of chromosomes,” says Evans “which is the big piece of material in every cell that contains genes and DNA packed inside. Dorothy discovered that in certain kids with leukemia, one piece of a chromosome had broken off and moved to another, causing the abnormality. That helped us move from the chromosome level up to looking at individual letters in the DNA code.”
Simone is credited with recruiting high-caliber scientists and leaders — among them Dr. Peter Doherty, who headed St. Jude’s immunology department and in 1996 was awarded the Nobel Prize for Medicine for discovery of how the immune system recognizes virus-infected cells.
After Simone left in 1992 for Memorial Sloan Kettering Cancer Center in New York City, Dr. Arthur Nienhuis, a prominent researcher with the National Institutes of Health, took the helm. Bringing with him strong expertise in the scientific frontiers of bone marrow transplants, gene therapy, and genetic testing, Nienhuis founded a genetics department and a cell and gene therapy program that would develop treatments based on gene transfer technology. Several advances were made during his leadership, including breakthroughs in sickle cell disease and hematological disorders, the opening of a department of developmental neurobiology, and completion of a $1 billion hospital expansion. Though no longer director, Nienhuis continues to serve St. Jude as a researcher in hematology.
“Powerful examples of what a child inherits . . .”
When Evans succeeded Nienhuis as director and CEO in 2004, he had already served as the chair of the pharmaceutical sciences department and as the hospital’s scientific director. He also spent a sabbatical year studying pharmacogenomics, and his field of research — for which he has received three consecutive NIH grant awards, a rare accomplishment — probes the effects of antileukemic drugs in children and why each child processes and responds to a drug in a certain way. “For years we were giving every child the same amount of each drug based on how much he or she weighed,” explains Evans. “But some children get rid of a certain drug very fast, some not. So, we set out to find if those who absorbed a specific drug quickly needed more of the drug to have the desired effect on the leukemic cells. A series of studies showed that was true. We needed to adjust the drug dose on those kids.”
More recently, genetic research is playing an even larger role in determining drugs and dosages for each patient and how the drugs are best administered. “Powerful examples of what a child inherits from his parents determine almost totally if he can tolerate the standard dose of a drug,” says Evans. “If you gave him the same amount as everybody else, he’d be admitted to ICU with toxicity in a few days. Once we understood the genetics, we found we could treat them with 10 percent of the normal dose and they’d have the same blood level as other kids and the same outcome, with no toxicity. These findings led to a diagnostic test developed in the 1990s that we now give everybody.”
Also working on risk-adjusted chemotherapy and sophisticated patient monitoring is Dr. Ching-Hon Pui, chair of the hospital’s department of oncology. who came to St. Jude from Hong Kong in 1977. Pui has been influential in stopping irradiation of the brain and central nervous system in patients with ALL. “We had discovered,” says Pui, “that patients with irradiation developed brain tumors. Radiation caused an enzyme deficiency that made them more prone to develop a second cancer. We discontinued irradiation in 1999. People say you have cancer, you get toxic. No, that’s not right. You don’t have to.”
“It brought us full circle. . .”
So what have these changes — in tailoring drug dosages and stopping radiation — accomplished? In the latest study, Total Therapy XV 2000-2007, scientists looked at 11 anticancer drugs that were administered either into the bloodstream or into the spinal cord fluid. Treatment was tailored based on each child’s genetic makeup and how he metabolized, absorbed, excreted, and responded to the drugs. Children treated at St. Jude for ALL in the Total Therapy XV study enjoyed a five-year survival rate of 94 percent and a projected 10-year cure rate of 90 percent, and their quality of life was expected to improve since they didn’t receive radiation. As for relapses to the central nervous system (CNS) after discontinuing radiation, the study cited 2 percent. And no patient has died from CNS relapse since 1999.
“It’s interesting,” says Evans. “When irradiation of the brain was first used in the 1960s, the cure rate went from 10 percent to — bam! — 50 percent. Fast-forward to 2000. We have more drugs, better drugs, we know how to dose them and give them in the spinal fluid. Once we did that, Dr. Pui said, ‘I think we can eliminate radiation.’ So starting brain irradiation put St Jude on the map, stopping it brought us full circle, to show you can cure kids without it.”
Pui strives to educate scientists around the world about alternatives to radiation. “Some say it’s easier than spinal chemo tap. Zap it and done. I’m on a crusade to stop that,” says Pui, who has paved the way for improved leukemia treatment in developing countries. His risk-adjusted approach to therapy has also raised the cure rate to nearly 90 percent for older adolescents with ALL who have traditionally not fared as well as younger patients.
“It would take 26 Pyramids to hold all the data.”
As the institution moves into its second half-century under Evans’ direction, St. Jude is leading the way with advanced genetic studies. In January 2010, the hospital launched the Pediatric Cancer Genome Project in collaboration with Washington University School of Medicine in St. Louis to identify the genetic changes that trigger the most deadly childhood cancers. This involves decoding the genomes — which essentially contain all the biological information needed to build and maintain life — of more than 600 young cancer patients who have contributed tumor samples for the study. Scientists working on this $65 million project will sequence the entire genomes of both normal cells and cancer cells, from each patient, comparing differences in the DNA to pinpoint genetic mistakes that lead to cancer.
As Evans explains, “We’re sequencing all 3 billion letters in the DNA code of cancer cells and in the DNA of normal cells and comparing those two ‘sentences,’ if you will. And we’ll sequence every one 30 times to be sure we have it right. That will help us find out where mutations occur, and to discover what causes a white blood cell to become a leukemic cell, or a brain cell to become a brain tumor.”
To indicate the size and breadth of the project, he says if you took all the information from those DNA code “sentences” and typed it on letter-size paper, front and back, standard font, single-spaced, then put the papers in file drawers and stacked them on top of each other, “it would take 26 Pyramids to hold all the data.”
St. Jude scientists came up with algorithms for sequencing and created new software to help align the data to find the differences. “Now that we’re mining those genomes, we’re learning what drugs already work against some of the abnormal cells, so we can go on with clinical trials,” says Evans. “With some other mutations, we don’t have the drugs on the shelf, so our chemical biology department can screen some of the 1 million compounds that are candidate drugs sitting in our buildings. Without targets, we don’t know what to screen. Now we’re finding the targets.”
Evans adds that St. Jude has published the study’s software and accompanying manual and offers it free to other institutions who ask for it. “We get probably two requests for it each week,” he says. “All data will be in the public domain. We believe in sharing what we have. We’re going one step further and creating a website to make it easier for other institutions or scientists to key in a gene and it will give them back all mutations found in that gene.”
“You don’t know where the next great idea will come from.”
Asked if he foresees the cure of childhood leukemia in his lifetime, Evans says, “No. Nature and biology are always evolving. Cancer is not one disease, it’s hundreds. The more we slice it down to the DNA level, we see more subtypes. It’s hard to get 100 percent of anything.” He does, however, think it may be possible to prevent the disease. “The more we learn about genetics, the closer we get to finding out how to prevent it, or diagnose it earlier, or perhaps identify the kids at highest risk and monitor them more closely.”
Making steady progress over 50 years, St. Jude has pushed not only ALL’s survival rate to new heights; overall survival rates for childhood cancers combined now approach 80 percent. Evans says the key is sustained improvements over time. “Every time you add 5 percent to the cure rate, that’s amazing. Every increment matters.” And he believes St. Jude’s success is a tribute to the idea Pinkel and Thomas had from the start: “To hire people in multiple disciplines — physicians, pharmacists, nurses, all areas of science, providing care and conducting the studies — and to listen to everybody. You don’t know where the next great idea will come from. I work hard as CEO to maintain that culture today. Strategic plans are important, but culture trumps strategy. We insist on doctors and scientists knowing each other.
“Sure, we try to get the smartest, most committed people on the planet to come here, and we think our mission, facilities, and culture make that happen,” concludes Evans. “But at the end of the day, more progress is made because people want to collaborate.”
“Wait a minute. These kids can’t opt out.”
A few months ago, Dr. Donald Pinkel came back to visit St. Jude, and the hospital recorded a conversation he had with Evans. Some of his comments reflect just how overwhelming his job had been, trying to help children who were likely to die. “There were times,” he told Evans, “when I thought, ‘I can’t handle another day of this.’ It was devastating me emotionally. But I thought, ‘Wait a minute. These kids can’t opt out. These parents can’t opt out. What’s wrong with me?’ And my colleagues reminded me that some kids were living longer. They were free of leukemia, very likely cured.” That experience took place shortly before the success of Total V — which showed just how successful his approach had been.
Pinkel’s comments also reflect his pride in the institution he helped make world-famous and that has saved countless lives. “Visitors would say, ‘You need a Rockefeller Institute here, or an NIH.’ I said, ‘No, we don’t. We stay innovative, we stay true to what we do, we make our own decisions about where we go with our science. And we have done that. St. Jude is unique all by itself.”
The book From His Promise provided some background information for this article.