On Stem Cells and Optimism:
A Lesson from Gleevec
The scene was the New York Stem Cell Foundation's (NYSCF) First Annual Translational Stem Cell Research Conference: Curing Disease from Lab Bench to Bedside, held at Rockefeller University October 23-24. The non-profit organization, dedicated to supporting research using hES cells and somatic cell nuclear transfer (SCNT), was co-founded in 2005 by Susan Solomon and Mary Elizabeth Bunzel because, in the words of Solomon, "we weren't satisfied with the pace of the field." These two remarkable women have children with type 1 diabetes. Among their many accomplishments, they managed to raise $10 million to fund a "safe haven" laboratory for stem cell research, whereabouts top secret. It's been described as a first stop on a scientific underground railroad of sorts. (No, I'm not making this up.) They also assembled a who's who of the field for the inaugural conference, which was a smash hit as far as I'm concerned.
As the talks began to wind down, though, I became uneasy, feeling overwhelmed with hopelessness. I struggled to keep up with the slides showing the complex signal transduction pathways that cells follow when deciding what to be, which one speaker compared to the blueprints for a rocket. I marveled at how much we still do not know, and began to worry about the stark disconnect between the public's oversimplified view of stem cell science (to quote the New York Times, "Stem cells are master cells that can evolve into blood, liver, muscles and other cells") and how utterly complicated the actual science is. Would the momentum from this wonderful organization be enough to truly sustain the "bench to bedside" trajectory? I thought not.
And then I remembered Erin Zammett Ruddy.
I met Erin just 2 hours before the stem cell conference began. She is an editor at Glamour magazine, a publication that I read religiously when I was her age, 28. (It also achieved fame as the object of George Costanza's sexual fantasies on a memorable Seinfeld episode.) When Erin was 23, she had a routine physical exam - she hadn't gone for awhile because she was so healthy and athletic - and learned, soon afterwards, that she had chronic myelogenous leukemia (CML). She has chronicled her "battle" with cancer since then in the pages of Glamour [here], and in a terrific book, "My (So-Called) Normal Life" (Overlook Duckworth, 2005). I had asked to meet with her about possibly telling her story in one of my biology textbooks.
I put "battle" in quotes because Erin never felt sick, although the bone marrow biopsies that she still undergoes were not quite a walk in the park. She looks the picture of health, a tall, striking natural redhead. The reason: Gleevec. If ever there is a miracle drug, this is it. And it all came to pass because of basic research into the mechanism behind a disease that once routinely killed children and young adults.
The story of Gleevec started on August 13, 1958, when two men entered hospitals in Philadelphia, complaining of weeks of fatigue. They had CML. Blood samples wound up in the laboratory of Peter Nowell, a young assistant professor at the University of Pennsylvania, and he and his graduate student, David Hungerford, found in those aberrant white blood cells a clue: a small, unusual chromosome, eventually dubbed the Philadelphia chromosome (Nowell & Hungerford). '
Fast forward to 1972. Janet Rowley, at the University of Chicago, applied the just-perfected new dyes that stained chromosomes into distinctive patterns, revealing that the telltale Philadelphia chromosome was built of parts of chromosomes 9 and 22 (Rowley). Within two years, researchers had identified the breakpoints where the two chromosome parts joined. Then researchers found that parts of two genes were shoved together at the breakpoint, their partnership forming an ominous oncogene that encodes an equally ominous "fusion" protein. The protein is an aberrant tyrosine kinase, a pretty common signaling molecule that binds a phosphate to another molecule, sending the cell a signal to divide. In CML, the deranged tyrosine kinase is active for too long, and the white blood cell cell divides ceaselessly. Leukemia results.
Once researchers knew what to fix, a rational treatment for CML became possible. Brian Druker, a hematologist then at the Dana-Farber Cancer Institute in Boston, working with researchers at Novartis, sorted through hundreds of small molecules to finally find one that fits into the pocket on the oncoprotein where phosphates would otherwise bind, without interfering with other signals. Much work crafted that molecule, as it was sculpted from "CGP57148B" to "STI571" to, finally, imatinib or Gleevec. (Druker et al). I remember being so astonished at the report in The New England Journal of Medicine that I read the same sentence in the abstract 3 times: "Complete hematologic responses were observed in 53 of 54 patients treated with daily doses of 300 mg or more and typically occurred in the first four weeks of therapy."
I'd read correctly. FDA approved Gleevec on May 10, 2001, 10 weeks after Novartis submitted the New Drug Application. Record time.
Gleevec has since transformed treatment of CML. It has found other applications, and new drugs are available that work when people become resistant to it. In September, Gleevec was approved as a front-line treatment for CML in children.
Thanks to Gleevec, Erin Zammett Ruddy never went bald, never bruised, and never felt too tired to work. On a microscopic level, she was healing too, achieving first "cytogenetic remission" (goodbye, Philadelphia chromosomes) and then "molecular remission" (goodbye fusion oncoproteins), terms that became part of her everyday vocabulary. Today she goes around the country as a spokesperson for the Leukemia and Lymphoma Society, educating young people about using Gleevec to keep their CML to undetectable levels.
And a most astonishing thing has happened, Erin told me. Noncompliance has become a problem! Some young people with CML -- never having experienced the chemo drip or the classic cancer-fear that turns your insides instantly to jelly and that only another cancer survivor can understand -- forget to take their Gleevec pills! They regard it as a nuisance! It's a new disease, this chemo-complacency. Neither Erin nor I get it.
So after the stem cell conference at Rockefeller, I headed back to the train station, growing depressed with my head replaying images of the morass of signal transduction pathways. How will treatments ever emerge? Won't it take years? But they can. And they will. For Gleevec led the way.
I look forward to the day when the greatest challenge that someone with (INSERT ONE: ALS, Parkinson disease, heart disease, Alzheimer disease, spinal cord injury, Huntington disease, diabetes, multiple sclerosis, or any number of illnesses and injuries we haven't yet thought of) faces is to remember to show up for a routine stem cell infusion. It will happen.
- Ricki Lewis
