Cancerland

by David Scadden

  Doug’s confidence was evident in the direct way he addressed people at meetings. He knew that audiences, even scientific audiences, really want to be told a story. Make the narrative simple and people will get it, remember it, and seek you out for more. As one of my colleagues points out, “No one walks out of a lecture and says, ‘I wish that was more complicated.’” Doug is a master of the well-told scientific story.

  With his narratives Doug can create enthusiasm, and find support, for projects that might languish in the imagination of someone with less drive and creativity. It’s hard to overstate the importance of personal qualities when it comes to getting things done in science, despite what people often think about scientists as robotic in their dedication to work. It’s just not true that scientists are the impersonal eccentrics often portrayed in popular media. Passion, creativity, and personality drive science as much as any field and are particularly crucial in new fields like stem cell biology. Doug was able to bring people and monetary support to stem cell research, not by the force of his personality—he is actually quite soft-spoken—but by making coherent scientific arguments and cultivating collaboration. Unlike some high-level scientists, Doug recognized the value of what others could bring to a project, and that included everyone from clinicians who worked with patients to venture capitalists who brought money to science. He looked around the Cambridge/Boston community and saw an unmatched human and technical resource.

  For much of the prior two decades, Doug has conducted painstaking explorations of the ways that genetic code is written and transferred to create new life. He did devote much of his time to developing and testing methods for looking inside molecules to discover how so-called messenger RNA control the factory functions that link amino acids together inside a cell. A great deal of what he did involved eggs of the same Xenopus laevis, or African clawed frog, that John Gurdon had cloned. Xenopus are good test subjects because they are hardy, they produce a lot of large, resilient eggs, and they are a decent genetic model.

  Science became a lot less abstract and much more personal for Doug when his six-month-old son, Sam, was diagnosed with type 1 diabetes. (His daughter has it too.) Type 1, which is the immune-based form of the disease, arises when the pancreas fails to produce insulin at a level needed for the body to process and use nutrients. Insulin insufficiency, which can be fatal, causes a host of terrible symptoms, including seizures. It can be difficult to diagnose in infants, and the Meltons went through much anguish as they watched Sam suffer and waited to learn the cause.

  The experience, and the understanding that Sam faced a lifelong chronic condition with potentially dire consequences, motivated Doug to shift the focus of his science completely. This almost never happens in science because of the nature of funding—you can only convince funders of your future success by proposing to directly build on prior success. Doug was supported by the Howard Hughes Medical Institute and so was not subject to the same constraints; he could shift focus with their support. And so he did, deciding to focus his science directly on diabetes and on stem cells that he rightly envisioned might produce a true cure. The stem cells that create the pancreas and populate it with new functioning cells during the lifespan fall into two categories. One kind creates enzymes that digest food. The second type of cell is founded in scattered pancreatic “islets” where they produce, store, and release insulin and other hormones that regulate our metabolism and other functions. People with type 1 diabetes have too few of the insulin-producing “beta” cells, as they are called, generally because of an autoimmune disorder that selectively destroys insulin-producing cells.

  For Melton and others, the beta cell problem seemed ripe for a solution that might one day involve using stem cells to create an ongoing supply of productive islets. (Direct transplants from cadavers had been tried with success but were extremely complicated, required multiple donors for enough cells for one recipient, and often gradually declined in effectiveness over time.) However, a great deal of basic science had to be done before a treatment involving stem cells could be considered. Many questions had to be answered about how the cells that created the pancreas developed in the embryo and fetus and then came to sustain the organ throughout life. Working in animals, Doug studied, among other things, molecules called hedgehog ligands, which regulate how embryos develop different parts of the body. These ligands, and the pathways they travel to do their work, were also implicated in some cancers. This was no surprise as, over and over again, science was revealing that the mechanisms that governed development and growth were often implicated in the wildfire of malignancy.

  In work done with frog embryos, Doug made key basic discoveries about how cells in the newly fertilized egg begin to create the neural tissue that will become the spinal cord, the brain, and the nervous system. This development process depends, as Melton and his group found, on communication from one group of cells that sparks changes in others. Although it would seem esoteric to many laypeople, this work answered some key questions about how complicated life-forms emerge from an amorphous ball of cells that are the pre-embryo.

  Inevitably, however, Doug and other embryologists would run into the limits of animal studies. Big disappointments with drugs that worked in animals but not human beings showed that only so much could be learned from studying mice or frogs or other species. (One big problem is that they don’t develop under the guidance of all the same chemicals.) Like others, Doug turned to the study of human embryonic stem cells. Since not all embryonic stem cells have the same functional properties, he developed many new lines using the fertilized eggs abandoned by couples seeking in vitro fertilization. These he made readily available to any scientist in the world who sought them to study. He was able to do so because of the Howard Hughes funding. Government bans on using federal money were already in place.

  Unlike others who had been discouraged by the controversy around stem cells, Thomson and Gearhart had been able to create privately funded projects to advance their science. Thomson would eventually reveal that he had also been denied access to University of Wisconsin funds by those fearing negative publicity. The answer to his money problems came from an entrepreneur named Michael West, whose company, Geron, sought to develop, for lack of a better term, fountain-of-youth technologies. West had a doctorate in biology and had spent his entire career investigating aging and searching for ways to slow or even reverse the process. Because they venture close to concepts that can seem fantastical, scientists who work in this area must fight against being perceived as crackpots. West’s interests were quite legitimate. He was intrigued by telomeres, which appeared to govern the vitality of chromosomes. And he was fascinated by stem cells.

  Funded by Geron, which also backed Gearhart, Thomson set up in a freestanding facility with equipment he acquired on his own, and he used the same techniques he had employed in primate research. Frozen blastocysts were thawed, placed in nutrients, and processed so the stem cells could be isolated. Once established, colonies of cells had to be monitored closely and separated with pipettes to keep them from overpopulating their environments and differentiating into various subtypes of stem cells (for muscle, bone, nerves, etc.). Properly nourished and safeguarded, the cell lines, as they were called, were essentially immortal. They could reproduce almost indefinitely and supply researchers around the world with cells for research.

  The ES cell lines that Thomson produced were available for purchase, but at a price and with reporting requirements that were extraordinary for scientific reagents. This hampered many from working in the field. Doug’s lines were available more inexpensively. However, they were still being developed in the early days of the field and so had less characterization. Both depended on private money to be generated, a highly inefficient method for developing reagents of such dramatic potential. A disconnect between funding and importance is not uncommon in life science research, but to have a primary driving force of science, the federal government, speak out and ban an area of uncontestably impor
tant work is extraordinary. Private foundation funding could help, corporate investment could help. Unfortunately, the latter source was rare because of the distance from ongoing work and clinical application, keeping even the company that might risk the public relations issues, at considerable distance. Private funding was possible, but the scale of need versus available capital seemed to create an enormous barrier. We needed to assemble scientists to improve the pace of discovery and to be better at making a case to potential donors. Harvard is spectacular at assembling great talent, including philanthropic talent, and needed only an activation signal to become a leading stem cell program.

  Doug was, to my mind, one of the leading stem cell experts in the world and one of Harvard’s best scientists. (He was also a member of the National Academy of Sciences, which is one of the most elite scientific groups in the world.) Doug was succeeding, but it seemed that the whole enterprise of stem cell research required a more concerted effort drawing more people into a team. I heard he thought the same thing. When I went to see him to suggest we create an interdisciplinary stem cell institute, I was a bit worried that this fellow who was truly a superstar in embryology might not be receptive to a lunch-pail hematologist.

  People are often surprised to hear a doctor or scientist express the kind of insecurity I felt when I went to see Doug. Often they assume that someone who has survived medical school and works in the clinic or lab must surely be completely confident and at ease. But confidence about doctoring does not translate into confidence about science. I was, after all, trained to be an expert in interpreting people’s words, symptoms, x-rays, and how their stomach felt or lungs sounded; that was no more about fundamental biology than selling a product is to making it. They are very different worlds and I was a newcomer to refined haunts of basic science in which Doug had come of age. One thing I did have, though, was confidence that I could connect with people. I had learned that at people’s bedside. It didn’t hurt that I have outside interests to which people can connect. Sometimes that is parenting escapades, a good book recently read, or love of the outdoors. My offbeat passion for fishing even helped. Few things center my being like being on or in water, throwing a fly line and occasionally connecting with vitality itself when a fish strikes. For many years I kept a boat in Boston Harbor and often rose before dawn so I could spend an hour or two on the water throwing flies I had tied before getting to work at eight o’clock. I generally released what I caught but when I netted a particularly big fish I delivered it to a restaurant near Mass General. I always gave them the fish, and they never let me pay for a lunch.

  I don’t recall if I went fishing on the day I went to see Doug, but he would likely say I didn’t betray any of my insecurities. We immediately connected on both a personal level and in our desire to see stem cell biology deliver medicines that could make a difference in people’s lives. He spoke to me about his desire to see his work translated into treatments and he would be happy to accept help anywhere he could find it. Embryology, his specialty, could yield therapies, and it seemed likely that by studying how pancreatic cells were created, he could devise a cure for type 1 diabetes. This would be no small accomplishment. More than 1.2 million American adults have this form of diabetes, and children are diagnosed with it every day. It exacts a huge toll in terms of human suffering and health care costs. A stem cell–based cure that could lead to normal pancreatic function would be a godsend. However, Doug’s basic science related to all of cell biology and had the potential to seed breakthroughs in many other areas of research, including oncology, if only various labs and individual investigators were able to collaborate more freely.

  As a large bureaucracy, Harvard was a balkanized place where brilliant and generally competitive people pursued their ideas with such intensity that they might not notice that someone nearby was doing closely related work. Funding methods generally supported single projects and not collaborations. In addition to this limitation, Harvard scientists, like all American-based researchers, faced the obstacle of constricted federal funding and controversy that made philanthropists and foundations wary of getting involved. The situation left the United States vulnerable to being overtaken by other countries in this area of science and medicine, but it also created an opportunity for institutions where leaders were willing and able to invest their own resources. Geron had done this by getting behind Gearhart and Thomson, but those efforts had been relatively small in scale compared with what Harvard and its affiliated hospitals could do.

  Doug agreed that Harvard needed more than a passive approach to stem cells and by the time our meeting came to an end, we had sculpted out a vision for a trans-Harvard initiative. More importantly, I think we both felt we had found a partner to make it happen. I had deep roots in the medical community and knew how the hospitals worked, Doug was an established leader in the Faculty of Arts and Sciences and was fully connected to University power centers. We also represented the spectrum of what was needed to make stem cells deliver. He was a superstar in the world of fundamental biology and I had some traction in the applied science of medicine. We knew Harvard had little precedent for organizing people across the broad universe of institutions that comprised it, but we also knew that scientists, though skeptical, would welcome the chance to engage in a larger effort. Finally, we were confident that Harvard alumni would look favorably on the university leading such a potentially transformative field and would get behind us financially.

  Many factors would work against us in this endeavor. First of all, lots of people want to get Harvard’s money for their work, and even with its big endowment, the university had only so much cash and fund-raising muscle to go around. Second, we were asking the university to take the risk of putting its imprimatur on work that some powerful people didn’t want done. Also, we had to allow for the fact that this kind of research rarely proceeds in a straight line. To use the wildcatter term, we were bound to drill some dry holes. And there was no guarantee that our successes in basic science would produce treatments and royalty payments to sustain an ongoing effort. Although we would contribute to the public good and make Harvard a leader in the field, this could be science for the sake of science.

  Neither of us would consider that success. We were in it to make new therapies and benefit those for whom stem cell science offered hope. We named our planned organization the Harvard Stem Cell Institute (HSCI), intentionally leaving out the word research. We did not want to simply foster great research.

  Moving the HSCI from concept to reality was only possible if we could convince the leaders of the university, medical school, and hospitals that something positive would result. To that end, I had one advantage that I couldn’t reveal to Doug at the time but which I can write about here. In 1983, I had been one of the doctors who treated a young Harvard professor named Lawrence Summers for Hodgkin’s lymphoma. This type of white blood cell cancer can cause lots of unpleasant symptoms, including pain and fever and weight loss. It can be treated (generally with chemotherapy and radiation), but not everyone survives.

  Larry had become quite sick and it was initially unclear what he had. He was finally admitted to the hospital where I was the fellow (a term for a subspecialty trainee) on the consulting Hematology team. We had to conduct numerous tests, including a bone marrow biopsy, that finally revealed his diagnosis. He spent considerable time in the hospital, where I was often involved in his care and got to know him reasonably well. To me, he was a smart, ever-curious patient stuck with a lousy fate. I knew he was an academic economist, but I only later learned that he was what might be called academic royalty. His mother and father were both professors at the University of Pennsylvania and by the time he finished undergraduate studies at the Massachusetts Institute of Technology, two of his uncles—Paul Samuelson and Kenneth Arrow—had been awarded the Nobel Prize in economics. Larry was following their footsteps with a reputation for brilliance in macroeconomics until his diagnosis, when his health became his first concern. But Hodgkin’s’ d
idn’t affect his mind. Each time I saw him he asked so many good questions that I made him a proposition:

  “I’ll teach you medicine,” I told him. “You teach me economics.”

  Summers took the deal and in the course of his treatment, which led to remission and cure, I learned a great deal (much of it now forgotten) about how national and global economies work. More importantly, I learned that he was fearless intellectually and personally. He would never shy away from anything, particularly an opportunity to do something important. Once recovered, he resumed his extremely active life of teaching and research and consulting. In 1991, he left Harvard to head the World Bank. He joined the Clinton administration in 1993 and ended his work for the president in the position of secretary of the treasury. When President Bush replaced Clinton, Larry returned to Harvard to take the job of university president. At age forty-six, he was one of the youngest men—to this point, all Harvard presidents were men—ever appointed to the job. And since Harvard presidents rival popes when it comes to their longevity in office, it was possible that he could serve for decades.

  Summers’s investiture took place on a sunny October day in a ceremony in Harvard Yard. He was accompanied by much of his family, including his twin daughters, who were eleven years old. In his inaugural address, he stressed only one major research goal, which he called a “Revolution in Science.” This revolution would occur, he said, during the coming “century of biological and life science” and would be driven by the need to comprehend “the biological and chemical basis of life.” Summers understood the context of this moment. He noted the “multi-billion-dollar projects [to] sequence the genome” and acknowledged that the university would have to “adapt its traditional structures to most effectively engage the adventure of science.”