Cancerland

by David Scadden

  I try to set that tone, regardless of my frustrations or sense of urgency to move forward. Scientists come to our lab from many different cultures, and this can influence whether someone speaks up or hangs back. Temperament and personality come into play and gender is certainly something to which I try to be very attuned. It is a terrible loss for all when young women feel unsupported in science. Helping without patronizing, supporting while encouraging improvement, and being fair to all is my goal. Inevitably it is tested and nothing provokes me more than a sense of entitlement that disrespects others. One of the most hyperaggressive scientists I ever managed was a woman who seemed to think that a lab coat gave her the right to say and do whatever she pleased. No matter how much I value supporting women scientists, it cannot be at the repeated expense of others and our lab culture. That provoked the fortunately very rare moment of dismissing someone from the lab.

  Being in an academic lab is inevitably a short-term experience. The point is to train people; educate them, and give them the skills needed for a successful career ahead. It is entirely different from a business where you hang on to talent. But we are not just educators, our product has to be new knowledge in addition to training effective seekers of new knowledge. We must be pushing innovation and testing new ideas of sufficient impact that we can fulfill our broader goal and frankly, gain funding. That creates an inherent tension of constantly taking in new talent, getting them up to speed and guiding them to move on successfully while also pushing to discover and deliver on the trust society gives us to make better medical care

  Scientists in training are in a challenging spot. They have already spent years getting their degrees, five to six years for a Ph.D., four years plus three to eight years clinical training for an M.D., seven years plus clinical training for an M.D., Ph.D. The post-doc training is the apprenticeship they need to then get a job in a university or medical center; some may go to industry without this. The postdoctoral trainee spends three to seven years building a sufficiently impressive body of work to convince employers to hire them and a platform on which they can build their future independent research. Once hired, they usually have three years of “start-up” funding before they are expected to have produced work to gain the grants that will allow them to be fully independent. Once they are, they are essentially independent contractors, needing to find funding to do their work. Most universities provide only minimal if any research support. Some universities provide salary support, but hospital-based faculty do not receive this at Harvard and those based at the university (I am at both) get a portion of their salary covered for teaching (25 percent). The rest is theirs to go out and get. It adds an entrepreneurial edge that keeps people from getting stale, but it also pushes people to areas they think will fund them, not the ones that will allow them to be the most innovative.

  Yet, innovators are what we need and we look for in hiring. My own trainee selection gives special attention to what I think might be a creative spark. They have to be willing to test a new idea. But failing at that could kill their career, so my job is to guide and shape them, and give the ideas the greatest chance of success. It is also to give them a safety net if they fall short. To do that, I have to encourage some who do not seem on track to choose another path, and do so quickly. Those are the toughest discussions. When people come to my lab they become family. Tough love is never painlessly administered, but finding a path that better connects with talents is part of the process. Life sciences now offer so many opportunities for fulfilling careers that the discussions about alternative career paths are getting much easier. The challenge now is to encourage the multitalented to see academics as a way forward. They are the ones who will sow the seeds of our futures through their teaching, mentoring, and research. The lack of stability and lower financial rewards are harder to accept when the industry offers so much good science and remuneration. Labs like mine have to help build the field in both private and academic settings, so we focus on building skills that serve them well wherever they go. Defending ideas, seeking and judging input from others, and clear communication are the keys.

  Our Lab Meetings, Journal Clubs (reviewing published work by others), and Blue Sky, Bubbles, and Beer sessions (quarterly, end of day, big-idea debates) all try to push the skill sets and push the imagination. These are the give-and-take sessions where people expose their ideas, and that is not easy. It can feel personal when criticism comes your way, but it is essential to gain comfort with that and to interact with respect. Science is a small world and the person at the bench next to you today could be judging your grant application next year.

  These sessions also reveal who has the habits of mind to be a first-rate scientist. What I’m talking about here is not a matter of intelligence, but of intellectual character. Basic honesty, integrity, and humility motivate good scientists to evaluate their own work and interpret their findings not just with creativity, but with caution. Seeing the bigger implications of any experiment is an essential trait for making contributions of substance. However, it can also lead to fiction. Clear-eyed analysis makes the difference. It is those who see with sharp focus the boundaries of their data, but allow themselves to squint and soft sketch a horizon in the distance, who make an impact.

  Science takes grit. In fact, contrary to the nerd cliché most people conjure when they think about scientists, you’ll find a remarkable number of athletes or fierce competitors in other domains in a typical lab. The first postdocs in my lab were sometimes hard to find because they were off heliskiing. One of my students performed cello for the Queen of England more than once and rock climbing is the workout of choice for my current lab group (subgroup meetings in the ER have been known to occur). Open chess games were what we did when I was a postdoc and losing was agony, made worse when a friend gave me a checkers set to commemorate a humiliating checkmate. Not quite the intensity of board games when I was a kid, when we would spend rainy afternoons plotting world domination in the game called Risk. (Scratch a scientist my age and you’re more than likely to discover someone who played Risk.) Our games could get so heated that body slams would ensue and one of us ended up stuck, bottom first, dangling out of the drywall. Fortunately, this didn’t happen at the Scadden house.

  Transfer the intensity of those kids playing Risk to an arena where the same types of people are devoting years of their lives to work that may or may not achieve a breakthrough and you get some idea of the context in which high-level science is done. With vast amounts of money on the line and people literally dying for want of cures, the pressure to succeed is intense. It is amplified by the fact that it is a competitive enterprise, with people all over the world seeking to win the same game. In many countries governments invested heavily in biological research in a highly targeted and highly structured way because they recognized that progress might open big, valuable markets for medicines that the world would eagerly pay to receive.

  In the United States stem cell science was clouded by ethical and regulatory debates. Here and in many other countries religion set policy in a certain direction. Those that were predominantly Catholic tended toward bans that reflected the traditionalist belief that at the moment an egg is fertilized it has the full status of a person. Israel, guided by the Jewish belief that human life doesn’t begin until forty days after fertilization, and full status must await birth, almost every avenue of stem cell and regenerative research could be followed. The same was true in much of Asia, where government and religion occupied strictly separate realms. (The ethicist Art Caplan has said China is “an almost scientistic” nation where religion plays almost no role in policy development.)

  With few social constraints, several Asian countries seized the opportunity to develop big research efforts with an eye toward the vast industry and profits that might arise out of the science. Most notable was South Korea, where government, universities, and industry came together to fund an ambitious agenda with $80 million and was centrally planned for maximum efficiency. Bureaucr
ats determined which research areas would be pursued by each lab, and overlap was discouraged. After visiting one of the labs engaged in this project, in late 2003, President Roh Moo-hyun said he would “not spare anything” in the pursuit of cloning research. The lab that inspired this comment, and the president’s confession that he felt “electrified” by recent breakthroughs, was run by a Seoul National University animal cloning expert named Hwang Woo-suk. His main claim to fame was that he had used cloning to create animals that were resistant to so-called mad cow disease, which destroys nerve and brain cells and can be transmitted to humans.

  The mad cow phenomenon led to news reports that showed wobbly and crippled cows and references to the tiny but terrifying possibility of human infection. As so often happens, the same people who might raise the loudest alarms because they feared some types of science were among those who wanted rapid and sweeping scientific responses in moments of crisis. News about Professor Hwang’s cloned cow was followed by a surprise announcement that he had produced a clone of human cells by using one of the cells that surround a woman’s egg at the time of ovulation—a cumulus cell—and the egg itself. He reported that he had transferred the DNA containing the nucleus of one cell and put it into a human egg cell. Egg cells have only one copy of DNA until fertilized by sperm and cannot divide or develop into embryos. Hwang claimed he had done for humans what John Gurdon had done for frog cells, moving the nucleus of a mature cell with two copies of DNA into an egg so it could now start dividing and making a new embryo.

  The word bombshell doesn’t go far enough to describe the impact of the results reported from South Korea. First, rumors of a cloned human embryo spread on the internet. Then press in Asia and the United States broke an embargo set by the journal Science, which was set to publish Hwang’s paper on his success. HUMAN EMBRYO SUCCESSFULLY CLONED IN SEOUL, trumpeted The Wall Street Journal. The New York Times headline also used the terms cloning and human embryos, and its imprimatur made the world take notice. Americans who had made similar efforts, in many cases for years, were both amazed and astonished.

  The first hints of trouble with the Hwang claim arose when he and the director of a South Korean stem cell research center joined with an editor for Science to meet with reporters. The problem wasn’t that they seemed cold and aloof; in fact, they had so much fun dealing with the press, joking about chopsticks and chocolate, that they completely charmed the reporters. The seeds of doubt lingered in the caveats they offered about the difficulties of their work. First, they said that the cloning had been attempted with more than 240 cells, but they had succeeded with only one, ever. They also predicted that anyone who tried to replicate their success would have a very difficult time doing it.

  Everyone who worked in nuclear transfer understood it was a technically challenging endeavor. And human eggs were particularly difficult to work with. For these reasons, the cautions raised by the South Koreans were sensible. However, they also had ample reasons to help others replicate what they had done. Without a second clone, produced by someone else, their achievement would be subject to doubt. Scientists from around the world, including three teams from the United States, sought to establish partnerships with the South Koreans. When Hwang elaborated on his technique, explaining he had slit the egg to make it more receptive to the insertion of cells, his success seemed more plausible to those who had worked with human eggs and found it difficult to pierce them with needles without causing too much disturbance.

  In the months that followed the reported cloning, scientists, clerics, and politicians speculated about the potential cures that could arise and the moral hazards. Activists who opposed embryonic stem cell research raised alarms and pushed the United Nations to back a global ban on this work. Hwang fueled much of the speculation himself as he talked to visitors about experimenting with cell transplants in rats with spinal cord injuries and then, within two or three years, trying this therapy with human subjects in South Korea and the United States. He told heartwarming stories about his rough childhood and the seven-days-a-week, round-the-clock work done by his team. He spoke of having staff members speak to the eggs they worked with so they wouldn’t become lonely. South Koreans celebrated their nation’s triumph over many wealthier scientific competitors, especially Japan and the United States. A stamp was issued to commemorate the clone. (It featured a person leaping out of a wheelchair.) Hwang’s lab received big funding increases from the South Korean government, and in a move that could only be described as cheeky, he announced he would visit the British lab that produced Dolly to see if it was technically advanced enough to permit a collaboration.

  Amid all the swaggering celebration, one of Hwang’s young associates began to feel grave misgivings. Ryu Young-joon had authored the first draft on one of Hwang’s most important papers but then left the lab for a new job. His departure prompted many more, and he knew that the work later claimed by Hwang could not have been accomplished by the team that remained. When he heard that his former boss had promised to perform an experimental treatment on a ten-year-old with a spinal cord injury, he became alarmed.

  “I was furious,” he would later recall. “I wanted to stop that.”

  Ryu took his concerns to a Korean TV news network, which began an intense investigation and soon discovered that Hwang’s egg donors had included two women who worked on his staff, which was a violation of scientific ethics. Then came news that the majority of his lab’s donors had received either money or low-cost fertility treatments as payment. Evidence of sloppy work, including mixed-up photos submitted to journals, was followed by a critique signed by thirty members of the faculty at Seoul National University. These experts expressed serious doubts about whether Hwang’s results were genuine. Tests of the genetic markers in the supposed clones did not verify his claims. The credibility of South Korean science had been undermined by Hwang’s work, they wrote, and only a serious investigation would resolve the looming crisis.

  With its reputation at stake, the university created an investigating group that dug into Hwang’s published papers, his records, and the methods used at his lab. Many on the panel were younger medical scientists with international experience and a commitment to the ethics that ensure both the value of scientific studies and the support of the public at large, without which science is impossible. In less than a year’s time, they reached the conclusion that Hwang had fabricated his original claim of a human embryo clone and all his subsequent ones related to human embryos. (A rambunctious little Afghan hound named Snuppy—Time magazine’s Invention of the Year—turned out to be an authentic animal clone.) Having turned Hwang and his colleagues into national heroes, the South Korean government and public were forced to accept that he was, in fact, a con artist.

  The South Korean nation and scientific establishment moved quickly to accept the outcome of the investigation. Hwang’s colleagues spoke of the way their probe asserted higher standards and signaled the world that they wanted to work in the mainstream. The government commenced a criminal probe. In his first response to the findings of the investigators, Hwang admitted his wrongdoing, saying, “I feel so miserable that it’s difficult even to say sorry.” However, he also tried to shift blame to his associates, and he continued to promote the idea that his work would lead to treatments in a very short time, insisting, “I think we can create patient-specific stem cells in six months if eggs are sufficiently provided.” Eventually Hwang would be convicted of ethics law violations and embezzlement, but he would be spared prison time when a judge gave him a suspended sentence. When last seen in the press, Hwang was selling his services to dog owners, who, for $100,000, could have him clone their pets.

  Hwang had generated such attention in part because of the “yuck” factor: could a person really be the next Dolly? Horrible politicians now in droves? Great material for late-night comedians, frightening in its potential for really awful misuse. What excited most scientists I know was not about making new genetically identical twins. That just wa
sn’t going to happen unless women would agree to carry such a creature in their womb, medical centers would agree to let such procedures be done in their facilities, governments wouldn’t ban such efforts (which they did), and nature didn’t prevent the process from being extremely rare and as often resulting in deformed creatures as viable ones. What was exciting was the prospect that reprogramming of nuclei could be done such that pluripotent cells could be cultured. That would mean cells that were genetically identical to cells from an adult but which had the potential to make any cell in the body of a real person. Even if the eggs and sperm came from related donors, the ES cells could not be any more closely related to someone than a sibling or a cousin would be. By cloning using nuclear transfer, the DNA would be identical to the donor of the nucleus and therefore the cells would be too. That degree of genetic sameness had powerful implications for generating cells that ultimately might be used to replace a person’s cells lost to disease. It also had implications for being able to study the basis for someone’s illness. What it didn’t relieve, though, was the ethical freight of stem cell research.

  The process of cloning by nuclear transfer had one critical requirement for success: lots and lots of human eggs. It is very uncomfortable and quite risky for women to donate their eggs. Hwang had first gotten into trouble, not because he was a fraud, but because he was coercing women in his laboratory to donate eggs. States like Massachusetts banned compensating women for donating eggs for research (despite allowing it for “reproductive purposes,” like would-be parents soliciting Ivy League women to donate for large sums of money so they could improve the odds of a star child in the family). Exposing the Hwang fraud helped reduce the concern about egg donor coercion, but the ethical stains on stem cell research were mounting up. It didn’t take much work for those opposed to stem cells to find a range of issues of concern from destroying embryos, to making clones, to exploiting women. Virtually all of the concerns were not real in substance, but perceptions can be all the matters, particularly among politicians—and they, of course, control the purse strings for research.