Book Summary: The Puzzle People

Memoirs of a Transplant Surgeon

Thomas Starzl's The Puzzle People is a few things: the autobiography of a pioneering transplant surgeon, a fascinating perspective on a bygone medical system, and, honestly, a simultaneously inspiring and intimidating example of work ethic. Its also a lyrical and moving autobiography, and one of the best-written books on medicine I’ve ever read.

Origins

To set the scene: Starzl was born in 1926, trained and practiced medicine from the 1950's to the 1990's, a gloriously productive time of medicine which also had a dark side: exclusion of US Blacks and women from medical school for the first few decades; sub-standard care for minority patients, and a workaholic culture that puts modern-day hard-driving surgeons to shame.

Like many scientific pioneers, he was gifted from a young age. He performed very well in school, was a decent musician, and played a few sports. More than his ability, however, what stands out in these pages is his abnormal and frankly unhuman work ethic. We witness the following juggling act early on: while in medical school, he finds the time to work nights and weekends as a medical assistant for an industrial surgeon and perform genuinely useful and important research in neurophysiology for a PHD. In addition, he also acquires a cadaver of his own to further practice anatomy, and dissects it on the weekends. Thus, even as a young man, Starzl displays his core trait of extreme drive, along with excellence in basic research, and devotion to patient care.

Residency at Hopkins

He ends up at Hopkins, the only time when his colleagues seem as inhuman as him: in those days, Hopkins had a pyramidal style surgical training program, where only 2 of the 18 starting surgical interns would actually finish the training program. The rest, gradually, would leave to other programs. They were on call 24/7, every day of the year except a one-week vacation each year. He sticks it out nearly to the end, but is told he would not be offered a 6th year of residency, so he leaves to Jackson Hospital.

There we find stark descriptions of the primitive conditions physicians worked under: patients with kidney failure simply died in the era before dialysis and transplants; vascular and cardiac surgery required cadaver vessels that surgeons had to acquire themselves; and once, in the midst of a complicated operation, the power in the hospital simply went out, and Starzl had to continue operating with the assistance of nurses holding hand-held flashlights and ophthalmoscopes.

Much of Florida was deeply segregated in those times, and Black patients were given worse medical care in worse facilities, and often barred from medical education altogether. He tells the story of a Black research assistant back at Hopkins, Vivien Thomas, who was a collaborator of Dr. Alfred Blalock, a key figure in the history of surgery who made important advances in the treatment of shock and in cardiac surgery. Thomas began work in his lab as a research assistant, received pay as a janitor, but was effectively a postdoctoral researcher for Blalock. Late in life he obtained many of the honors he deserved, receiving an honorary doctoral degree, though never an MD.

Starzl's lifelong interest in the liver seems to have begun sometime here. As he describes it, he "felt like a missile looking for a trajectory", full of drive, but paralyzed by the fear that he was wasting his talents in dead ends of research. After Florida he takes a one-year fellowship in thoracic (chest) surgery, though he continues liver research on the side. In Chicago, he and his wife perform garage experiments on dogs, trying to transplant livers and generally failing, as the dogs die in days.

In some ways, 1958 is Starzl's first big break: he passed his boards, is awarded an NIH grant for research, and then receives an additional Markle scholarship. The stage is set for him to devote his full energy to research, and in short order, Starzl and a surgical resident have perfected the technical aspects of a liver transplant. Dogs now die in a week from immunological rejection, not from the physical trauma of the operation.

This consists of a two-part advance: they figure out a better preservation strategy for the liver involving a cooled saline solution instead of an ice bath; and a venous bypass system to maintain normal circulation while the liver is being transplanted. While other surgeons are working on approximately the same problem, Starzl's group has slightly better survival times. Still, Starzl knows that without a treatment for rejection, transplantation between non-identical persons is useless.

He delves into a research dead-end in the 1960's with multi-organ transplant, under the hope that transplanting multiple organs at a time will overcome the host response, but this fails. There had also been earlier failures in other labs of using whole-body radiation therapy to cause immunosuppression— while this worked for preventing rejection, it worked too well, and the animals all died of overwhelming infection. The first glimmer of hope comes with the introduction of 6-mercaptopurine by Zukowski and Calne, two other researchers. Kidney-transplanted animals treated with 6-MP could live as long a month, constantly veering between too much and too little immunosuppression.

Around the same time as he received his initial research funding, Starzl had moved his growing family to better accommodations. This brought with it higher expenses, and due to some administrative restrictions, he was not permitted to do extra clinical (higher-paying) work at the hospital where he did his research. Again, Starzl's extreme energy shines— instead of doing the sane thing and finding a new position, he instead decides to begin working at nearby private hospital simultaneously.

He operates in the early mornings, then fulfills research obligations and clinical duties at his main hospital in the afternoon and evenings. His description of this time:

Life had become a round-the-clock nightmare. I made a special arrangement with the Lutheran sisters that allowed me to operate early in the morning beginning at 6:00 or 6:30 A.M., complete a major case, and arrive in the experimental laboratory at North-western University or on the clinical ward at the Cook County Hospital by 9:00 or 10:00 in the morning. Work there usually lasted long past dinner time so that evening rounds or examination of patients to be operated on the following day put off returning home even more. Knowing that fatigue was my enemy, I learned to fall asleep in strange places by closing my eyes tightly and imagining a tapestry of bright colors or a maze of glittering lights. When these began to turn and spin, sleep was close behind. It was like self-hypnosis. I was always wide awake or sound asleep, never in between

Move to Denver

Even Starzl could not maintain this pace for long. He gets offered a position at the University of Denver as Chair of Surgery, with the personal mission of making liver transplantation a clinical reality. Of course, since even kidney transplants are dismal failures at this time, the "road to the liver was through the kidney". Here's an interesting aside: while Starzl acknowledges the intellectual debt owed to Dr. Joseph Murray, who performed the first successful kidney transplantation between identical twins and won the Nobel prize, it is clear that he thought the biggest hurdle was rejection, and seems to hold Sir Peter Medawar, the father of acquired immunity, in higher esteem than Murray.

In 1962, with the combination of 6-MP, steroids, and some radiation, Starzl and his team successfully transplant a kidney from a mother into her sick son, and it works for a few years. They have a few more successes in this vein that embolden them, and by March 1963, they try the world's first liver transplant on a 3-year old, Bennie Solis, who was born with biliary atresia.

Reflecting on this evolution of events in the early 1960s, Willis Potts, a pioneer pediatric surgeon in Chicago, described biliary atresia as the blackest chapter in pediatrics. The victims of the disease seem normal at first, and they remain that way long enough to come into their new families, be loved, and leave those images which have no time to be created by the hapless stillborn infants or babies who die just after birth. The children with biliary atresia have personalities. In some cases, their slow transformation to physical pariahs only increases the affection which they receive. Their spindly and easily broken limbs often grow in the wrong direction off globular bodies that are increasingly bloated by enlargement of the liver and spleen, and by the accumulation of free fluid in the abdominal cavity (ascites). When death finally comes, it usually is from coma caused by the liver failure, or bleeding caused by the portal vein blockage combined with the inability of the failed liver to make clotting factors.

They fail, and Bennie dies on the operating table from massive bleeding. This teaches a valuable lesson: the coagulation problem that patients in liver failure experience must be addressed before an operation, or their inability to clot will mean death from exsanguination. They fix this problem with the infusion of clotting agents intraoperatively, and perform a handful of liver transplant cases, but patients died within 30 days or so, from clots in their lungs. The team enters a self-imposed moratorium (a point Starzl returns to repeatedly: the self-regulation by physicians on ethical and pragmatic grounds, before any formal system of "bioethics") on liver transplants and focuses on kidney transplantation, where they achieve the world's best results in long-term survival using the combination of high-dose steroids and 6-MP. Starzl publishes a case series on this, then a book, Experience in Renal Transplantation , which are initially met with incredulity by other surgeons.

Kidney Transplantation Becomes Reality

Gradually, they come to believe his team's results. The net effect of Starzl's protocol was to make living related-donor kidney transplantation a somewhat clinically practical treatment, and in a phenomena that will recur later on, opens a clinical "gold rush". Other centers send surgeons to learn from Starzl's team so they can open up their own transplant centers, and these go on to become the leaders in kidney transplantation for years to come. Starzl's center becomes a kind of modernist medical temple for surgeons to take pilgrimages to. Another physician, Roy Calne in the UK, reappears periodically in this story as a kind of mirror to Starzl, who is pushing the field forward in his own country.

And yet Starzl is acutely aware of how far is left to go: state laws in the 1960's still used cardiac death instead of brain death, which meant cadaver kidneys inevitably faced some degree of hypoxic injury; living donors were in short supply; and the immunosuppressive regimen (still principally high-dose steroids and 6-MP) they used was causing severe disease years after the surgery in the form of bone disease, peripheral neuropathy, diabetes, exotic viral infections, and cancers.

There's also a personal setback: Starzl becomes quite ill with Hepatitis B, as do many other transplant surgeons, because many of their transplant patients were harboring the virus, and at that time there was no antigen test or vaccine for it. The next research focus of Starzl is tissue matching, which unfolds into a dark tale of bureaucratic obstruction and retaliation.

Outside of better immunosuppressive drugs, quantifying the degree of similarity between donor and recipient with tissue matching should theoretically lead to better outcomes through less rejection. Paul Terasaki, a gifted scientist who did very important work on the Human Leukocyte Antigen, collaborates with Starzl on trying to develop a tissue matching test for unrelated living donors. Their early tests in 1966 show some promise, but by 1969, they both conclude that it doesn't predict graft survival.

 By 1969 the NIH had poured quite a bit of money into this research program, and "a cottage industry of clinical tissue typing" had grown up. When Starzl and Terasaki report their subsequent negative findings in 1970, they both face various kinds of reprisal from the NIH, and have their funding unexpectedly ended after emergency site visits.

Starzl's group refocuses on liver transplantation in dogs, which in contrast to kidney transplantation, had not yet produced any long-term survivors. Over time, as their surgical technique and medical regimen are perfected, they produce a handful of long-term survivors, some of which, intriguingly, manage to avoid rejection after medication discontinuation. This mysterious property of liver transplants, in which some recipients develop long-term tolerance to their graft, is still today poorly understood.

While these successes were interesting, a fundamental problem remained: the dogs had received living liver grafts, not cadaver grafts. Since people have only one liver, all liver grafts had to be cadaver grafts, and so the results were fundamentally inapplicable to patient care. To Starzl, the failure of tissue matching to improve outcomes, as well as the still low rates of success with cadaver kidneys, meant that better medications were the only way forward.

Thus, when Medawar gave a lecture on the possibility of using anti-lymphocyte serum on transplant patients, Starzl was already preparing for clinical trials with an anti lymphoid globulin solution his team had devised. There is a valuable digression here from Starzl on the downside of scientific societies-- Starzl, who was an early founder and vice-President of the American Transplantation Society, viewed the dogma that he himself had developed, of 6-MP and steroids, as impediments to progress. Clinicians were reluctant to accept that a new medication regimen might be better and clung to past habits.

In 1966, the trials at Denver demonstrated ALS's value in preventing rejection early on, and Starzl moves on to attempt liver transplantation once again. This time, of the 7 children transplanted, all survive the immediate post-operative period, demonstrating the improved surgical technique, the progress with replacing clotting factors, and improved anti-rejection medication. However, 4 die within 2-6 months, and the other three survive only about a year after transplant.

Much work remained to be done on better anti-rejection medications, as complications of that or recurrences of cancer had been the main killers of this early group of patients. Though Starzl's group treated about 170 patients with liver transplantation from 1963 and 1979, only 29 had survived into the 1990's, implying relatively poor survival rates.

Perhaps somewhat deflated by these lackluster results, Starzl effectively puts his research programme into liver transplantation on life support when he became the Chairman of Surgery at Denver. There were some important discoveries made by his group, such as the hepatotrophic role of insulin, but for the few years he was chairman, he made comparatively little research contributions. The fundamental need for better anti-rejection medication remained.

In 1973, the federal government extended Medicare coverage for patients with end-stage renal disease. As Starzl puts it:

The economic plight of patients and their families was relieved in 1973 by the federally mandated End-Stage Renal Disease (ESRD) program. The new system originated in 1972 with an amendment to the Social Security Act. It was one of the most noble examples of health care legislation in history and a step toward "socialized" medicine. In fact, it was socialized medicine for end-stage disease of one organ, the kidney. This legislation created overnight a national network for the care of patients with kidney failure. The govern-ment would pay the bill for both dialysis and transplantation At the same moment, the federal flow of gold created a potential economic aristocracy of medical kidney specialists who provided artificial kidney services, and a disincentive for transplantation. In Denver, for example, where the only artificial kidney facility had been at the University of Colorado with Joe Holmes, a dozen private facilities sprang up overnight. There were too many centers to be profitable if their patient ranks were thinned by systematic removal of patients for transplantation.

Starzl demonstrates intellectual integrity by calling out, at a medical conference, the inadequacy of current medication regimens for cadaver kidneys and the captive world ESRD patients found themselves in. In late 1978, when he meets with his friend Roy Calne, another transplant legend, he learns about a promising new drug, cyclosporine. Early results were very promising, and by 1979, Dave Winters, formerly head of life sciences at NASA, and who was now working at Sandoz Pharmaceuticals, had worked with Starzl to start a US trial at Denver. Guided by early pathology results and intuition, Starzl and his team make the decision to modify the trial from the European methods-- Starzl decides to use Cyclosporine in combination with steroids and thoracic duct drainage (which effectively filtered white blood cells from lymph) instead of Cyclosporine alone.

By the time some more negative results from Europe have been published in Nature, the Denver trials had commenced. It was a wise decision. The cyclosporine-only trials in Europe and in the US are failures, while the cyclosporine + steroids +/- thoracic duct drainage trails have great results. Cadaver kidney survival rates are 85%, much higher than before. If Starzl had not pushed for a modification of the trial methods, it is very likely the drug would not have been approved, at least not that quickly. Starzl, as ever, refocuses his attention on his first love, the liver.

Back to the Liver

In 1980, he runs a small trial of liver transplantation with the cyclosporine and steroid combination, and the results are very positive. In combination with a government committee designating liver transplantation as non-experimental, this unleashes a feeding frenzy, as other centers start their own liver transplantation centers. During this time period, Starzl had divorced his first wife and fallen for a research assistant, Joy Conger, who for personal reasons was not able to stay in Denver. At the same time, Starzl's time as Chief of Surgery was coming to an end, and Denver was devolving into inter-departmental infighting. Starzl almost moves to UCLA, but departmental politics there prevent that transition-- instead, he goes to Pittsburgh.

By 1981, they are ready to continue trials there. Here Starzl encounters a new breed of enemy-- the IRB. The story of just how self-appointed "bioethicists" had come to occupy such positions of authority is the subject of another book, but the important thing to note is the following: the power of IRB's and ethics committees more generally was at that time quite new. Starzl had previously operated in a more practical ethical framework, as had most doctors. In consultation with patients and their personal conscience, as well as their peers, doctors largely went with their moral gut.

The context of this conflict was that Starzl and his team, who had spearheaded very positive results with cyclosporine and steroids, thought the superiority of cyclosporine + steroids to 6-MP + steroids was obvious. For that reason, they thought an RCT comparing those two regimens was unethical. One of the ethical pillars of an RCT is clinical equipoise-- the idea that for a new medical treatment, uncertainty about whether it works better or worse than the established treatment means it is ethical to randomize patients to new or old therapy. To Starzl and his team, emboldened by a positive trial in Denver, this principle did not apply, since they weren't uncertain about the superiority of this treatment relative to standard of care.

In fact, though the IRB insisted on a randomized trial comparing these treatments for cadaver kidney grafts, they allowed experimental-only arms for the heart, liver, and repeat recipients, which was a "tacit admission of cyclosporine's superiority". In this case, Starzl's view turns out to be correct: 1-year survival rates of 90 and 50 percent, respectively, in the experimental vs conventional arms. I'm no trial expert, but that kind of difference is so large that it probably would have been picked up with a single-arm trial using a historical control arm. In this case, then, the anti-RCT perspective seems to have been right.

Another ethical problem Starzl had with RCT's was their abrogation of patient choice. Patients in RCT's could only choose to be in the trial, not which arm, which is in some sense a restriction on their freedom. My view on this, for what it's worth, is that RCT's are an imperfect solution to two problems: the generally small effect size of medical treatments; and poor understanding of biology. If a new drug or treatment has a large effect size, beneficial effects can be detected early on, and in an adaptive trial framework, the trial stopped early and all patients transitioned to the better drug. If the effect is that large, even a single-arm trial would probably reliably detect the effect. Unfortunately, biology is complex enough, and our understanding of it so primitive, that we are generally unsure about a given treatment's effectiveness, and since most drug candidates fail, it seems impossible to know whether an RCT is overkill for the clinical question. In the case of heart and liver transplants, where no previous treatments had worked, a single-arm RCT seems quite appropriate, since practically any outcome but failure would have been obvious.

 By 1981, Starzl's team has begun liver transplants, and after a few failures, begin to see consistent success. Another team working on heart transplants sees similar results. Cyclosporine and steroids have opened a new chapter for transplants, but the next challenge is convincing the government to pay for it. While kidney transplants were now mostly covered by insurance, heart and liver transplants were still considered "experimental". Since Medicare didn't cover them, insurance companies didn't either.

He meets with Everett Koop, the Surgeon General, and Koop proposes a Consensus Development conference, where all the big shots in liver transplantation will try to persuade NIH, HCFA, and the VA that liver transplantation is worth it. They succeed, and the gold rush is on. As with kidney transplantation, the first wave of transplant surgeons arrives to soak up knowledge from Starzl's team, and when sated, return to their home programs to start liver transplant programs. A series of surgical and technological innovations in the early 1980's, ranging from better preservation techniques and a venous-bypass to allow for a less rushed transplant operation, made the operation less technically challenging, and thus more accessible.

Transplantation Grows Up

Then followed the bureaucratization and formalization that signifies the gradual maturity of a technology: the passage of the Gore Bill and the Jonasson Committee, administrative turf wars in Pittsburgh, and more. No account of the history of medicine would be complete without a digression on healthcare costs, and this book is no exception. In 1987, the Governor of Colorado, Richard Lamm, who had previously criticized excessive healthcare for the elderly, published an article titled "Healthcare as an Economic Cancer". In it he criticized a 76-year old woman receiving a liver transplant. Starzl responds by noting that transplantation, while extremely expensive was the only effective treatment for liver failure, and that endless ICU care was less effective and just as expensive. Starzl correctly points that that the debate is really between "statistical morality" and the duty of the physician to an individual patient. And yet Starzl's argument is somewhat hypocritical-- he has just spent much time and effort advocating for the coverage of transplantation services by the government and insurance, which is not part of his duty to individual patients. In my view, if you advocate for public policy changes, you should at least attempt to address the utilitarian argument against you on those terms.

Lamm on healthcare:

Health care is clearly entering into a new era: Infinite health needs have run into finite resources. The miracles of medicine have outstripped some thoughtful and equitable thinking has to be done to ensure that America gets the most health care for its limited dollars. It is a very serious mistake to deny that a major change is in the wings. No sector of the economy, no matter how important, can continue to grow at two-and-a half times the rate of inflation. We are heading rapidly toward an America that has rusting plants, closed factories, staggering trade deficits. Health care cannot continue to operate under the illusion that it can continue with business as usual.

While cyclosporine and steroids allowed for large-scale transplant programs, the late 1980's brought a better drug-- Tacrolimus, known then as FK506. In-vitro reports were promising, and though some early European studies in various animals showed apparent toxicity, a trial was begun in Pittsburgh in patients that were rejecting their liver transplant on maximal cyclosporine dosing. The drug had never been tested in healthy humans, given its potential toxicity. It worked very well, was used in heart and kidney transplants, and surgeons were convinced it worked better than their older treatments. Another debate with the IRB's ensues over whether RCT' were necessary, though this time the IRB's between different institutions disagreed.

Starzl ends the book with a beautiful passage on the natural lifecycle of scientist:

Most of the key professional figures of the early days of trans-plantation are still alive and some still practice medicine. Now they are working their way one by one to the side of the stage. Passage into the wings is done by steps, minuet style. One device to get there is with a conference at which past contributions and efforts are celebrated by one's friends and former foes. These have become frequent occasions lately; they resemble the tours from city to city made by aging baseball stars, some modest and some not, who are in their final season of play. The meetings are not designed to discover why these men and women did what they did. The secrets are within them, hidden beneath a pile of emotional stones which only they have a right or the knowledge to probe.