Photos by Matt Hagen for Fred Hutch & Bo Jungmayer / Fred Hutch News Service
We want to recognize the excellent work and achievements of our staff and faculty and will be regularly highlighting them in this space. Here are some recent notable accomplishments:
Study explores new source of stem cells and gene therapy
Transplantation with adult hematopoietic stem cells, or HSCs, is the only effective treatment for certain blood cancers, such as multiple myeloma and lymphoma. But sources of such stem cells for autologous transplantation (using the patient's own stem cells) are limited to the bone marrow and peripheral blood, both of which pose the threat of harvesting cancerous blood cells along with healthy ones.
Collecting adult stem cells from the blood and bone marrow also can be difficult in patients who’ve undergone high-dose chemotherapy to treat their cancer prior to transplantation, because such treatment reduces the production of stem cells.
To increase the repertoire of healthy stem cells available for autologous transplantation and gene therapy, Dr. Hans-Peter Kiem and colleagues in the Clinical Research Division at Fred Hutch are working on ways to derive blood stem cells from a new source: induced pluripotent stem cells, or iPSCs. Such cells can be gleaned from readily accessible tissues such as the skin and lining of the mouth. As their name suggests – derived from the Latin plurimus, meaning “very many,” and potens, meaning “having power” – they can differentiate into not only blood cells but tissues such as muscle, bone and nerves.
While iPSCs are versatile and easily accessible, in clinical studies they’ve been limited in their potential as a source for stem-cell transplantation because they do not readily create the population of blood cells required for successful, long-term engraftment.
Recent laboratory findings by Kiem and colleagues, published in the Journal of Clinical Investigation, reports a way around this obstacle. They found that introducing the presence of endothelial cells, which make up the lining of blood vessels, in the cell culture improves the ability of pluripotent cells to differentiate into hematopoietic stem cells.
“If we can safely derive HSCs from iPSCs, then in the setting of autologous transplantation we could increase the number of available blood stem cells and also avoid any tumor contamination,” Kiem said. He also sees the promise of using iPSC-derived blood stem cells in gene therapy applications, particularly for single-gene blood disorders such as sickle cell disease, thalassemia, Fanconi anemia and other bone-marrow-failure syndromes in which stem cell availability is limited either due to inadequate production or collection.
“If we could correct the early iPSC-derived blood stem cells and then expand them to very large numbers, we could likely accomplish correction of certain genetic diseases with little pre-transplant conditioning with chemotherapy,” he said. “The more HSCs we have, the better the engraftment in the patient.”
For their study, which was conducted in a mouse model, Kiem and colleagues cultured PSCs in the presence or absence of endothelial cells. PSCs grown along with endothelial cells were capable of long-term engraftment similar to levels seen in clinical studies of transplantation with umbilical cord blood, another source of stem cells.
As for the potential mechanisms behind this finding, Kiem said, “We think endothelial cells produce a lot of the important factors necessary to make and sustain HSCs.”
Researchers from the University of Washington, Weill Cornell Medical College and Angiocrine Bioscience collaborated on the study.
Insights into B-cell fate could enhance vaccine design
Dr. Justin Taylor, who joined Fred Hutch’s Vaccine and Infectious Disease Division last year, recently published a paper in Science describing the path or paths individual naive B cells can take to maturity. The findings ultimately could help researchers craft new and better vaccines against HIV and other challenging viruses.
B cells, a critical component of the immune system, are responsible for producing antibodies that help recognize and neutralize health threats. Naive B cells are so called because they haven’t yet been exposed to, and thus triggered by, the foreign or abnormal molecule, called an antigen, for which they are specific.
Taylor’s work, which he began as a postdoctoral fellow at the University of Minnesota, required the development of novel approaches to isolating individual naive B cells so their fates, and the factors that influence them, could be studied in detail.
Researchers have learned that when naive B cells encounter their matching antigen, they can differentiate into three different subtypes: short-lived plasma cells, which rapidly churn out antibodies to help neutralize the immediate health threat; germinal center cells, which undergo high rates of mutation, spinning off variations on the original cell, some of which may be even more effective at responding to the pathogen; and germinal-center–independent memory cells, which survive long term to help mount a defense if the same threat resurfaces in the future.
Leveraging his new techniques, as well as support from Hutch team members and collaborators who helped him complete the final experiments needed to publish his findings, Taylor revealed that some naive B cells go down only one of the three roads to maturity while others have the potential to spawn all three B-cell subtypes.
Such insights into basic B-cell biology are vital to developing more effective vaccines. For example, understanding how these cells differentiate will help researchers design vaccines that nudge naive B cells down the path to becoming the most potent versions of their mature selves. This includes versions with the capacity to produce broadly neutralizing antibodies, which, because they are effective against multiple strains of a virus, would be the ideal products of a vaccine for highly variable viruses like HIV.
Fred Hutch graduate student Nitobe London among 2015 Weintraub award winners
Nitobe London, a graduate student in the joint University of Washington/Fred Hutch Molecular and Cellular Biology Graduate Program, is one of 13 recipients of the 2015 Harold M. Weintraub Graduate Student Award.
The award, now in its 16th year, is one of the country’s most prestigious prizes given to doctoral students. It is sponsored by Fred Hutch’s Basic Sciences Division, but nominations are solicited internationally and winners were selected by a committee based on the quality, originality and significance of their work.
London, who is completing his doctoral research in Dr. Sue Biggins’ laboratory, is interested in how cells segregate the correct number of chromosomes to each daughter cell during division. He studies a cellular failsafe system called the “spindle checkpoint” that ensures cells don’t divide until all the pieces are in place for chromosomes to shuffle correctly to each new cell. London has identified key interactions that happen between spindle checkpoint proteins to turn on this surveillance and how those proteins themselves are regulated.
The Weintraub award honors the late Dr. Harold (Hal) Weintraub, a founding member of the Basic Sciences Division who died in 1995 of brain cancer. Weintraub was an international leader in the field of molecular biology; among his many contributions, he identified genes responsible for instructing cells to differentiate, or develop, into specific tissues such as muscle and bone.
London has conducted research in the division for 10 years — he was a technician in Dr. Jim Priess’ lab before joining Biggins’ team — and said Weintraub’s influence is deeply felt, even decades after his death.
“His contribution to the culture has influenced my experience here,” London said. “I’m very fortunate to have that as part of my training.”