The Price of Progress

Bennie Solis was three years old when he changed medicine forever. But you almost certainly have never heard his name.

Bennie, tragically, was born in the early 1960s marked for death. He had a rare, peculiar condition called biliary atresia — a disease defined by the absence of a conduit for bile to travel from his liver to his intestinal tract. Bile acid produced in the liver normally travels to the intestines much like water from a spring travels via ever-larger channels to eventually empty into the ocean. Bile produced in the liver with nowhere to go dams up in the liver and starts to destroy it.

That the liver is a hardy organ was a fact known to the ancient Greeks, who told the tale of the punishment given to the god Prometheus for stealing fire from the gods. Chained to a mountain, an eagle would feast on his liver by day. The liver would regenerate by night to allow the eagle a full meal on its return, making this a truly eternal punishment.

So it is that the poisoned human liver remarkably continues to function, allowing beautiful, normal-appearing children to be born. It would make the eventual discovery of the disease all the more painful. How could that beautiful child harbor something so black inside?

When Bennie was born, every child with his condition had one fate: death.

And it did not come slowly. As the liver becomes progressively damaged and scarred, the flow of blood through the liver is impeded. The obstructed blood, seeking a way to return to the heart, travels through collateral channels. These vessels, normally minute and invisible in the esophagus and stomach, become engorged, thin-walled, and prone to rupture. Complicating matters further, the body lacks clotting factors that were normally synthesized by the liver, giving blood the consistency of water. The horrors only multiply. Blood pours from the mouth and rectum when vessels rupture, free fluid fills the abdominal cavity, the lack of bile in the intestine means fat isn’t absorbed, and the body starves. When death mercifully does intervene, it arrives as the liver completely loses its ability to manage toxins, sending the children into a coma.

Bennie and his parents were walking down this path when they met a young surgeon named Thomas Starzl in Colorado. Starzl was a transplant specialist who felt the only hope for Bennie and children like him was a liver transplant. Organ transplantation in this era of medicine was a fringe science. The prior decade had seen some limited success with kidney transplantation, but the liver posed much greater technical challenges. But by the time Starzl met Bennie and his desperate parents, he was buoyed by lessons learned from having performed nearly 200 liver transplants in dogs.

And so on a cold spring day, little Bennie — on an inexorable march to death — was wheeled to the operating room in a desperate attempt to replace his diseased liver with a healthy, functioning one and save his life.

They never stood a chance.

It took hours to even enter the abdomen, and every piece of tissue they cut into contained veins under high pressure that bled unceasingly. It was an elementary observation, obvious only in hindsight, that the team had glossed over. Operating on the healthy liver of a dog with normal portal pressures and normal levels of clotting factors was quite a different matter than operating on a diseased liver severely deficient in clotting factors. Unable to stop the bleeding, the surgical team watched helplessly as little Bennie died hemorrhaging. The date was March 1st, 1963.

The lesson from Bennie’s case was clear — something would be needed to make the blood clot for the next operation. And so it was that months later, with clotting factors transfusing, an adult patient with advanced liver disease successfully underwent a liver transplant. He was awake the following day, with the transplanted liver producing large amounts of clear bile.

Three more patients were transplanted successfully. But these successes were short-lived. All of the patients died of surgical complications in the weeks that followed. It turned out that the plastic tubing being used to reroute venous blood from the lower extremities while the new liver was being sewn in served as a nidus for blood clots that found their way into the lungs. There they caused abscesses and damage that contributed to the cause of death in all the recipients.

The initial liver transplant trials had failed, and a self-imposed moratorium was put into place. Kidney transplantation progressed at a rapid pace, but hope waned that liver transplantation was possible. A rising star because of the progress made transplanting kidneys, Starzl was offered leadership roles at surgical programs around the country — with the understanding that he would start a kidney transplant program. Viewing liver transplant as a dead end, many of those programs wanted nothing to do with a liver transplant program.

I pause this story to wonder if Starzl was clinically mad. At this point, he had failed repeatedly and spectacularly. His peers certainly thought he was mad — and unethical to boot. The medical and research community was particularly harsh. Immunologists shrieked: you can’t just take one person’s organs and put them in another. It was impossible. What would a surgeon know of these things? It would seem the most important quality Starzl possessed was not understanding what was impossible. It was true that many members of the team were surgeons with no formal background in immunology. This may seem a disadvantage to some, but to Starzl this simply meant they lacked the “pessimism fashionable among some of the learned.”

It is precisely these “learned” who opposed any further attempts at liver transplantation on ethical grounds. How was it ethical to proceed with this “purely experimental” process given the preceding devastating failures? Starzl defended himself and liver transplantation by proxy at the 48th Annual Session of the American College of Physicians, held in San Francisco in 1967:

“The clinical trial of new therapeutic methods is based more firmly than ever on prior animal experimentation. Virtually all practices in cardiac as well as in transplantation surgery have been transferred, almost without change, from the laboratory to the clinical ward or operating room.

Not infrequently the transition has been made with haste and with an air of urgency that, the generous may concede, was fed by the needs and wishes of desperate patients who had the misfortune of not becoming ill at a later and more convenient time. Historically, the decisions to proceed have often been wrong. Nevertheless, they have almost invariably been based on the hope, however fleeting or erroneously conceived, of potential benefit to the individual patient.

Right or wrong, the actions are eventually subject to implacable scrutiny, principally by other members of the scientific community but also by intelligent and informed outsiders. Inaccuracies in reporting, claims that cannot be reproduced, and procedures that neither relieve suffering nor prolong life are rapidly identified. Harmful practices are snuffed out quickly; homeopathic ones may suffer a lingering death, but they also ultimately disappear from the scene.

The system is ruthless and without pity and demands a policy of nonconcealment from those who would innovate in medicine. It is not sufficient to report only successes. Failures must also be fully documented, no matter how painful and humiliating these may be, in order to prevent repetition by others of the same mistakes. In general, such openness has characterized efforts in the field of transplantation.”

Part of Starzl’s fortitude lay in his perception of what he was doing. He never viewed the liver transplant attempts as causing death. These were patients already consigned to die a horrid death. Those who favor not trying talk frequently of the dignity of death, but that phrase implies there is a good death to be had. The parents of children with biliary atresia would watch their beautiful children waste away — the only treatment towards the end was socks on their hands, because the itching from elevated bilirubin levels was so intense that children would scratch their skin off. Sometimes there isn’t a good death. Importantly, family members and parents of those who died did not blame Starzl. There is also peace and dignity to be had in knowing that no stone had been left unturned in a desperate attempt to save a loved one.

Battle lines were drawn. At Starzl’s home institution — Colorado — the Chairman of Pediatrics, who had also been Bennie’s pediatrician, would support the trials in children. The Department of Internal Medicine would not.

And it was for this reason that when Starzl tried again, the next seven patients were children. The surgeries were long, arduous affairs matched only by the stays in the intensive care unit that followed. There were no teams of intensivists at the time. There was only Carl Groth, a surgeon on the Starzl team from Sweden, who would spend night and day at the bedside caring for these seven children — massaging hearts when they stopped, inserting breathing tubes for collapsed lungs, and returning to the operating room at all hours to treat infections. At the time, the outcome was remarkable. These children actually left the hospital. The bond between surgeon and patient was palpable. Pictured below is an iconic image of Carl Groth with three of the children

Professor Carl Groth with 3 long-surviving liver recipients in the summer of 1967. Julie Rodriguez is on Groth’s knee. From “The Puzzle People: Memoirs of a Transplant Surgeon” by Thomas E. Starzl, University of Pittsburgh Press, 1992.

These outcomes were markedly better than before and proved to the world that liver transplantation was a technical possibility. But there were still large obstacles to overcome. Four children died within six months due to infections that developed in the transplanted liver. The three surviving children died one or two years later. There were so many painful lessons to learn. Two of the surviving three children had been transplanted under the belief that primary unresectable liver cancer could be treated with a liver transplant, at a time when X-rays were the primary tool used to look for metastatic disease. Recurrent, widespread cancer claimed these two children. The child that remained was Randy Bennett. He was two and a half when he was transplanted. He died at four and a half of complications related to chronic rejection of his transplanted liver.

The tale of the tape was harsh. By 1969, 26 patients had received a liver transplant. Six lived beyond a year. All were dead within two and a half years of transplant. And still, the team kept going. From 1963 to 1979, 170 patients were transplanted. Only 29 survived. The question asked with growing urgency of the few centers that still persisted was how they could keep going. It was the rare successes that gave the transplant team hope. The pessimists focused on failure.

It turned out that the barrier to long-term survival was not the surgery, but dealing with post-operative rejection of the transplanted organ by its host. Long-term survival would require advances in the nascent field of immunology as applied to solid organ transplants. The hero in this tale was a Swiss pharmaceutical company called the Sandoz Corporation, which had discovered a drug called cyclosporine. One of their immunologists, Jean Borel, had shown that this drug narrowly suppressed the immune system, and the subsequent animal experiments with rejection had been remarkable. The story was almost too little, too late — Sandoz Corporation executives had decided to abandon the drug due to cost and what was perceived as a limited market. Luckily, a team in London led by an English transplant surgeon named Roy Calne flew to Basel, Switzerland, to appeal the decision and allow human clinical trials with the new drug for kidney transplant to proceed.

The English had a head start on Starzl, but the early data from England gave him pause. Cyclosporine turned out to be toxic to the kidneys at the dosages being used. A close collaboration between a Sandoz scientist named David Winter and Starzl began as they planned clinical trials in the United States. Over the phone, David Winter read the pathology reports of kidney biopsies that demonstrated, first, kidney injury from the drug and, second, injury from uncontrolled rejection. Starzl decided that monotherapy with cyclosporine would be the wrong approach for the US trials. Using prednisone concomitantly with cyclosporine early on would allow lower doses of cyclosporine and less drug-related nephrotoxicity. Luckily, David Winter from Sandoz agreed, and the trials began. Just days later, results from the English team were published. Starzl’s fears had proven well founded — all the patients in the English trial had evidence of kidney damage, three patients had developed leukemia, and five of the patients died.

Opposition to the trials from the medical community was now significant. In England, Roy Calne faced opposition from anesthesiologists who refused to participate, deeming the surgeries “macabre and unethical.” Nephrologists at Starzl’s home institution circulated a letter to all nephrologists in Colorado inviting comments on “immoral and unethical situations” that had been observed related to transplant.

Yet Starzl persisted, and this round of kidney transplants with cyclosporine was a stunning success. Just as negative results from Europe and Boston were pouring into Sandoz and the company again contemplated abandonment of the drug, the Colorado protocol kept cyclosporine alive. Replication of the Colorado results in other US centers was more than proof of life, and a new era in transplantation finally dawned.

The next steps and hurdles to overcome would take place where I grew up, in Pittsburgh, Pennsylvania. The Colorado transplant program was falling apart, and the University of Pittsburgh’s Chair of Surgery — who had trained with Starzl at Johns Hopkins — recruited him with a promise to support his liver transplant endeavors. Starzl arrived in Pittsburgh and quickly got to work. Unfortunately, the first four liver transplant recipients in Pittsburgh died.

The pressure was intense. Callers into local radio stations demanded that the program be closed.

But the fifth transplant recipient lived. And so did the next 22.

The success transformed Pittsburgh into a haven for patients from around the world who had no interest in dying with dignity from their liver disease. The hospital wards filled with patients at the edge of death. The influx of these patients to the medical services was resisted by the medical residents and interns. On June 30th, 1981, the entire medical training program signed a resolution denouncing liver transplantation as an unrealistic objective and an “unethical pursuit.” Starzl shrugged, and from that point on admitted all these patients to his own surgical service, which at the time consisted of two surgical residents and two attendings.

Thomas Starzl was a steamroller, a crusader imbued with religious zeal. Once biology had bowed to him, administrative and bureaucratic obstacles were like annoying gnats to be swatted away.

The story is an important one because in 2026, we are seemingly awash in medical therapies that either don’t work or produce marginal benefits, driven by a permissive regulatory structure that all too often bends the knee to those primarily motivated to improve shareholder value. The rare disease community of patients has, at times, been used as pawns in a larger game to put products on the market that not only do not extend life, but may prematurely end it. The difficulty for evaluators of medical evidence is that a too-rigid structure for assessing clinical value risks filtering out therapies that actually help desperate patients. Progress in science — and especially in medicine — is a very messy affair, punctuated by repeated failure.

A trial that fails to show benefit doesn’t necessarily mean the therapy tested has no effect. Researchers and clinicians embedded in the research enterprise may be the only ones with the insight to identify a subgroup of patients that could benefit. Closing holes in the heart thought to be a conduit for strokes was tested in a set of randomized controlled trials that were all resoundingly negative — but that was because the patient selection criteria had been too broad. Three additional trials using stricter entry criteria did show benefit. It may be hard to see, but failures like these aren’t a bug in the system. They are a design feature.

The optics of doctors and researchers working with industry naturally leads to public skepticism about financial motives coloring research outcomes. The immediate impulse is to dismiss any research from this union as suspect, but industry-supported research has been responsible for some of the biggest breakthroughs of the last century. Everyone knows someone who is alive today because of an advance made in the lab of a private corporation. Starzl worked closely with companies that had promising immunosuppressive agents. Thank goodness he did.

Starzl’s rise came at the same time the US FDA was moving to standardize the evaluation of new therapies, following the 1962 Kefauver-Harris Amendment signed into law by President Kennedy. No longer could pharmaceutical companies market their products to physicians and let physicians decide whether to prescribe them — a therapy now needed a stamp of approval from the FDA that it actually worked. This was to protect the public from a medical-industrial complex that was foisting non-working therapies onto a gullible public. New therapies needed to be tested, as much as possible, with randomized controlled trials comparing control arms to treatment arms. Starzl was furious. He decried the ethics of taking a drug that had very strong data in what amounted to a single-arm trial in his hands, and then being forced to randomize a patient who was rejecting a transplanted organ to possibly receive a placebo. He even coined a term to describe the new era: randomized trialomania.

There were many who opposed Starzl and liver transplantation for ethical reasons, and they were not bad people. They just could not see what Starzl saw. And it is certainly the case that for every man like Starzl there are countless other Don Quixotes, futilely charging at windmills with no chance of success. A working system quickly figures out what works and what doesn’t. A poorly working system gets stuck in a dead-end loop. I fear the system has gotten worse, not better, since Starzl’s time. We are more compassionate than ever when it comes to funding treatments for patients with rare diseases through government programs, but this means zombie therapies survive longer because a government billing code is essentially forever.

An example of a zombie therapy in Starzl’s time was whole-body irradiation for immunosuppression, modeled after the observation that some survivors of massive radiation disasters — like Chernobyl, Hiroshima, and Nagasaki — were left severely immunodeficient. Doctors created protocols to irradiate patients after transplanting organs in order to weaken their immune systems enough to accept the foreign organ they needed to survive. There was some longer-term success with this approach in fraternal twins, but everyone else died fairly rapidly of cancer or infection. This approach was abandoned quickly once medications that suppressed the immune system were discovered. But I wonder how long this therapy would have lasted if there had been a billion-dollar company selling the technology — one with influence over politicians and the FDA, and an army of retail investors with a financial interest in keeping the revenue flowing.

Regardless of the era, the pessimist is a vital part of the epistemic landscape, because most attempts at progress in medicine will fail and need to be called out in real time. But we also need the relentless optimists, because just maybe one of them will break through and make the impossible possible.

Some have a utopian ideal that advancement in medicine may take place in some sanitized fashion that avoids needless dead ends. Yet travel in uncharted territory means that dead ends aren’t known beforehand. The eventual success of organ transplant was built on the crumpled, tiny bodies of children. Knowing what we know now, it seems utterly foolish that Starzl would have attempted that first transplant on Bennie Solis. But he did.

And I can’t thank him and Bennie enough.

Because twenty-seven years later, another little girl was transplanted. This time it was my 13-month-old daughter. She had been diagnosed with biliary atresia when she was three months old. I remember the phone call and the details of the day I found out like it was yesterday. On arriving home from the doctor’s office, I cradled her little body in my arms, took her to my bed, and sobbed. Transplant was mentioned, but I couldn’t comprehend it. The truth is that most physicians don’t know much about transplants because it remains a relatively rare procedure done at a smattering of academic centers. Pediatric transplants are even rarer. Transplant was no great solution in my mind — what I knew about transplant as a cardiologist in training came from dealing with sick patients on inpatient heart failure units suffering complications of rejection or immunosuppression. But as the year progressed and my little girl got worse, a transplant became her only hope. Ten months later she was in the hands of transplant surgeons in Pittsburgh, in an operating room where Starzl, now retired, still loomed large. Hours later she emerged. She had been yellow for as long as I could remember.

And now she wasn’t.

By the time Ishani was transplanted, five-year survival was close to 95%. The procedure had become routine. Today, it is rare to die from biliary atresia. A little girl transplanted in 1970 — at a time when most wanted Starzl to stop what he was doing — Kim Hudson, was alive and thriving in 2012. She has the distinction of being the longest-living liver transplant recipient.

As of this writing, that little girl marked for certain death when she was born has just started her freshman year in college. A miraculous gift, to be sure. Being a physician dad has its advantages, but it also instills a very specific set of worries as I look into the future. There is little question that the highly corporatized version of healthcare we have now commodifies physicians to an extreme degree and burdens them with a very heavy bureaucratic hand. Starzl was no stranger to navigating hospital and even national politics to forge a path, but it certainly feels like the paths to radical innovation are narrowing.

Starzl believed the system was ruthless and without pity — that harmful practices would be snuffed out quickly and the rest would ultimately disappear from the scene. I’m not sure that’s still true. The system he trusted to self-correct may have grown too large, too entangled, and too profitable to fail cleanly.

Thomas Kuhn, an American historian and philosopher of science who influenced Starzl greatly, noted that the barrier to scientific revolution was scientific dogma committed to existing paradigms. Starzl wryly noted that the changes he sought to bring into practice were resisted by members of the transplant community who were hung up on protocols he himself had written ten years earlier. There have been no fundamental paradigm shifts in the world of transplant since Thomas Starzl. What exists today is the surgery he developed and the same immunosuppressant he helped bring to fruition: FK506, or Tacrolimus. What we have is light-years ahead of the early days of transplant — but is this the best we can do? Is Starzl’s long dream of protocols to allow tolerance of a transplanted organ without the need for lifelong immunosuppression a pipe dream? Or has the system made it too hard for the next Starzl to overturn established dogma?

Innovation, revolution, and paradigm shifts are not easy in any system, but they are a hallmark of successful civilizations — and conversely, the fall of great empires is often heralded by the capture of important institutions by incompetent bureaucrats. There certainly appears to be a problem in the FDA-biotech-NIH ecosystem, which seems increasingly gamed by researchers and companies alike to spend an enormous share of the nation’s dollars on marginally useful or outright harmful therapies. When I then hear physicians who run institutional medicine talk about making healthcare great by focusing on food deserts, population health outcomes, public reporting, and value-based care, I wonder if we have reached a tipping point we cannot return from.

Because none of that is what made healthcare great.

It was always the people — Thomas Starzl, Carl Groth, David Winter, Bennie Solis, Julie Rodriguez and countless others whose names won’t be recorded anywhere. The challenge now, more than ever, is to figure out how to get out of their way.

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Thomas Starzl passed away peacefully at his home in Pittsburgh March 4th, 2017. Ishani started her freshman year of college in the fall of 2025.

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Anish Koka is a Cardiologist in Philadelphia. He writes on medicine and health policy. Follow him on @X : @anish_koka