Someone whose opinion he trusted told him he was going in the wrong direction. Every indication for years suggested success was as elusive four years after failing as it had been during his first unsuccessful attempt.
“It didn’t look very good,” confided Z. Josh Huang, a scientist at Cold Spring Harbor Laboratories. In those first years, he wondered if he should do something else.
Sticking with it, however, paid off, especially in the last few years. Huang and his team have made important discoveries about a type of neuronal cell in the cerebral cortex called chandelier cells.
Huang has not only been able to label these cells and watch them in action, but he has also figured out where and when they develop, before they move to their position inside the cerebral cortex (the part of the brain that is responsible for processing sensory information, for thinking and reasoning and for directing movement).
These chandelier cells are likely to be the most powerful cells in the cerebral cortex. They are only found in the cerebral cortex and humans appear to have more of them than other mammals, including monkeys and mice.
They got their name from the way their branches jut out from the main body of the cell. Their axon arbor looks like a chandelier light. Researchers believe they serve an important role in keeping order in the nervous system, quieting other nerve cells from vying for attention all at once.
Francis Crick, who won the Nobel Prize in 1962 for discovering the double-helical nature of DNA with James Watson, first suggested four decades ago that these cells had “veto” power, according to Huang.
“When the chandelier cell ‘speaks,’ it is like the president. All these other cells will be quiet, regardless of their urge to speak,” Huang explained.
While that metaphor hasn’t been proven precisely yet, Huang said the evidence is mounting to support Crick’s original contention. Huang’s research is testing this specific assertion.
Some medical challenges, including schizophrenia and epilepsy, have been linked to problems with chandelier cells.
“A variety of molecular markers were altered or reduced in the pre-frontal cortex in schizophrenia patients,” Huang explained. “That has been a very reliable finding from many labs.”
The possible explanation is that if these cells are compromised, the excitatory neurons will not function coherently. Some treatments are looking at ways to boost the output of the chandelier cells by enhancing the so-called GABA receptor.
GABA, named for the neurotransmitter gamma amino-butyric acid, is the only inhibitory neurotransmitter in the brain. GABAergic inhibitory cells, including chandelier cells, organize neuronal populations into groups that guide behavior.
Some of Huang’s early work, which proved so challenging, involved following the pathway of these chandelier cells, which develop outside the cortex and move to their central locations during development. When he started looking for ways to track these cells, scientists were using dyes, which weren’t reliable.
Huang built a better animal model system to track these cells. Now, he can see them every time they are active.
“You can activate them or silence them and see the consequence,” he explained. “It’s extremely powerful.”
In the latest finding, Huang discovered that these important cells start out in a region of the embryonic brain he called the ventral germinal zone. This part of the brain didn’t have a name because it wasn’t clear what types of cells it produced.
Chandelier cells are “born” after another region that is responsible for producing different neurological inhibitor cells disappears.
Huang’s work was published last month in the journal Science. Earlier this year, he also served as co-author on three papers in Nature, another prestigious scientific journal.
“This has been an amazing year,” he concedes. “It took us four years to fail, to build this experimental system” to make these findings.
Huang, who has been at Cold Spring Harbor for a dozen years, lives in Woodbury with his wife May Lim, a radiation oncologist in Queens, and his two daughters, Vivien, 12, and Julienne, 8.
In graduate school, he added the first name “Josh” because it has some phonetic resemblance to his Chinese first name.
In terms of his research, Huang said he received supportive advice from colleagues and advisors along the way, much of which he took to heart during the years that weren’t quite as productive as this one.
“What I came away with is to do something that is very fundamentally important and to stay the course,” he offered.