Researchers at the National Institute of Environmental Health Sciences and the University of California at Davis report that one of the body's approximately 70,000 proteins, called fertilin-beta, is essential for bringing together sperm and egg for fertilization. The research team, led by Chunghee Cho of UC-Davis, presented findings that will be a milestone in understanding how a new life begins.
The researchers believe this finding can pave the way for a non-hormonal approach to family planning and the diagnosis and treatment of some types of infertility.
Twenty years of work by the UC-Davis investigators established that fertilin-beta plays an important role in fusion of the sperm to the egg in fertilization. In this latest study, a collaboration with NIEHS scientists, mice were produced with a knockout of the fertilin-beta gene. The investigators were not surprised that sperm from these mice were unable to fuse with eggs. However, they did not expect to find that the sperm could not travel up the oviduct or bind to the zona pellucida, the envelope surrounding the egg.
The study, which appears in the journal Science, Vol. 281, pp. 1857-1859, was authored by Chunghee Cho, Ph.D.; Paul Primakoff, Ph.D.; and Diana G. Myles, Ph.D., all of University of California, Davis; and Eugenia H. Goulding; Edward M. Eddy, Ph.D.; and Donna O'Dell Bunch, Ph.D., of the Laboratory of Reproductive and Developmental Toxicology, NIEHS; and Jean-Emmanuel Faure, Ph.D., Ecole Normale Superieure de Lyon, Lyon, France.
Dr. Cho, first author on the paper, said that "astronomers study the Big Bang, the moment when the Universe began. In life, sperm-egg fusion is the Big Bang and we now understand more about the few seconds before and few seconds after this event" said Dr. Cho. "With all the current concerns about the possible effects of endocrine disruptors on fertility and of hormone-based contraceptives on the development of some forms of cancer, this protein provides a new avenue to approach family planning, and diagnosis and treatment of some infertility problems as well," Dr. Eddy said.
Dr. Bunch said that a vaccine to human fertilin-beta could provide women with a successful, non-hormonal means of birth control. "Right now we see this as a contraceptive for women rather than men."
At the heart of this research advance is Eugenia Goulding who is an expert in a key method used in developing knockout mice, that is, mice genetically altered to be unable to produce a specific protein. The absence of this protein can then show scientists what functions the protein serves in animals with normal genes.
In a critical step of the process, Ms. Goulding sits in a darkened room before a binocular microscope and a television monitor showing the highly magnified view through the microscope. She manipulates a blastula-stage mouse embryo, a hollow ball of about sixty four cells, with a needle a fraction of the width of a hair, and injects cells lacking a specific gene into the blastula. These blastulas are then surgically introduced into female mice that serve as surrogate mothers.
Some of the offspring born two and one-half weeks later are chimeras, mice bearing a mixture of cells from the blastula and the injected cells with a knock-out of the fertilin-beta gene. These chimeras have a distinctive coat color that makes them easy to identify.
Though the process is straightforward in theory, making it all happen can take years. Dr. Bunch recalls that her son, a year old at the time her part of the study began, is now starting kindergarten. However, she says that the knockout mouse studies are a direct way of gaining knowledge that we could not learn any other way and lay the groundwork for important health advances for the future.
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