Harvard Stem Cell Institute researchers work across disease areas and disciplines to improve patients’ lives, from investigating fundamental biological mechanisms to developing advanced therapies. In 2020, HSCI researchers published over 260 studies — here, we highlight just a few examples.
Type 1 diabetes is an autoimmune disease, where immune cells attack the insulin-producing beta cells of the pancreas. To better understand the root causes of this process, HSCI researchers led by Douglas Melton, Ph.D., developed a way to model human disease in a lab dish. They used induced pluripotent stem cells from patients to make beta cells, then introduced immune cells from the same individuals to observe an autoimmune reaction. The method can be used to study the cells’ interactions in further detail, and to test beta cell transplants for possible reactions.
In a separate study conducted in mice, Stephan Kissler, Ph.D., and Peng Yi, Ph.D., identified a potential strategy to protect beta cells from immune attack. The researchers used a CRISPR screening method to search the genome, looking for gene mutations that protected the beta cell. They found that cells lacking the renalase gene were protected from immune attack. Further, the FDA-approved drug pargyline was able to inhibit renalase and increase beta cell survival. The results may lead to the development of new drugs that could help protect transplanted beta cells, or even slow the original onset of the disease.
HSCI researchers led by William Pu, M.D., successfully tested a gene therapy in mice for Barth syndrome, a rare disease that can cause life-threatening heart failure. The researchers previously studied a stem cell model of Barth syndrome and found that the gene TAZ is responsible for heart dysfunction. Based on that work, the researchers developed a mouse model that lacked TAZ to study the disease’s whole-body effects. The animals’ hearts had more scarring, thinner walls, and lower pumping capacity. When the researchers used gene therapy to replace TAZ in the mice, the symptoms were reversed, demonstrating the potential for using the approach to treat patients.
In the rare blood disease dyskeratosis congenita, cells have defects in their telomeres — the protective caps on the ends of chromosomes — that cause them to age prematurely. HSCI researchers led by Suneet Agarwal, M.D., Ph.D., had previously studied genetic mutations in patients and found a faulty biological pathway related to telomerase, the protein that builds up telomeres. Based on that result, they screened over 100,000 small molecules to identify ones that targeted the pathway. The researchers then tested the compounds in patient stem cells and found a subset that successfully restored telomere length. This approach could improve the regenerative ability of cells in telomere-specific diseases. More broadly, it could also be therapeutically beneficial during normal aging to help counteract the typical telomere shortening that occurs over time.
Scientists have been recreating human skin in the lab for decades, but all of these models have lacked many of the component cells and structures of normal skin, including hair. HSCI researchers led by Karl Koehler, Ph.D., developed improved skin organoids, or miniature 3D cell cultures, that better model the skin. Made using human induced pluripotent stem cells, the organoids accurately developed into the top and bottom layers of the skin. The interactions and signaling between the layers led to the development of hair follicles, fat cells, and nerves. When the researchers transplanted the organoids onto mice, the transplanted skin grew hair and other human skin structures. The improved technique for culturing skin could be applied to drug testing in the lab and therapeutic uses such as burn and wound treatments.
Acute myeloid leukemia is a blood cancer that can be treated with chemotherapy, but has a high rate of relapse. For a longer-lasting therapeutic approach, David Scadden, M.D., and David Mooney, Ph.D., collaborated on an injectable biomaterial-based vaccine. They created a “cryogel” scaffold that contained different molecules to attract and activate immune cells, and to teach the immune system to recognize and attack cancer cells. When tested in mice, the vaccine successfully led to lasting recovery and immunity, demonstrating the potential of this bioengineering approach.