New Blood
Daley Discusses Potential to Make Blood in the Lab
Photo: Chia-Chi Charlie Chang
Imagine if blood cells could be manufactured, offering an unlimited, universal blood supply for transfusions, transplants and other therapeutic uses. So many would benefit; millions of lives could be saved. It may sound far-fetched, but decades of research have brought us much closer to the possibility.
“After more than 20 years of effort, working doggedly to try to develop human hematopoietic stem cells from a petri dish, we’re tantalizingly close to being able to say we’ve got it working,” said Dr. George Q. Daley, a hematologist, professor and dean at Harvard Medical School. He spoke recently as part of NHLBI’s 70th anniversary lecture series in Lister Hill Auditorium.
“I started thinking about the possibilities of deriving blood cells from embryonic stem cells even when I was a graduate student in Dr. David Baltimore’s lab,” said Daley. In the late 1980s, in Nobel laureate Baltimore’s lab, Daley linked an oncogene to chronic myeloid leukemia, a type of blood cancer that was fatal without a bone marrow transplant. The discovery paved the way for an effective treatment for CML.
“At that time, the standard of care was a sibling transplant, but there was growing interest in crossing immunologic boundaries using unrelated donors,” said Daley.
Early on, his lab was culturing mouse embryonic stem cells, prodding them to differentiate into blood. It proved challenging, though, to customize stem cells to make them rejection-proof.
In 2001, equipped with his first human stem cell grant from NHLBI, Daley began differentiating human embryonic stem cells into blood, and later succeeded in making induced pluripotent stem cells (iPS), which are adult stem cells reprogrammed back into an embryonic stem cell (ESC)-like state so they can develop into other cell types for therapy. Daley made iPS cells from patients with various blood diseases.
Bolstered by advances in gene-editing techniques, Daley took disease models, corrected them in vitro, creating a control for diseased iPS cells and a repair stem cell that could be replicated in the petri dish and coaxed into blood lineages.
Recently, with NHLBI funding, Daley used disease-specific iPS cells from a patient with diamond blackfin anemia to configure a drug screen that identified a compound that is headed for human clinical trials.
“This is the beginning of what I hope will be an increasing number of drugs that will find their way to the clinic by virtue of having been tested in these iPS systems,” said Daley. “It’s my longstanding hope—going back those 30 years or so—in thinking about being able to rescue patients with a curative bone marrow transplant, [to use] human ES or iPS intermediates for that purpose.”
ES and iPS cells also potentially could provide a predictable supply of platelets for the millions of units transfused into patients annually. Recipients traditionally rely on blood donations, which can be erratic, especially in Daley’s hometown of Boston, where harsh winters sometimes prevent donors from traveling to give blood. Manufactured platelets could help circumvent several challenges of donated platelets, providing an inexhaustible, reliable, pathogen-free supply.
Photo: Chia-Chi Charlie Chang
In a recent project, Daley has collaborated with Japanese researchers to convert iPS cells into self-renewing platelet progenitors that become platelets that are structurally and functionally comparable to human platelets. The process, however, is prohibitively expensive for a tiny yield. Daley’s lab is now exploiting live cell confocal imaging to identify rare subclones of cells with greatly increased platelet production. This new platform, which is proving much more efficient but still isn’t cost-effective for commercial production, will soon go into a first-in-human clinical trial at Boston’s Dana-Farber Cancer Institute.
“I predict, in the future—5, 10, 15 years down the road—we will see an increasing dependency on in vitro manufactured platelets and red blood cells to replace, and provide advantages over, donor-derived cells,” said Daley.
Another research area is cancer immunotherapy. The process of engineering CAR T cells and re-infusing them into patients to target malignant tumors is labor-intensive and currently costs hundreds of thousands of dollars.
“One appealing alternative is to change a patient-specific strategy into an off-the-shelf strategy,” Daley said. Some of his preliminary research has produced robust iPS-derived T cells that hold promise for enabling wider access to this potentially curative technology.
Daley continues culturing and gene modifying hematopoietic (blood-forming) stem cells toward producing cloneable, immortal stem cells in the lab. “For the many dozens of hematopoietic diseases for which there is still lacking any kind of gene therapy,” said Daley, “this would be a single common platform for combined gene and cell therapy.”
Hematopoietic stem cells are particularly challenging to manufacture, said Daley, because blood develops in waves. The first wave of embryonic red cells is transient, then lifelong blood formation develops from a second wave. Now, investigators can employ markers for mature stem cell and lymphoid development that can help researchers manipulate stem cells into blood cells for therapy.
Some experiments show great promise. Daley’s lab has reached the point where they can generate hematopoietic stem cells from human ES and iPS cells in a petri dish on a small scale. The cell dose is only adequate for a mouse.
“We have to imagine an engineering solution that would allow us to scale up, maybe 1,000-fold, to have a dose of hematopoietic stem cells that could transplant even a pediatric patient,” Daley said. “So there’s more work to be done. There’s still a long way to go before clinical use, but we’re motivated to press on.”