[Skip to Content]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 54.197.90.95. Please contact the publisher to request reinstatement.
Sign In
Individual Sign In
Create an Account
Institutional Sign In
OpenAthens Shibboleth
[Skip to Content Landing]
Download PDF

George Daley, MD, PhD

Scientists hope that research with human embryonic cells will lead to important advances in treating a variety of diseases.

Original Contribution
February 16, 2005

George Daley, MD, PhD, Talks About the Clinical Promise of Stem Cell Research

JAMA. 2005;293(7):783-789. doi:10.1001/jama.293.7.787

Boston—Letting the imagination take hold and transport you beyond what you are working on in the laboratory is what makes science fun, says stem cell biologist George Daley, MD, PhD. But the intense competition for research dollars, he adds, tends to discourage this type of risk taking in grant proposals.

Now Daley has the chance to follow his imagination, as one of 9 scientists named by the National Institutes of Health (NIH) last fall as the first recipients of the NIH Director’s Pioneer Award. The Pioneer program enables a select group of biomedical researchers to pursue creative new research directions that they otherwise might not be able to follow. The intention is that the award, which provides funding of up to $500 000 per year for 5 years, will foster innovative ideas that will accelerate advances in human health.

“What was so appealing and exciting about the whole Pioneer process was that you’re given license to freely speculate to come up with ideas that are as provocative as you can make them—as long as you can justify them, of course,” said Daley, associate director of the Stem Cell/Developmental Biology Research Program at Children’s Hospital, Boston, and associate professor of biological chemistry and molecular pharmacology at Harvard Medical School in Boston. In this case, he said, proposals were judged by the “nature of the idea rather than the nature of the data we’d already mustered.”

BLOOD FROM A STEM CELL

Daley has mustered a good deal of data in various areas of stem cell research throughout his career. As an oncologist, he began to study stem cells from the perspective of cancer. One of his main foci became the hematopoietic stem cell. This cell is not only the object of malignant transformation in chronic myeloid leukemia—a disease for which he helped identify the initiating chromosomal defect, the BCR-ABL gene translocation—but also the therapeutic tool of bone marrow transplantation.

“I’m fundamentally interested in blood development and the origins of the hematopoietic stem cell,” said Daley, whose group has been using embryonic stem cells to study the genetic regulation and cell biology involved in this process.

One of Daley’s goals is to harness this process to make hematopoietic cells that could be used for transplantation in patients. Although bone marrow transplantation is a useful approach to treat a number of diseases, it has limitations, such as lack of an adequate number of HLA-matched bone marrow donors as well as the morbidity and mortality associated with immune rejection and treatment to suppress it in bone marrow transplant recipients.

The idea Daley is pursuing is to generate a customized, genetically matched embryonic stem cell line for each transplant recipient, from which histocompatible hematopoietic stem cells could be derived.

CUSTOMIZING CELLS

To do this in mice, Daley’s group has coupled embryonic stem cell technology to somatic cell nuclear transfer, an experimental technique also referred to as therapeutic cloning. Nuclear transfer involves removing the DNA-containing nucleus from a mature cell, such as a skin cell, inserting it into an oocyte that has had its nucleus removed, and allowing the cell to grow into an embryonic stem cell line. The resulting cells are almost genetically identical to the individual animal from which the nucleus was taken and therefore should not elicit an immune response if transplanted back into that same animal.

Daley worked with Rudolph Jaenisch, PhD, a biologist at the Massachusetts Institute of Technology, Cambridge, who runs one of the world’s leading laboratories in nuclear transfer, in generating cloned embryonic stem cell lines to answer basic questions about development.

But the technology can also be used to model disease and disease treatment, said Daley. He, Jaenisch, and colleagues demonstrated this by using a stem cell transplant to cure a mouse with a genetic form of immune deficiency (Rideout et al. Cell. 2002;109:29-37). The mouse lacked a gene needed for the immune system to form and could not produce B or T cells.

Taking a cell from the mouse’s tail, the researchers removed the cell nucleus and deposited it into an enucleated oocyte from another mouse. In a few days the cell developed into a blastocyst-stage embryo. Cells from the inner-cell mass were removed to generate an embryonic stem cell line genetically matched to the immune-deficient mouse—complete with the same genetic immune deficiency.

To correct this defect, Daley explained, the researchers then used a standard technique of molecular biology called homologous recombination to replace the faulty gene with a normal copy. Daley noted that combining gene repair with cell therapy in this way allows the exact gene locus to be corrected, in contrast with methods of gene therapy that rely on viral vectors to deliver a gene to a cell, an approach that carries the risk of random insertion of a gene that creates a cancer-causing mutation.

After correcting the defect, the researchers coaxed the genetically repaired embryonic stem cells to differentiate into hematopoietic stem cells and then transplanted them into the mouse. “Essentially we were giving an autologous graft that gets in with much less morbidity, much greater tolerance,” said Daley.

Daley and colleagues are continuing their work modeling the treatment of immune deficiency in mice. Their research has now extended to the treatment in mice with β-thalassemia, which would be a model for treating all genetic bone marrow disorders.

“We’re pretty confident those systems are working reasonably well in mice,” said Daley. His goal for the next decade or so is to translate the platform—all the fundamental principles learned in mice—to human cells.

Daley said he can imagine in the future applying the same methods of nuclear transfer to cure a patient with sickle cell anemia or thalassemia—or possibly any other genetic defect—by creating a genetically matched, pluripotent embryonic stem cell line, correcting the genetic defect, stimulating hematopoietic stem cell differentiation, and then transplanting the cells.

Daley sounded a note of caution in taking this technology into humans, pointing out that “we have to be as conservative as possible and also anticipate that it’s going to be much more difficult than we think right now.”

GERM OF AN IDEA

One limiting feature for human nuclear transfer is the availability of eggs, said Daley. His group has been interested in coming up with strategies that do not depend on female egg donors, an expensive and impractical approach for research.

To circumvent the need for female donors, Daley and colleagues have tried to derive mouse oocytes from embryonic stem cells. However, instead of eggs, sperm cells were produced (Geijsen et al. Nature. 2004;427:148-154). While this accomplishment was noteworthy—the research was cited by the journal Science as one of the top 10 breakthroughs of 2003—Daley is still intent on achieving his goal of generating oocytes from pluripotent stem cells, as another group was able to do (Hubner et al. Science. 2003;300:251-256).

Through this work, Daley and colleagues have developed techniques to investigate some basic aspects of germ cell biology. As the germ lineage develops, he explained, certain genes are activated to separate it from the somatic lineages of the developing embryo. The germ cells undergo broad-based epigenetic remodeling, which includes reversible changes such as methylation that are involved in gene regulation. Understanding the details of how this occurs is an important problem to be solved.

The techniques can also be used to explore how a mature somatic cell is reprogrammed to become a less differentiated cell, or even how a somatic cellmight be changed from one cell type to another. “That’s a very, very hot topic right now,” said Daley, “but it’s unclear how this actually happens.”

Reprogramming through nuclear transfer causes a somatic cell to lose its differentiation and return to a pluripotent state, said Daley, who used this approach in the mouse experiment described above. But although they know the technique works, they do not know how.

“Maybe in the next 10 to 20 years we’ll understand how to reprogram a somatic cell from one fate directly into another using chemical means alone,” said Daley, “but currently that’s very much a pipe dream.”

But turning such dreams into reality is what the Pioneer Award seeks to do. By funding Daley’s proposal to marshal the strategies developed in the team’s germ cell research to study the molecular mechanisms involved in normal germ cell development and in the experimental manipulation of somatic cell nuclear transfer, the NIH award may help move stem cell research closer to therapeutic solutions for medicine.

FACTS OF LIFE

Daley noted that the current presidential policy that limits federal spending on research with human embryonic stem cell lines may restrict some of the questions he can explore with his NIH funding. Because harvesting cells from embryos requires that the embryos be destroyed, a presidential ban limits researchers to only a limited set of stem cell lines created before August 9, 2001, the date the presidential ban was issued. (A new study suggests that these stem cell lines may be unsuitable for use in humans; see next story.)

While a consensus may never be reached about the morality of harvesting cells from embryos, Daley hopes that the debate about stem cell research will eventually sort itself out and these restrictions will become a footnote. Numerous discussions with members of both political parties have reassured him of the sincerity and depth of interest about stem cell research in Washington, he says. Most of these policymakers, he feels, want to “do the right thing.”

As a biologist and a physician, Daley is not impervious to the concerns about the ethical issues related to research involving human embryos. “I have a huge respect for life, for the moral sanctity of being,” he says. “But I also see the life of a cell as very different and distinct from the integrated life of an individual, a person, a being. I don’t think individual cells are beings.”

Daley emphasized the importance in realizing the potential of embryonic stem cell research in treating disease. “I have no moral quandary whatsoever about working with the cells in the first few stages of development, when they’re single cells, when they’re a small cluster of relatively unspecified, unspecialized cells,” he said. “It is these cells that can help push the frontiers of healing and medicine to relieve enormous suffering.”

×