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The Promise of the Future

Three scientists at Johns Hopkins who study blood disorders discuss which therapies hold the greatest promise.

In 2006, when Japanese researcher Shinya Yamanaka reprogrammed adult cells to resemble embryonic stem cells, he turned the ethical debate surrounding the use of embryonic stem cells on its head. Not only can these induced pluripotent stem cells, or iPS cells, generate any cell type in the body (as is the case with embryonic stem cells), they may also have a therapeutic advantage: Patients injected with iPS cells from their own body instead of embryonic stem cells from another "body" would no longer have to worry about transplant rejection. Nonetheless, researchers remain cautious about therapies using iPS cells because many steps have yet to be tested.

Therapeutic use of embryonic stem cells and iPS cells, however, comes with its own set of challenges. In terms of simple logistics, they are finicky in the lab. Thus, despite their theoretic ability to morph into any cell type in the body, scientists currently have a hard time getting them to specialize (differentiate) into certain cell types. In addition, embryonic stem cells and iPS cells tested in mice have the potential to generate tumors after transplant. If injected cells contain undifferentiated (or unspecialized) iPS cells, tumors may form after transplantation.

These challenges have prompted many scientists to continue novel stem cell research using adult stem cells, although they have their own limitations. These researchers note that the bone marrow transplant, a procedure involving the transplant of adult blood stem cells, has cured patients of a host of blood disorders, including leukemia, sickle cell anemia and aplastic anemia, since its inception more than 30 years ago.

Rick J. Jones, M.D., Professor of Oncology at the Johns Hopkins Kimmel Cancer Center

Of course, we should study everything, but personally I doubt that embryonic stem cells will ultimately demonstrate advantages over tissue stem cells. Every tissue has adult stem cells. They are the closest thing to what you want them to do. With an embryonic stem cell, you have to get them to differentiate toward the organ you want and then get that organ to grow. If you already have those adult cells around, why not use them instead? There are lots of other issues with embryonic stem cells. I think there's no reason to think that adult tissue-specific stem cells can't do everything we want them to do.

The bottom line is that I think the issue of getting an embryonic stem cell to do what you want it to do is actually more difficult than taking a tissue stem cell and allowing it to do what it's already programmed to do.

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Robert Brodsky, M.D., Professor of Medicine and Chief of Hematology

At least for the diseases that I treat—aplastic anemia and sickle cell disease—I don't see embryonic stem cells having an advantage over the adult bone marrow stem cells for at least the next 10 to 15 years. One of the major obstacles with embryonic stem cells is getting enough of the tissue-specific stem cell that you're trying to treat. For example, if your disease is a blood disease, can you make enough stem cells to safely put them into a human being and get them to take? You would need a lot of cells. We don't have the ability to grow them right now. But every year they're making strides in that direction.

A major concern with the induced pluripotent stem cells is that you're having to put four genes into a cell, often with a retrovirus, to get them to be in a stem-cell like state. I think there's going to be enormous safety concerns there, vis a vis cancers. Advances are being made, but there's a long way to go. This field is still in its infancy.

There are benefits to embryonic stem and iPS cell technologies, however. If you could, for example, take a stem cell from a patient with sickle cell and correct it in the laboratory and then grow up enough of those corrected cells to put it back into the patient, then you wouldn't have to worry about the whole issue of graft-versus-host disease [a situation where the transplanted immune system fails to recognize the host’s body and attacks it] because the donor and patient are the same person. Similarly, if you could make an unlimited supply of cells, then you could stock the blood supply with very specific blood types, especially rare blood types. But currently the field isn't even at the point where they could make enough blood to transfuse a mouse. 

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Linzhao Cheng, Ph.D., Associate Professor, Johns Hopkins Institute for Cell Engineering

Using iPS cells to treat blood disorders has two main advantages over using embryonic stem cells. One, you don't have any ethical issues relating to human embryos. Two, for cell therapies, you can derive cells from the original patient. Therefore, it's a perfect genetic match and transplant rejection is no longer a concern.

There are dangers that we need to work out with regard to using iPS cells. For one, iPS cells do not have much inhibition of their potential, just like a newborn. They have the potential, by definition, to morph into any cell type in your body.  This can be good for various diseases, but it could also be bad if we do not manage them correctly. When you do a blood transplant, for example, you don't want the blood cells to turn into bone cells.

Unfortunately, current stem cell transplants can only treat blood and bone marrow diseases. By contrast, in the case of brain injuries and disease, what would be your cell source? Are you going to open a patient's skull to isolate adult stem cells? That's not a viable approach. With iPS technology, you can take cells from a patient's skin or blood and turn it into other cell types in the laboratory. For instance, you can push adult cells into the neural cell types needed to treat diseases such as Parkinson's or Alzheimer's. Even for blood diseases, reprogramming or iPS cell technologies have potential for several applications, as my colleague Professor Brodsky outlined.

The reprogramming technology also makes it possible to reverse adult cells such as blood cells back to committed adult stem cells such as blood stem cells, without the need to go back all the way to iPS cells (a process called trans-differentiation). We are working together toward all these objectives.  It may take five to10 years, or even longer, for this novel technology to move to clinical settings, as happened with the development of bone marrow transplantation 40 years ago. As scientists, our job is to develop novel technologies to find solutions for the unmet needs of patients. 

--Interviewed by Sujata Gupta

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