The Xeno Chronicles

Excerpt

A cold day was dawning when Dr. David H. Sachs left his home and headed to his Boston laboratory, a few miles distant. He was praying that experimental animal no. 15502 -- a cloned, genetically engineered pig -- had arrived safely overnight from its birthplace in Missouri.

It was Friday, February 7, 2003.

Ordinarily a calm and measured man, Sachs had fretted for weeks over this young animal, whose unusual DNA might help save untold thousands of human lives. He worried about the weather, so frigid that Boston Harbor had iced over and pipes in the animal facility had frozen, fortunately without harm to the stock. He worried that the pig would become sick before getting to Boston. He had decided against transporting it by truck, for a winter storm could prove disastrous -- so then he worried about flying it up. What type of aircraft should they use? Commercial? Charter? Which airport in the congested metropolitan area would be safest?

"Use your best judgment," Sachs had told the staff veterinarian he assigned to bring the pig north. "Just don't lose this pig!"

A surgeon and immunologist, Sachs had distinguished himself in the field of conventional transplantation, in which human organs are used. His lab, the Transplantation Biology Research Center, was a part of Massachusetts General Hospital, where he was on staff. He was a professor at the Harvard Medical School. He belonged to the National Academy of Sciences's Institute of Medicine. He was fluent in four languages. He had written or co-written more than 700 professional papers. Science came as naturally to Sachs as breathing.

One achievement, however, still eluded him.

For more than three decades, Sachs had tried to find a way to get the diseased human body to accept parts from healthy animals.

Many scientists over many years had tried to achieve what Sachs sought. So far, the idea remained a dream.

Xenotransplantation had the potential to save thousands of people who die every year because of a chronic shortage of human organs. Sachs envisioned a time when patients needing a new heart, liver or kidney would simply have their doctor order one up from the biomedical farm. Children born with defects and older people with all manner of ailment would benefit. And while riches didn't compel Sachs, xeno, as insiders often called their field, could become a multi-billion-dollar business. You couldn't buy or sell a human organ, at least not in America and most countries of the world. But there were no laws against commerce in animal parts.

Many scientists over many years had tried to achieve what Sachs sought.

So far, the idea remained a dream.

A man of average height, Sachs was on a diet but still carried a few too many pounds, a fact he jokingly acknowledged when describing himself as "chubby." With his full head of graying hair and his jolly face, the image of a Teddy bear came to mind -- an image that was reinforced when he laughed, which was often. Sachs favored button-down shirt, tie, khaki slacks, a rumpled suit jacket, and wingtip shoes. Unless you looked closely, you would not notice that his right foot was larger than his left, a remnant of his childhood when, at the age of 4 1/2, he contracted polio, the childhood scourge of the 1940s. Sachs spent weeks at Manhattan's Hospital for the Ruptured and Crippled, an institution on 42nd Street and Lexington whose very name evoked suffering. His polio affected only his lower body, so Sachs did not require an iron lung, a more terrifying symbol still.

Sachs eventually went home -- with the doctors' prognosis that he might never walk again. But he did walk again, perfectly normally.

"It just never seemed possible to me that I wouldn't," Sachs said. "It just seemed to me that I had to get over this problem. I've never had a defeatist attitude toward anything. I always feel that it's just a matter of being able to figure it out, make it work. That's my attitude toward everything."

	But Sachs could not stop the clock. He was past 60 now and increasingly aware of his mortality. He occasionally joked about wanting to be frozen, like Ted Williams.

But Sachs could not stop the clock. He was past 60 now and increasingly aware of his mortality. He occasionally joked about wanting to be frozen, like Ted Williams, so that if they ever solved the thawing end of cryonics he might return to experience the marvels of a distant age -- an age, he believed, when disease would have left the earth.

"Only recently I have started to realize how finite my lifespan is," he said. "Of course I've known that since I could think, but as you get older you realize that nobody lives past 100 and I'll be lucky if I get over 80 and I'm already 61. So I don't have a hell of a lot of time left."

In his darker moments, Sachs wondered if he would ever achieve his grand ambition. Experimental animal no. 15502 -- a creature small enough to fit into a baby stroller -- might well be the beginning of his last chance.

Sachs parked his Saturn, then cleared the guards with their walkie-talkies and closed-circuit TVs in the lobby. He needed a card key to operate the elevator and to open the outer door to his lab on a floor upstairs. Another lock secured the administrative suite, with yet one more protecting his inner office.

Once inside, the atmosphere was delightful: this was a bright, open, corner space with a commanding view of Boston Harbor, and Sachs had decorated it with photographs of colleagues, mentors, and friends, and his wife, Kristina, and their four children. The scientist felt blessed with having so many good people in his life, and he still marveled at having three daughters and a son after Kristina's first three pregnancies had ended in miscarriage and her obstetrician had predicted she would never give birth. Except for the books and professional journals, one of the only clues into the nature of Sachs's work was a pink stuffed pig.

It was nearing eight o'clock.

Sachs checked his e-mail -- those messages that had come in since he'd last checked, at home over breakfast. He put on a lab coat, left his office, and passed through the main conference room, which featured a photograph of a Little League team that he had sponsored and a large bulletin board for laboratory business.

Alongside the ordinary notices and schedules was a clip of one of the few stories about Sachs that had appeared in the mainstream press. It was a piece from the August 11, 2001, San Francisco Chronicle, and it concerned a precursor animal to no. 15502. "This little piggy may be what the doctor ordered," the headline read. The clip included a photo of Sachs, posed behind a beaker. The writer listed some of the reasons the miniature breed of pigs that Sachs used were the current focus of xeno research: their organs are similar in size and function to a human's, and nearly 100 million pigs of all sizes already are slaughtered for food every year in the U.S. alone with little protest from anyone. And unlike chimpanzees, who were immunologically closer to people -- and who looked more like people than any other animal -- pigs were pigs.

The Chronicle story was straightforward and informative, but a printout of an Internet page that someone had posted suggested that the pursuit of xeno could prompt a quirky humor.

"The U.S. is critically low on organ donations. What is the nation's medical community doing to address the shortage?" the page read. One answer offered was: "Removing David Crosby's new liver and giving it to a more deserving person." Another was: "Allowing recipient's body to reject maximum of two hearts; after that, no more favors for Mr. Picky." A third was: "Experiment with tofu-based organ substitutes." Xeno humor wasn't confined to this bulletin board. An unsigned editorial comment in a recent issue of Xenotransplantation -- which Sachs founded and which a senior member of his staff now edited -- noted that some surgeons are considering face transplants. "This is unlikely to be an area in which the xenotransplanters can become involved," the editorialist wrote.

Sachs left the conference room and went to a separate facility, which was secured by yet another electrically-locked door. He opened it with his cardkey and stepped into a windowless domain constructed of cinderblocks painted a glossy institutional beige and lit with fluorescent bulbs. This was the animal area, where experiments were conducted and where he gathered his scientists every Friday at eight for large-animal rounds.

At any given time, Sachs's staff included nearly 90 scientists, technicians, assistants, administrative aides and secretaries. Many were research fellows: young men and women who stayed a year or two before moving on in their careers. Although Sachs was no household name, his reputation inside medical science was large, and competition for his fellowships was intense. Over the years, he had attracted scientists from all over the world.

Some two dozen men and women, most wearing white coats, awaited Sachs on that February 7. They lined a wall of the animal area's central corridor, which separated the baboon room and the pig rooms from the operating suites. A strict, if unwritten, hierarchy was observed: non-scientists stood at the ends of the line, with the middle held by two of Sachs's senior staff researchers. One was Dr. David K.C. Cooper, 62, a tall, refined British surgeon (the K.C. stood for Kempton Cartwright) who had transplanted hundreds of human hearts and had worked in South Africa with Dr. Christiaan N. Barnard, who transplanted the first heart, in 1967. The other was Dr. Kazuhiko Yamada, 43, a Japanese surgeon who so impressed Sachs with his surgical prowess and innovative ideas during his 1990s fellowship that Sachs brought him on staff. Both doctors conducted research on allotransplantion -- same-species transplants -- but, like their boss, they held special passion for xeno.

Sachs took his place in the precise center of the line, bid everyone good morning, and large-animal rounds were underway.

"Goldie is here," veterinarian Mike Duggan announced.

One by one, scientists stepped to a chalkboard that held dozens of paper cutouts in the shape of a pig. Each cutout had a number that corresponded to an animal. The scientists described the status of each of his or her experiments and Sachs, who had no notes but held the most minute details in his head, asked questions and made suggestions. Although he no longer personally conducted experiments, Sachs supervised all those that took place in his lab. He was not overbearing or arrogant, just frightfully smart. Only when one of his people was clearly headed in the wrong direction, which was infrequent, would he overrule.

Most experiments involved transplanting organs from one pig to another, a model that mimicked conventional human transplantation. In their efforts to make transplants simpler and safer, the Sachs researchers experimented with drugs, radiation, bone marrow, and the thymus, a small gland that plays a large role in the immune system. The Holy Grail was tolerance: eliminating the need for the immunosuppressive drugs that a recipient must take for life to prevent rejection. Such drugs can cause cancer and many other side effects, some potentially deadly and some cosmetically unappealing, and they leave a recipient at increased risk of infection. "A cold that you or I would get over in a day or two can be life-threatening," Sachs said. Weight gain and hair growth didn't kill, but for women especially, they could be depressing.

Here, Sachs had enjoyed success: working with colleagues at Mass. General, and building on a long body of research by other doctors, he had devised a way to manipulate the immune system so that a recipient would accept a transplanted organ without having to remain on drugs. The method involved bone-marrow transplantation, and was one of many ways that had been attempted to achieve tolerance. After years of research with pigs, Sachs had helped move it from the lab to the clinic -- where a few people had already benefited, including a woman who was still alive and well and immunosuppressive-free three years after a kidney transplant.

The woman, Janet McCourt, a Massachusetts resident, was the first patient to try the tolerance protocol devised by Sachs and his colleagues.

She had been on dialysis and hated its constraints -- being married to a machine was not her idea of living -- and she was willing to try anything to get off, including a treatment that had only been tried in laboratory animals. "They told me the odds were unknown, because this had never been tried in a human," the middle-age McCourt told a Mass. General publication. "But when we found that my sister was an excellent match and that she was willing to be the donor, I decided to go ahead and risk it. If I couldn't have the kind of active life I wanted, if I couldn't play with my grandchildren, I simply didn't want to live."

More work remained to be done so that more people could benefit, but the success of McCourt and a handful of others who followed was a breakthrough for Sachs and his colleagues. It was big news, not only in the scientific literature but in the mainstream press. It was the sort of work a Nobel committee might pay attention to.

But the excitement at this morning's large animal rounds was not for bone marrow-induced tolerance. It was for the overnight arrival of a 21-pound pig.

"Goldie is here," veterinarian Mike Duggan announced.

Sachs, of course, was aware of xeno's colorful past: of quacks who had implanted goat testicles into impotent men in the 1920s, of legitimate scientists in the 1960s and 1970s who had transplanted monkey, baboon and chimpanzee organs into people. He knew about Baby Fae, the most famous xeno patient ever. He knew of the renewed enthusiasm for xenotransplantation in the 1990s, when scientists had made several major advances and large corporations had invested heavily in the field, only to be disappointed when xeno failed to reach the clinic -- and return anything on their investments.

Sachs knew, too, of other emerging technologies in what was called regenerative medicine: stem-cell science, tissue engineering, and artificial organs. He knew all this and still believed that if xeno could be perfected, it would play a major role in health care.

"I see xeno as a possible answer to the organ shortage in the short-term," he said. "Adult stem cells and tissue engineering have great appeal because they can potentially provide organs that are composed of `self' tissues, thus avoiding the immune response. Fetal or embryonic stem cells are creating a lot of hype, but the tissues and organs derived from these sources would be just as foreign as allogeneic transplants.

"For simple tissues -- like islets or skin -- stem cells and tissue engineering may provide solutions in the near future. However, for organs I think we are many, many years away from a solution. There is too much we don't know about the intra- and inter-cellular signaling required to make a complex organ to expect rapid development of the technology. Artificial organs have the problem of a power supply, and until we can harness nuclear energy in a practical form, organs like the heart will require too large a battery pack to be practical. Also, people do not want to be dependent on an external source of energy that could be interrupted -- e.g., blackouts. The xenograft uses nature's own way of deriving energy."

II. Dolly.

Starting in 1973, when he was at the National Institutes of Health, Sachs had bred a line of miniature swine for use in his many transplant experiments. By now, he had bred more than 10,000 of the pigs, and his current colony numbered about 450, but he had never named one. It served no good purpose, he reasoned, for anyone to become emotionally attached to a creature unlikely to see ripe old age.

But no. 15502 was unlike any of Sach's other pigs.

After years of trying, scientists at Immerge BioTherapeutics, a Massachusetts biotechnology firm with which Sachs collaborated, had succeeded in removing -- knocking out, the geneticists called it -- both copies of the gene that produces a sugar molecule found on the surface of ordinary pig cells. These sugar molecules are harmless to the pig -- but when a pig organ was transplanted into a baboon (or a person), the recipient's immune system recognized them as the calling cards of an invader. Within minutes, white blood cells attacked and destroyed the organ, leaving it a dark, useless mess. Hyperacute rejection was the scientific term for this vengeance, which evolution created as a life-saver: the same sugar found on pig cells is also found on the surface of certain parasites, viruses, and bacteria, some of which are fatal to the human. Evolution had not anticipated transplantation.

Sachs hoped that the pig's organs might provide protection against more delayed varieties of rejection, which can set in weeks or months after a transplant. He hoped, too, that fewer drugs would be needed with this pig's organs. That would be a step toward tolerance, the Holy Grail.

Sachs and Immerge also collaborated with the National Swine Research and Resource Center at the University of Missouri's College of Agriculture, Food and Natural Resources -- and it was scientists there who had cloned animal no. 15502 from a cell lacking both copies of the sugar gene that Immerge BioTherapeutics had supplied. The Missouri scientists wanted to name the pig, born a week before Thanksgiving -- and the name they chose for the so-called double-knockout pig was Goldie. Goldie had a fairy tale-like feel. Goldie captured the medical promise of the piglet and its commercial prospects as well. Immerge BioTherapeutics aimed to get a decent share of that business.

Duggan recounted his journey to fetch Goldie, and it was good that Sachs was learning the details after the fact.

The flight down, in a chartered twin-engine plane that had left Worcester airport the morning before, Duggan said, had been uneventful -- at first. But just after refueling, in Ohio, the airplane's heater blew and the temperature in the cabin dropped below zero. "At that point I was more concerned about my well-being than any pig!" Duggan said. Three hours later the plane touched down safely in Missouri, where mechanics fixed the heater and a veterinarian drove up with Goldie.

Hand-fed since birth, and pampered perhaps more than any experimental pig ever, Goldie had never left her home in Missouri.

Now she was inside a dog crate, flipping out.

"She had always been in a single room by herself with a lot of human contact," Duggan said, "and now she was taken from that environment, put into a crate, put into the back of a truck, driven to an airport. Then she was being taken out of that environment into the strange environment of a plane -- loud engines, the whole issue of takeoff, everything. All of that was very stressful." Duggan feared that on the trip north, the stress would induce shipping fever -- a pneumonia-like affliction, well-known to horse breeders and veterinarians, that can kill. Duggan considered sedating Goldie -- but talking to her and offering her bottle calmed her down, and no sedative, which carried its own risks, was needed. "The same way as if I'm flying with my own child," the veterinarian explained. Three-month-old Goldie also found comfort in her ball and teddy bear. Soon, she was asleep.

Skirting a storm, the plane returned to Worcester at about 9 p.m. Goldie was transferred to a van and driven to Sachs's lab, where she was placed -- with her bottle, ball, and teddy bear -- in a cage lined with lambs wool. The cage provided Goldie with a constant flow of filtered air, to keep the dust and germs away. Duggan settled the pig in and hand-fed her a dinner of fruit. It was nearing midnight when he dimmed the lights. "Goodnight, I'm off to bed," Duggan said. "See you in the morning." Goldie passed a restful night and was happy and playful at breakfast that morning.

Duggan told the group in the corridor: "She does interact well with people." It would be fine to pet her, he said -- with gloves.

"I don't think you need to pet her," Sachs said.

"It should be minimized," Duggan agreed. "It shouldn't be like a circus back there."

Animal rounds ended with a review of the current xeno experiments, which involved transplanting organs from pigs that had the sugar gene into baboons, whose immune systems are similar to a human's. Although Goldie and others like her that would be produced seemed the best chance of solving the xeno puzzle, other approaches using other protocols and another type of genetically modified pig had been tried over the years, at Sachs's center and elsewhere. The best success was a transgenic pig heart that Cooper transplanted into a baboon that beat for 139 days before being rejected. These particular pigs were not Sachs's own: he had gotten them from Imutran, a once-promising British xeno firm that had developed them in the 1990s.

But neither Cooper nor anyone else had been able to get another pig heart to last anywhere close to as 139 days, and he, like his boss, believed the best chance was with double-knockout pigs.

Goldie stood in her special cage, her ball and teddy bear at her feet. "Should be a different color or something, don't you think?" said a scientist. But she was a pretty shade of pink like the other pigs, and she was uncommonly cute. She bore an eerie resemblance to Babe.

Sachs put on rubber gloves and reached into the cage. Goldie came to him without hesitation.

Sachs patted the animal, felt her ears, tickled her snout. Goldie snorted agreeably, but Sachs said nothing. He was listening to her breathing to confirm that her lungs were clear -- that she was healthy. She was.

And he was thinking about the animal's importance. "A lot of hopes are riding on this pig," he said.

A magnet held Goldie's paper cutout to the board at large animal rounds the following Friday, Valentine's Day, but it would be a fleeting presence: this was the last such meeting before, as Duggan put it, "Goldie gives it up for science."

On Wednesday, February 19, the animal's heart, kidneys, thymus, and bone marrow would be transplanted into four separate baboons. As far as anyone in Boston knew, nothing like this had been attempted before -- five animals, four operating tables, six surgeons, six technicians and assistants, one operating room supervisor, all on one day. Just getting the organs moved into their proper places would be an accomplishment. Sachs saw no value in a rehearsal -- these were accomplished surgeons, after all -- but he, Cooper, Yamada and the staff had spent hours devising a written plan.

"Only people who are really essential go into the OR that day," Sachs said. "Don't come in unless you're asked."

Another concern was preventing publicity of next Wednesday's events: Sachs did not want word leaking out to reporters or animal rights activists. He ordered inquiring calls be referred to him.

"When the time comes," Sachs said, "I want the news to be correct."

But as it would happen, reporters and animal rights activists would prove to be among the least of the scientist's concerns.

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