Four tons of spinach. 5,000 mice. One metaphorical and one real tortilla. These numbers tell a story. Each part of this story leads back The University of Texas at Austin and is carried by hope.
Dr. Richard Finnell is beginning a new chapter in his career as a pediatric geneticist in the Department of Nutritional Sciences in the School of Human Ecology at The University of Texas at Austin.Finnell was formerly the Margaret M. Alkek Professor of Medical Genetics and Regents Professor at the Institute for Biosciences and Technology at the Texas A&M Health Science Center. He will have a joint appointment with the Department of Chemistry and Biochemistry.
“It is hard to live in Texas and not be impressed by the outstanding research environment of the University of Texas," said Finnell. "Once they decided to place an emphasis on children's health with the development of the Dell Pediatric Research Institute, I knew that I wanted to get in on the ground floor and do whatever I could to make it a success.”
Finnell will be involved in teaching undergraduates and supervising the research of graduate students, while continuing and extending his own research program. His research examines the interaction between specific genes and environmental toxins as they influence normal embryonic development.
While his primary research focuses on discovering the role of folic acid in the prevention of birth defects, his laboratory is also working to identify the gene or genes that determine susceptibility to human neural tube defects (NTDs) and orofacial clefts.
Finnell is studying teratogenic agents, both pharmaceutical compounds and those found in the environment, that contribute to the population burden of birth defects. Given the recent oil spill a few hundred miles offshore from Houston, he is acutely aware of the potential threat to human health stemming from this environmental catastrophe and hopes to work with teams of new colleagues at the university as they assess, and perhaps remedy, the reproductive risks associated with the oil slick.
Finnell will officially begin his appointment on September 1, 2010. The move will be epic.
FKBP8 A.K.A. Stacey
Humans and mice share about 99 percent of their genes. Nearly all mouse genes have a human analog. Mice require little space to roam, have fairly simple dietary requirements, and reach sexual maturity quickly. They are able to successfully produce litters about 50 days after birth and have a gestation period of about 18 days. These characteristics make them perfect genetic stand-ins for human beings.
As part of his research effort as the Executive Director of Texas A&M Institute for Genomic Medicine, Finnell’s team developed a mouse with damage to a gene called FKBP8, that portion of the mouse’s genome is artificially “knocked out.” He called this knockout mouse progenitor “Stacey.” When asked about the name, Finnell says, “The press has really picked up on that. I thought that FKBP8 lacked a certain sex appeal. ‘Stacey’ is a much sexier name.”
And sex is the name of Stacey’s game. The FKBP8 gene controls embryonic development of the spinal column. Damage to the FKBP8 gene causes Stacey’s offspring to develop with abnormal spines that closely mimic the development of spina bifida in human beings. Spina bifida, a congenital defect in the neural tube disorder (NTD) spectrum, is a caused by incomplete closure of the neural tube which becomes the spinal column. Spina bifida can, in the most severe cases, result in paralysis and a slew of other health complications. Finnell’s research examines the interaction amongst contaminants found in air, food, water quality, and the environment at large, and how they impact embryonic development. With abnormal development of the spinal columns of Stacey’s pups assured by damage to her FKBP8 gene, Finnell and other scientists can then test to see how the addition of micronutrients like folic acid to Stacey’s diet impacts the viability of her litters.
Finnell will not arrive at the university alone. In addition to thousands of knockout and transgenic mice like Stacey, Finnell will bring with him five research scientists who will become faculty in the College of Natural Sciences' School of Human Ecology, two postdoctoral researchers, and will be looking for new graduate students who will support and extend his research program.
Finnell’s laboratory operations will be moved from their current locations in Houston to the Dell Pediatric Research Institute in Austin. A move of this magnitude is bound to present a logistical challenge for Finnell’s team.
“Holy moly, what a nightmare," he says. "Moving trucks for the lab, for the mice, for the freezers, moving trucks for my family and those of my faculty. All happening during August! Torchy’s better put on extra staff to feed everyone during this exodus out of Houston.”
Four Tons of Spinach and a Metaphorical Tortilla
In the early 1940s, Esmond Snell, Herschel Mitchell and Roger Williams, all of them at the Biochemical Institute in the Department of Chemistry, managed, no doubt with the help of many graduate students, to carry four tons of spinach to the attic of Welch Hall where they had constructed a steam kettle and a filter press.
The pungent liquid yielded an astonishing discovery. Snell, Mitchell and Williams had isolated a B vitamin, vitamin B9, which they named "folic acid."
Finnell adds, “This is another reason I wanted to be at The University of Texas at Austin. It is the home of folic acid. What could be more fitting?”
Folic acid (the synthesized form) and folate (the naturally occurring form), both of which must be ingested, play a vital role in the healthy development of organisms from simple organisms like yeast to complex organisms like humans, that much is clear. And while research in laboratories around the world have cemented folic acid’s role in the reduction of risks associated with the development of NTDs, the complex environmental, genetic and nutritional causality that leads to NTDs has prevented the identification of just how this occurs mechanistically.
Working with Professor Dean Appling of the Department of Chemistry and Biochemistry, Finnell places this task on the highest rungs of his priority list.
Very early in embryonic development, the notochord, a primitive form of the spinal column, signals to the specialized cell layer above it to form the thick and flat neural plate. The neural plate folds in upon itself, much as a tortilla can be folded, to form the neural tube, which will later differentiate into the spinal cord and the brain, eventually forming the central nervous system. This process happens between the 19 and the 28 days of gestation in humans, often before a woman even knows that she is pregnant. Neural tube defects (NTDs) occur when this process is incomplete. Failure for the neural tube to close gives rise to spina bifida. When the anterior end of the neural tube fails to close or fails to close completely a child can be born with anencephaly, lack of a brain and cranial vault, or encephloceles, protrusion of the brain and meninges through the skull.
Richard Finnell will be joining forces with exceptional researchers like Dr. John Wallingford, a developmental biologist, whose research focuses on cell differentiation and cell signaling in early embryonic development. A research collaboration featuring Finnell, Wallingford and Edward Marcotte, the William and Gwyn Shive Endowed Professor in the Department of Chemistry and Biochemistry, has placed their research on the cover of the October 2009 edition of the journal Nature Cell Biology.
“Wallingford and Marcotte are brilliant and enterprising scientists. It is an honor to be working with them,” Finnell said.
Tragedy in Northern Mexico and One Real Tortilla
Currently, there are NTD "hotspots" all over the globe. Azerbaijan, steeped in oil refineries, chemical, and metallurgic industries, the Shanxi Provence China, producer of 1/3 of China’s coal, and Matamoros, Mexico, dotted with maquiladoras, factories which produce goods for export.
On July 1, 1998, the FDA, responding in part to studies that arose in the wake of the 1991 Brownsville/Matamoros NTD cluster, and at the urging of the March of Dimes and Texas Department of Health, began the folic acid fortification program, requiring manufacturers of flour and recommending that the manufacturers of cereals and breads fortify their products with folic acid. Scientists with the March of Dimes have noted that fortification has caused a two-fold increase in blood folate in women aged 20-39 years.
In a research paper published in 2005, Dr. Mark Canfield with the Epidemiology and Surveillance Branch of the Texas State Department of Health confirmed that there has been a reduction in the occurrence of NTDs in representative regions in the United States the post-fortification (1998-2001) era. But research conducted by the Texas Department of State Health is also revealing that certain birth defects have higher rates for some racial, ethnic or regional groups than others. For example, Hispanic women are significantly more likely than non-Hispanic women to have a baby with a the NTD anencephaly.
In November 2009, the March of Dimes convened experts, scientists, public health officials and medical professionals to a planning and policy review meeting called “State of the Science: Folic Acid.”
Finnell was one of the scientists contributing to the panel’s findings which, in turn, will direct the public policy efforts of the March of Dimes and other public health agencies. The challenge set before the panel was to provide an evaluation of evidence related to folic acid fortification and its health impacts. The panel was charged with determining the next steps in the campaign to prevent NTDs.
Among the recommendations, the panel recommended that, in order to address the elevated risks of NTDs in the Hispanic population in the United States, corn masa flour, like wheat flour, should be fortified with folic acid. It is hoped that the fortification of the main ingredient of corn tortillas will reduce the racial/ethnic disparity in folic acid status by improving intake in the Hispanic population.
Hope
There are many potential factors contributing to the occurrence of NTDs: maternal diet, folic acid deficiency, vitamin B-12 deficiency, pollutants tainting air and water, naturally occurring toxins, and genetic predispositions. These factors are examined singly at the cellular level and across whole populations. They are examined in terms of geographic influence and they are studied in individual cases.
It will take teams of physicians, public health specialists, nutritionists, cell biologists and geneticists working in collaboration to find the cause of NTDs. As more world-class researchers move laboratory operations to the Dell Pediatric Research Institute and the Dell Children’s Medical Center of Central Texas (DCMC), these facilities are bridging the gap between pure research and medical practice.
Dr. Timothy George, Director of Pediatric Neurosurgery/Neuroscience at Dell Children’s, described Finnell’s new role as Director of Genetic and Genomic Research.
"It will serve as a key component in bridging these institutions [DCMC and The University of Texas at Austin] by overseeing the translation of genomic research from the patient care arenas to the wet labs space of The University,” he said.
DPRI as a research extension of the university and DCMC are addressing through research, patient treatment, and outreach the health issues that disproportionately and negatively affect the present and future lives of children: traumatic brain injury, birth defects, cancer and obesity.
This hope translates. Every woman, worldwide, will have the knowledge and will be empowered to ensure that the child she carries will begin a healthy life.
- By Meghan Mullaney, School of Human Ecology
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