Introducing Clifford Woolf, MD, PhD
Integrated, multidisciplinary basic research is fundamental to progress in diagnosing and treating nervous system disorders at Children’s Hospital Boston. We believe that the bedrock of translational research is the highest quality basic science. Our approach to research is two-pronged: expand our understanding of how the brain develops and then identify and capture targets that are ripe for translation.
We are pleased to announce the arrival of renowned neurobiologist and pioneer in the field of pain research, Clifford Woolf, MD, PhD, to Children’s as the director of the neurobiology program and of the F.M. Kirby Neurobiology Center. Woolf is an international authority on neural plasticity, mechanisms of pain perception, regeneration of the injured nervous system and the formation of neural circuitry during development.
Woolf’s appointment to Children’s demonstrates our commitment to the highest quality research and its successful translation to novel therapeutics. His fundamental contributions to science have furthered our understanding of basic pain mechanisms. Most notably, the discovery of central sensitization——abnormal excitability of neurons within the CNS, which is often responsible for pain hypersensitivity in clinical conditions—has led to the development of new therapeutic approaches for managing pain.
This issue of Neural Networks focuses on translational research in the neurosciences at Children’s, though it is by no means an exhaustive list. Armed with knowledge garnered from mouse models, our researchers have created novel therapeutics, currently being tested in human clinical trials, to treat such intractable conditions as autism and epilepsy.
Woolf’s appointment to Children’s solidifies our standing as the premier translational research institution. We look forward to a fruitful collaboration, from bench to bedside.
David R. DeMaso, MD, chair of Psychiatry
Scott L. Pomeroy, MD, PhD, chair of Neurology
R. Michael Scott, MD, chair of Neurosurgery
The hunt is on for human pain genes
Pain sensitivity and the risk of developing chronic pain are, in large part, hard-wired. Unlocking ‘pain genes’ will reveal a wealth of knowledge about patients’ susceptibility to pain and improve treatment. It is a major step toward personalizing medicine.
“Genes give us an amazing and powerful tool to understand how pain is generated,” says Clifford Woolf, MD, PhD, director of the F.M. Kirby Neurobiology Center at Children’s Hospital Boston. Fifty percent of the variation in pain sensitivity is inherited. In 2006, Woolf’s laboratory identified the first pain gene in humans, GCH1, which encodes for an enzyme that affects neurotransmitter production.
Woolf’s hunt for human pain genes continues in fruit flies, which are excellent candidates for large-scale genetic screens. This is due to to their short generation time and the ease of creating mutants. Humans and fruit flies share many genes, but bridging the genetic gap between species requires a breadth of expertise and technology not found at many institutions.
A NOVEL PAIN GENE, α2δ3, is found in fruit flies, mice and humans. This gene is believed to activate the brain’s higher pain centers in response to noxious heat. Illustration: Patrick Bibbins
“In order for our research to be successful,” says Woolf, “we need multiple approaches, outstanding investigators, and common research platforms.”
Woolf’s team and their collaborators at the Institute of Molecular Biotechnology in Vienna, led by Joseph Penninger, PhD, used RNA interference (RNAi) to target nearly 12,000 genes in nerve cells of fruit flies. Mutants that didn’t respond to noxious heat were singled out as possibly having pain genes silenced by RNAi.
Out of nearly 600 potential pain genes, the team chose one gene—alpha 2 delta 3 (α2δ3)—for further study. It is known to encode part of a calcium channel, which influences nerve excitability. Woolf’s team moved their research into mouse models to characterize the α2δ3 gene. As with mutant flies, mice with deleted α2δ3 genes didn’t respond to noxious heat. Functional MRI imaging of their brains showed that pain signals arrived in the thalamus but did not travel to the cortex’s higher pain centers.
To find out if α2δ3 played a similar role in humans, Michael Costigan, PhD, an assistant professor (neurology) at Children’s, and collaborators from the University of Pittsburgh and the University of North Carolina focused on four single nucleotide polymorphisms (SNPs), or single letter variations in the DNA code, within or close to the α2δ3 gene family in healthy human volunteers and surgical patients.
Healthy patients with less common SNPs had reduced pain sensitivity when exposed to noxious heat, and surgical patients with the same SNPs experienced less persistent chronic pain. The results were reported in the journal Cell.
Results were similar for a different study of the pain gene KCNS1. SNP variations accounted for differences in acute and chronic pain sensitivities in both patients and healthy volunteers.
The genes KCNS1, α2δ3 and GCH1 may constitute a pain panel that reflects a patient’s risk profile for chronic or acute pain. Investigating the panel and the more than 600 pain gene candidates found in the fruit fly study is the team’s current focus.