Originally created 04/07/01

MCG doctor battles for theory's approval



In a white turtleneck and gray-and-brown V-neck sweater, Dr. Gurkirpal Sohal doesn't look like a revolutionary.

But sallying forth from his laboratory at the Medical College of Georgia, he is trying to set the world of developmental biology on its ear.

Despite early rejection and "humiliating" reviews of his work from peers, Dr. Sohal is now getting government grants and battling for acceptance for what appears to be a previously undiscovered cell type that might hold the key to some birth defects and the way adult tissues regenerate.

He calls them VENT cells, for ventrally emigrating neural tube cells. Conventional wisdom says that early on in the embryo, cells are organized into three basic tissue types that give rise to the different tissues of the body, one layer contributing muscle, one layer contributing the digestive system, and so forth.

"So the initial location of the cell then basically locks its fate," Dr. Sohal said. "This is the fundamental concept in human development."

It is also known that the neural tube forms the brain and central nervous system and that during the formation of the neural tube cells called neural crest cells detach to form the peripheral nerve system.

"In other words, the neural tube does not contribute to the development of any of the other parts of the body," Dr. Sohal said.

When he was studying embryos, however, he noticed a curious population of cells outside the neural tube near the trigeminal nerve that goes to the face - cells where there should not be cells. After labeling them for tracking purposes, Dr. Sohal found the cells migrated out along the nerves to other parts of the embryo and turned into liver cells, heart muscle cells, cells in the digestive system and part of the facial muscles.

It was a startling discovery. It also was widely panned.

"The first three years were pretty bad: papers getting rejected, grants getting rejected, humiliating reviews basically telling us that we don't even understand some of the basic concepts of the field," Dr. Sohal said.

But he did not give up. He continued to present his findings at conferences and discussed them with colleagues. He received some encouragement from Dr. Harold C. Slavkin, then director of the National Institute of Dental and Craniofacial Research. Dr. Slavkin has since returned to the University of Southern California to become dean of its school of dentistry.

"I just found (Dr. Sohal's theory) fascinating," Dr. Slavkin said. "We talked about the different ways of confirming it and maybe using different lines of evidence to support the idea. I encouraged him, and was delighted when he submitted his research and it went through the competitive review and it was funded."

EVEN AFTER THE first few papers were published, there was still widespread skepticism about this new population of cells, said Dr. Carol A. Erickson, professor of molecular and cellular biology at the University of California-Davis. She, along with Dr. James Weston at the University of Oregon, reviewed Dr. Sohal's work for the journal Trends in Neuroscience.

"Most of my colleagues discount it entirely," Dr. Erickson said. "Some of us, like Jim and myself, say it's an idea that needs a hearing. It's important to give it a fair hearing."

She and others would like to see certain questions answered, such as whether the viral marker used to tag the cells wasn't in fact spreading to other cells, which could make it appear the neural tube cells migrated and became other kinds of cells.

Dr. Sohal said he has switched techniques, transplanting a quail neural tube into a chicken embryo, then using a species-specific test to follow where the quail cells go. He has $1.7 million from two different institutes at the National Institutes of Health, one to confirm his earlier studies and one to look specifically at the development of the inner ear.

"The ear has always puzzled me," Dr. Sohal said.

The inner ear develops two kinds of cells - auditory cells responsible for hearing and vestibular cells responsible for maintaining balance and equilibrium within the body.

"How could they develop, two very different ones, from the same cell?" Dr. Sohal asked. VENT cells apparently migrate to the ear early on and bring "the ability to develop into two different systems," he said.

EVEN MORE INTRIGUING are Dr. Sohal's theories as to why the VENT cells migrate out of the neural tube into the rest of the body.

"We think that the VENT cells are not limited in terms of being an additional source of cells for the formation of various structures in the body," Dr. Sohal said. "We think that they may have multiple roles. One would be that they go into various tissues and partly differentiate into those cell types so that the respective nerves can recognize this as being their final target. This may be a mechanism for some sort of intermediate step by which the brain is able to connect with these target tissues accurately, relatively early on."

Dr. Sohal sees implications even beyond the cells' making sure the brain and nervous system are connected properly to the rest of the developing body. The neural tube itself, one of the first structures formed in the embryo, might call the shots for the rest of the embryo.

"We generally think of the role of the brain being in controlling various parts in the adult," Dr. Sohal said. "The developing brain may have a role as well to coordinate the development of the body."

It is that kind of speculation that can cause even open-minded colleagues to be taken aback.

"To say that the neural tube has some kind of regulative role in that strikes me as being bizarre," Dr. Erickson said.

FIGURING OUT THE role of these cells in development might give scientists clues into how birth defects form, Dr. Sohal said. And the VENT cells might have implications for adult stem cells, which help the body replace cells such as skin cells or blood cells, Dr. Sohal said. Adult stem cells are provoking great excitement among researchers, particularly because they have been found in the brain, which was previously thought to be unable to replace its neurons but now has been shown it can.

The stem cells are sometimes called "mother cells" because they are capable of recreating themselves in addition to creating other cell types. The VENT cells might in fact be the mother of the mother cells, Dr. Sohal speculated.

"No one knows where the stem cells come from," Dr. Sohal said. "And this may be the mechanism to seed the entire body with stem cells."

Even his supporters say Dr. Sohal must provide further proof for his VENT cells.

"I think what the investigators need to do is to try to validate the observation in more than one animal model," Dr. Slavkin said. "If it's true for a bird, it should be true for a mouse and a zebra fish (another animal used for development studies) if it's fundamental."

TWO OTHER LABORATORIES, one at NIH and one in London, have looked or are looking for the cells in mice, Dr. Sohal said.

If VENT cells are capable of transforming into other tissues, Dr. Erickson said, she would like to see Dr. Sohal prove that by directly converting those cells using the factors from the other tissues in the embryo.

"I'm enthusiastic about the possibilities," Dr. Slavkin said. "Through comparative studies using zebra fish and avian models and mouse, and being able to critically establish fate maps and getting at the functional genomics, this is likely to open up a renaissance in the biology of neural crest cells."

If proved, Dr. Sohal muses in his office, the VENT cells would cause a rewrite in every book on the shelves before him and what medical students are taught. Yet even with more proof, acceptance might take time, Dr. Sohal acknowledged. Scientists are the same as everyone else, he said: They can become entrenched in their thinking.

"Part of the problem is, when a new idea comes along, and also a relatively simple idea, the immediate response is that this cannot be so," Dr. Sohal said. "Look at all these people who have studied embryos for so many years. How come they didn't discover it?

"The way things are in science, some people have accepted this from the very beginning; some people have accepted it gradually. And some people will probably never accept it, or it will take them a long time."

Still, the revolution goes on.

Reach Tom Corwin at (706) 823-3213.