Freireich's Fight: Making Progress Against All Odds

Emil J. Freireich, MD, DSc

Emil J. Freireich, MD, DSc, was the originator of combination chemotherapy, the primary architect of the first cure for a systemic cancer, a major contributor to the cures for half a dozen other systemic cancers and, quite possibly, the man who did the most to transform MD Anderson from a minor facility to one of the world’s leading cancer centers.

He is also a man who has been fired 8 times during his career—a fact that astonishes both total strangers and his closest friends. Strangers are naturally amazed that a man who ranks among the greatest medical researchers of the past century has ever been fired. Friends, on the other hand, tend to be amazed that the 90-year-old has not been fired more frequently.

Many scientists fancy themselves daring truth seekers who follow the evidence wherever it leads, damn the consequences, damn the bureaucracy, and damn the feelings of those who are too timid or too dense to embrace the truth. Freireich actually is such a man, and his unrelenting commitment to all-out war against cancer has led to a life of both incredible achievement and unending conflict, not only with the disease that he swore to defeat, but also with many of his ostensible allies in the war against it.

He is credited with establishing the efficacy of combination chemotherapy and neoadjuvant therapy in acute lymphoblastic leukemia (ALL). He also advanced the science of allogeneic bone marrow grafts and has helped pioneer and molecular genetics in patient care.

Freireich still lives with his wife, Haroldine Lee Cunningham Freireich, in the home they bought after a single day of house hunting 50 years ago for the simple reason that he’s been busy with more important things for the past half-century. “I will keep working, assuming they will not actually have security throw me out,” said Freireich, who is the Ruth Harriet Ainsworth Chair, Developmental Therapeutics, at MD Anderson. “I will not stop until I die. I do not want to relax. There is nothing else. I want to cure cancer, and I’m willing to suffer whatever abuse I need suffer to test as many ideas as possible. I could even endure all those 20-somethings in Washington telling me I know nothing about cancer, but for the fact that they control all the grant money.”

Blood Transfusion Breakthroughs

Actually, Freireich would welcome the insults of 20-somethings, if they were mocking an old man’s conservatism. Science, he believes, progresses when the daring ideas of each new generation unseat the ossified convictions of its elders. What terrifies him is that an overly conservative system has so neutered younger scientists that they are more timid than researchers who supplement their salaries with Social Security.Things were very different in 1955, when a 27-year-old Freireich took a job with the National Cancer Institute (NCI) to escape the draft and, on the strength of a hematology residency, ended up in charge of the pediatric leukemia ward, free to give children nearly any treatment he found promising. The resources at the brand-new facility were unbelievably plentiful. Staff outnumbered patients. Labs stocked every conceivable new technology. Researchers received whatever funding they needed.

The most important advantages, however, may have been several intangibles. Freireich took his job less than a decade after the invention of the modern medical trial, and he was among the first people to apply the technique to cancer. He also had the good fortune to serve a generation of people forged by World War II, people who thought it normal to take great risks in pursuit of great ends. When he received the job assignment, his new boss said, “I’ve got a good idea for you. Cure leukemia.” He meant it.

Still, it would have been hard for a visitor in the pediatric leukemia ward circa 1955 to imagine that such advantages would have enabled Freireich to save any of his young patients. Only a few years had passed since Sidney Farber had devised the first treatments that had any effect on systemic cancers, and the newest treatments available to Freireich only managed to let the children suffer a few extra months before they died.

The ward looked like a butcher shop. Children bled from their eyes, ears, mouths, noses, and the skin around their nails. Nurses repeatedly changed each patient’s bloodied sheets, and they spent their idle minutes scrubbing blood off the walls. Idle minutes were scarce, however, even in a half-empty ward, because the staff spent so much time racing from emergency to emergency, trying to keep internal bleeds from killing patients.

Freireich decided that the only way to buy himself enough time to address his patients’ leukemia was to get the bleeding under control, so he began to study their blood. What he saw looked normal, except for a near total absence of platelets. He therefore took his own platelet-rich blood, mixed it into patient blood, and found that the platelets made it behave normally.

Others had made similar observations long before Freireich, but he was the first to isolate the clot-inducing lipid inside platelets (now known as platelet factor 3) and, more importantly, the first to figure out why it was impossible to reproduce the results of the blood-mixing experiment by giving patients with leukemia banked blood from healthy donors. Platelets in donor blood, his simple observations revealed, disintegrated in about 48 hours regardless of whether the blood was refrigerated or stored at room temperature.

Freireich hypothesized that transfusions of fresh blood would prevent his patients from bleeding to death, so he enlisted 30 volunteers to provide a full transfusion for a single patient. The fresh blood stopped what would have been a fatal bleed and enabled Freireich’s 4-year-old patient to form clots normally for a couple days. The bleeding then returned, but fresh transfusions kept stopping it, so Freireich inferred that fresh blood would help all his patients, and he demanded it from the blood bank. The blood bank, however, refused on grounds that success with a single patient was not enough to overturn conventional wisdom about the efficacy of blood storage and justify the enormous effort required to provide fresh blood.

Freireich denounced this logic in terms that made a lifetime enemy of the man who ran the blood bank, a man who demanded a randomized trial of fresh blood before he would supply it and then, when the results demonstrated that fresh blood virtually eliminated bleeding problems, accused Freireich of rigging outcomes and tried to prevent the resulting paper from being published. Fortunately, Freireich’s boss backed him and the paper’s publication in the New England Journal of Medicine proved a breakthrough, not only in the treatment of leukemia but in the treatment of many diseases that cause dangerous bleeding.

Freireich and a colleague then experimented to see just how many platelets, and how frequently they were given, would keep patients safe from bleeding, while he and another colleague built a system for sending a unit of drawn blood directly to a centrifuge that spun out the platelet-rich plasma, returned the rest of the blood to the donor, and pushed the plasma into a bag that held a unit of normal blood, taken at the same time from the same donor.

Freireich and a third colleague then paid homeless men to participate in a trial that demonstrated that healthy donors could safely give 2 units of double-platelet blood per week. This output, by a very happy coincidence, was exactly enough to sustain a bleed-prone patient for a week. Essentially, Freireich figured out that a single person could safely donate enough blood to keep a loved one clotting normally forever, and he built a system that made the whole process easy. Subsequent research has made some improvements, but the basic system remains in use today and it has saved millions of lives.

Once Freireich had the bleeding under control, he turned to the next most pressing problem, which still was not leukemia itself. It was infection, which had been killing nearly every patient who didn’t bleed to death. Careful examination revealed that the blood of patients with leukemia had virtually no neutrophils, and careful experimentation demonstrated that people needed a certain concentration of these neutrophils to fight off infections normally. The relationship between neutrophils and infections was, in almost every respect, a perfect parallel with the relationship between platelets and bleeding, but the transfusions that stopped the bleeding provided far too few neutrophils to defend against infection. The only way to protect patients against infection was to regularly give them the number of neutrophils contained in all the blood of a healthy donor.

It was, Freireich quickly realized, impossibly arduous to get enough neutrophils for a large number of patients by drawing donor blood pint-by-pint and putting each pint into a centrifuge. He needed a device that could separate a continuous flow of donor blood and send the neutrophils into a bag while it sent the rest of the blood back into the donor. Just as he was imagining this device— which would have to work fast enough to separate an entire body’s worth of blood in a reasonably short time—an IBM engineer, whose son was being treated at NCI, knocked on his door and asked if he could do anything useful to help with cancer research. Freireich gave the person a list of the 7 properties he thought a continuous blood separator would need and hoped for the best.

The engineer, whose name was George Judson, convinced IBM not only to give him a paid sabbatical so he could design the device, but also to donate parts. He set up shop at NCI and spent the next few months assembling prototypes out of spare parts while Freireich tested them with expired blood from the blood bank. When they thought they had a device that worked pretty well, Freireich went to his boss and asked to test the absurd-looking and unprecedented contraption on human subjects. Somehow, he got the green light. The pumps worked poorly and the seals leaked, but the device worked well enough to serve as proof-of-concept. Freireich and Judson had clearly achieved a breakthrough.

The NCI paid IBM to make a professional version of the same basic design and the resulting product dominated the market for continuous blood separators for more than 5 decades. It was another world-changing advance that saved millions of lives and gave researchers a powerful new tool that has benefited every corner of hematology.

“These days, getting permission to undertake any individual step in the platelet or neutrophil projects would take longer than the entire actual duration of either project back then. Worse, there is no way you could get permission to undertake many of those steps today, not unless you wasted the better part of a decade with intermediate steps. A young researcher who suggested using that jury-rigged blood separator on a live human today would probably be fired on the spot, and anyone who thinks this reflects well on modern safety procedures is a fool who doesn’t understand how to weigh potential risks and benefits,” Freireich said.

Combination Chemotherapy

“It isn’t like no one sounded the alarms back then. There were plenty of people who denounced the experiments we did. But we had the guts to tell them they were fools, and we had the incredible luck to have a boss named C. Gordon Zubrod, who understood what people working all-out can accomplish,” said Freireich, referring to the longtime scientific director of the NCI. “He put his career on the line time and time again to help us keep moving quickly on something of real importance.”When Freireich first came to NCI, methotrexate, corticosteroids, and 6-mercaptopurine (6-MP) were the only drugs known to have some therapeutic effect in patients with ALL. Methotrexate, often produced remissions of 2 or 3 months, but the cancer always returned. The other 2 drugs just slowed the cancer’s progression slightly.

Each of the 3 drugs was always used as a monotherapy until Freireich read how medications that only ameliorated tuberculosis when used sequentially could cure the disease when used together. He advocated a combination that added two-thirds the normal dose of methotrexate to two-thirds the normal dose of 6-MP. A few weeks later, Freireich was running trials with several colleagues and finding that remissions were becoming more common and more durable. He added a full dose of the steroid prednisone, and the remissions were more common and more durable—but they were never permanent.

The missing piece came when Eli Lilly tried to sell the NCI vincristine, a new drug derived from periwinkle. Many experts, including Freireich’s boss, thought the new drug was more likely to harm patients with ALL than to help them, but Freireich talked Zubrod into approving a tiny trial by arguing that even the worst poison couldn’t harm the patients who were days away from death. The drug produced an almost immediate remission in the first patient, and the second, and the third.

The overall response rate in the first trial of vincristine on pediatric ALL was 55%, which was far more than any drug before it. Still, the cancer kept coming back. This changed when Freireich asked for permission to add vincristine to the other 3 drugs and give all 4 in a combination that came to be known as VAMP. Even Zubrod and Freireich’s adventurous colleagues at NCI thought it nearly mad to propose a 4-drug combination that included a virtually untested drug; yet, Freireich sold them on what became another big step forward. All but one of the first 12 children went into remission with a single course of the combination, which was delivered over 2 weeks.

Leadership in Field

Freireich, however, knew that even the most impressive remissions were no proof of cure, so he proposed something even more radical: giving patients another 3 courses of the VAMP protocol while they remained in remission and appeared healthy. He again secured permission to proceed and produced one of the most celebrated trials in the history of cancer treatment. Most of the first 27 patients to receive the extra treatments still relapsed, but almost a quarter of them were permanently cured—a first in the battle against systemic cancer that would have been utterly unthinkable just a few years before.Just a few months later, when Freireich should have been gracing magazine covers, he was effectively fired from the NCI. Zubrod had just moved on, and Freireich, for all his achievements, could not survive without his protector.

“If they gave the Nobel prize in medicine for clinical advancements, rather purely scientific discoveries, Emil J. Freireich—who’s known to friends as Jay—would have been on at least 3 different prize-winning teams for the work he did at NCI. The thing is his run did not end there. After he jumped to MD Anderson in ’65, he put together a team that leveraged his insights in combination chemotherapy and other areas to create treatments that have become curative for many other cancers,” said Bart Barlogie, MD, a Freireich protégé who has made breakthrough advances in the treatment of multiple myeloma and built a world-class myeloma institute at the University of Arkansas for Medical Sciences.

“He did as much as anyone to make Anderson the top cancer research center in the world. He attracted a huge amount of young talent that would have gone anywhere to work with him,” said Barlogie, who is now at Mount Sinai Health System in New York City. He also made those researchers enormously productive by repeatedly urging them to be bold. Even administrators couldn’t stop him and his team from pursuing what was in the best interest of patient care.

Today, even Freireich’s detractors acknowledge the importance of his breakthroughs, but it would be a mistake to think that anything like universal acclaim greeted many of his discoveries. Many of the nation’s pediatricians initially refused to use the VAMP protocol on grounds that it was inherently monstrous to poison children so aggressively. This was true even among pediatricians who specialized in cancer care. Medical journals published savage attacks on VAMP and those who had created it.

Indeed, when Freireich went to MD Anderson to head the pediatric cancer division, the doctors who nominally worked under him refused to treat pediatric ALL with VAMP. Instead, they gave the medications individually, which produced temporary remissions but eventually ended in patients’ deaths. When Freireich tried to change this, they argued that his lack of formal pediatric training made him unfit to care for children and they forced the administration to give him a different job.

Part of this, no doubt, had no cause beyond the extraordinary novelty of combination chemotherapy and its horrific toxicity, but many believe that Freireich’s tendency to denounce skeptics, rather than persuade them, reduced his influence and kept him from achieving even more. Freireich, on the other hand, believes the blunt truth is a scientist’s best friend and regrets nothing—except the proliferation of red tape that does ever more to hinder human accomplishment.

“Every time someone makes a mistake, someone else adds a procedure to prevent that particular type of mistake, and it has had a devastating effect on researcher productivity. Every minute a talented researcher spends filling in a form is a minute that researcher cannot use for actual research,” he said. “The other problem with all these procedures is they create both a terror of failure and a terror of any success that pisses off important people. I am not arguing that researchers should not weigh the potential costs and benefits of experiments. I am arguing that small groups can weigh such matters over the course of a few days as effectively as large ones can weigh them over the course of a few months. I am arguing that 10 lives lost to inactivity is worse than 1 life lost to an experimental treatment. And I’m arguing that the best way to spread knowledge is to speak the truth bluntly.”