Mapping the Other Brain by R. Douglas Fields

09/04/13
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R. Douglas Fields

R. Douglas Fields is a developmental neurobiologist and author of The Other Brain, a popular book about the discovery of brain cells (called glia) that communicate without using electricity.

The World Science Festival Salon “Mapping the Brain: A Grand Challenge” assembled a panel of experts to discuss President Obama’s brain mapping initiative in an open public forum on June 1, 2013. In doing so, the Festival not only succeeded in its mission of sharing science, it became a participant in advancing it. This is evident by a commentary on the brain mapping proposal published in the Sept. 5, 2013 edition of the journal Nature, arguing for the inclusion of non-neuronal brain cells (glia) in the bold initiative to map and monitor connections between neurons in the brain.[1] This opinion also emerged during the panel discussion at the WSF Salon and generated some vigorous discussion.[2]

President Obama’s April 2, 2013 announcement of the Brain Research through Advancing Innovative Technologies (BRAIN) is an inspiring and daunting challenge: to map and monitor electrical activity among all the neurons in the brains of experimental animals and eventually the entire human cerebral cortex. This would be accomplished by massively scaling up present efforts in a “big science” collaboration between government and industry. Modeled after the human genome project or NASA’s race to the moon, the 15 year-long effort would require the development of new technologies to achieve the goal. [3,4]

The neuroscience community in general welcomes the proposal and is reluctant to criticize it. Research on the brain is so important and funding for research is so badly needed. I too strongly endorse the effort to undertake a major expedition to understand how the brain works at a cellular level, and I am grateful that the President of the United States recognizes the importance of this endeavor. The human brain is among the greatest of mysteries, and new treatments for neurological and psychological disorders would relieve enormous human suffering. The scientists who inspired this initiative, many of whom were on the discussion panel in the WSF Salon, are to be congratulated.

There is concern, however, whether the inspirational proposal can achieve its promised goal in terms of curing disease and providing new understanding of mysterious brain functions. Others fear that the estimated $3.8 billion expenditure could drain funds from other research that might generate critical new understanding of brain function and disease. Many are dubious about the experimental approach.

From my perspective, most people seem to think that there is nothing other than neurons in the brain. So it is with the BRAIN proposal. In fact the brain is perhaps the only bodily organ that we attempt to understand while ignoring the majority of cells in it—glia. These are diverse types of brain cells that do not generate electrical impulses. Research on glia is a century behind research on neurons, because glia were ignored by most neuroscientists in their quest to understand electrical signaling between neurons.

Recently neuroscientists have discovered that glia communicate using chemical signaling; by releasing neurotransmitters and detecting them using the same membrane receptors that allow neurons to communicate at synapses. This neurotransmitter signaling mechanism engages glia in the same communication networks used by neurons. By releasing and taking up neurotransmitters (and other signaling molecules), glia can sense electrical activity in neurons, and they can control it. Moreover, glia can monitor communications between neurons at one synapse or groups of synapses, control that communication locally, and then transmit information non-electrically through glial networks to regulate synaptic communication in a different part of the brain-—all of this operating outside the neuronal “connectome” targeted by the BRAIN initiative.

There are many different kinds of glia and they all contribute in unique ways to information processing, neurological, and psychiatric disorders. I highlight some of these in the Nature commentary and have done so in more depth elsewhere. I will not repeat that here, but rather, I wish to call attention to the tremendous opportunity before us.

Now is a pivotal moment in neuroscience. Scientific revolutions often erupt suddenly from a shift in perspective. Just as the startling realization that the Earth is not the center of the universe, it may not be correct to view neurons as the center of brain function. Pioneering neuroscientists are beginning to see the cellular basis of brain function as a partnership between cells that use electricity to communicate rapidly (neurons) and others (glia) that do not. Neither cell functions alone.

Glia have been neglected for three reasons:
(1) Neuroscientists believed and they are taught that all information processing in the brain takes place by electrical communication between neurons communicating across synapses. This is the Neuron Doctrine, conceived by 1906 Nobel Prize winning neuroscientist, Ramòn y Cajal. This doctrine is the foundation upon which all theories of how the brain works at a cellular level rests, but much has changed since the horse and buggy days of 1906. We now know that this doctrine, while a brilliant deduction of major importance, is not entirely correct.

(2) Neuroscientists missed glial communication because they used the wrong tools for the job. Since glia do not communicate using electrical impulses, the probing electrodes neuroscientists used to study neurons were deaf to glial communication. Glial communication was revealed in the 1980s when new methods of seeing the flux of calcium ions in cells became possible by using fluorescent calcium-sensitive dyes. As soon as researchers applied the technique to study brain tissue they were amazed to see waves of calcium flowing through glial networks in response to electrical signals in neurons.

(3) The business aspect of science impeded discovery of “the other brain” (glia). Research that was not perceived as being important did not fare well in competitive grant funding. Similarly, research on glia was not likely to be published in the high-impact journals, because it was not perceived as being important or of “broad interest.” As a consequence few scientists outside specialized circles learned about the new discoveries being made, and those pioneering researchers studying glia often suffered a lack of recognition.

There is nothing sinister about this; it is simply the way science as a collective enterprise works. Those in the audience at the WSF Salon must have appreciated that they were seeing science in action as the panelists probed and questioned the issues. The history of science shows us that these same three factors (preconceptions, tools, the scientific establishment) are often at work against emerging areas of science, and the BRAIN initiative perpetuates all of them. It assumes that neurons and the Neuron Doctrine is how the brain operates at a cellular level. It proposes to develop new techniques to monitor electrical signaling in neurons, which is not what is needed to monitor and map glial signaling. It has been argued that information about glia will emerge as a byproduct of studying neurons, but this thinking is what has perpetuated the comparative ignorance about glia. The concern about including glia in the BRAIN initiative is not a scientific one, but rather the practical worry that if funding is provided to include glial research, there will be less money to map neurons.

This brings into focus the essential question of how best to allocate the estimated $3.8 billion investment in brain research. Exploring neural networks and developing new tools to do so are important goals, but it is not clear that the approach of simply massively scaling up the effort will deliver to the promised benefits. Proponents argue that “emergent” properties will appear from scaling up capacity to reach the ultimate goal of “recording every spike in every neuron.” [3,4] There are two problems with this. While it is certainly possible that new properties of neural network function will emerge if sufficiently large numbers of neurons can be monitored simultaneously, this is by no means assured. Secondly, the public and their representatives in congress are not likely to support such a large project on the basis of the promise that unknown properties will emerge. This is not a sufficiently tangible outcome to win public support.

On a scientific level there are reasons for concern about whether or not the desired results are achievable and if they are achieved, whether the “big data” information obtained would be comprehensible. Unlike sequencing the human genome, where the principles of gene coding and regulation were quite well understood when the project was launched, an engineering approach to record massive amounts of data on neuronal activity and connectivity lacks the same solid foundation. Indeed the assumed result of the BRAIN initiative is that such understanding will emerge from the data. Consider, however, that the connectome of all 302 neurons in the nematode worm C. elegans has been known since the 1980’s and it still presents a conundrum.

To appreciate the magnitude of the proposal, imagine mapping and monitoring all of the conversations among 41,000 spectators in the Washington Nationals Ball Park and making some sense of it. Expand that, as the BRAIN initiative proposes to do with neurons over a decade, to recording conversations from every one of the 638,000 inhabitants of Washington, DC. Would multiplying that capability to monitor the 1.2 million population of Dallas Texas (comparable to the number of neurons in the zebra fish brain) bring greater insight? By 15 years of research the BRAIN initiative foresees expanding this capacity to map and monitor the human cerebral cortex where it would take 32 million years just to count all the synapses at a rate of one per second. [5]

According to White House science advisor Philip Rubin, who participated on the WSF panel discussion, this initial period in the BRAIN initiative is intended to stimulate discussion and debate among scientists and administrators. It is in this spirit and my wish to see it succeed that I offer these suggestions. The public will understand and endorse a major effort to launch an exploration into the unknown regions of the brain to study the cells that are the source of brain cancer and other neurological and psychiatric diseases, and that are beginning to be seen as equal partners with neurons in information processing. This exploration to map “the other brain” must be done together with the proposed studies of neurons, and it cannot be achieved as a byproduct of tracing neurons.

Notes
[1] Fields, R. Douglas (2013) Map the other brain. Nature, Sept. 5 vol 501, p. 25-27.
[2] Sherman, Carl (2013) “World Science Festival: Mapping the Brain, Dana foundation, June 4, 2013, danapress.typepad.com/weblog/2013/06/world-science-festival-mapping-the-brain.html
[3] Alivisatos, A.P. et al., (2012) The brain activity map project and the challenge of functional connectomics. Neuron 74: 970-74
[4] Alivisatos, A.P. et al., (2013) The brain activity map. Science 339: 1284-85.
[5] Edelman, G.E. and Tononi, G. Consciousness (Penguin Press, London, 2000, page 38)