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I recently attended an event at Johns Hopkins School of Medicine “Celebrating 200+ Women Professors”. The celebration of these women and their careers inspired me, especially as a “young” woman and an assistant professor. It was also humbling to hear about their successes in spite of the many challenges they faced solely due to their sex.
How does the brain work? It’s a question on a lot of people’s minds these days, especially with the launch of massive new research efforts like the American BRAIN Initiative and the European Human Brain Project. It’s also a systems question because after all, the brain is a key part of the nervous system, like the skull is a key part of the skeletal system or the heart is a key part of the circulatory system. The basic approach to understanding how any system works has been clear since Greek and Roman times two thousand years ago: understand what the system does, make a parts list, describe how each part works, and then determine how the parts interact to carry out the various functions of the system.
Science is based on observing nature and testing resulting hypotheses to understand functional mechanisms. And major progress comes from the most general hypotheses—theoretical frameworks at the systems level: paradigms. Famous examples include Copernicus organizing the sun and planets with the earth rather than the sun at the center, Mendeleev arranging the basic chemical elements of all matter into a periodic table, and Watson and Crick’s model of the molecular basis of heredity—in terms of how the four nucleotide building blocks of DNA are arranged spatially in a double helix.
Systems neuroscience does not have a comparable theoretical framework, leaving it in a pre-Watson and Crick, or maybe even better, a pre-Darwin state of affairs. The solution is simple, obvious, and attainable—but essentially ignored in current “big science” approaches to neuroscience. Watson and Crick’s model of DNA led 50 years later to the sequencing of the human genome. At first, this project was widely criticized as frivolous, but it proved to be seminal in many ways, not the least of which is establishing the scope of the problem—the basic overall organization of the chromosomes—and allowing the relatively fast and cheap assaying of genome-wide expression patterns on a tiny chip. Getting the structural sequence was only the first step, but it was a necessary step, allowing all of functional, mechanistic understanding to follow logically, in a classic hypothesis-driven way.
The analogous solution for neuroscience is figuring out the basic wiring diagram of the nervous system, and this has to start with the connectome, essentially a table of connections between the parts. From this connectome a blueprint of the nervous system can be developed, like the architectural drawings for an office building, the plans for an airliner, or the schematics for a motherboard. The basic circuit diagram is like a skeleton, a basic framework for understanding the function of the nervous system. It is hard to imagine building and fixing a modern skyscraper, airplane, or computer without detailed and accurate schematics—and the same applies to understanding mechanisms underlying brain function and fixing problems scientifically.
Everybody knows that the brain is the most complex object on earth, so a viable strategy for solving the wiring diagram is essential. The approach here is also obvious—start with the simplest level of analysis, and progress to deeper and deeper levels. The simplest level is the wiring diagram between basic parts, and there are about 500 of them in mammals. This is analogous to displaying the airline routes between major cities around the world. The next level is the wiring diagram at the level of neuron types that make up each part—there are probably 2,500 to 5,000 neuron types in mammals. And the next level after that is the wiring diagram between all of the individual nerve cells that make up each of the neuron types—hundreds of millions to billions in mammals. The simplest, most general level can be solved now with current technology in rodents. Why not do it, and develop more efficient technology at the same time—just like the history of the genome project. Developing effective ways to interact between animal connectomes based on histology at cellular resolution and human connectomes based on MRI—and correlating both with genomic information—is the wave of the future. Great progress in diagnosing, treating, and understanding the etiology of nervous system diseases can be expected by correlating the results of genome-wide association studies with connectome-wide association studies.
Headline image credit: Diagram of brain synapses. Image by Allan Ajifo, aboutmodafinil.com. CC BY 2.0 via Wikimedia Commons.
Biologically-produced toxins include some of the most interesting substances in nature. As advanced as the chemical sciences are, nothing beats nature in terms of the wide variety of structures with specific biochemical properties. Toxins are one of the most effective mechanisms of defense or predation, generally used by organisms lacking traits like sheer size, strength, fast speed, agility, the ability to fly, or the capacity of technological intelligence (yes, this last one is us). I find this one of the most fascinating aspects of biology. As I said in the very first paragraph of my PhD dissertation:
“Nature is the best chemist. During the course of evolution, through literally millions of years, a wide variety of organisms have developed substances used for defense against predators, or to become predators themselves. As part of the evolutionary process, chemical structures beneficial for the survival of the organism are conserved; many of these molecules include small organic toxins.”
If you think about it, it is amazing how many different organisms use chemical compounds as a survival strategy. Such compounds represent the difference between survival and death in these organisms. Once we realize the true extent of chemical diversity in nature, it is no wonder that this embarrassment of riches is used by life. For example, plants and microorganisms account for about half a million unique compounds. According to Richard Firn in Nature’s Chemicals, plants alone are estimated to produce about a million tons (!) of chemical compounds every year.
One of the best-known, and paradoxically least understood toxins is called tetrodotoxin (TTX). This is a rather mysterious molecule. It was originally discovered in a species of pufferfish, of fugu fame (a delicacy in Japan) in 1909, but the toxic properties of pufferfish have been known since at least the 1700s. Its mechanism of action entails the blocking of certain ion channels that control neuromuscular function. There is no antidote. TTX is present in quite a few other types of marine organisms, including the blue-ringed octopus, several crab species as well as a variety of worms (including polyclad flatworms), snails and starfish among many others. Remarkably, amphibians like certain frogs and newts also possess TTX. The most likely mechanism through which organisms acquire this toxin seems to be symbiotic bacteria, but this has not been demonstrated in every single case, especially in terrestrial species. To add more complexity to the matter, there are at least twelve “versions” of tetrodotoxin.
Up until very recently, despite the widespread distribution of TTX in nature, it was never observed in any known invertebrate species. Here’s where flatworms come in.
Like many planarians, the land variety displays rather sophisticated “hunting” behaviors. Upon encountering an earthworm, the flatworm performs a maneuver called “capping” where it covers the earthworm’s head region, minimizing its escape behavior, even in individuals significantly larger than the flatworm. In fact, upon capping, the earthworm frequently seems to be paralyzed, which hinted at the presence of a toxin.
These observations ignited the curiosity of Dr. Amber N. Stokes, of the Department of Biology at California State University and collaborators, who hypothesized that the toxin in question was TTX, based on the behavioral response of salamanders that were fed with certain land planarians. In a recent paper, they reported that the planarian toxin seems to be TTX in the two species of land planarians studied, Bipalium adventitium and Bipalium kewense. Their results suggest that these flatworms use tetrodotoxin for both predation and defense. In addition to the documented paralysis-like state that the planarians induced in earthworms, the authors observed that salamanders offered these planarians as food tended to reject them and that in the case of B. adventitium, TTX accumulates in their egg capsules. Research is underway to conclusively demonstrate that tetrodotoxin is the actual toxic agent in these flatworms.
This is just one example of the usefulness of planarians as experimental organisms beyond their traditional use in regeneration and developmental biology research. These fascinating worms are experiencing a “scientific renaissance”, particularly in the areas of pharmacology, toxicology, and the neurosciences. They are ideal, tractable subjects to investigate aspects of these disciplines in an integrated way, as they can be easily examined from the molecular to the behavioral level.
Neuroanatomical Terminology by Larry Swanson supplies the first global, historically documented, hierarchically organized human nervous system parts list. This defined vocabulary accurately and systematically describes every human nervous system structural feature that can be observed with current imaging methods, and provides a framework for describing accurately the nervous system in all animals including invertebrates and vertebrates alike. Just how well do you know your neuroanatomical terminology? Test your knowledge!