Interviewed by Amber Dance

R. Douglas Fields

The Other Brain

For R. Douglas Fields, the revelation came one day in 1994. He had witnessed the flash of calcium-sensitive dye many times as he stimulated neurons under the microscope. But for the first time that day, ensconced in the microscope room at the National Institute of Child Health and Human Development (NICHD) in Bethesda, Maryland,

Fields added Schwann cells to the culture—and they lit up just like the neurons. With that experiment, Fields joined a scientific sea change that ultimately would proclaim glia as so much more than boring “neural glue.”

Fields recounts this episode, complete with his trepidation over a hypothesis about to be tested and the thrill of discovery, in his book, The Other Brain: From Dementia to Schizophrenia, How New Discoveries about the Brain Are Revolutionizing Medicine and Science. The book, out in paperback 11 January 2011, is published by Simon & Schuster. In it, Fields invites readers into his own and other labs as scientists probe the nature of glia and their contributions to the brain in health and disease.

Fields is ideally suited for the task; he straddles the divide between Ivory Tower academia and mass media communications. He is chief of the Section on Nervous System Development and Plasticity at NICHD, editor-in-chief of the journal Neuron Glia Biology, and a regular contributor to both Scientific American and the children’s science magazine Odyssey.

Glia, ranging in shape from starry astrocytes to jelly-roll Schwann cells, make up 85 percent of the brain. They do not just eavesdrop on the neural conversation, but they also talk back. In addition, they actively feed, protect, and insulate neurons; mop up after those that spew their neurotransmitters; and gobble up useless synapses. In November 2010, Science ran a special section on glia, and Science Signaling devoted much of a companion issue to the same topic.

Glia’s role in disease is now undisputed (see ARF related news story and ARF Live Discussion). In neurodegeneration, the same globs of protein that clog neurons also fill aging, weakening glia. Alois Alzheimer himself noticed that microglia surround β amyloid plaques. Astrocytes both assist microglia in clearing those plaques and make more of the β amyloid that fills plaques (see ARF related news story). The neurotoxin MPTP, a contaminant in recreational drugs that induces parkinsonism, only damages the substantia nigra when astrocytes are around. Multiple sclerosis attacks oligodendrocytes. Astrocyte activity following a stroke can kill neurons left alive by the initial injury. And in amyotrophic lateral sclerosis, mutant protein in glia appears to be key to disease progression (Boilée et al., 2006).

In The Other Brain, Fields narrates the story that neuroscientists are unfolding for a non-scientific audience. He invokes characters ranging from Alzheimer and Santiago Ramón y Cajal, the nineteenth-century neuroanatomist whose neuron doctrine left out glia, to ballpark hero Lou Gehrig and superstar astrophysicist Stephen Hawking, who suffer with the disease that bears Gehrig’s name. He describes how glia went ignored for so long and how scientists finally caught on to the truth.

In unwrapping the tale, Fields exposes the twists and turns of the scientific process. Far from a straight upward path to enlightenment, Fields depicts science as a cycling spiral where scientists build up hypotheses, knock them down with new insight, and construct new, hopefully more accurate hypotheses. The rise of glia is hardly the first such shift. Indeed, Fields notes, none other than Theodore Schwann of the eponymous glial type was ridiculed for his assertion that cells called yeast mediate fermentation. Scientific progress, after all, is all about the righting of erroneous concepts: the sun that supposedly revolved around Earth; the cells that supposedly arose by spontaneous generation; the animals that supposedly acquired long necks or big muscles simply because their parents strove to develop those features.

ARF caught up with Fields between poster sessions at the annual meeting of the Society for Neuroscience, held 13-17 November 2010 in San Diego, California, and sat him down for a chat about his opus.

ARF: Why did you write this book?

DF: We hear about turning points in science, but to have one happen in real time, right now, is very exciting. How did we overlook half the brain for 100 years? I wanted the reader to be able to see this turning point through the eyes of somebody involved.

ARF: Why were glia ignored for so long?

DF: A few reasons. First, the neuron doctrine: Information flows through neurons across synapses. Glia have been completely left out of most textbooks, or covered very superficially. That is what we studied, and that is what we believed.

Second, we used the wrong tools for the job. Glia do not communicate with electricity; they communicate chemically. We were never going to understand glia using microelectrodes. Calcium imaging forced us to realize that these cells are communicating differently.

Third, the establishment of science did not support glia research. Glia were not thought to be important, so glia researchers fared poorly in fierce competition for funding. They did not get published in premier journals. I started a new journal, called Neuron Glia Biology, a few years ago with many other scientists to make glia more widely appreciated within science.

It is now understood that glia are extremely important, and have been vastly overlooked. There is no doubt that glia have a special association with neurons. To say we have four kinds of glia is naïve. There are probably as many kinds of glia as there are neurons.

ARF: How do you balance being a scientist and a journalist?

DF: It is hard to balance them both. Science has to work through the scientific method, which means removing the person from the process. You do not want self-promotion, or to have the individual become a factor in the findings. So scientists who interact with the press are not always welcome. But I am stubborn, and I try to do both. After all, public funding supports everything I do. All they ask in return is that we tell them what we did with the money.

Also, a scientist-author has an advantage. We know what is going to happen in our field five years from now, because we are reviewing papers, we are sitting on grant review sessions. While I am at meetings and hearing the latest work that is not even published, I am thinking of how much fun it would be to share this with people at the right time. That is how I was able to have the book be so current.

ARF: What was most interesting as you put this book together?

DF: To find that writing a book is much like doing science, in that the most exciting part of writing the book was the research. You are dealing with data and trying to determine the truth. You have to go to original sources. That meant traveling around the world, going to the laboratories of famous scientists from the 1800s, looking at their notebooks, getting charcoal on my hands from their kymograph recordings.

ARF: How can we use the new understanding of glia to understand disease?

DF: The knowledge of glia is illuminating every aspect of neurological disease from Alzheimer’s to Parkinson’s because glia are the first responders to disease and injury. For example, it turns out that chronic pain involves glia. Microglia and astrocytes respond to injury by releasing inflammatory cytokines, chemokines, and other substances. This is normal in the early stages of pain, a part of the healing process. But in chronic disease, the glia do not get shut off. [Editor’s note: For more information, see Fields, 2010; Fields, 2009.]

Amyotrophic lateral sclerosis is a good example. For years, doctors and neuroscientists studied motor neurons because it was a motor neuron pathology. But if you put the abnormal ALS-associated SOD1 gene in astrocytes or Schwann cells, or even microglia, then mice get the disease. [Editor’s note: See ARF related news story on Lobsiger et al., 2009.]

One of the surprises was that glia would be involved in psychiatric illness. People thought that psychiatric illnesses were problems in thought, but now psychiatric illnesses are thought to be imbalances in neurotransmitters. Astrocytes are the cells that control the levels of neurotransmitters in the synapse. All of our psychiatric treatments, like SSRIs for depression, are drugs that change the level of neurotransmitters.

ARF: Tell us about your research at NIH.

DF: I have always been interested in plasticity. I study how activity regulates the development of the brain. [Editor’s note: See Fields and Nelson, 1992.] The human brain, unlike the brains of lots of animals, develops for the first 25 years of life. That is the key to the success of our species. We develop the brain in the environment we are born into, rather than an environment encoded in our genes. We cheat evolution that way.

If the environment is going to affect the wiring of the brain, then there has to be a change in the genes in the neurons. In our head, our environment is coded in the patterns of neural impulse activity, so patterns of activity must be able to regulate our genes and neurons. Most of my work is done in cell culture, where we grow neurons and stimulate them to fire. We can turn on and turn off genes by making neurons fire in different patterns.

I am interested now in how the oligodendrocytes that form the electrical insulation on axons could be involved in learning. [Editor's note: See ARF related news story on Ishibashi et al., 2006.] Myelination in the human brain continues until you are about 25. If it is just insulation, why wasn’t it done when you were born? Over the past 15 years we have found that electrical activities communicate to oligodendrocytes to make them form more myelin. Once a bare axon gets myelinated, it conducts 50 times faster. That is going to have a big effect on the circuitry in the brain. This is a new aspect of learning. [Editor’s note: See Fields, 2008; Fields, 2010.]

ARF: You do science, write, scuba dive, build guitars, rock climb—how do you fit it all in?

DF: During the day, I’m doing science. At night, while the glue is drying on my guitar, I write. The more I have to do, the more I get done.

ARF: Thank you for this interview.

DF: My pleasure.