A candid conversation with veterinarian Ralph Brinster, 'Father of Transgenesis' - DVM
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A candid conversation with veterinarian Ralph Brinster, 'Father of Transgenesis'
Penn researcher shares insights of 50 years studying mammalian germ line.


DVM: You started using stem cells in the 1970s, demonstrating that non-embryo-injected cells become part of the developing mouse. Why did you start that research?

Brinster: I believed that the introduction of stem cells early in development would allow them to take part in maturation of tissues. These are the studies that resulted in the teratocarcinoma cells being injected into blastocysts.

While we were trying to explore techniques to get better teratocarcinoma cells or similar cells to enter the germ line, I began developing techniques that might allow the introduction of genes directly into fertilized eggs. At first we worked with chromosomes, but they were difficult to handle. Fortunately, other scientists were developing recombinant DNA techniques, which made pure populations of specific genes available.

It was difficult to obtain funding for these studies because the probability of success appeared very low. To obtain funding for this type of study, injecting eggs with nucleic acids, I began studies putting messages for proteins into eggs to study the mechanisms by which the egg produced the specific proteins. One of the proteins I planned to study was ova albumin, and Richard Palmiter had done excellent studies with this protein. I contacted him to obtain the messenger RNA. However, he had stopped working on ova albumin and was working with metallothionein genes. Although I was already working with several molecular biologists and trying to introduce new genes into eggs, I was interested in other possible genes, but the metallothionein gene was present in mice, and there was no good assay to distinguish it from the endogenous protein.

However, I used the ova albumin messenger RNA for my protein studies, and later described these studies to Richard. At that time, he told me he was fusing the metallothionein promoter to the herpes simplex virus thymidine kinase gene, for which I had an assay. So I asked Richard to send me the fusion gene, and we began collaborating on microinjection of the gene into eggs. In the spring of 1981, we obtained transgenic mice expressing the metallothionein thymidine kinase fusion gene, and Richard and I then published the results of these studies in Cell several months later.

DVM: Tell us about the giant-mouse experiment of the early 1980s.

Brinster: I was very interested in making changes in the biology of the mouse using the transgenic technology, and one of the changes I envisioned was a correction of genetic defects. Richard and I discussed this project, which eventually led to the use of the metallothionein-growth hormone fusion gene in an attempt to correct the genetic defect in the "little" mice. The experiment was a success and was published in Nature 30 years ago this December. The effect was dramatic, and the experiment catalyzed interest in the transgenic technique among scientists as well as the general public. A picture of a large mouse next to its normal-sized sibling was published on the cover of Nature and appeared on the front page of most newspapers throughout the world.

DVM: I remember that photo. I was stunned by it and the research it represented. That must have been exciting for you, to get that much recognition for your work.

Brinster: Yes, I was surprised. The phone did not stop ringing for the entire day the picture appeared on the Nature cover. It brought a great deal of recognition to the scientific area and to our work, as well as the experiments of others working and contributing in this area.

DVM: What are your thoughts on the state of veterinary stem cell research today?

Brinster: It is critically important to understand how tissues develop, both normally and abnormally. I am not surprised that researchers are now studying the stem cell basis of cancer. I felt in the 1970s, when I was studying the teratocarcinoma cell, that all cancers must have a stem cell basis. It seemed logical that the cancer, like any self-perpetuating tissue, must have a stem cell basis, as well as a differentiation process, which is unregulated in cancer. The study of stem cells, including those of cancer, is an important area of investigation within veterinary medicine. Many veterinary schools are currently involved in innovative stem cell research.


Source: DVM360 MAGAZINE,
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