Cancerland

by David Scadden

  Harvard had missed a number of chances to lead in biology since I had been there and one was particularly poignant in my field. A young, wonderful physician/scientist named Brian Druker was affiliated with the university and Dana-Farber. He was particularly interested in proteins called kinases, which are able to activate molecules by transferring a high-energy phosphate onto them. Druker was especially interested in kinases that regulate the production of white blood cells. This process is a bit complicated, as stem cells first produce so-called “progenitor” cells that then supply the body with what become mature white blood cells. When stem or progenitor cells get genetic defects they can cause cancer, and one of the first cancers in which this was realized is a disease called chronic myeloid leukemia (CML). The genetic defect was known as the Philadelphia chromosome.

  The most important work on the Philadelphia chromosome’s role in CML had been done by physician-turned-scientist Janet Rowley at the University of Chicago. Rowley was a child prodigy who got her undergraduate degree at age nineteen but was shut out of medical school when she first applied because the university had filled its quota of women. (They admitted three for every sixty men.) The University of Chicago’s Prtizger School of Medicine admitted her the following year, and she graduated at age twenty-three.

  Rowley became interested in genetics while working as a physician at a clinic for children who had Down syndrome. (People with Down syndrome have an extra copy of chromosome 21.) Rowley moved from medicine into science when she accompanied her pathologist husband to England for his sabbatical and a prominent hematologist named Lazslo Lajtha gave her a job in his laboratory at Churchill Hospital in Oxford. Known as an “atomic hematologist,” Lajtha’s work included research into radiation-related illnesses. In Lajtha’s lab, Rowley began to study chromosomal defects. When she returned to Chicago, she met with another well-known leukemia specialist named Leon Jacobson and persuaded him to provide her with a special microscope and a darkroom so she could take photos of the chromosomes she studied and enlarge them. It had already been noted by two scientists—Peter Nowell and David Hungerford—in, of course, Philadelphia, that people with CML had an abnormally small chromosome 22, but it was Rowley who understood why.

  Since genes deal in chemical conversations, Rowley’s discovery hinted at what must be going awry. It was subsequently shown that a kinase on chromosome 9 had been shifted over to chromosome 22, and in so doing was fused with another gene such that the kinase was always turned on. An always-active kinase was forcing the cells to continuously grow, a very destructive kind of communication. It was also a potential point of vulnerability since it was evident that chemicals could inhibit kinases. This is where Brian Druker entered the picture. He was intrigued by the idea that the genetic error identified by Rowley might be fixed with a chemical that would turn off the runaway production of cells.

  The big challenge would be to identify exactly the right chemical that would do the trick without messing with others related to growth and energy production. A dogged investigator with a well-honed scientific mind, Druker had been, like me, a child chemist free to experiment despite the occasional fumes released into his parents’ home. Serious and self-effacing, he had just the right temperament, including the ability to be self-critical, to do top-notch science. As a physician, he had treated CML patients and took their deaths quite personally, allowing the losses to motivate his research. He also believed, like I did, that by working with a readily studied cancer of the blood and bone, he could understand principles key to cancer more generally.

  Unfortunately (more for Dana-Farber and Harvard than for him), Druker ran into a roadblock that made it impossible for him to get the kind of backing he wanted. The problem was that the key chemical compounds he wanted to work on, named STI571, were owned by Ciba-Geigy, a Swiss pharmaceutical company. Dana-Farber had entered into an agreement for related research on products made by the company’s rival, Sandoz. Despite the fact that Druker had encouraged Ciba-Geigy scientist Nick Lydon to develop drugs like STI571 since they would be targeted therapies very different from the general poisons used by oncologists, the logjam could not be broken. Stymied at Dana-Farber, Druker decided to move across the country to the Oregon Health and Science University in Portland, where the administration was ramping up its committment to research.

  Supplied with a small amount of Ciba-Geigy’s chemical, Druker tested it in lab dishes that contained both normal white blood cells and CML cells. To his astonishment, it killed 90 percent of the CML cells but none of the normal ones. He reported this finding to his Swiss corporate partner in 1994. Next would come animal trials, which also went very well.

  The role of major drug companies in basic research was both essential, as a matter of finance and expertise, and fraught. The money kept scientists around the world working on innovative concepts, and the larger companies operated facilities that could support them with the production of needed chemicals in substantial quantities. However, the relationship between industry and science was complicated by the need for profit, and by the varied activities undertaken by corporate conglomerates.

  Drug companies are often engaged in such complex mergers and acquisitions that projects often just get lost in the high-stakes games of corporate strategy and corporate careers. A perfect example of this arose as Ciba-Geigy and Sandoz merged to create the second-largest drug company in the world, Novartis.

  Novartis had little interest in developing drugs for rare diseases as they represented small markets and, per the wisdom of the day, would not generate large enough profits. Pushing STI571 forward for a disease that worldwide only represented 30,000 patients was challenging and were it not for the unrelenting efforts of Druker, the result would likely have been quite different. He got Novartis to at least support a first study. In that study, he had to rely on patients who had already reached the limits of other therapies. Nearly 150, including six children, were enrolled to take the compound in pill form, every day, in varying doses. As first one patient, then another, and then another began to improve, Druker began to feel excited. None of the trial subjects experienced serious side effects, and many got better. The improvement could be seen in their level of energy and function and in their blood tests, which showed that STI571 was normalizing their blood counts and reducing the presence of cells with the Philadelphia chromosome. If this finding held up, Novartis would have the first cancer drug that fixed a specific genetic defect that caused malignancy.

  The phase I results were nothing short of remarkable, but there was no commitment from Novartis that more studies would proceed. Indeed, Novartis had not made enough of the drug to do a bigger second study. But in an early example of social media making an impact, a patient-driven petition landed on the desks of Novartis executives and expanded trials got quickly under way. Hematologists who had never heard of STI571 learned of it from patients who wanted to be enrolled in trials.

  * * *

  In December 1999, I was in the convention hall in New Orleans as Brian Druker gave one of the closing talks at the American Society of Hematology’s annual meeting. Although efforts had been made to keep the results of the drug trial confidential, the press had reported that some big news was coming, and it was a topic of great speculation at the conference. Every seat was filled as Druker began to speak, and the room was so silent you could hear the sounds made as people scratched notes as he described the parameters of the trial. As he described it, every one of the patients who got the drug were in a late stage of the disease and their doctors had exhausted all other options. Some were obviously dying. This factor alone made the odds for successful treatment quite daunting.

  A slender guy with thinning hair and a quiet voice, Druker is not the type to show a lot of emotion. But on this afternoon in New Orleans, he looked like he was having trouble controlling his excitement. He described the research group’s efforts to identify a proper dose and schedule for treatment and months of waiting for results. Finally, as the regime
n was refined to three 100-milligram capsules per day, the benefits became apparent. All thirty-one patients experienced what seemed to be complete remission, with their white blood cells returning to normal and their health restored. In some cases, the chromosomal abnormality that caused the disease began to disappear. Indeed, when they studied blood samples, Druker’s group couldn’t find any evidence of the Philadelphia chromosome in some of their patients. The only side effects reported were fatigue, muscle cramps, and stomach upsets.

  I think that most of us who listened to Druker’s talk reflected on CML patients who had died and others who had suffered the grueling experience of bone marrow transplants, which only worked a quarter of the time. In comparison, STI571 seemed like a miracle, and scientists generally don’t believe in miracles. Druker acknowledged this when he spoke with the press. “One of the problems I’ve had with this project,” he said, “is that I oftentimes have difficulty convincing people that this isn’t too good to be true. One of the major goals of cancer research has been to identify differences between cancer cells and normal cells so that these differences can be targeted with more effective and less toxic treatments. That’s exactly what we’ve seen happen in these patients.”

  Eventually named Gleevec, the chemical that excited the conference in New Orleans would prove to be so effective in early trails that the Food and Drug Administration used a fast-track process to consider its approval for use. Approval came on May 10, 2001. Novartis, which had been gearing up for the moment, began shipping the drug the very next day. In less than six hours, every advance order for the drug—more than five thousand of them—had been filled and shipped. Soon doctors and patients all over the world were seeing dramatic remissions like the ones recorded in early trials. The number of cells bearing the Philadelphia defect declined. Healthy ones increased in number. People faced with imminent death recovered their strength, began eating, put on weight, and resumed their previous lives. I saw this happen and was astonished.

  The basic action of Gleevec was so different from the cell poisoning done with traditional chemotherapies that most scientists and physicians hoped it would work for nearly all people with CML and provide a lasting cure. Strong evidence that the problem mutation was being eradicated with treatment reinforced this hope. Similar optimism attached to the idea that a new cancer therapy paradigm had arrived. If Gleevec could essentially cancel out the effects of a mutation that caused one cancer, perhaps it could do the same with others.

  Soon after it got FDA approval, physicians led by my colleague George Dimetri gave Gleevec to patients with a gastrointestinal tumor that can be caused by a mutation similar to the one that causes most CML. It worked in about 60 percent of cases. Other trials found it effective against additional bone marrow–related diseases and against an extremely rare kind of skin tumor. However, the list of malignancies helped by Gleevec stopped at this handful. And the much-hoped-for cascade of breakthrough drugs that would work similar molecular magic did not develop at the pace many hoped to see. Indeed, while Gleevac could control CML, it didn’t cure it—patients required chronic therapy and some inevitably developed resistance to the drug. Still, it opened the door for developing drug therapies specifically for the genetic abnormalities driving the disease. That was entirely new in the drug industy and signaled a major shift in thinking.

  Gleevec opened a vast biological territory. It showed that forms of kryptonite could be developed against the superpowers evidenced by many cancer cells. Gene sequencing could be used to identify specific abnormalities and drugs would be found to attack them. That rational approach was as compelling as it was difficult, but much progress has been made using this basic paradigm. Generally not curative, such therapies at least provide a temporary benefit for many patients and the agents can be used in a way tailored for the specific abnormalities seen in a patient’s tumor. Instead of all patients with a given diagnosis made by the last century’s techniques of what it looks like under the microscope, most major cancer centers now genetically characterize tumors and select the medicines to be used based on that information. Indeed, a cancer drug has recently been approved by the FDA for treating a specific genetic abnormality regardless of the kind of cancer in which the abnormality appears.

  * * *

  The office of Harvard University’s president occupies part of Massachusetts Hall, which is the oldest building on campus and the second-oldest college building in the United States. (The oldest, the Sir Christopher Wren Building, is at the College of William and Mary in Virginia.) Once a barracks for Revolutionary War soldiers, who likely absconded with much of its hardware, the building so reeks of history that you can almost feel the weight of the centuries as you enter. When Doug and I went to see President Summers to discuss stem cell research, we breathed in the atmosphere for a moment, noted the historic references, and then got to the point.

  At the time when we went to see him, Summers was one of the most well-known academic leaders in America. On campus, he was so popular with students that many asked him to sign dollars bills that bore his signature from his time as secretary of the treasury. (He generally obliged them.) In this time, before controversies inevitably arose, he was considered a brilliant if occasionally difficult man. He is a tough nut, and if you went to him with a half-formed idea, he was likely to crack it open and demonstrate its deficiencies. Those who felt personally offended when he didn’t act on their ideas thought Summers was insensitive. “Bull in a china shop” was the cliché most often cited. I never felt this way about him. In fact, in my experience, he was politically astute and always more interested in learning what he could from a given encounter than in forcing his ideas on others. He was very good at synthesizing a variety of ideas and opinions and pushing toward a consensus.

  Larry understood the nature of bureaucracies, and as his inaugural address showed, he appreciated the importance of the research. These two points of agreement were not unexpected. However, Doug and I were pleasantly surprised to learn that he saw the difference between the genome project, which was essentially an engineering task accomplished by the massive application of technology, and the less predictable business of stem cell biology. Of course, there was a place for computing power in our work, but we would also argue that the systems we studied were so variable and interdependent that it was extremely difficult to construct a mathematical approach to the science. We believed that biology, interdisciplinary consultation, and even intuition, the tangential product of the human mind’s computing power, can produce unexpected but valuable insights.

  With rare exceptions, only universities provide the kind of support that tolerates the cross-pollination, and risk of failure, we thought a big stem cell program required. In academic settings, it is the power of your idea, and not your connections or money, that matters most. This isn’t always true in industry, where executives fear risking capital on open-ended research or in big-government bureaucracies, where ideas are typically just one of the important currencies that matter.

  Although economics is widely assumed to be a numbers game, it is also energized by psychology, which explains much of what occurs in markets. Summers appreciated this aspect of his own discipline. One of his most noted works concerned a prescient description of the social effects of economic booms, which spread a kind of euphoria that causes people to deny the obvious risks in their actions, which then produce calamity. This was, in economics terms, a “theory of mind” description of events, based almost entirely on psychological insights, that was more predictive than anyone in attendance could have imagined.

  In our discussion, Summers was able to appreciate the points we made about the less-than-linear aspects of our science. He was excited by the suggestion that Harvard had the opportunity to build the right culture for leaps forward in biology. As a person who had overcome cancer, he was enthusiastic about the therapeutic possibilities in our work. And he had no qualms about the morality of the science. However, he was concerned about the possibili
ty of resistance we might encounter from others.

  “Do you think this is the kind of thing that could get grassroots support, both inside and outside support, that would let you get traction?” asked Summers.

  The term inside referred to the university community. Here we could meet some resistance from those who had staked out areas for research and might feel we were encroaching on their territories. However, we already had an eye on the folks we wanted in our collaboration, and we expected that most, if not all, would see the value in what we proposed. The “outside” community included all the political, academic, scientific, philanthropic, and even religious leaders engaged in stem cell issues and the general public. Nothing had occurred to make stem cell science less controversial, and with George W. Bush’s election, we expected things to become more troublesome, not less.

  “This is why we need to lead,” I said to Summers. “The usual base of support—government and philanthropy and industry—is just not there. If we don’t step up, who will?”

  The leadership needed was a matter of inspiring, rallying, and directing the development of a stem cell institute, as well as helping to fund it. As much as scientists may wish it isn’t so, money is so important to our efforts that without a steady supply most research ideas won’t reach maturity. In some cases, money can even give a team time to fail, perhaps multiple times, on the way to success. If Summers could get us financial backing from the university and pitch us to the major donors who regularly supported Harvard, we had a shot at getting sustained funding for a long-term effort.

  At the end of our meeting at Massachusetts Hall, Summers said he would get behind everything we sought. He would even give us a lead position in his meetings with donors, asking them to support us with their checkbooks. Doug and I would sometimes be required to shine our shoes and put on neckties to help this effort, but we could rely on him and the clout of the university to make those connections and, more importantly, put the university’s credibility behind what we proposed to do. This factor wouldn’t be enough to change the minds of politicians who were opposed to federal funding for stem cell work, but it would assure the world that what we were doing would be mainstream science in a responsible way.