Two Yale teams among Science Top 10 for 2005

Genetic mutations linked to brain development and disease were among last year’s leading discoveries.

Two findings by Yale scientists have been included in Science magazine’s list of the 10 leading scientific breakthroughs of 2005. The teams found evidence that both Tourette syndrome (TS) and dyslexia could stem from genetic defects linked to brain development. Their work was among research cited under the category “Miswiring the Brain.” Although the article did not name specific scientists or institutions, it cited “clues about the mechanisms of diverse disorders including schizophrenia, Tourette syndrome, and dyslexia. A common theme seems to be emerging: Many of the genes involved appear to play a role in brain development.”

Matthew W. State, M.D., Ph.D. ’01, the Harris Assistant Professor of Child Psychiatry and assistant professor of genetics, and the senior author of a report in the October 14 issue of Science, led the team that identified for the first time a genetic mutation associated with TS. The gene, which contributes to neuronal growth and communication, accounts for less than 2 percent of TS cases, but its discovery after years of searching offers the best chance yet to penetrate this socially debilitating disease. How the mutations participate with other genetic and environmental factors to increase risk for the disease is unknown. “We hope the clues this gene will give us will have widespread ramifications for understanding the basic biology of this disorder,” said State.

In its search for “that one unusual patient who would lead us to a gene,” State’s team found a child, diagnosed with TS and attention deficit hyperactivity disorder, who had a telltale break on chromosome 13. That clue led researchers to the nearby SLITRK1 (Slit and Trk-like family member 1) gene, which had already been recognized to be active in the developing brains of rodents and to function in neuron growth. When they analyzed the gene from 174 people with TS, they found three individuals with mutations. No mutations of any kind were found in several hundred unaffected people, providing strong evidence that SLITRK1 was contributing to the disease. Studying SLITRK1 gives a starting point, said State, who likened their discovery to a string the researchers can now pull on to start to unravel the rest of the disease.

Another team at the School of Medicine found a genetic link to dyslexia, the reading disorder that affects millions of children and adults. A mutated version of a gene, located on chromosome 6 and called DCDC2, disrupts the formation of brain circuits that make reading possible. The findings deepen the “understanding of how the reading process works on a molecular level,” said Jeffrey R. Gruen, M.D., HS ’84, FW ’88, associate professor of pediatrics and lead author of the study published in a special issue of Proceedings of the National Academy of Sciences in November.

In a study of DNA markers in 153 dyslexic families, Gruen’s team found that up to 20 percent of cases of dyslexia are due to defects in the DCDC2 gene. In the mutated version of the gene, a large regulatory region is deleted. Locating this gene explains, in part, why dyslexia occurs and could lead to early and more accurate diagnoses and more effective educational programs for dyslexic children.

—Pat McCaffrey

New twist on experiment unleashes the brain’s potential for healing

When we pour concrete for a sidewalk or foundation, we want the material to be as fluid as possible, so that it will easily assume the shape we have in mind. But for our structure to be durable and useful, we want the concrete to harden—quickly.

The brain’s early development is a similarly delicate balancing act between malleability and permanence. The areas of an infant’s cerebral cortex devoted to sensory systems are highly plastic, so that cortical circuits can be efficiently sculpted in response to the sights, sounds and smells that make up the baby’s world. But as soon as a baby has had enough time to acquire adequate sensory experience—a developmental window known as the “critical period”—neural circuits become hard-wired.

Fixed neural circuits ensure that cortical function is stable and reliable, but stability comes at a cost: if the brain or spinal cord is damaged by trauma, disease or stroke, it can rarely repair itself well enough to restore function.

How the brain shuts the door on plasticity and how that process might be blocked to regenerate or repair neural circuits are the focus of the laboratory of Stephen M. Strittmatter, M.D., Ph.D., the Vincent Coates Professor of Neurology.

In 2000, Strittmatter identified a protein called Nogo that suppresses self-repair in damaged axons. In order to establish whether Nogo shuts down plasticity more generally, Strittmatter and Nigel W. Daw, Ph.D., professor of ophthalmology and visual science, married genetic techniques with a classic experiment devised by Nobel prize-winning neurobiologists David H. Hubel, M.D., and Torsten N. Wiesel, M.D., in the early 1960s.

Normally the visual cortex is divided equally between inputs from each eye into regions known as ocular dominance columns, but Hubel and Wiesel showed that if one of an animal’s eyes is kept shut during the highly plastic critical period, the active eye’s inputs will appropriate a larger share of the visual region, leaving vision in the other eye irreversibly impaired. However, as reported in the September 30 issue of Science, when Strittmatter, Daw and postdoctoral fellows Aaron W. McGee, Ph.D., and Yupeng Yang, Ph.D., performed the same experiment with mice specially bred to lack a functional Nogo receptor, the cortex remained plastic after the critical period, and an active eye could usurp cortical real estate from a deprived eye well into adulthood.

Encouraged by these and other results, Strittmatter is searching for Nogo blockers that he hopes will revive the capacity for plasticity, and healing, of the damaged or diseased brain and spinal cord. “Limited nerve cell regeneration and plasticity are central to a range of neurological disorders,” he said, “including stroke, head trauma, multiple sclerosis and neurodegenerative disease.”

—Peter Farley

et cetera

Protection against mad cow disease

In 1996, during an epidemic of mad cow disease—bovine spongiform encephalopathy—in British cattle, epidemiologists predicted that up to 100,000 people could contract variant Creutzfeldt-Jakob disease (vCJD), a rapidly progressing, invariably fatal neurodegenerative condition, from infected beef. But that nightmarish scenario has not yet come to pass: 10 years later, only 151 cases of vCJD have been verified.

Laura M. Manuelidis, M.D. ’67, HS ’70, FW ’70, professor and chief of surgery (neuropathology), may have discerned why. Manuelidis and colleagues reported in Science in October that exposure to less-virulent strains of CJD may protect against infection with the newly evolved bovine strain. The team found that when neuronal cell cultures were infected with either a weak or sporadic form of CJD, or with agents that cause sheep scrapie, a disease similar to CJD, they resisted infection by the more-virulent strain.

—P.F.

Taste and smell—the nose knows

Although our taste buds distinguish sweet, sour, salty, savory and bitter, flavor arises from a combination of tastes with odors that enter our nasal passages through the back of the mouth. These “retronasal” odors get special treatment from the brain, according to a new study led by Dana Small, M.Sc., Ph.D., assistant professor of surgery (otolaryngology) and psychology at Yale and an assistant fellow at the John B. Pierce Laboratory.

In a report published in Neuron in August, Small and colleagues at Yale and in Germany inserted tubes that pumped odors such as chocolate into subjects’ noses, either to the front of the nostrils or to the back of the nasal cavity. They found that a single odor could activate different brain regions, depending on the route it traveled. Odors presented retronasally activated brain areas devoted to the mouth, which Small said is “evidence of the existence of distinct olfactory subsystems”—one specialized for sensing objects at a distance, the other for sensing objects in the mouth.

—P.F.


			Originally published in Yale Medicine, Spring 2006. Copyright © 2006 Yale University School of Medicine. All rights reserved.