You Be the Giant (2)
Dr. Shumway strode down the corridor with urgent purpose, as if someone’s life hung in the balance. Who knows—perhaps it did. Heart transplantation is among the most sophisticated and complex procedures in modern medicine. The process generally unfolds like this: a heart is harvested from a brain-dead donor and implanted into a waiting recipient. How do you remove and insert a heart without killing the patient? Very, very carefully.
They rely on a cardiopulmonary bypass machine, a device that temporarily assumes the roles of the heart and lungs. The technology already existed in the 1970s. Blood is pumped out, oxygenated, and returned to the body. The heart itself is stopped for the duration of the operation, which, as you can imagine, complicates matters considerably.
Yet even after a successful transplant, the ordeal is far from over. When an organ from another person is introduced, the body often mounts a rejection response. The recipient’s immune system recognizes the new tissue as foreign and attacks it. This is known as host-versus-graft disease. In some cases the reverse can occur as well. At the cellular level, the host’s T-lymphocytes identify the major histocompatibility complex (MHC) presented by the transplanted organ, label the cells as threats, and destroy them. The patient usually dies.
In the early days of organ transplantation, procedures were performed without immunosuppression. Recipients and laboratory animals alike perished quickly. Later physicians experimented with various immunosuppressive regimens and tissue-matching techniques. The first heart transplant patient in 1967 survived only nineteen days.
Then, in time, Dr. Shumway’s team developed the first truly effective approach to cardiac transplantation.
In the 1970s, organ transplantation relied on steroids and broad-spectrum immunosuppressants for immune control. A logical choice, on paper. The problem was that steroids carried severe side effects, and blanket immune suppression left patients dangerously vulnerable to infection.
Think of it as a restaurant. The head chef dies, so you hire a new chef who uses a wheelchair. To make the kitchen accessible you remove the front door—only to discover that rats have now taken up residence. Meanwhile the staff fail to recognize the new chef and occasionally beat him. Analogy over.
The human body resists bacterial invasion through macrophage recruitment, fever, antibody production by B-lymphocytes, and a host of other mechanisms. Broad immunosuppression and steroids shut all of them down. The side effects are substantial. Cyclosporine, by contrast, selectively inhibits T-lymphocyte activity, averting many of those complications while still preventing rejection.
Back in the Stanford library, Dr. Shumway was rifling through the latest immunology journals with obvious impatience.
“Where’s the cyclosporine article?”
“Just a moment…”
I retrieved the journal from the shelf and handed it to him. He opened it immediately, expression grave.
“Here it is.”
“Immunology. By Dr. Borel. ‘The Effects in Animals of a New Anti-Lymphocytic Peptide, Cyclosporine.’ Published a few months ago.”
It was still only animal data, yet for those of us working on transplantation it felt like the Holy Grail.
As Dr. Shumway scanned the pages, his face went pale, as though he had seen a ghost.
“What on earth… Do you memorize every paper published in the current year?”
“I’m doing my best to stay current.”
Because I already knew what to look for. Even when a topic held revolutionary potential, many such insights had languished for years simply because there was no efficient way to locate them. This era had no search engines; the only option was to comb through journals by hand.
Dr. Shumway tucked the paper under his arm.
“Why don’t we have residents like you in cardiothoracic surgery? It would be wonderful to have more young physicians who actually conduct research.”
“Thank you, sir.”
“Let’s see how quickly we can begin clinical trials. If we can achieve immunosuppression without high-dose steroids or marrow suppressants, we could save a great many transplant patients.”
I nodded, equally serious.
“You’ll participate as well, of course? After all, the idea originated with you.”
“I’d be honored.”
“Are there any transplant patients available? I should start by checking on current kidney recipients…”
Still muttering to himself, the professor left the library. The sooner we started trials, the sooner we would have patients to treat and results to publish. I could not agree more.
I returned to the internal medicine residents’ lounge. In any case, I intended to condense our earlier conversation into a short paper. A concise letter outlining the underlying principle would suffice—one that could guide the direction of future research. What should the title be? Something like The Mechanism of Organ Rejection and the Possibility of Selective Immunosuppressive Therapy seemed appropriate.
I began writing at once. The sooner it was sent, the better. I planned to submit this one to Nature. No matter how the academic landscape shifted, Nature remained the undisputed pinnacle. A case report might have gone elsewhere, but this was different.
I wrote steadily, page after page.
Dean Rich looked up from the draft I had submitted, his expression once again one of pure bewilderment. It was my cyclosporine paper. Organ transplantation was, predictably, a field that demanded conservatism.
“Dr. Parks. Are you aware how dangerous immunosuppressive therapy is in the context of organ transplantation? And you want to attempt treatment with a drug discovered only this year…”
“I intend to proceed together with Dr. Shumway. We’ll combine it with milder immunosuppression using existing agents such as steroids.”
Dean Rich took a moment to explain the transplant procedure in detail and the myriad risks involved in managing immunosuppressed patients.
“Is the evidence solid?”
“Yes. The theory is sound.”
Historically, it was more than sound.
The dean frowned again. He seemed to have finally registered exactly what he was reading.
“Dr. Parks. This is another paper you wrote. Does it seem appropriate to cite your own previous work as supporting evidence?”
I nodded.
“Professor, the theoretical foundation for transplant rejection discussed here rests on the discovery of antigen presentation, which clarified the mechanisms of acquired immunity.”
“Correct. And?”
“It was a paper I authored in Professor McDevitt’s laboratory while studying H-2 proteins.”
Dean Rich exhaled slowly, as though a missing piece had finally clicked into place.
“Yes… I suppose you’re right on all counts.”
“There’s no need for concern. Dr. Shumway and I will proceed with every safety precaution. We’ll also consult the researchers who developed the compound.”
“Very well. Good luck. And if you win any awards, be sure to mention in your acceptance speech that I offered my full support.”
I bowed respectfully and left the dean’s office.
Meanwhile, across the ocean.
London, at the editorial offices of Nature—the beating heart of global academia. An ivory tower that decided which new research would see daylight and which would be consigned to oblivion.
“Not this man again…?”
Dr. Fairchild frowned. The usually bustling editorial floor converged around his desk.
“We haven’t even finished reviewing the gene-amplification paper from last time, and he’s already back.”
“So it seems.”
Just thinking about him brought on a headache. Dr. Fairchild pressed his temples. It was that American again. A resident—not even board-certified—who had already submitted ten papers to Nature. He held only a master’s degree, not a doctorate. An utterly peculiar individual.
Most of his submissions appeared to have been dashed off in a day or two, complex ideas condensed into focused case reports or bold hypotheses. Yet despite the best efforts of Britain’s notoriously conservative medical establishment, Nature had never rejected a single one of his papers.
The reason was simple: the topics were simply too important to ignore.
“Ah, it’s him again.”
“What could it possibly be this time?”
Dr. Fairchild sighed and opened the yellow envelope that had arrived from Stanford.
The Mechanism of Organ Rejection and the Possibility of Selective Immunosuppressive Therapy
Organ transplant therapy has made groundbreaking advances over the past several years. Nevertheless, significant challenges remain, including the infectious complications of immunosuppressive treatment and the persistent problem of organ rejection.
This paper presents a hypothesis demonstrating that the newly discovered cyclosporine may resolve the issue of transplant rejection through an understanding of the underlying immunological mechanisms.
Another brief letter. Undoubtedly another groundbreaking hypothesis or mechanistic revelation. The man had already done this ten times.
Dr. Fairchild sighed again. What exactly was Stanford producing, and who was this person? He was almost tempted to fly to America simply to meet him face to face.
He hoped, against all precedent, that this might finally be a paper they could reject.
With solemn expressions, the Nature editorial staff withdrew the manuscript from its brown envelope. Once again, it appeared they were looking at something extraordinary.