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Lauren Orefice Wins 2019 Eppendorf & Science Prize for Neurobiology

Lauren Orefice
Orefice received the 2019 Prize for her work with peripheral neurons, showing that autism spectrum disorders are not exclusively linked to brain function. | Ken Richardson

Lauren Orefice has been named the 2019 grand prize winner of the annual international competition, The Eppendorf and Science Prize for Neurobiology, for research that shows how neurons outside of the brain — those that control the sensation of touch — can alter brain function and shape select behaviors associated with autism spectrum disorders (ASD). Her work in mice demonstrates that these cells, called peripheral somatosensory neurons, may be effective therapeutic targets for improving some ASD-related symptoms.

"Dr. Orefice's research adds an unexpected novel aspect to the basic scientific understanding of autism, providing a surprising revision of widely-held views that link autism spectrum disorders exclusively to brain function," said senior Science editor Peter Stern.

ASD are highly diverse disorders with steadily increasing prevalence; one in 59 people in the U.S. are reported to be living with ASD. The disorders are associated with a wide variety of symptoms, including difficulty with social interaction and communication, repetitive behaviors and interests and abnormal reactivity to sensory stimuli, such as light, sound, pressure and heat.

Because the genetics and behaviors underlying ASD are so varied and complex, finding consistent links among these components remains a challenge. To date, the wide variety of ASD-related symptoms has been largely attributed to dysfunctional neuronal activity in the brain. In her prize-winning essay, "Outside-in: Rethinking the etiology of autism spectrum disorders," Orefice, an assistant professor of molecular biology at Massachusetts General Hospital and genetics at Harvard Medical School, suggests that this view is incomplete.

One of the more overlooked, yet commonly observed, symptoms in patients with ASD is over-reactivity to touch, whereby a gentle breeze or hug could be unpleasant or possibly painful. The first steps in touch perception occur in peripheral somatosensory neurons, which receive inputs from the whole body. Therefore, Orefice, her colleague David Ginty and their team reasoned that exploring somatosensory neuron function throughout the nervous system, even outside the brain, might lead to promising insights into the understanding of ASD.

Using mouse models for ASD, Orefice and her colleagues searched for cells in which ASD-related genes Mecp2, Gabrb3 and Shank3 might affect sensitivity to gentle touch.

Deleting these genes in different somatosensory cell types throughout the nervous system, the researchers found that the loss of these genes in brain-residing excitatory neurons produced no major symptoms associated with ASD. Rather, genetic mutations in neurons that receive light touch signals from the skin correlated with increased sensitivity to touch.

"We were initially quite surprised by the finding that peripheral sensory neuron dysfunction contributes to abnormal touch behaviors in ASD mice," said Orefice.

In addition to being over-reactive to touch, mice lacking Mecp2, Gabrb3 or Shank3 in peripheral sensory neurons exhibited social impairment and anxiety-like behaviors reminiscent of those observed in patients with ASD. Restoring these genes selectively in peripheral neurons normalized some — but not all — ASD-associated symptoms in the mice.

"The importance of peripheral neurons for touch processing is interesting, but the general behaviors of the conditional mutant mice were even more remarkable," said Orefice in her essay.

Based on these findings, Orefice and her colleagues postulated that if the sensation of touch was altered through mutations in neurons outside of the brain, these same mutations might also alter behaviors thought to be controlled by neuronal circuits in the brain. Therefore, improving peripheral neuron function to reduce sensitivity to touch might also help relieve other ASD-related symptoms.

The researchers tested this hypothesis in six different ASD mouse models. Increasing signals that inhibit some of the sensory activity in peripheral neurons reduced hypersensitivity to touch, they found. In addition, long-term application of this treatment in mice with Mecp2 and Shank3 mutations led to major improvements in brain development, anxiety-like behaviors and some social impairments.

Importantly, this treatment did not cross the blood-brain barrier, lowering the chance of triggering harmful side effects ascribed to some drugs that act on the brain.

"I am really excited about our findings and the directions my lab is now exploring," said Orefice. Her lab aims to pinpoint exactly how altered sensory input due to peripheral sensory neuron dysfunction impacts brain development and complex behaviors. They will also continue investigating how the activity of somatosensory neurons in other areas of the body, like the gastrointestinal tract, are affected in ASD.

Orefice hopes these findings will lead to the development of new compounds that act selectively on peripheral somatosensory neurons — reducing their excitability — while sparing the brain.

"We will need to determine which people with ASD exhibit over-reactivity to light touch stimuli and therefore who would benefit from this type of treatment," she said.

Orefice and the following finalists will be recognized at a prize ceremony on Oct. 20, 2019 at the St. Jane Hotel in Chicago.

  • András Szőnyi, for his essay "Conducting memory formation: The nucleus incertus in the brainstem orchestrates the formation of contextual memories." Szőnyi received undergraduate degrees in medicine and a Ph.D. in neurosciences from the Semmelweis University in Budapest, Hungary. He performed research in the Institute of Experimental Medicine of the Hungarian Academy of Sciences. Currently, Szőnyi is a postdoctoral fellow in the Friedrich Miescher Institute for Biomedical Research in Basel, Switzerland. He studies the cellular mechanisms of learning and memory formation in mice using in vivo imaging and optogenetics.
  • Zvonimir Vrselja, for his essay "Destined for destruction? Restoring brain circulation and cell functions after prolonged global anoxia." Vrselja received his M.D. and Ph.D. from J.J. Strossmayer University in Croatia. After completing his graduate education, he started his postdoctoral training at Yale University. He currently holds the position of associate research scientist in the Sestan Laboratory at the Yale School of Medicine. His research focuses on the development of a system that preserves global anatomical organization, as well as cellular organization; attenuates cell death; and restores neuronal, glial and vascular functionality, along with global metabolism, in isolated large mammalian brains several hours after death.

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Juwon Song

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