Eoin C. Whelan, PhD, a senior research investigator in the laboratory of Ralph L. Brinster, VMD, PhD, has shown that male testis tissue that is cryopreserved can be reimplanted after more than 20 years and will go on to make viable sperm. This has implications for boys facing cancer treatments associated with diminished fertility later in life. A potential treatment would be to harvest, freeze, and, after the cancer is cured, reimplant the testicular tissue, which contains stem cells that could give rise to sperm.
According to Dr. Brinster, another important message of the research is that the outcome is likely relevant to the damage to all stem cells of being frozen for long periods. Dr. Brinster noted that it is very difficult to measure this functional deterioration in other stem cell dependent tissues. Other stem cell dependent systems do not have such a definitive functional endpoint, which is easily measured both quantitatively and qualitatively. Spermatogonial stem cell self-renewal and differentiation is highly organized, and its quality can be measured with the spermatogonial stem cell transplantation technique—published by The Brinster Lab in 1994—that is now in wide use.
The current research was published in PLOS Biology, and has garnered significant media attention. Dr. Whelan interviewed with New Scientist, WebMD, and Reuters Health (via Medscape; registration required). Reports of the study were carried by over 100 national and international outlets, including US News & World Report, Newsweek, New York Post, and Metro UK. As of this writing, the paper is #19,728 out of more than 21 million outputs, which means it is in the top 0.1% of all research outputs tracked by Altmetric. Congratulations to The Brinster Lab!
In a major step forward for regenerating light-sensing photoreceptor cells in the retina to treat vision disorders, a multi-institutional research team led by William Beltran, DVM, PhD injected immature photoreceptor cells into the eyes of dogs with a retinal disorder. The transplanted cells survived for months and began integrating with others in the retina, marking progress toward a potential vision-restoring cell-based therapy.
Results of the current study were published in Stem Cell Reports.
The next stage for this project will be to continue optimizing the therapy and then test whether vision is improved in its recipients.
Research led by P. Jeremy Wang, MD, PhD has discovered that the enzyme DOT1L, a stem cell renewal factor, is essential for mice to produce sperm throughout their adult lives. Scientists have discovered only a handful of such stem cell renewal factors, so the finding, published in the journal Genes & Development, adds another entity to a rarified group.
A longer-term goal is using factors like DOT1L and others involved in germline stem cell self-renewal to help people who have fertility challenges. The concept is to create germ cells from the ground up.
New research by Kotaro Sasaki, MD, PhD, published in Science Advances, may inform diagnostics and treatment for Addison’s disease and other endocrine system disorders.
Currently, people with Addison’s disease are treated with a lifelong steroid replacement therapy, using synthetic hormones to substitute for those that their bodies can’t make on their own. This treatment is not a cure and comes with serious side effects.
In future work, Dr. Sasaki and colleagues hope to lay the groundwork in the lab to generate the adrenal cortex, employing inducible pluripotent stem cells, cells derived from blood or skin that can be induced to become a variety of different cell types. With such an approach, they could coax the stem cells to follow the normal developmental pathway toward becoming adrenal tissue. While in its early stages, this could enable a cell-based therapy for primary adrenal insufficiency, ideally avoiding some of the drawbacks of hormone replacement therapy.
Immunologists led by Christopher A. Hunter, PhD and doctoral student Joseph Perry have published a new study in Nature Immunology showing that checkpoint inhibitors—important tools in the cancer-fighting arsenal—can encourage the activity of cancer killing T cells, but they can, in some cases, also activate a population of regulatory T cells that serve the opposing function—to rein in that attack. More specifically, they discovered that blocking the activity of the checkpoint protein PD-L1, which interacts with a T cell receptor PD-1, enhanced the activity of a subset of T cells known as effector regulatory T cells, or effector Tregs. This intervention unexpectedly reduced the ability of mice to control a parasite infection. The findings could have implications not only in refining cancer checkpoint inhibitor therapies but also in conceiving new strategies for treating autoimmune disease.
Cryptosporidium is a leading cause of diarrheal disease in young children around the world. The intestinal parasite contributes to childhood mortality and causes malnutrition and stunting. How a parasite like this one reproduces and completes its life cycle has significant impact on child health. In a new paper in PLOS Biology, Boris Striepen, PhD and colleagues in his lab tread new ground in understanding how Cryptosporidium reproduces inside a host.
Using an advanced imaging technique allowed the scientists to observe the entire lifecycle in the laboratory. They found the parasite completes three cycles of asexual replication and then directly switches to male and female sexual forms. Their observations refute an intermediate stage that was introduced in the 1970s and align well with the original description of physician and parasitologist Edward Tyzzer who discovered this pathogen more than a century ago.
Future research will focus on the molecular mechanism of commitment to understand how this life cycle is programmed into the parasite’s biology. Understanding the life cycle of Cryptosporidium is critical in thinking about how to create a vaccine or therapy for the disease.
Long Kwan Metthew Lam, PhD, has been awarded a two-year inaugural postdoctoral fellowship through the newly established Institute for Infectious and Zoonotic Diseases (IIZD) at Penn Vet. Lam was selected for his innovative approach to salient scientific questions regarding mammalian immune response within the context of disease transmission.
Under the mentorship of Nilam S. Mangalmurti, MD, a physician-scientist at the University of Pennsylvania’s Perelman School of Medicine (PSOM), Lam will use comparative immunology to decipher the nucleic acid sensing functions of bat, human, and mouse red blood cells to understand vector-borne viruses. The long-term goal is to identify novel methods to reduce cross-species disease transmission.
During a recent visit to the Galápagos, Daniel Beiting, PhD, along with Penn students and local collaborators, spent time investigating one of the consequences of human and wildlife cohabitation: sanitation challenges. Using portable molecular biology tools, the Penn scientists evaluated water quality and trained Galapagueño scientists and students to perform the same tests themselves. Part of the larger Galapagos Education and Research Alliance (GERA), co-directed by the School of Arts & Sciences’ Michael Weisberg, PhD, a goal of this project is to empower residents with the knowledge and capacity to keep tabs on water quality in their own home, contributing to environmental and public health research.
The first canine C-11 positron emission tomography (PET) scans at PennPET Explorer were completed by Brian Flesner, DVM, MSc, DACVIM and the Penn Vet Veterinary Clinical Investigations Center (VCIC) in collaboration with other University partners. PET is a common imaging modality used to detect and monitor cancer in people. Recently, researchers at Penn Vet have collaborated with both industry, intramural, and government agencies to make PET scans available for animals at Penn. Penn Vet’s oncology group has joined a collaborative effort to harmonize PET imaging across the Comparative Oncology Trials Consortium institutions through the National Cancer Institute. Penn is one of only six COTC institutions with PET capabilities.
Jennifer L. Huck, DVM
Jennifer L. Huck, DVM was the co-PI, along with Dr. Keith Cengel of the Penn Medicine Department of Radiation Oncology, on a study investigating the effects of FLASH proton beam radiation on canine osteosarcoma tumor cells and normal tissues as compared to proton beam radiation. In conjunction with the Penn Vet Veterinary Clinical Investigations Center (VCIC) and Comprehensive Cancer Care team, patients presented to the Ryan Veterinary Hospital for treatment for osteosarcoma were screened and enrolled; supervised during the delivery of radiation; and provided standard of care therapy following radiation treatment, including amputation and chemotherapy. This was the first study that investigated FLASH proton radiation effects in canine tissues. The results of this research helped to provide a foundation for a $12.3M NIH grant to Penn Medicine and will serve as a guide to future studies investigating the unique role of this treatment on radiosensitive tumors in veterinary patients.
A sampling of stories from April/May 2022 highlighting the work of Penn Vet and its faculty.