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 studied animal science as an undergraduate at the Cook School of Agriculture, Rutgers University, New Brunswick, NJ and completed his B.S. in 1953. While he was in college, the Korean Conflict began, and he volunteered for service. He was a USAF second lieutenant in Korea during the last year of the combat period and after being assigned to the U.S. Army was stationed north of Seoul with an Army Battalion. He returned from military service and earned his V.M.D. (Veterinariae Medicinae Doctoris) (1960) and his Ph.D. in Physiology (1964) from the University of Pennsylvania.
Research impact Ralph Brinster is acknowledged as one of the seminal founders of the field of mammalian transgenesis."Ralph L. Brinster Winner of Wolf Prize in Medicine - 2003". Wolf Foundation. Retrieved February 7, 2019."Ralph L. Brinster". Gairdner Foundation. Retrieved February 7, 2019."1997 Carl G. Hartman Award Ralph L. Brinster" (PDF). March 15, 2004. Retrieved February 7,2019. 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."President Obama Honors Nation's Top Scientists and Innovators". The White House. September 27, 2011. Retrieved February 7, 2019. . In 2006, Brinster received a Canada Gairdner Foundation International Award for pioneering discoveries in germline modification in mammals. In part the citation read, "his range of contributions is unmatched in the field". Germline cells are at the foundation of species continuity and are responsible for propagation of individuals of varying genetic content that is critical for evolutionary competition. Specifically, the genetic composition of these cells is the essence of their importance. Brinster's seminal studies on mammalian egg manipulation strategies and his pioneering research on spermatogonial stem cells are today the foundation for all studies in this field, including the controversial potential for modifying the human germline.
Some have suggested that "the experimental genetic manipulation of the animal germline initially by pronuclear injection of cloned DNA into zygotes represents one of the most significant milestones in the history of human civilization," Behringer et al, in Manipulating the Mouse Embryo (Cold Spring Harbor Laboratory Press, pg14, 2014). Germline modification has existed for hundreds of millions of years and has contributed to the evolution of species through interaction with their environment. Purposeful germline modification by man began about 10,000 years ago in the fertile crescent of southwest Asia with domestication of plants and animals, giving rise to agriculture and modern civilization. The initial concept of domesticating wild species may be viewed as the first of four critical advances in man's intervention in evolutionary germline modification and is considered by many as representing the beginning of modern human history. The subsequent realization that selecting and breeding desirable phenotypes would lead to valuable alterations in domesticated species symbolizes the second advance. The identification and characterization of hereditary elements, which began with the studies of Mendel and continues today with the sequencing of genomes, represents the third significant development. These three conceptual advances are often considered to be the foundation of agriculture and modern civilization. Experimental addition or modification of individual DNA sequences and genes in the germline, known as transgenesis, exemplifies a fourth unique conceptual advance in man's purposeful modification of the germline. Thus, the generation of transgenic animals is an extraordinary, creative development in man's historical interaction with other species and of enormous importance in biology and medicine (see NICHD 2003 Hall of Honor and 2012 Colloquium External links below).
During the 1960s, Brinster pioneered the development of techniques to manipulate mouse embryos, and his techniques have made the mouse the major genetic model for understanding the basis of human biology and disease. His research has provided the experimental foundation for progress in germline genetic modification in a range of species, which has generated a revolution in biology, medicine, and agriculture.
In July 2024, Dr. Brinster had 411 total publications, approximately 322 are in peer-reviewed journals and 89 are chapters/reviews. Included in the publications are: 30 in Nature, 18 in Cell, 13 in Science, and 35 in Proc. Natl. Acad. Sci.
His research contribution/impact is ranked 1st of 173,000 contributors in Veterinary Medicine in the world and 8th of one million contributors in Agriculture and Natural Resources in the world in Scholars GPS with an h-index = 153.
He is ranked #128 in the world and # 96 in the United States among top scientists for 2024 in Research.com with a D-index (Discipline h-index) = 152.
Research history
Culture of mammalian eggs and embryos While a Ph.D. candidate in the 1960s, Brinster developed the first reliable in vitro culture system for early mammalian embryos. His initial studies were on fertilized eggs of the mouse. In 1963, he described a culture method consisting of micro drops of medium under oil, which remains the primary culture technique for mammalian eggs of all species, including human eggs during in vitro fertilization. During the next 10 years, Brinster studied many aspects of mouse egg metabolism and defined characteristics common to eggs of all mammalian species. From these studies he developed a culture medium and embryo manipulation strategies that are the basis of all egg culture media and manipulation methods in use today. He published more than 60 papers in the general area of egg metabolism and culture and is the scientist who laid the foundation for subsequent research involving mammalian egg culture. His studies provided a reliable method to manipulate all stages of preimplantation development in the mouse and other mammalian species (See Figure 1).
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.
Stem cells injection into mouse embryos produce the first prototype transgenic animal Brinster used the foundation of his culture and manipulation strategies to study techniques to alter the genetic makeup of developing embryos and their germ cells. In the early 1970s, he injected stem cells into embryos (blastocysts) in a series of imaginative experiments which were of enormous importance and changed the way scientists thought about the possibility of modifying genes in the germline. He was the first scientist to demonstrate that foreign teratocarcinoma cells could combine with native blastocyst cells to form adult "chimeric" mice, demonstrating the feasibility of this novel approach to change the genetic character of mice (Fig. 2). The introduction of foreign cells and new genes into these chimeric mice generated the first prototype transgenic animals. In addition, this discovery stimulated the search for embryonic stem cells and ultimately led to the development of the "knock-out mouse".
Transgenesis and the giant mouse 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).
Brinster then collaborated with Richard Palmiter, a prominent molecular biologist at the University of Washington, to pioneer and develop the transfer of foreign genes into mammals, and they utilized these methods to elucidate the activity and function of many genes. Their seminal experiments catalyzed a worldwide revolution in genetic engineering in the 1980s. 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.
In short, Brinster's egg injection technique was the first used to produce transgenic animals and is now the major method for making all genetic alterations in all species.
Modifying genes in sperm