The Stem Cell Hope, page 27
Jessell had already spent the better part of two decades pursuing this systematic strategy—not with stem cells, but with methodical investigations of the various genes and molecules that together converge to dictate first which nerves out of the body’s five thousand to ten thousand classes become motor neurons, the specialized nerves that connect to muscles, and then how these motor neurons link up with their designated muscle mates among the six hundred different muscle groups in the body. And he had made considerable headway, identifying a family of genes that seemed to regulate this process.
“Then I was told to stop wasting my time and start thinking about how to apply some of these basic sets of questions and observations to something that actually might be useful to someone at some point,” he says, laughing, of his initial meeting with Valerie.
Jessell wasn’t a fan of the stem cell approach at first. In fact, the focus on using embryonic stem cells to generate a source of new tissue to transplant into patients made him wary. “I was a little bit reluctant to get involved with the field, because the biology and science weren’t so far advanced, and were open to conjectures and hypotheses that didn’t have much rigorous scientific basis.”
A bright postdoctoral fellow in the lab, however, convinced him otherwise. Hynek Wichterle was completing his Ph.D. at the Rockefeller University, studying nerve development in the brain, when the first human embryonic stem cells were isolated. He became intrigued with the idea of using the stem cells to make new neurons, but not for any clinical purpose—his work was deeply embedded in the intricate cellular processes that drove neural precursors to form the five thousand to ten thousand different subtypes of nerves. He simply wanted to tease out all the steps it would take to bring a motor neuron all the way from an embryonic stem cell to its final specialized state. After two attempts, he finally convinced Jessell to let him try. “I thought that was a far-fetched idea, because if motor neurons form as one in one thousand possibilities from a neural progenitor, then there is even less potential of forming a motor neuron from an embryonic stem cell, more like one in ten thousand or one in fifty thousand,” says Jessell. He gave Wichterle six months. If the postdoc wasn’t successful, then he would have to move on to another project.
In short order, Wichterle proved to Jessell that his skepticism was unfounded. With the deft application of the two decades of accumulated work on nerve development that his mentor had amassed, Wichterle managed to march mouse embryonic stem cells through their various developmental stages from neural progenitors into motor neurons. What’s more, he also introduced his lab-made cells into the spinal cords of chick embryos and showed that they adapted and functioned just as well as normally formed motor neurons in enervating limbs.
Maybe stem cells, Jessell had to admit, were not so bad after all.
Wichterle’s success was a milestone in the nascent stem cell field. It was the first demonstration that a specific type of cell could be coaxed to develop from an embryonic stem cell. Yes, it was in mice, but if it was possible in mice, it would likely be possible with human cells. And indeed it was. Others, including Wichterle, repeated the process using human ES cells, although the efficiency was much lower. It also took longer for the human motor neurons to show themselves, something that initially confused Wichterle. “I tried the exact same protocol I used for the mouse, which took seven days, and it failed,” he says. He extended the study to fourteen days. Still nothing, Then twenty-one days. No motor neurons. It would take about a month for the human nerves to develop, which highlighted for Wichterle how critical using human cells would be, especially to understand differentiation from embryonic stem cells. As useful as mouse models are, they are, as scientists learn over and over again, not always good stand-ins for man.
Wichterle’s next steps were to put Jessell’s two decades of work to the test, using the recipes that Jessell had written for developing the various types of motor neurons to figure out which ones were dying in a disease like ALS and which ones were not. “Not all motor neurons are dying equally fast in ALS,” says Jessell. “So the rationale is to make motor neurons that never die in the disease, and to make motor neurons that are extremely prone to death, and understand what the differences between them are. Then you have a rational approach to understanding how to think about a treatment intervention.”
In order to do that, however, they would need human stem cell lines. And that’s where Project A.L.S. could help. In 2006, Valerie and Meredith opened the laboratory named after their sister, hoping it would become a safe harbor for anyone who wanted to work with human ES cells but could not because of federal restrictions. They were not making a political statement per se, but at the same time they were loath to see anyone not pursue a line of research simply because they couldn’t. “They came with the idea, and were willing to fund this lab to work on human motor neurons and solve all these issues that bureaucratically made it a very unpleasant idea to start work on human cells in my own lab at Columbia,” Wichterle tells me. He admits that were it not for Project A.L.S. providing the space and the funding for expanding his studies into human cells, he would probably not be doing them at all. “If there was not the option of this lab, I would not be involved in the work on human motor neurons; I would not be involved in the more directed work of trying to find some clinical application for motor neurons,” he confesses. “I would probably be asking questions about basic development, like what underlies motor neuron diversity.”
The Estess sisters were certainly not alone. With the government funding only a limited number of human embryonic stem cell studies, patients—and researchers—were finding other ways to get the research done. It was not an ideal situation—private philanthropy, while powerful, can never match the deep coffers of the government when it comes to supporting biomedical research—but it was something.
And, as Valerie Estess and her scientific brain trust were discovering, there was an advantage to being small and sleek. They could move more quickly than a behemoth like the NIH to pick up new ideas, test them, and drop them if they proved unworthy. There was a nimbleness to their approach that was beginning to appeal to researchers accustomed to the inertia of bureaucracy.
And that was the idea behind the New York Stem Cell Foundation (NYSCF).
On one of those humid August evenings in New York City in 2005, an impressive group of scientists and patient advocates were assembling in Manhattan at the request of Susan Solomon. Dark-haired and motherly, Solomon, a corporate attorney who describes herself as more comfortable behind the scenes, was not accustomed to taking charge in this way, but she had finally had enough. Raising a son with type 1 diabetes and caring for a mother in the last stages of Alzheimer’s disease, she felt the government’s restrictive stem cell policy was unacceptable. But it wasn’t until she received a call from Harold Varmus that she was spurred into action.
Varmus, who was by then president of Memorial Sloan-Kettering Cancer Center, had not forgotten the stem cell fight that had occupied his last days in Washington. And three years into Bush’s policy, he was perplexed by the lack of hue and cry he had expected to hear from the patient advocates. Solomon, whom Varmus had gotten to know after his move to Manhattan, was an active member of JDRF. Where, he asked her, were all the patient groups? Why weren’t they standing up for stem cell science?
“The large disease advocacy organizations were using a political calculus,” Solomon says as we talk in her offices near Lincoln Center. “They were triaging. They felt it was too early to come out in favor of stem cell research and risk the almost certain ire of the administration They thought they could serve their constituents better by staying silent, staying on the sidelines, and pushing for their own NIH allocations. And that was too bad.”
The more Solomon thought about it, the more she realized, as Melton had, that the burden of taking the promise of stem cell science and turning it into cures would lie with private groups. But it couldn’t be just any non–federally funded groups—they had to be willing to make stem cell research a priority, even if it proved unpopular and financially risky. It had to be grassroots.
Recruiting Varmus and then Doug Melton, as well as Tom Jessell and Paul Nurse, a Nobel laureate from the Rockefeller University, and a handful of the field’s leading experts to the medical advisory board, Solomon rounded out the foundation’s think tank with prominent patient advocates, including Chuck Close, the photo-realist who had suffered a seizure that left him partially paralyzed. An anonymous donation of one million dollars got the nonprofit on its feet.
And at that muggy dinner, the board checked off the top three critical needs in the field: a pipeline of young researchers to ensure a next generation of scientists who would continue the work that pioneers like Melton and Jessell had started; a community to nurture stem cell scientists, feeding them both intellectually and psychically; and a safe haven lab where they were welcome to and not restricted from conducting work on human embryonic stem cells.
It was Nurse who gave NYSCF its first and most important mission that evening—to fund training grants for young scientists who might be scared off from stem cell studies by the government’s restrictive policies. “He said we have already lost a generation and people don’t realize it,” Solomon says. Graduate students and postdoctoral fellows were wary of entering a field in which the largest grant-giving institution had shrunk its pipeline down to a trickle. Many were being steered toward neuroscience and advised that stem cells were simply too volatile.
With the scientific stem cell community still a fractured group, Solomon also saw an opportunity for the newly formed foundation to serve as facilitator for bringing researchers together to share their findings and exchange ideas. With so few scientists able to raise the private funding necessary to support work on human embryonic stem cells, there was little opportunity for them to gather and learn from one another. So the following year, NYSCF launched the first of its annual research conferences, themed Curing Disease from Lab Bench to Bedside. Solomon, like the Estesses, did not want the scientists to forget why they were there.
That year, the foundation also named its first NYSCF fellow, a Rockefeller University postdoc, for her proposal to study embryonic stem cells in hair cells and cancers of the skin. The foundation now funds seventeen fellows in the New York area, who were attracted to NYSCF not only for the financial backing but for something far more important to a budding scientist—the access it granted to a state-of-the-art lab on the Columbia University campus, just down the hall from Project A.L.S.
The NYSCF lab was a refuge for stem cell studies, and indeed its first project in 2006 was Kevin Eggan and Doug Melton’s program to generate human ES cells using nuclear transfer. At the time, Massachusetts governor Mitt Romney was opposed to all forms of cloning, so to ensure he did not run afoul of state laws, Eggan performed his first cloning attempts with human eggs at the NYSCF lab. Eggan has since passed on his expertise to a postdoc who is an NYSCF fellow and carries on the legacy of perfecting the technique with human cells. In 2009, the New York state legislature passed a law allowing researchers to compensate women for donating eggs for research, and Solomon is hopeful that the move will spur enough volunteers to donate so the research can continue.
The lab remains one of the few in the country where scientists—both those in training and those further along in their careers—can learn this critical technique. And with the academic institutes nervous about cross-pollinating resources from federal and non-federal entities, the lab was a welcome option. “We act like Switzerland,” says Scott Noggle, director of the laboratory. “Our mission is to collaborate and provide a safe haven as an independent research foundation.”
As Melton’s did, Noggle’s group also derives its own human embryonic stem cell lines from excess IVF embryos, and distributes them to labs that need them. And as the science evolves, the foundation is tagging along for the ride. As knowledge about how to manipulate embryonic stem cells and turn them into specialized cells matures, the needs of the researchers will grow as well. Already, for example, as CIRM is finding out, scientists are turning their attention to using stem cell lines to screen for new drugs, something NYSCF is planning for as well, by adding the ability to survey thousands of compounds in the same way start-up biotech companies would.
NYSCF may have been born out of political need, says Solomon, but it will leave a scientific footprint that will far outlast any policy. “You start something because you need to have a safe haven lab because of political issues,” she says. “But then you end up aggregating expertise that becomes its own sticky community.”
That’s also true for the previously disparate scientists Valerie Estess managed to “lock up” to work on ALS. Working together, the neurologists and the stem cell scientists have already exposed a new culprit that may be responsible for picking off motor neurons in the disease. The neurons, it turns out, may not be faulty themselves but merely the victims of the toxic by-products of other nearby nerve cells. It’s a clue pointing toward a potential treatment, and while it may or may not yield anything useful, it is, says Estess, a step forward. “And Jenifer taught me that, that you always have to move forward.”
11
A Jolt from Japan
The city of Kyoto holds a special place in Japanese history. As the twelve-hundred-year-old second capital of the country, it is home to the original imperial palace, and is the cultural heart of all things Japan, from the ritualistic tea ceremony to artisanal skills in bamboo craft and textiles. Serene ryokans, the elegant, paper-walled domiciles of the ancient court that once dominated Kyoto society, preserve a lifestyle devoted to the pursuit of peace and harmony with nature. Stone gardens, the Zen oases of carefully raked sand, still attract millions of visitors, both native and otherwise, in search of spiritual meaning and serenity.
Flowing down from the Kitayama Mountains that border Kyoto’s northern limits, the Kamo-gawa River is a pure and narrow conduit into the center of the city. With the precision of a samurai’s sword, it slices through Kyoto, creating unequal halves of the urban and the ancient. The riverbed is well worn, etched into the earth by centuries of gushing waters that seemed to flow, by design, alongside the palace just to quench the thirst of the King and his imperial party.
The riverbanks are renowned for inspiring meditation, and the cherry tree–lined Path of Philosophy is named for the countless thinkers of Japan who wandered its riverside borders. In modern Kyoto, the canals also serve to demarcate past and present: On the western banks of the river sits the Kyoto Imperial Palace, while just opposite sprawls Kyoto University, with a glistening new structure boasting all of the latest innovations in high-tech science. If the palace signifies Kyoto’s storied past, then the university symbolizes its cutting-edge future.
It was here, in a second-floor lab on the school’s campus, that the single most important breakthrough in stem cell science occurred. In 2006, Shinya Yamanaka turned back cellular time.
Bespectacled and lean, the modest Yamanaka betrays none of the arrogance of a scientist or even the swagger of a surgeon, which is how he began his career. He is a modern blend of the culturally polite Japanese and casually friendly American, an artifact of his days as a fellow in California, where he still maintains a lab. He likes to disarm new acquaintances—including the thousands that now crowd every presentation he gives at scientific conferences—with a few laughs. At the International Society for Stem Cell Research (ISSCR) conference in Barcelona, Spain, in 2009, Yamanaka bookended his presentation with two slides of his lab members. The photos are practically a prerequisite for these talks, a way for senior investigators to acknowledge and recognize the efforts of the students and postdocs who are the lifeblood of their labs. Yamanaka, however, can’t resist the opportunity to lighten the mood at the generally serious sessions. Breaking with tradition, he opens with a group photo, pointing to a male student decked out in the elaborate costume of a geisha; in the final slide, the same student appears again, this time in a blue bunny costume. “That boy is still strange,” he says, to a room of appreciative laughs.
Before I enter Yamanaka’s office, on the second floor of the Institute for Frontier Medical Sciences, I am greeted by a makeshift sign in Japanese, printed from a computer and taped between two tensile barriers like the kind you see at airports to corral wayward crowds. THE LABORATORIES ARE CLOSED TO ALL UNAUTHORIZED PEOPLE, the sign warns. THANK YOU FOR KEEPING OFF.
It’s a consequence of the enormous fame and recognition that the introverted scientist now commands, an attention that he is only reluctantly beginning to accept. Outside are more signs of his influence: Steps away, a gigantic construction tarp shrouds what will be Yamanaka’s new home—the five-story Center for iPS Cell Research and Application (CiRA), a facility dedicated to nurturing the remarkable stem cells that Yamanaka has created.
Inside his moderately sized office, two huge arrangements of orchids spill their shower of white flowers over a conference table. Just two weeks ago, he was recognized with a Lasker Award, a coveted prize honoring scientific achievement that many feel is a prelude to the Nobel Prize, and the flowers are a congratulatory gesture from well-wishers. The room is very professional, and functional; aside from the flowers, there are few signs of personal effects that betray anything of the personality of the scientist who occupies it. Taking up the most space in the office is the long conference table that turns the small area into a meeting room for lab members.
It was around this table, and in this room, that Yamanaka worked out the details of how to reprogram adult cells. The technique, in retrospect, is at once simple and brilliant, and represented a true leap of scientific faith. But, as with many such breakthroughs, scientific and otherwise, it almost didn’t happen.
