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hen TV and newspaper reporters showed up 10
years ago at N.C. State University to hear the story of the states first test-tube calves, Dr. Charlotte Farin told them she was excited as all get out. As we continue to make embryos in the lab, she said, we are more confident that they are like embryos made by Mother Nature.
But it wasnt long before Farin began questioning her early assumptions. As more and more calves were born following in vitro fertilization (IVF ), Farin and her colleagues started noticing subtle distinctions.
For one thing, the IVF calves were noticeably heavier as embryos and at birth. Their surrogate mothers were less likely to carry them to term. They required more care at birth. Even their muscle was a bit different.
Farin, an associate professor in the Department of Animal Science, has spent the past decade trying to pinpoint those differences and to figure out why they occurred. While her research provides cattle breeders with insights that should ultimately allow them to better manage IVF pregnancies, it also raises broader questions about IVF and related techniques, including genetic engineering and cloning.
Farin, her husband, Dr. Peter Farin of N.C. States College of Veterinary Medicine, and their students have documented that IVF embryos express the genes that normally control fetal growth differently than do calves conceived naturally.
The scientists start with eggs harvested from a Holstein, then fertilize those eggs in a laboratory dish with semen from a Holstein bull. A week later, the embryos are put into surrogate mothers that carry out the pregnancies. At different stages of gestation, the researchers harvest embryos and compare them to embryos sired naturally by the same bull.
By day 17 of pregnancy, the IVF embryos are twice as long as embryos sired naturally. And by day 70 of pregnancy, the scientists are able to detect differences in gene expression. In particular, they have noted higher levels of Insulin-like Growth Factor II in livers of fetuses from IVF embryos. IGF-II is a major hormone that controls the growth of fetuses of cattle and many other mammals.
The researchers believe that the changes occur because IVF disrupts a process, called genomic imprinting, that can change the expression of genes important in regulating fetal and placental development.
That, said Farin, would help explain why the IVF calves are, on average, 17 percent heavier than siblings with the same father. The phenomenon, dubbed large offspring syndrome, has also been observed in IVF sheep, goats and mice, and it is found even more prominently in clones of these animals.
What we have found is something that we didnt expect when we started out. In 1991, when we had the small project to make cow embryos through in vitro fertilization, our forgone conclusion was that these embryos would be the same as embryos made in a cow.
I personally went from We are just going to prove this is fine to This produces results that are not always normal, Farin said. The point is that things done during embryonic life can have significant effects on the animal, not only through fetal life but also at birth and throughout life.
Now that we can recognize differences, the question is, How do we fix it?
The answer, she said, is not yet clear. But because IVF and other assisted reproductive technologies hold tremendous promise both in food production and medicine, its imperative that scientists gain a better understanding of their consequences, Farin said.
Since she came to N.C. State in 1990, Farin has focused on discovering more about the molecular processes involved in embryo development both in vitro and in vivo. Her early successes in the laboratory drew national recognition, earning her the prestigious Presidential Young Investigator Award from the National Science Foundation just months before her first IVF calves were born.
Shes continued to make breakthroughs in investigating both the basic mechanisms that control the progression of meiosis in bovine eggs and the post-fertilization develop-ment and survival of embryos produced through in vitro fertilization. As a result, she publishes frequently in such journals as Molecular Endocrinology, Biology of Reproduction and the Journal of Animal Science.
The light that she and her colleagues have shed in these areas, and particularly on the mechanisms underlying large offspring syndrome, could help lead to diagnostic tests that identify earlier the fetuses that will be most affected by the syndrome. Such early identification could allow producers to discard embryos before they are implanted or to take steps to better manage pregnancies.
Moreover, she said, the research could lead to the development of IVF methods that eliminate the syndrome completely so that it can become more widely used in livestock production.
Thats important because creating embryos in an established IVF laboratory is about five times less expensive than using traditional in vivo methods, Farin said. And it allows for faster genetic improvement in a livestock herd because producers can save superior female animals for producing eggs and use other cows to carry out the pregnancy. With in vitro techniques, one female with desirable traits can produce embryos for more than 30 offspring annually.
In vitro techniques are also the important first step in the production of transgenic and cloned animals. Such animals could be used to produce human health products, including medicines and organs that can be used for human transplants. Transgenic sheep, goats, pigs and cattle are being developed to yield drugs to treat such diseases as hemophilia, heart disease, emphysema and other degenerative lung diseases.
Because of her conviction that biotechnology holds such great promise, Farin often reaches out beyond her Polk Hall Laboratory. She has made time to help middle school and high school students and their teachers, and shes an award-winning undergraduate and graduate teacher.
Farin is a regular contributor to Expanding Your Horizons workshops for middle-school girls interested in science, and she has served as a mentor for high-school teachers and students enrolled in summer programs promoting awareness of food and agricultural science disciplines and careers to underrepresented groups.
Shes also helped to create and demonstrate to high-school agriculture teachers a new animal biotechnology curriculum. The curriculum, being used by teachers nationwide, includes hands-on lab exercises involving gamete recovery, evaluation, DNA extractions from gametes and gel electrophoresis of extracted DNA.
Dr. Beth Wilson, who chaired the curriculum development committee, called Farins involvement in the training and curriculum development irreplaceable.
She has a wonderful ability to make complex information understandable, interesting and challenging at the same time, said Wilson, a faculty member in the Department of Agricultural and Extension Education. She is a great scientist who has the ability to communicate her subject at all levels.
Part of that ability comes, suggested Wilson, from Farins passion for science and for biotechnology.
As Farin put it, With the way the worlds population is growing, I think its clear that we need these technologies if we are going to have an adequate food supply.
On the other hand, these technologies have been adopted very rapidly, and we need to be cognizant that when we adopt new technologies we can be making changes that we dont readily know about. We need to consider the consequences.
What Im suggesting is that you can, and should, look at this glass from many sides, she said. Its the same glass.