The Stem Cell Hope, page 33
Still, with every trial that the FDA reviews, its comfort with the standards and precedents it sets grows. That’s something that Advanced Cell Technology (ACT), of Marlborough, Massachusetts, is exploiting with its own stem cell trial. ACT’s is only the second such therapy that the agency has approved, and chief scientific officer Robert Lanza says ACT has already benefited from the progress made since Geron submitted its application—using more advanced imaging techniques, for instance, ACT scientists can detect a single undifferentiated cell in a teeming population of one million cells.
And to ensure that the stem cell therapy is as safe as possible, ACT chose to develop a treatment for retinal diseases such as macular degeneration and retinitis pigmentosa, in which the light-sensing photoreceptor cells in the retina begin to deteriorate. The retina is an ideal location for a novel therapy, because its cavity is an enclosed space, where cells rarely migrate in or out. It is also walled off from the immune system, so transplanted cells that are not immunologically matched to the host are safe from the body’s cellular defenses. ACT’s therapy is an injection of retinal pigment epithelium cells that are grown up from human embryonic stem cells. In treated animals, says Lanza, the thinning retinal cells in a diseased eye are built back up to a normal thickness of five to seven layers of cells.
“Whoever goes in there first has an incredible responsibility,” he says of the pressure associated with the first stem cell–based human trials. “I can’t tell you how many nights I’ve lost sleep thinking, ‘Is there anything we’re missing?’ ”
Regardless of the outcome of either the Geron or the ACT trials, the human studies will have been both necessary and worthwhile. “We have learned an awful lot, and asked a lot of questions,” says Lebkowski of the process so far. “There are not studies that we can do in animal models that will say these cells are a hundred percent safe in humans. We can’t do that until we move into the clinic. We can never be sure until we test this out in humans.”
And no matter the result, those in the field are hoping that the research will only continue to grow and evolve. “This field has moved faster than we could have hoped,” says Melton. “Because this is a very rich biology. It is going to change biomedicine.”
Epilogue
Around noon on March 9, 2009, President Barack Obama signed a much anticipated executive order that lifted an eight-year stranglehold on stem cell research in the United States. Among those in attendance at the White House to witness the moment were familiar faces in the stem cell debate—patient advocates, some of the field’s most stalwart scientific champions, as well as its rising stars. Harold Varmus. James Thomson. John Gearhart. Shinya Yamanaka. Irving Weissman. Susan Solomon. Zach Hall.
In explaining his reasons for signing the order, President Obama recognized the larger concern that had loomed over stem cell policy for nearly a decade—that politics and ideology had hampered the progress of science. “In recent years, when it comes to stem cell research, rather than furthering discovery, our government has forced what I believe is a false choice between sound science and moral values,” he said. “In this case, I believe the two are not inconsistent. I believe we have been given the capacity and will to pursue this research—and the humanity and conscience to do so responsibly.”
Doug Melton was not in Washington, choosing instead to take in the moment in Boston, in the lab with his students. “I bought a cake and some chocolate eggs, and we had a big celebration with thirty people,” he tells me when I call him a few hours after the address. “I feel absolutely delighted and relieved.”
One of the first things Melton mentions is the freedom he now feels upon being released from his regulatory cage. “Looking back, I realize how restrained and constrained we were by working in a silo imposed on us by the previous administration,” he says. “Science is best done when there is an open exchange of ideas, reagents, and data. We were segregated from that.”
His in-box, he said, was already full with even more requests for a few vials of his seventy human embryonic stem cell lines, which would eventually be added to the NIH registry. Many of the writers had been waiting for eight years to send those requests. There were a lot of questions to answer, and there was a lot of science to do.
Sam Melton, Jordan Klein, and Katie Zucker are in their early twenties now—young adults, with a strong sense of what President Obama’s action means for them. For them, the address was the second such speech from a chief executive on stem cells that they had witnessed. They have lived through the political push-and-pull over the research, and the ups and downs of the regulatory seesaw. What happens to stem cell research will have a greater affect on them than on any scientist or legislator. They are, in essence, relying on and growing up alongside the science, maturing and developing just as it is.
In one way or another, they will be the first to benefit from the work researchers begin today. It might be in the form of a drug that comes from studying how beta cells made from embryonic stem cells lose their ability to make insulin. They might be spared having to become volunteers in testing a potentially toxic insulin-regulating compound, because it has already been screened with their iPS-derived cells and deemed unsafe for further development. Or maybe, just maybe, they could be the first recipients of an injection of beta cells grown up in the lab from stem cells.
They are realistic enough not to expect too much too soon. But they have also been following the research closely enough to know that something has to change.
Looking like a younger version of his father, Sam, unlike others his age, is accustomed to planning ahead—he has to be, in order to ensure that he adjusts his insulin levels according to how his body is responding. “If I were sick or didn’t want to eat, or a friend asked if we wanted to play basketball, it caused chaos in terms of adjusting for the extra activity,” he tells me. He is also accustomed to filling his pockets with Snickers and juice boxes, just in case his blood sugar levels drop.
He knows what his father has sacrificed in order to find a cure. He knows how hard his mother has worked to ensure that his life is as normal and unaffected by his disease as it can possibly be, despite the blood checks and the insulin shots. He knows the insults critics have leveled at his father, and what they think of the work he is doing with stem cells. He knows this because he was there, in the back of the room, when those opposed to embryonic research called his father an abomination. “It definitely made me angry. To me, there is nothing better than his research.”
It’s the same for Katie, recently graduated from New York University, having lived with diabetes for so long that she cannot imagine life without it and fighting just as long for the research that could lead to a cure. She was in the room, often curled up on the couch or sitting at the dinner table, when her parents gathered California’s leading stem cell scientists at their home to figure out a way around the restrictive federal policy. In eighth grade, when her class was instructed to draw a political cartoon, she sketched a giant trash bin with a little stem cell sitting on its edge, with a caption that read, “I could have cured cancer.”
As a twelve–year-old, Katie traveled to Washington to describe to members of Congress what it was like to live with diabetes. She couldn’t appreciate it at the time, but she was there to fight a bill that would criminalize research on embryonic stem cells, the very cells that just might let her live without carrying around a bag full of needles and insulin and a glucose monitor. Nervous, she was afraid to say anything until one representative began telling her parents how the lives of the embryos had to be preserved. Confused, she finally spoke up. “What about my life?” she asked. “Doesn’t that count for something?”
Jordan Klein was there too, to fight the same bill. He told senator John Kerry about what would happen if he slipped up and lost track of his blood sugar levels. He described the kidney failure, the blindness, the amputations, and the pain that would tear through his body if he forgot to do his blood checks or failed to give himself insulin when he needed it. After hearing his son relate all of this, his father had had second thoughts about bringing Jordan to Capitol Hill. Maybe, he told his son, it was too much. Maybe he shouldn’t be doing this. “Don’t worry,” Jordan told his dad. “Life is life. Everyone is dying; I’m just dying a little faster.”
Tall and lanky, with a head of tousled brown hair, Jordan knows what it’s like to wake up every morning feeling as if his tissues have turned to stone, his body flooded with ketones that built up during the night. Growth hormone, secreted more copiously while he sleeps, sends his blood sugar levels through the roof, making mornings a challenge. For a while, he was afraid to go to sleep at night, fearing he would not wake up the next day.
“When I was younger, I definitely hoped for a cure soon,” he admits. “But now . . . I’ll just be ecstatic when it happens; I’d be so happy. But I’m not crossing my fingers or anything.”
The caution seems odd for someone so young, someone who has seen a lot of hope in his short lifetime, from breakthroughs in the lab to less dramatic but still undeniable progress in policy. But it’s a deliberation that comes from experience, from knowing victory often comes with a price.
Following the relief from President Obama’s expansion of federally eligible stem cell studies, Jordan, Katie, and Sam were reminded yet again of how fleeting such triumphs can be in a science that remains controversial because of its embryonic origins. In a 2010 lawsuit reminiscent of the original one filed a decade earlier, Nightlight Christian Adoptions, along with some researchers focused on stem cells, sued the Obama administration for similar transgressions, alleging that any government grants for embryonic stem cell studies violated the Dickey-Wicker amendment. And in a shock to the stem cell community, a federal judge agreed with them and forced the NIH to temporarily suspend its grants for embryonic stem cell studies. Even more astounding, the judge’s decision appeared to preclude government support of all embryonic stem cell studies, including those that President Bush had allowed in his 2001 executive order. After an appeal by the White House, an appellate court issued a stay on the ban, but the suit will likely take another year to resolve in the courts, keeping embryo research on unsteady legal footing.
It’s a reminder to the next generation of both scientists and patients that the fight over stem cells is hardly over, even with the existence of iPS cells. Before these newer versions can prove themselves equal to or even better than their embryonic predecessors, they will have to be compared side by side with them. And that means that at least for the time being, embryonic cell lines will continue to be a necessary part of stem cell studies, with all the political uncertainty and legal tensions that entails. The only resolution to the back-and-forth would be a law that establishes, with the same authority as Dickey-Wicker, what Harold Varmus had asked the Health and Human Services attorney to determine—that while Dickey-Wicker prohibited government funding of the creation of human embryonic stem cell lines, it did not preclude the NIH from offering grants to those who wanted to study the lines once they existed. Such legislation has been proposed in the House, several times, but like any issue before Congress, passing the bill is as much a matter of political agendas and motives as it is an issue of merit or urgency.
In the meantime, like any patient living with a chronic disease, Sam, too, is thinking about the cure. “I remember asking my parents when there would be a cure,” he says, admitting it was an abstract concept for him then that has only recently become more tantalizingly concrete. For now, as he appreciates what it would take to find a permanent solution for diabetes, he, like his father, is convinced that stem cells will play some role in changing the way the disease impacts his life, even if it doesn’t relieve him of his daily insulin shots. “I definitely think stem cells will contribute,” he says.
He, along with the rest of world, is waiting to see how.
GLOSSARY
blastocyst. The four–to five-day stage of a developing embryo, containing the inner cell mass and the trophoblast, which goes on to become the placenta.
differentiate. To develop and specialize into a specific type of cell.
ectoderm. One of three primitive germ layers of embryo cells. It generates skin, hair, nails, epithelium, sense organs, mouth, and nervous tissue.
embryonal carcinoma (EC) cell. An abnormally growing cancer cell from the embryo that divides indefinitely.
embryonic stem (ES) cell. A stem cell obtained from an embryo, capable of generating the three basic germ layers (endoderm, ectoderm, and mesoderm), which create the more than two hundred different cell types in the human body. See also stem cell.
endoderm. One of three primitive germ layers of embryo cells. It generates the lining of the eustachian tube, trachea, lungs, gut, bladder, and vagina.
induced pluripotent stem cell (iPS). A stem cell made by reprogramming an adult cell (usually from the skin) back to its embryonic state using four transcription factors (genes), or by using their RNA equivalents. See also stem cell.
inner cell mass (ICM). The group of cells that form in the interior of a blastocyst and give rise to the embryonic stem cells.
mesoderm. One of three primitive germ layers of embryo cells. It generates muscle, cartilage, bone, bone marrow, blood vessels, kidneys, sex organs, and other tissues.
multipotent. Capable of developing into a limited number of the body’s different cell types, such as bone marrow, which generates the blood and immune cells.
nuclear transfer, or somatic cell nuclear transfer. The process through which an adult cell is cloned by inserting its nucleus into an egg that has had its own nucleus removed. This is the procedure that resulted in Dolly, the first cloned mammal.
pluripotent. Capable of developing into nearly all of the body’s different cell types. Embryonic stem cells are pluripotent, since they can create all but the placental cells of an embryo.
stem cell. A cell with the ability to develop into a variety of cell types.
therapeutic cloning. Nuclear transfer with the sole purpose of generating patient-specific stem cells by cloning that patient’s cells.
trophectoderm. The exterior layer of cells of a blastocyst. It gives rise to the placenta.
unipotent. Capable of developing into only a single type of cell.
SOURCES
Preface
Interviews
Sinisa Hrvatin, November 19, 2009, Harvard University, Cambridge, Mass.; Robert Lanza, June 11, 2010, Marlborough, Mass.
Like any other cells Robert Lanza, J. Gearhart, B. Hogan, D. Melton, R. Pedersen, E. D. Thomas, J. Thomson, and M. West, eds., Essentials of Stem Cell Biology (Burlington, San Diego, London: Academic Press, 2006), xix.
So too do the recently isolated induced pluripotent stem (iPS) cells Kazutoshi Takahashi and Shinya Yamanaka, “Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors,” Cell 126 (2006): 663–676; Kazutoshi Takahashi, K. Tanabe, M. Ohnuki, M. Narita, T. Ichisaka, K. Tomoda, S. Yamanaka, “Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors,” Cell 131 (2007): 861–872.
It’s been only a decade since James Thomson, J. Itskovitz-Eldor, S. S. Shapiro, M. A. Waknitz, J. J. Swiergiel, V. S. Marshall, J. M. Jones, “Embryonic Stem Cell Lines Derived from Human Blastocysts,” Science 282 (1998): 1145–1147.
the defective nerves that fail to stimulate muscles in patients with amyotrophic lateral sclerosis (ALS) John T. Dimos, K. T. Rodolfa, K. Niakan, L. M. Weisenthal, H. Mitsumoto, W. Chung, G. F. Croft, et al., “Induced Pluripotent Stem Cells Generated from Patients with ALS Can Be Differentiated into Motor Neurons, Science 321 (2008): 1218–1221.
toxic compound released by the glial cell Francesco Paolo Di Giorgio, G. L. Boulting, S. Bobrowicz, K. C. Eggan, “Human Embryonic Stem Cell-Derived Motor Neurons Are Sensitive to the Toxic Effect of Glial Cells Carrying an ALX-Causing Mutation,” Cell Stem Cell 3 (2008): 637–648.
as a matter of debate in Congress Cloning and stem cell research have been the subject of special hearings in both the House and Senate, beginning December 2, 1998, Subcommittee of the Committee on Appropriations, United States Senate, Special Hearing Stem Cell Research, http://www.access.gpo.gov/congress/senate.
even the courts Sherley et al. v. Sebelius et al. (U.S. District Court for the District of Columbia, Case 1:09-cv-01575-RCL, August 23, 2010).
legislated a ban Public Law 104-99, 104th Congress (January 26, 1996).
President George W. Bush also acted, issuing an executive order President George W. Bush statement from Crawford, Texas (August 9, 2001), http://www.edition.cnn.com/2001/allpolitics/08/09/bush,transcript/index.html; Bush Executive Order no. 13,435, Expanding Approved Stem Cell Lines in Ethically Responsible Ways (June 22, 2007), http://www.archives.gov/federal-register/executive-orders/2007.html.
after President Obama removed these restrictions President Barack Obama Executive Order no. 13,505, Removing Barriers to Responsible Scientific Research Involving Human Stem Cells (March 9, 2009), http://www.archives.gov/federal-register/executive-orders/2009-obama.html.
Chapter 1
