David Scadden is the Gerald and Darlene Jordan Professor of Medicine at Harvard University. He is a hematologist/oncologist who focuses on bringing stem cell biology to patient care. He founded and directs the Center for Regenerative Medicine at the Massachusetts General Hospital and with Douglas Melton, co-founded and co-directs the Harvard Stem Cell Institute and the Harvard University Department of Stem Cell and Regenerative Biology. He is a member of the American Academy of Arts and Sciences, the Institute of Medicine of the National Academies of Science, the Board of External Experts for the National Heart, Lung and Blood Institute and a former member of the National Cancer Institute’s Board of Scientific Counselors. StemBook caught up with David to talk with him about his research, trends in bone marrow transplants, AIDS, and more.
Below is an edited version of David’s conversation with StemBook’s editor, Lisa Girard
Could you give StemBook readers a brief overview of the research in your lab?
Sure, as a hematologist-oncologist I became involved in stem cell research because of the power of stem cells for patients, literally bringing a patient back from the brink of death. For patients with severe blood disorders, stem cell transplant can be their only hope and when it works, it can restore people to a full, vigorous life. But, it is available to only the minority of patients who could benefit from it. If we can provide therapy of that power for more people with more varied diseases, then stem cell biology will have fulfilled its promise. My lab is trying to understand some of basic principles by which the body regulates blood stem cells so we can better take advantage of those mechanisms to improve regeneration in settings like stem cell transplants and AIDS. And we want to understand how those processes become corrupted in malignant diseases like myelodysplasia and leukemia. We think the microenvironment where stem cells live has a lot to teach us about how nature has engineered the controls; how the body turns on and off the blood stem cell to make the more than 100 billion new blood cells that we need every day.
The HSC niche in the bone marrow used to be viewed as fairly homogenous, but has since emerged to be more heterogeneous with specialized niches informing the differentiation of HSCs and immune progenitor cells. I wondering if you could tell us what the state of the state in thinking about that is?
The concept of a specialized niche regulating stem cells was something that was first proposed in the context of the blood back in 1978 but not experimentally demonstrated until it was worked on in the context of C. elegans and drosophila in the 1990s. Looking at germ cell stem cells in those invertebrates, there were clear relationships between the germ cell stem cell and a non-stem cell. So the notion that there might be a one-to-one correspondence between a regulating non-stem cell and a stem cell population was the initial paradigm. When we were thinking about what experiments to do for blood stem cells we decided that bone marrow was in bone presumably because bone did something special for the blood stem cells. We connected with terrific bone biologists at the MGH (Dr. Henry Kronenberg and his lab) and together looked at some of his mice where specific bone cells were perturbed. We found that blood stem cells were also perturbed and that got things in motion. It turned out that colleagues at the Stowers Institute (Dr. Linheng Li and his lab) were also examining a mouse model where bone cells were altered and saw a similar change in primitive blood cells. We published the results together in 2003 in what I think was the first demonstration of specific niche cells for stem cells in a mammalian tissue. Multiple labs have added enormously to the story and now it is clear that the niche is actually a complex tissue with multiple interconnected parts playing a role. In some ways it is what you would expect since the stem cells is powerful and potentially dangerous beast. It is not likely to have a single caretaker. Our lives depend on stem cells being in control and to be able to respond to special needs. That means command is likely to have many layers and many back-ups. We are still working on finding the individual participants in that command so that we can ultimately learn how each interconnects and how we might predictably modify the command to achieve better outcomes for people.
So, switching gears a bit more of a clinical question. As far as bone marrow transplants, what is currently happening in terms of the number patients receiving peripheral blood stem cell treatments compared to bone marrow transplants and how do you balance the Graft-vs-Host-Disease (GVHD) risk in making those determinations and finally, how do you see these trends evolving?
There are three major sources of stem cells in transplants. One is umbilical cord blood, the other bone marrow, and the third so called mobilized peripheral blood, which is essentially stem cells from the marrow that have been moved into the bloodstream by medications so that the cells can be harvested in the blood bank rather than the operating room. When there's a setting in which a donor is a relative and a good immunologic match, peripheral blood or bone marrow is used and because of the ease of collection, people have favored peripheral blood. It is clear, however, that along with the stem cells comes T cells and they are particularly abundant when peripheral blood is the source. Those T cells can attack the recipient and cause what is known as graft versus host disease, a really difficult, sometimes life-threatening problem. Because of this issue, there is some movement back to bone marrow as the preferred source but much of this depends on the center and the donor. In the setting where there is no relative who is a good match, any of the three sources of stem cells can be used and cord blood is often the only one where a match can be found. The beauty of cord blood is that the samples are in the bank, well characterized and can be obtained in a matter of days. It’s a much more efficient and reliable source than seeking out a willing donor and going through a lengthy clearance and stem cell collection process. But cord blood has only a small number of stem cells. While it also has few T cells and therefore graft versus host is less of an issue, poor recovery of blood counts and immune function can be very problematic.
Has T cell depletion prior to transplantation be tried?
Yes, but manipulation of the graft is complicated and at the moment, still experimental. Some of the clinical trials testing methods to do this look quite promising, but those methods are not yet routinely available.
I know another one of your interests is in stem cell therapy for AIDS. Could you tell us a little bit about the work going on in your lab related to that?
As a postdoc, I was working on retroviruses as a model of leukemia and gene transfer, and the AIDS epidemic was roaring. There were very few hematologists and oncologists that were seeing AIDS patients when they developed cancer, which they did with unusual frequency. I thought that knowing something about the virus and having the training to take care of the tumors and blood problems AIDS patients were getting made it my responsibility to get involved. I helped set up a program through the National Cancer Institute that still exists today to combine clinical trials and laboratory efforts to develop new therapies for AIDS related malignancies. I tried to combine my lab and clinical efforts by using retroviruses to make stem cells resistant to HIV and in that way, give AIDS patients a new, HIV impervious immune system. The problem was that in those early days of stem cell transplant it was unclear if stem cell transplant was safe for people with AIDS and whether or not you could get the anti-HIV genes into stem cells. We ended up treating people who had lymphoma as a malignant complication of HIV and found that we could transplant them safely. What we, the field, couldn't do was gene modification to make the stem cells HIV resistant and still engraft. In the meantime, technology for genetic modification has improved and the only known case of a patient being cured of AIDS is with stem cell transplant. That patient takes no anti-HIV drugs and is free of virus now more than 5 years after stem cell transplant. Those developments seem to me to be good reason to try again and we are actively testing methods to get efficient stem cell engraftment with low toxicity and cost. Lifelong therapy with expensive and toxic drugs works for HIV disease, but is undesirable for many and untenable in the places where the epidemic is worst. I don’t know that we can ever get to a point where someone’s stem cells can be made HIV resistant and re-engrafted without major complications or costs, but I think it is an effort we should make.
David, thank you very much
Sure, thank you very much.