Alpha-gal was not the only barrier to success—it seemed that the immune response to pig organs even without this protein present was still stronger than what we saw in allotransplants. With this barrier, and the discovery of a retrovirus omnipresent in pigs (sadly named PERV, for porcine endogenous retrovirus), excitement about the future of xenotransplant, along with industry funding, essentially dried up.
This all changed with the discovery of CRISPR/Cas9, the gene-editing system that can remove genes with reliability from the embryo of an animal (or even insert new ones), making it possible to generate modified animals ready for experimentation in a matter of months. Since this discovery, numerous advances have been made over the last few years. George Church’s group at Harvard successfully generated pigs with all copies of PERV inactivated, a huge accomplishment and one that allayed fears over the possibility of unleashing xenoviruses on humankind, a potential major barrier to FDA approval of trials in xenotransplantation. Multiple companies have been formed that are rapidly modifying the genes of pigs to make their organs look more human, knocking out proteins in an effort to minimize the chances of rejection after transplantation. One pharmaceutical company, United Therapeutics, has pumped more than a hundred million dollars into similar efforts, partnering with academic leaders at universities, including Alabama and Maryland. The company also has plans to break ground later this year on a massive farm with the capacity to produce a thousand pig organs per year. The farm even has spots for helicopter pads, so organs can be flown out as needed.
So, is this going to happen? Maybe. There has been a conglomeration of scientific superstars and clinical leaders in transplantation/xenotransplantation at a few centers, and industrial support has been pouring in. While the survival rate for life-sustaining organs such as kidneys from pigs into primates has been on the order of a year or more, intense immunosuppression is still required. Despite all the barriers, though, we’ve come a long way.
As I look at the investigators involved in these efforts, I can’t help but be reminded of the pioneers who made transplant a reality despite all the resistance: Starzl, Murray, Shumway, Barnard, Hume, Moore, and the others. I see all the same qualities: drive, focus, confidence that things will work, the courage to try. I predict we will see trials in the next few years. I also predict that the outcomes will be okay but not great. With the introduction of every new procedure, drug, or technique, there is always a learning curve, the black years when you have to go from the occasional success to a true and realistic option for patients. Will these new pioneers be able to hang in there, stay positive, and keep up their courage during the struggle? We shall see.
18
So, You Want to Be a
Transplant Surgeon?
He dressed and found himself thinking about the operation again. Should I have tacked the sigmoid colon to the abdominal wall to prevent it twisting again? Didn’t I see Stone do this? Colopexy, I think he called it. Had Stone spoken to me about the danger of a colopexy and warned against it, or had he recommended it? I hope we took out all the sponges. Should have counted once more. I should’ve taken one more look. Checked for bleeders while I was at it. He recalled Stone saying, When the abdomen is open you control it. But once you close it, it controls you. “I understand just what you mean, Thomas,” Ghosh said, as he walked out of the theater.
— ABRAHAM VERGHESE, CUTTING FOR STONE
Finally, there is something about the practice of surgery that has meant the most to me—more than the intellectual challenge of solving a puzzle, more than the rewards of trying to help others, and more than the gratitude of those you have tried to help. In our patients, we witness human nature in the raw—fear, despair, courage, understanding, hope, resignation, heroism. Our patients teach us about life. In particular, they teach us how to deal with adversity.
— JOE MURRAY, SURGERY OF THE SOUL
Back when I was a third-year medical student, I started thinking about a career in surgery. I can’t say I had any earth-shattering revelation regarding choosing this specialty. I’d just enjoyed my time on the rotations. I liked the intensity, the idea that you had to train really hard, but that, eventually, you would have a really special skill that would allow you to open people up and fix things. I liked that surgery deals primarily with problems that can be solved, as opposed to managing long-term conditions that never really go away. And I thought surgery was ballsy. I’d always felt that I was calm under pressure, and I was really curious whether I could be that way as a surgeon. And I’d always loved Hawkeye Pierce.
There is a book that is famous among medical students, titled So You Want to Be a Surgeon. It’s filled with helpful information on how to apply for residency, what steps to take to make your application stronger, which programs to consider. It also lists the character traits that fit a surgical personality: you should like “working on a team”; “embrace responsibility and the opportunity to make a positive impact”; “share the excitement of a surgical team anticipating a great case”; “enjoy watching your patients improve daily after major injuries or surgical procedures. ”
At the time I first started thinking about becoming a surgeon, I already knew about the excitement of working on a team, the rapid pace at which a surgical service moves, and what it was like to anticipate a big operation. What I didn’t yet understand was the level of responsibility that comes with making so many decisions every day that can have a major impact on people’s lives. I also didn’t realize how much time I would spend worrying about those decisions, how guilty I would feel about mistakes I made, or how stressed out I would be watching patients struggle after operations even when everything went well. I assumed that by the time I was an attending surgeon, I would have a massive bank of information and experience that would guide me through anything. But by the time I got to my chief year (the last year of residency), I realized that you never get that blast of enlightenment, that moment when suddenly everything becomes clear. You just become more comfortable putting together whatever information you have, which is always too little, and then making decisions that are based more on your gut than anything else. Now, after more than a decade on staff, and two decades after medical school, I feel the same way. I have made thousands—no, millions of decisions about patients, some big, some small, some right, some not, and almost all of which had some consequence. Many—no, the majority of those decisions were right, but so many were wrong. Most of my patients have done well, and yet I can vividly remember almost every one who didn’t. I can remember what they looked like when they were suffering or dying, the desperate sadness of their families, who felt helpless to make them better.
Those of us in surgery develop a coping mechanism for dealing with bad outcomes, including blaming our patients or those around us, drinking large quantities of alcohol, or not thinking much about bad outcomes at all. Still, we get a lot of support from our colleagues, and some of us find comfort in presenting our data to the local or national community. In the field of liver transplantation, where patients have become much sicker, and where severe complications and postoperative deaths have become more common, I realize that you can get used to bad outcomes. When you go see a liver recipient before a transplant, and he is in the ICU, with a breathing tube down his throat and an IV drip keeping his blood pressure compatible with life, all you can think is, I’ll give it my best shot. He will surely die without a transplant.
Of course I want all my patients to do well, and of course I feel empathy and sadness, not to mention responsibility, when talking to the families after a patient dies or has a major complication. At the same time, though, after you walk away from the surgery and go back to the office, or at least by the next morning, when the next case starts, you force yourself to move on. You have to. Nevertheless, each bad outcome, each death, each time you tell family members that their loved one is gone, it takes a little more out of you—and makes it just a little bit harder to put away that box of bad outcomes when you go home at night.
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I often think about what the pioneers went through in the early days of transplant. They each had bad outcomes almost continually over decades, with the occasional “success” defined by a patient who stayed alive for a year. There was no guarantee transplant would ever work, many of their colleagues in their hospitals and throughout the medical community thought they were crazy, and there was legitimate concern that they could end up in jail. So how did they persist? What type of personality would be appropriate to take on this kind of challenge? Do people like these trailblazers still exist in surgery? And could similar trailblazing happen now?
A lot of different personalities are represented in the pioneers of transplant. Joe Murray was analytical and religious, a believer. After each failure, he’d review the data, figure out what he could do differently, and move on. Despite bad outcome after bad outcome, he never questioned that his team would one day succeed.
David Hume was an energetic whirling dervish who exuded excitement and who, like Murray, never questioned his chances for ultimate success. He inspired those around him, rarely slept, and was always trying something new.
Roy Calne seems to me the least affected of the bunch. He enjoyed those early days of experimentation immensely, and he has a lightness, a sense of happiness almost, when he recounts those experiences. Calne is the right mix of surgeon and scientist, and he has liked both pursuits.
Norman Shumway, like Calne, inherently loved surgery, loved working with his trainees, and had general disdain for publicity and fame. He was happiest when in the OR, and would often tell residents during operations, “Isn’t this fun? Isn’t this easy? What could be better? Nothing could be better.”
As for Christiaan Barnard, he was much less of a natural surgeon, and much less comfortable in the OR. This is likely why he did so few transplants once he achieved the fame and fortune he was seeking. But he certainly was driven. Anyone who completes a surgical residency, does lab work, completes a thesis and a PhD, and learns two languages in two years is driven.
Walt Lillehei was able to deal with bad outcomes just by accepting them and moving on—patients die; such is life. Oh, and he also found that drinking numerous martinis every night helped, too. Perhaps facing his own near mortality at a young age, when he had cancer, caused him to have a closer relationship with death than most.
Tom Starzl was perhaps the most tortured of the bunch. He has been quoted numerous times stating how much he hated surgery, how he couldn’t eat or talk before cases, how he always feared he would screw up and kill the patient. Although he was the first to master what might be one of the hardest operations in the world, he was never comfortable in the OR, and he made those around him pay for it. His surgical personality (that is, how he behaved in the OR) was legendary for its harshness. One characteristic that may have served him well but also tortured him beyond belief was his insanely accurate memory. Once, on an airplane procuring organs (in bad weather, with the plane bouncing all over the place), he dictated a research paper. As he spoke into a tape recorder, he would refer to papers he wanted cited, stating, “Cite my seventh paper here . . . cite my twenty-eighth paper here . . . my two-hundredth paper here . . .” By the time the plane landed, he had completed the paper. Starzl also never forgot a patient, a bad outcome, the faces of a grieving family. He had no coping mechanism to deal with bad outcomes.
Despite their diverse personality traits and coping strategies, all the pioneers had one thing in common: courage. In their book on transplant surgeons, The Courage to Fail, leading sociologists and bioethicists Renee Fox and Judith Swazey write that it was courage that got these pioneers through the initial period of transplant in the 1950s and ’60s, when it was truly a pipe dream. It was courage that sustained them through the dark years of the 1970s, when outcomes were as bad as 20 to 50 percent chance of one-year survival, with many of the patients suffering miserable deaths secondary to infection and overimmunosuppression—a period that didn’t end until cyclosporine became a clinical reality in the early 1980s. According to Fox and Swazey, the pioneers who persisted despite the bad outcomes and the ridicule from colleagues and the public could live with this failure, and never gave up in the battle against death.
No doubt courage is at the heart of what drives a surgeon. But is it the courage to fail? I would argue that what separates the pioneers from the rest of us is the courage to succeed. Despite all the failures, despite the people around them telling them they were crazy, that they were murderers; despite the threats of dismissal, loss of their medical license, and even imprisonment, they never questioned for a second that they should persevere. This confidence, this courage, I believe, was built into their DNA, and they sustained it for years and years.
Some of the pioneers were also addicted to the act of surgery itself, couldn’t get enough of it. Shumway was one. “Surgery, not just heart surgery but all kinds of surgery, is so fascinating, and the responsibility is so acute, that it’s a terrible addiction,” he wrote. “I was just too consumed by it, and loved surgery so much. ” Lillehei, Denton Cooley, and Roy Calne all spoke of loving the act of operating. Hume and Moore loved everything about being surgical leaders and innovators, whether it was in the operating room, the lab, or the classroom. For these men, life as a surgeon was all they’d ever wanted; it defined them in every way. Indeed, they had little interest in life outside the OR.
Courageous pioneers still exist in the field. Dr. Nancy Ascher, chief of surgery at UCSF (the surgeon who donated a kidney to her sister), spent many years at the University of Minnesota as it was building its excellent liver transplant center in the 1970s and ’80s. She is known as a master surgeon who loves to operate. She keeps her OR totally quiet, so she can focus on (and be stimulated by) the operation at hand. Despite being in surgery for more than forty years, she still loves the actual task of operating, and her focus and her addiction have not dwindled in the least. She and her husband, John Roberts, ultimately went to UCSF in 1988 and built their liver program into one of the premier programs in the world. She also is one of the national leaders in living-donor liver transplantation, one of the most demanding disciplines.
I spoke with Dr. Ascher about the burden of being a surgeon, the responsibility that never goes away. Sure, she frets about patients, she told me, but she’s never seen that as a negative. It is an honor for her to perform her patients’ transplants, to take responsibility for their new organs, their surgeries, and their outcomes.
Allan Kirk, chairman of surgery at Duke University, last year reached the summit in academic medicine: election to the National Academy of Medicine. When Dr. Kirk was at Wisconsin, he was one of the few fellows able to conduct a clinical fellowship while still working in the lab on experiments with primates. One project he spearheaded during his training involved hooking up patients with fulminant liver failure to pig livers in order to filter the blood until the patients could get a human liver for transplantation. He did this a number of times, but one particular case was of a young girl whom he kept hooked up to a pig liver in a bucket for ten days! He never left the girl’s bedside, watching her blood flow out her femoral vein, through plastic tubing into the pig portal vein, and back out the cava and into a vein in her neck. She finally got a transplant, which went well, but sadly, she died afterward. He did ultimately have one long-term survivor of this cross-perfusion procedure, a seventeen-year-old girl who went on to graduate college and have a child after her human liver transplant. Nevertheless, the cross-perfusion procedure was ultimately abandoned due to its complicated nature and unclear benefit.
For Dr. Kirk, the practice of surgery is as much about the science and preclinical experimentation as it is about the operations themselves. If Dr. Ascher is addicted to the practice of surgery, Dr. Kirk is addicted to the life of an academic surgeon. He likes to operate, but the surgery alone is not what drives him.
I feel differently. While I like the challenge of operations, I am certainly not addicted to operating. In fact, I’m always
happy when a case is canceled, just as I’m happy when any meeting I’m supposed to attend is canceled. And while I like to push myself to be the best I can, and to accomplish academic work on top of my surgical career, I still don’t feel driven, or obsessed, the way pioneers must be. I have the courage to fail but maybe not the courage to succeed, the undying belief that I will always succeed—at least not against all odds.
Pioneers in the field of transplantation were and are special, driven beasts, as I like to call them. We all owe them a deep debt of gratitude, and I feel a sense of awe when I think about them.
But even if modern pioneers still exist, could the kind of experimentation and bad outcomes of the early pioneers be tolerated today? Roy Calne’s answer to this question was resolute: “Impossible.” Starzl felt differently. He thought it was already happening in other fields, such as cancer therapy and gene editing. “It happens right now in front of our eyes, and somebody suddenly does something unexpected, and wow, it’s all done. Yes, could happen again, has to happen again.”
Things are certainly different from how they were. A surgeon can’t just throw a chimpanzee heart or a baboon kidney into someone—and maybe that’s a good thing. A surgeon can’t just take organs from someone who shows up dead in the ER without talking to family members—again, a good thing. Just because someone is really sick, even dying, doesn’t justify trying something new on him or her without having some data supporting a chance of success. And again, this is the way it should be.
Franny Moore would have agreed. In reference to the controversial use of the world’s first mechanical heart, in 1969, he wrote:
Desperate measures like the interim substitution of a machine heart . . . call up for consideration a special ethical question . . . does the presence of a dying patient justify the doctor’s taking any conceivable step regardless of its degree of hopelessness? The answer to this question must be negative . . . There is simply no evidence to suggest that it would be helpful. It raises false hopes for the patient and his family, it calls into discredit all of biomedical science, and it gives the impression that physicians and surgeons are adventurers rather than circumspect persons seeking to help the suffering and dying by the use of hopeful measures . . . It is only by work in the laboratory and cautious trial in the living animal that “hopeless desperate measures” can become ones that carry with them some promise of reasonable assistance to the patient.
How Death Becomes Life Page 30
