Ralph L. Brinster

Ralph Lawrence Brinster (born March 10, 1932) is an American geneticist, National Medal of Science laureate, and Richard King Mellon Professor of Reproductive Physiology at the School of Veterinary Medicine, University of Pennsylvania.

Early life and education Brinster grew up on a small farm in Cedar Grove, New Jersey, where his parents raised purebred animals. He is known throughout the scientific community for his revolutionary research in early embryo development, embryonic-cell differentiation, mechanisms of gene control, and stem cell biology. . In 2006, Brinster received a Canada Gairdner Foundation International Award for pioneering discoveries in germline modification in mammals.

These techniques have been conserved to the present day and form the foundation for all experimentation with the mammalian embryo - including transgenic animals, embryonic stem cell research, human and mammalian in vitro fertilization, mammalian cloning, and knockout technology.

His in vitro culture and egg manipulation strategies have directly enabled foundational techniques in modern science such as embryo splitting, intracytoplasmic sperm injection, nuclear transplantation, and mitochondrial transplantation into eggs, among others, which occur in vitro using methods virtually unchanged since they were introduced by Brinster.

This "Brinster Method" of embryo manipulation is so ubiquitous in modern biology that other scientists rarely cite the work in current publications. The introduction of foreign cells and new genes into these chimeric mice generated the first prototype transgenic animals. Professor Brinster was the first scientist to microinject fertilized eggs with RNA and DNA, and was at the forefront of the field in applying these microinjection methods to generate transgenic mice. Direct injection of fertilized mouse eggs, pioneered by Brinster, was the first approach to achieve routine experimental germline modification and served as the basis for all subsequent techniques (Fig. 3). Transgenic mice are now used every day in thousands of laboratories around the world to investigate everything from cancer biology and cardiovascular disease to hair loss and abnormal behavior. Their experiments, for the first time, showed that new genes could be introduced into the mammalian germline with the potential to increase disease resistance, enhance growth, and produce vital proteins like blood-clotting factors needed by hemophiliacs. Perhaps their best known experiment was in generating the "Giant/Super Mouse", which catalyzed interest within the scientific community and in the general public about the enormous potential of the transgenic technology being developed and is credited with the initiation of the genetic revolution in biology, medicine and agriculture (Fig. 4). In addition, they provided the first proof of expression of transgenes, the first example of cancer arising from a transgene and the first proof of the targeted integration of DNA by egg injection. Together, Brinster and Palmiter developed many of the first animal models of human disease throughout the 1980s. Their partnership also yielded the first transgenic rabbits, sheep, and pigs.

This transcontinental collaboration constructed a body of work that formed the foundation for a generation of scientific progress in genetic modification via transgenesis, homologous recombination or "knock-out" techniques, and cloning; and the egg culture and manipulation strategies were essential for these experiments by Brinster and Palmiter, as well as for all other scientists working with eggs and embryos of all species. The egg culture and injection techniques developed by Brinster serve as the basis for the CRISPR/Cas9 system of genetic modification currently used for all types of gene changes in all species. left Fig. 5. Top panel. Recipient mouse testis that was injected with genetically modified spermatogonial stem cells containing a reporter transgene for Green Fluorescent Protein (GFP), which will fluoresce green. Bottom Panel. The testis will produce spermatozoa that transmitted the GFP transgene to offspring. In recent years, Brinster has continued to advance the field of stem cell biology by making a series of catalyzing, transformational discoveries utilizing male germline stem cells, called spermatogonial stem cells (SSCs). Spermatogonial stem cells in the testes are the only cells in the adult body that divide throughout life and transmit genes to the next generation, establishing them as a powerful resource to modify genes of any mammalian species. In elegant experiments published in 1994, Brinster demonstrated that these stem cells can be transplanted from the testis of a fertile male to the testis of an infertile male where they establish spermatogenesis and produce spermatozoa of donor haplotype (Fig. 5). He further demonstrated that the technique is applicable to all mammalian species examined, including humans. These changes in the stem cell genetic program resulting from cryopreservation must be identified and corrected to restore the original genetic program of the stem cell before clinical application. However, a solution could be to convert a somatic cell to a germ cell, particularly to the SSC, which may have fewer perturbations of the original stem cell genotype and would have enormous implications scientifically and in the treatment of clinically important fertility problems. thumb Professor Ralph Brinster receiving the National Medal of Science from President Barack Obama. The Elaine Redding Brinster Prize in Science or Medicine medallion.

Major scientific recognition

In 2003, Brinster was awarded the Wolf Prize in Medicine and was cited for "development of procedures to manipulate mouse ova and embryos, which has enabled transgenesis and its applications in mice. The first scientist to microinject fertilized eggs (with RNA), Brinster was at the forefront of applying these methods to generate transgenic mice".

Academic career Brinster has spent his entire academic career at the University of Pennsylvania School of Veterinary Medicine; from 1956 to 1960 as a veterinary student, from 1960 to 1964 as a postdoctoral fellow and PhD Candidate, and then continuing as a faculty member.

Personal history

In 1961, Brinster married Elaine Redding, a registered nurse and graduate of the Philadelphia General Hospital School of Nursing, and they currently reside in Gladwyne, PA. They have four children. Lauren R. Brinster earned her VMD from the School of Veterinary Medicine at the University of Pennsylvania. She is a veterinary pathologist at the National Institutes of Health, Bethesda, MD. Kristen A. Brinster earned her Juris Doctor from the University of Baltimore School of Law. She is a trial lawyer and the founding managing partner of Sutherland & Brinster, PA in Maryland. Derek R. Brinster earned his MD from the Perelman School of Medicine at the University of Pennsylvania. He is a Professor of Cardiovascular and Thoracic Surgery and Director of Aortic Surgery at Northwell Health, New York, NY. Clayton J. Brinster earned an MD from the Perelman School of Medicine at the University of Pennsylvania. He is an Associate Professor of Surgery and Director, Center for Genetic Aortopathy and Related Disorders at Keck Medicine of the University of Southern California. In 2021, the Elaine Redding Brinster Prize in Science or Medicine was established by the children to recognize the enormous contribution of Elaine to the achievements of the family. The $200,000 Prize and Medallion are to be awarded annually to an outstanding scientist from any country by the Institute for Regenerative Medicine of the University of Pennsylvania during the Annual Ralph L. Brinster Symposium.

Awards and honors 1960–1961 American Veterinary Medical Association Fellow University of Pennsylvania, Graduate School of Arts & Sciences 1961–1964 Pennsylvania Plan Scholar University of Pennsylvania, Graduate School of Arts & Sciences 1983 Award in Biological and Medical Sciences New York Academy of Sciences 1984 Harvey Society Lecturer 1986 Fellow of the American Academy of Arts and Sciences 1997 Bower Award and Prize for Achievement in Science Franklin Institute 1997 Carl Hartman Award of the Society for the Study of Reproduction 1998 Honored by a Special Festschrift Issue, dedicated to Dr. Brinster and the worldwide impact of his contributions; International Journal of Developmental Biology 1998 Pioneer in Reproduction Research Award National Institute of Child Health & Human Development 1999 George Hammel Cook Distinguished Alumni Award Rutgers, The State University of New Jersey 2000 Charlton Lecture Tufts University School of Medicine 2000 Honorary Doctor of Science Degree from Rutgers, The State University of New Jersey 2001 Ernst W. Bertner Award University of Texas M.D. Anderson Cancer Center, in recognition of pioneering contributions to cancer research. 2002 Highly Cited Researcher (1980-2000), Designated by the Institute for Scientific Information. About 1 in 1000 authors are in this category. 2003 Wolf Prize in Medicine, Israel "for the development of procedures to manipulate mouse ova and embryos, which has enabled transgenesis and its applications in mice". with Mario Capecchi and Oliver Smithies 2012 Lifetime Achievement Award. From the Alumni of the University of Pennsylvania School of Veterinary Medicine. 2012 Career Excellence in Theriogenology Award. From the Theriogenology Foundation on behalf of the American College of Theriogenologists and the Society for Theriogenology. 2015 Honorary Doctor of Laws, University of Calgary, Canada. 2015 Fellow of the American Physiological Society. 2017 Ralph L. Brinster President's Distinguished Professorship, University of Pennsylvania.