George Daley, MD, PhD
Scientists hope that research with human embryonic cells will lead to important advances in treating a variety of diseases.
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.”
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.
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
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,”
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
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
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
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.
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
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