Beauty and the Brain: Electrical Stimulation of the Brain Makes You Perceive Faces as More Attractive

Findings may lead to promising ways to treat and study neuropsychiatric disorders

Beauty is in the eye of the beholder, and—as researchers have now shown—in the brain as well.

The researchers, led by scientists at the California Institute of Technology (Caltech), have used a well-known, noninvasive technique to electrically stimulate a specific region deep inside the brain previously thought to be inaccessible. The stimulation, the scientists say, caused volunteers to judge faces as more attractive than before their brains were stimulated.

Being able to effect such behavioral changes means that this electrical stimulation tool could be used to noninvasively manipulate deep regions of the brain—and, therefore, that it could serve as a new approach to study and treat a variety of deep-brain neuropsychiatric disorders, such as Parkinson's disease and schizophrenia, the researchers say.

"This is very exciting because the primary means of inducing these kinds of deep-brain changes to date has been by administering drug treatments," says Vikram Chib, a postdoctoral scholar who led the study, which is being published in the June 11 issue of the journal Translational Psychiatry. "But the problem with drugs is that they're not location-specific—they act on the entire brain." Thus, drugs may carry unwanted side effects or, occasionally, won't work for certain patients—who then may need invasive treatments involving the implantation of electrodes into the brain.

So Chib and his colleagues turned to a technique called transcranial direct-current stimulation (tDCS), which, Chib notes, is cheap, simple, and safe. In this method, an anode and a cathode are placed at two different locations on the scalp. A weak electrical current—which can be powered by a nine-volt battery—runs from the cathode, through the brain, and to the anode. The electrical current is a mere 2 milliamps—10,000 times less than the 20 amps typically available from wall sockets. "All you feel is a little bit of tingling, and some people don't even feel that," he says.

"There have been many studies employing tDCS to affect behavior or change local neural activity," says Shinsuke Shimojo, the Gertrude Baltimore Professor of Experimental Psychology and a coauthor of the paper. For example, the technique has been used to treat depression and to help stroke patients rehabilitate their motor skills. "However, to our knowledge, virtually none of the previous studies actually examined and correlated both behavior and neural activity," he says. These studies also targeted the surface areas of the brain—not much more than a centimeter deep—which were thought to be the physical limit of how far tDCS could reach, Chib adds.

The researchers hypothesized that they could exploit known neural connections and use tDCS to stimulate deeper regions of the brain. In particular, they wanted to access the ventral midbrain—the center of the brain's reward-processing network, and about as deep as you can go. It is thought to be the source of dopamine, a chemical whose deficiency has been linked to many neuropsychiatric disorders.

The ventral midbrain is part of a neural circuit that includes the dorsolateral prefrontal cortex (DLPFC), which is located just above the temples, and the ventromedial prefrontal cortex (VMPFC), which is behind the forehead. Decreasing activity in the DLPFC boosts activity in the VMPFC, which in turn bumps up activity in the ventral midbrain. To manipulate the ventral midbrain, therefore, the researchers decided to try using tDCS to deactivate the DLPFC and activate the VMPFC.

To test their hypothesis, the researchers asked volunteers to judge the attractiveness of groups of faces both before and after the volunteers' brains had been stimulated with tDCS. Judging facial attractiveness is one of the simplest, most primal tasks that can activate the brain's reward network, and difficulty in evaluating faces and recognizing facial emotions is a common symptom of neuropsychiatric disorders. The study participants rated the faces while inside a functional magnetic resonance imaging (fMRI) scanner, which allowed the researchers to evaluate any changes in brain activity caused by the stimulation.

A total of 99 volunteers participated in the tDCS experiment and were divided into six stimulation groups. In the main stimulation group, composed of 19 subjects, the DLPFC was deactivated and the VMPFC activated with a stimulation configuration that the researchers theorized would ultimately activate the ventral midbrain. The other groups were used to test different stimulation configurations. For example, in one group, the placement of the cathode and anode were switched so that the DLPFC was activated and the VMPFC was deactivated—the opposite of the main group. Another was a "sham" group, in which the electrodes were placed on volunteers' heads, but no current was run.

Those in the main group rated the faces presented after stimulation as more attractive than those they saw before stimulation. There were no differences in the ratings from the control groups. This change in ratings in the main group suggests that tDCS is indeed able to activate the ventral midbrain, and that the resulting changes in brain activity in this deep-brain region are associated with changes in the evaluation of attractiveness.

In addition, the fMRI scans revealed that tDCS strengthened the correlation between VMPFC activity and ventral midbrain activity. In other words, stimulation appeared to enhance the neural connectivity between the two brain areas. And for those who showed the strongest connectivity, tDCS led to the biggest change in attractiveness ratings. Taken together, the researchers say these results show that tDCS is causing those shifts in perception by manipulating the ventral midbrain via the DLPFC and VMPFC.

"The fact that we haven't had a way to noninvasively manipulate a functional circuit in the brain has been a fundamental bottleneck in human behavioral neuroscience," Shimojo says. This new work, he adds, represents a big first step in removing that bottleneck.

Using tDCS to study and treat neuropsychiatric disorders hinges on the assumption that the technique directly influences dopamine production in the ventral midbrain, Chib explains. But because fMRI can't directly measure dopamine, this study was unable to make that determination. The next step, then, is to use methods that can—such as positron emission tomography (PET) scans.

More work also needs to be done to see how tDCS may be used for treating disorders and to precisely determine the duration of the stimulation effects—as a rule of thumb, the influence of tDCS lasts for twice the exposure time, Chib says. Future studies will also be needed to see what other behaviors this tDCS method can influence. Ultimately, clinical tests will be needed for medical applications.

In addition to Chib and Shimojo, the other authors of the paper are Kyongsik Yun, a former postdoctoral scholar at Caltech who is now at the Korea Advanced Institute of Science and Technology (KAIST), and Hidehiko Takahashi of the Kyoto University Graduate School of Medicine. The title of the Translational Psychiatry paper is "Noninvasive remote activation of the ventral midbrain by transcranial direct current stimulation of prefrontal cortex." This work was funded by the Exploratory Research for Advanced Technology (ERATO) and CREST programs of the Japan Science and Technology Agency (JST); the Caltech-Tamagawa gCOE (Global Center of Excellence) program; and a Japan-U.S. Brain Research Cooperative Program grant.

Marcus Woo
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Beauty and the Brain
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Keeping Stem Cells Strong

Caltech biologists show that an RNA molecule protects stem cells during inflammation

When infections occur in the body, stem cells in the blood often jump into action by multiplying and differentiating into mature immune cells that can fight off illness. But repeated infections and inflammation can deplete these cell populations, potentially leading to the development of serious blood conditions such as cancer. Now, a team of researchers led by biologists at the California Institute of Technology (Caltech) has found that, in mouse models, the molecule microRNA-146a (miR-146a) acts as a critical regulator and protector of blood-forming stem cells (called hematopoietic stem cells, or HSCs) during chronic inflammation, suggesting that a deficiency of miR-146a may be one important cause of blood cancers and bone marrow failure.

The team came to this conclusion by developing a mouse model that lacks miR-146a. RNA is a polymer structured like DNA, the chemical that makes up our genes. MicroRNAs, as the name implies, are a class of very short RNAs that can interfere with or regulate the activities of particular genes. When subjected to a state of chronic inflammation, mice lacking miR-146a showed a decline in the overall number and quality of their HSCs; normal mice producing the molecule, in contrast, were better able to maintain their levels of HSCs despite long-term inflammation. The researchers' findings are outlined in the May 21 issue of the new journal eLIFE.

"This mouse with genetic deletion of miR-146a is a wonderful model with which to understand chronic-inflammation-driven tumor formation and hematopoietic stem cell biology during chronic inflammation," says Jimmy Zhao, the lead author of the study and an MD/PhD student in the Caltech laboratory of David Baltimore, the Robert Andrews Millikan Professor of Biology. "It was surprising that a single microRNA plays such a crucial role. Deleting it produced a profound and dramatic pathology, which clearly highlights the critical and indispensable function of miR-146a in guarding the quality and longevity of HSCs."

The study findings provide, for the first time, a detailed molecular connection between chronic inflammation, and bone marrow failure and diseases of the blood. These findings could lead to the discovery and development of anti-inflammatory molecules that could be used as therapeutics for blood diseases. In fact, the researchers believe that miR-146a itself may ultimately become a very effective anti-inflammatory molecule, once RNA molecules or mimetics can be delivered more efficiently to the cells of interest.

The new mouse model, Zhao says, also mimics important aspects of human myelodysplastic syndrome (MDS)—a form of pre-leukemia that often causes severe anemia, can require frequent blood transfusions, and usually leads to acute myeloid leukemia. Further study of the model could lead to a better understanding of the condition and therefore potential new treatments for MDS.

"This study speaks to the importance of keeping chronic inflammation in check and provides a good rationale for broad use of safer and more effective anti-inflammatory molecules," says Baltimore, who is a coauthor of the study. "If we can understand what cell types and proteins are critically important in chronic-inflammation-driven tumor formation and stem cell exhaustion, we can potentially design better and safer drugs to intervene."

Funding for the research outlined in the eLIFE paper, titled "MicroRNA-146a acts as a guardian of the quality and longevity of hematopoietic stem cells in mice," was provided by the National Institute of Allergy and Infectious Disease; the National Heart, Lung, and Blood Institute; and the National Cancer Institute. Yvette Garcia-Flores, the lead technician in Baltimore's lab, also contributed to the study along with Dinesh Rao from UCLA and Ryan O'Connell from the University of Utah. eLIFE, a new open-access, high-impact journal, is backed by three of the world's leading funding agencies, the Howard Hughes Medical Institute, the Max Planck Society, and the Wellcome Trust. 

Katie Neith
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Fifty Years of Clearing the Skies

A Milestone in Environmental Science

Ringed by mountains and capped by a temperature inversion that traps bad air, Los Angeles has had bouts of smog since the turn of the 20th century. An outbreak in 1903 rendered the skies so dark that many people mistook it for a solar eclipse. Angelenos might now be living in a state of perpetual midnight—assuming we could live here at all—were it not for the work of Caltech Professor of Bio-organic Chemistry Arie Jan Haagen-Smit. How he did it is told here largely in his own words, excerpted from Caltech's Engineering & Science magazine between 1950 and 1962. (See "Related Links" for the original articles.)

Old timers, which in California means people who have lived here some 25 years, will remember the invigorating atmosphere of Los Angeles, the wonderful view of the mountains, and the towns surrounded by orange groves. Although there were some badly polluted industrial areas, it was possible to ignore them and live in more pleasant locations, especially the valleys . . . Just 20 years ago, the community was disagreeably surprised when the atmosphere was filled with a foreign substance that produced a strong irritation of the eyes. Fortunately, this was a passing interlude which ended with the closing up of a wartime synthetic rubber plant. (November 1962)

Alas, the "interlude" was an illusion. In the years following World War II, visibility often fell to a few blocks. The watery-eyed citizenry established the Los Angeles County Air Pollution Control District (LACAPCD) in 1947, the first such body in the nation. The obvious culprits—smoke-belching power plants, oil refineries, steel mills, and the like—were quickly regulated, yet the problem persisted. Worse, this smog was fundamentally different from air pollution elsewhere—the yellow, sulfur-dioxide-laced smog that killed 20 people in the Pennsylvania steel town of Donora in 1948, for example, or London's infamous pitch-black "pea-soupers," where the burning of low-grade, sulfur-rich coal added soot to the SO2. (The Great Smog of 1952 would carry off some 4,000 souls in four days.) By contrast, L.A.'s smog was brown and had an acrid odor all its own.

Haagen-Smit had honed his detective skills isolating and identifying the trace compounds responsible for the flavors of pineapples and fine wines, and in 1948 he began to turn his attention to smog.

Chemically, the most characteristic aspect of smog is its strong oxidizing action . . . The amount of oxidant can readily be determined through a quantitative measurement of iodine liberated from potassium iodide solution, or of the red color formed in the oxidation of phenolphthalin to the well-known acid-base indicator, phenolphthalein. To demonstrate these effects, it is only necessary to bubble a few liters of smog air through the colorless solutions. (December 1954)

His chief suspect was ozone, a highly reactive form of oxygen widely used as a bleach and a disinfectant. It's easy to make—a spark will suffice—and it's responsible for that crisp "blue" odor produced by an overloaded electric motor. But there was a problem:

During severe smog attacks, ozone concentrations of 0.5 ppm [parts per million], twenty times higher than in [clean] country air, have been measured. From such analyses the quantity of ozone present in the [Los Angeles] basin at that time is calculated to be about 500 tons.

Since ozone is subject to a continuous destruction in competition with its formation, we can estimate that several thousand tons of ozone are formed during a smog day. It is obvious that industrial sources or occasional electrical discharges do not release such tremendous quantities of ozone. (December 1954)

If ozone really was to blame, where was it coming from? An extraordinary challenge lay ahead:

The analysis of air contaminants has some special features, due to the minute amounts present in a large volume of air. The state in which these pollutants are present—as gases, liquids and solid particles of greatly different sizes—presents additional difficulties. The small particles of less than one micron diameter do not settle out, but are in a stable suspension and form so-called aerosols.

The analytical chemist has devoted a great deal of effort to devising methods for the collection of this heterogeneous material. Most of these methods are based on the principle that the particles are given enough speed to collide with each other or with collecting surfaces . . . A sample of Los Angeles' air shows numerous oily droplets of a size smaller than 0.5 micron, as well as crystalline deposits of metals and salts . . . When air is passed through a filter paper, the paper takes on a grey appearance, and extraction with organic solvents gives an oily material. (December 1950)

Haagen-Smit suspected that this oily material, a complex brew of organic acids and other partially oxidized hydrocarbons, was smog's secret ingredient. In 1950, he took a one-year leave of absence from Caltech to prove it, working full-time in a specially equipped lab set up for him by the LACAPCD. By the end of the year, he had done so.

Through investigations initiated at Caltech, we know that the main source of this smog is due to the release of two types of material. One is organic material—mostly hydrocarbons from gasoline—and the other is a mixture of oxides of nitrogen. Each one of these emissions by itself would be hardly noticed. However, in the presence of sunlight, a reaction occurs, resulting in products which give rise to the typical smog symptoms. The photochemical oxidation is initiated by the dissociation of NO2 into NO and atomic oxygen. This reactive oxygen attacks organic material, resulting in the formation of ozone and various oxidation products . . . The oxidation reactions are generally accompanied by haze or aerosol formation, and this combination aggravates the nuisance effects of the individual components of the smog complex. (November 1962)

Professor of Plant Physiology Frits Went was also on the case. Went ran Caltech's Earhart Plant Research Laboratory, which he proudly called the "phytotron," by analogy to the various "trons" operated by particle physicists. (Phyton is the Greek word for plant.) "Caltech's plant physiologists happen to believe that the phytotron is as marvellously complicated as any of the highly-touted 'atom-smashing' machines," Went wrote in E&S in 1949. "[It] is the first laboratory in the world in which plants can be grown under every possible climatic condition. Light, temperature, humidity, gas content of the air, wind, rain, and fog—all these factors can be simultaneously and independently controlled. The laboratory can create Sacramento Valley climate in one room and New England climate in another." Most of Los Angeles was still orchards and fields instead of tract houses, and the smog was hurting the produce. Went, the LACAPCD, and the UC Riverside agricultural station tested five particularly sensitive crops in the phytotron, Haagen-Smit wrote.

The smog indicator plants include spinach, sugar beet, endive, alfalfa and oats. The symptoms on the first three species are mainly silvering or bronzing of the underside of the leaf, whereas alfalfa and oats show bleaching effects. Some fifty compounds possibly present in the air were tested on their ability to cause smog damage—without success. However, when the reaction products of ozone with unsaturated hydrocarbons were tried, typical smog damage resulted. (December 1950)

And yet a third set of experiments was under way. Rubber tires were rotting from the smog at an alarming rate, cracking as they flexed while rolling along the road. Charles E. Bradley, a research associate in biology, turned this distressing development into a cheap and effective analytical tool by cutting rubber bands by the boxful into short segments. The segments—folded double, secured with a twist of wire, and set outside—would start to fall apart almost before one could close the window. "During severe smog initial cracking appears in about four minutes, as compared to an hour or more required on smog-free days, or at night," Haagen-Smit wrote in the December 1954 E&S.

The conclusion that airborne gasoline and nitrogen oxides (another chief constituent of automobile exhaust) were to blame for smog was not well received by the oil refineries, who hired their own expert to prove him wrong. Abe Zarem (MS '40, PhD '44), the manager and chairman of physics research for the Stanford Research Institute, opined that stratospheric ozone seeping down through the inversion layer was to blame. But seeing (or smelling) is believing, so Haagen-Smit fought back by giving public lectures in which he would whip up flasks full of artificial smog before the audience's eyes, which would soon be watering—especially if they were seated in the first few rows. By the end of his talk, the smog would fill the hall, and he became known throughout the Southland as Arie Haagen-Smog.

By 1954, he and Frits Went had carried the day.

[Plant] fumigations with the photochemical oxidation products of gasoline and nitrogen dioxide (NO2) was the basis of one of the most convincing arguments for the control of hydrocarbons by the oil industry. (December 1954)

It probably didn't hurt that an outbreak that October closed schools and shuttered factories for most of the month, and that angry voters were wearing gas masks to protest meetings. By then, there were some two million cars on the road in the metropolitan area, spewing a thousand tons of hydrocarbons daily.

Incomplete combustion of gasoline allows unburned and partially burned fuel to escape from the tailpipe. Seepage of gasoline, even in new cars, past piston rings into the crankcase, is responsible for 'blowby' or crankcase vent losses. Evaporation from carburetor and fuel tank are substantial contributions, especially on hot days. (November 1962)

Haagen-Smit was a founding member of California's Motor Vehicle Pollution Control Board, established in 1960. One of the board's first projects was testing positive crankcase ventilation (PCV) systems, which sucked the blown-by hydrocarbons out of the crankcase and recirculated them through the engine to be burned on the second pass. PCV systems were mandated on all new cars sold in California as of 1963. The blowby problem was thus easily solved—but, as Haagen-Smit noted in that same article, it was only the second-largest source, representing about 30 percent of the escaping hydrocarbons.

The preferred method of control of the tailpipe hydrocarbon emission is a better combustion in the engine itself. (The automobile industry has predicted the appearance of more efficiently burning engines in 1965. It is not known how efficient these will be, nor has it been revealed whether there will be an increase or decrease of oxides of nitrogen.) Other approaches to the control of the tailpipe gases involve completing the combustion in muffler-type afterburners. One type relies on the ignition of gases with a sparkplug or pilot-burner; the second type passes the gases through a catalyst bed which burns the gases at a lower temperature than is possible with the direct-flame burners. (November 1962)

Installing an afterburner in the muffler has some drawbacks, not the least of which is that the notion of tooling around town with an open flame under the floorboards might give some people the willies. Instead, catalytic converters became required equipment on California cars in 1975.

In 1968, the Motor Vehicle Pollution Control Board became the California Air Resources Board, with Haagen-Smit as its chair. He was a member of the 1969 President's Task Force on Air Pollution, and the standards he helped those two bodies develop would eventually be adopted by the Environmental Protection Agency, established in 1970—the year that also saw the first celebration of Earth Day. It was also the year when ozone levels in the Los Angeles basin peaked at 0.58 parts per million, nearly five times in excess of the 0.12 parts per million that the EPA would declare to be safe for human health. This reading even exceeded the 0.5 ppm that Haagen-Smit had measured back in 1954, but it was a triumph nonetheless—the number of cars in L.A. had doubled, yet the smog was little worse than it had always been. That was the year we turned the corner, in fact, and our ozone levels have been dropping ever since—despite the continued influx of cars and people to the region.

Haagen-Smit retired from Caltech in 1971 as the skies began to clear, but continued to lead the fight for clean air until his death in 1977—of lung cancer, ironically, after a lifetime of cigarettes. Today, his intellectual heirs, including professors Richard Flagan, Mitchio Okumura, John Seinfeld, and Paul Wennberg, use analytical instruments descended from ones Haagen-Smit would have recognized and computer models sophisticated beyond his wildest dreams to carry the torch—a clean-burning one, of course—forward.

Douglas Smith
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Caltech Senior Wins Gates Cambridge Scholarship

Catherine Bingchan Xie, a senior bioengineering major and English minor at Caltech, has been selected to receive a Gates Cambridge Scholarship, which will fund her graduate studies at the University of Cambridge for the next academic year. Xie, a Canadian citizen, is one of 51 new international recipients selected from a pool of more than 4,000 applicants based not only on intellectual ability, but also on leadership capacity and a commitment to improving the lives of others.

As a Gates Cambridge Scholar, Xie, 20, will pursue a Master of Philosophy in translational medicine and therapeutics. "The research program and the knowledge that I'm going to gain will provide me with an essential foundation for becoming a physician-scientist, translating research findings in the lab into revolutionary therapies," she says. "I'm really excited to join the Gates Cambridge community and be surrounded by people like me who want to make an impact on other people by taking on important roles and issues in society. I think the energy and enthusiasm of rising toward this common goal will be really invigorating."

Having lived in China, Australia, Canada, and the United States, Xie has been exposed to a variety of cultures—something that she says motivated her to want to become a highly involved leader in a diverse and multicultural society.

As an undergraduate student, Xie has taken full advantage of opportunities to pursue research projects in the laboratory with outstanding scientists. During her freshman year, she began working in the lab of Frances Arnold, the Dick and Barbara Dickinson Professor of Chemical Engineering, Bioengineering and Biochemistry, engineering ways to improve the thermostability of enzymes used to make biofuels. The summer following her sophomore year, Xie joined the lab of C. Garrison Fathman, professor of medicine and chief of the Division of Immunology and Rheumatology at the Stanford School of Medicine, to study a novel transcription factor regulator involved in the pathogenesis of Type I diabetes. When she returned to Caltech, she immediately joined the lab of David Baltimore, the Robert Andrews Millikan Professor of Biology, where she is currently working. There, her research focuses on microRNAs—tiny snippets of RNA that are only about 20 nucleotides long—and the regulatory role they play in the development of leukemia. 

"Catherine is a student with broad interests, an engaging personal style, and great effectiveness," Baltimore says. "She has been a pleasure to have in the laboratory, and I am not surprised that she has won this prestigious scholarship and chosen to broaden her knowledge by focusing on public health issues while she is at Cambridge."

Xie says her ultimate goal in life "is to be able to not only improve our understanding of disease mechanisms, but also to be able to use that understanding to create novel, innovative therapies in order to help people battle their diseases."

Xie's desire to help others was clear during her time at Caltech—she led Caltech Y service trips, during which she and other students helped to rebuild houses for low-income families, assisted in beach and riverbed cleanups, and worked at a homeless shelter. As a freshman, she started the annual Caltech Student Health Fair to make students more aware of the physical, mental, and emotional health resources on campus and throughout the community. She has also served on campus as the vice chair of the Academics and Research Committee and as a member of the Caltech Y Student Executive Committee.

"I'm so excited that Catherine has been chosen to receive this fellowship," says Athena Castro, executive director of the Caltech Y. "I just love her. She's enthusiastic, dedicated, positive, thoughtful, and committed."

In the summer of 2012, Xie broadened her horizons even more when she traveled to Switzerland as a recipient of Caltech's SanPietro Travel Prize. "Catherine demonstrated her ability to adapt quickly and truly engage in another culture on that trip," says Lauren Stolper, director of fellowships advising and study abroad. "She will represent Caltech well as a Gates Cambridge Scholar."

Xie says she is thankful to everyone who has contributed to her experience at Caltech. "My achievements wouldn't have been possible without people giving me opportunities, encouraging me, and providing me with feedback, allowing me to grow as a scientist and as an individual," she says. "Caltech has shown me that intellectual curiosity and passion are vital driving forces behind finding innovative solutions that will have a profound and meaningful impact on solving issues that confront society."

The 51 newly announced international scholars will join 39 new American Gates Cambridge Scholars. The Gates Cambridge Scholarship program was established in 2000 through a donation from the Bill and Melinda Gates Foundation to the University of Cambridge. Xie is the sixth Caltech undergraduate student to receive the fellowship. 

Kimm Fesenmaier
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Developing Our Sense of Smell

Caltech biologists pinpoint the origin of olfactory nerve cells

PASADENA, Calif.—When our noses pick up a scent, whether the aroma of a sweet rose or the sweat of a stranger at the gym, two types of sensory neurons are at work in sensing that odor or pheromone. These sensory neurons are particularly interesting because they are the only neurons in our bodies that regenerate throughout adult life—as some of our olfactory neurons die, they are soon replaced by newborns. Just where those neurons come from in the first place has long perplexed developmental biologists.

Previous hypotheses about the origin of these olfactory nerve cells have given credit to embryonic cells that develop into skin or the central nervous system, where ear and eye sensory neurons, respectively, are thought to originate. But biologists at the California Institute of Technology (Caltech) have now found that neural-crest stem cells—multipotent, migratory cells unique to vertebrates that give rise to many structures in the body such as facial bones and smooth muscle—also play a key role in building olfactory sensory neurons in the nose.

"Olfactory neurons have long been thought to be solely derived from a thickened portion of the ectoderm; our results directly refute that concept," says Marianne Bronner, the Albert Billings Ruddock Professor of Biology at Caltech and corresponding author of a paper published in the journal eLIFE on March 19 that outlines the findings.

The two main types of sensory neurons in the olfactory system are ciliated neurons, which detect volatile scents, and microvillous neurons, which usually sense pheromones. Both of these types are found in the tissue lining the inside of the nasal cavity and transmit sensory information to the central nervous system for processing.

In the new study, the researchers showed that during embryonic development, neural-crest stem cells differentiate into the microvillous neurons, which had long been assumed to arise from the same source as the odor-sensing ciliated neurons. Moreover, they demonstrated that different factors are necessary for the development of these two types of neurons. By eliminating a gene called Sox10, they were able to show that formation of microvillous neurons is blocked whereas ciliated neurons are unaffected.

They made this discovery by studying the development of the olfactory system in zebrafish—a useful model organism for developmental biology studies due to the optical clarity of the free-swimming embryo. Understanding the origins of olfactory neurons and the process of neuron formation is important for developing therapeutic applications for conditions like anosmia, or the inability to smell, says Bronner.

"A key question in developmental biology—the extent of neural-crest stem cell contribution to the olfactory system—has been addressed in our paper by multiple lines of experimentation," says Ankur Saxena, a postdoctoral scholar in Bronner's laboratory and lead author of the study. "Olfactory neurons are unique in their renewal capacity across species, so by learning how they form, we may gain insights into how neurons in general can be induced to differentiate or regenerate. That knowledge, in turn, may provide new avenues for pursuing treatment of neurological disorders or injury in humans."

Next, the researchers will examine what other genes, in addition to Sox10, play a role in the process by which neural-crest stem cells differentiate into microvillous neurons. They also plan to look at whether or not neural-crest cells give rise to new microvillous neurons during olfactory regeneration that happens after the embryonic stage of development.

Funding for the research outlined in the eLIFE paper, "Sox10-dependent neural crest origin of olfactory microvillous neurons in zebrafish," was provided by the National Institutes of Health and the Gordon Ross Postdoctoral Fellowship. Brian N. Peng, a former undergraduate student (BS '12) at Caltech, also contributed to the study. A new open-access, high-impact journal, eLIFE is backed by three of the most prestigious biomedical research funders in the world: the Howard Hughes Medical Institute, the Max Planck Society, and the Wellcome Trust. 

Katie Neith
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Monday, April 1, 2013
Center for Student Services, 3rd Floor, Brennan Conference Room – Center for Student Services

Head TA Network Kick-off Meeting & Happy Hour

The First Genetic-Linkage Map

From the Caltech Archives

One hundred years ago, in 1913, Alfred H. Sturtevant helped lay the foundations of modern biology by mapping the relative location of a series of genes on a chromosome. Chromosomes are the long threads in the cell's nucleus that had been discovered in the 1880s in cells undergoing division; however, their role in the process—if any—was unclear. Sturtevant was a graduate student at Columbia University at the time, studying patterns of heredity in Thomas Hunt Morgan's lab. Morgan would found Caltech's biology department in 1928, bringing Sturtevant with him as a professor.

Plants and animals have been bred to enhance specific traits—the speed of a stallion, or the sweetness of a grape—since the dawn of civilization. And everyone knew that if you were tall, blond, and blue-eyed, the odds were that your kids would be, too. But how these characteristics were passed down from parent to child—or whether they were simply products of one's environment and could be induced by, say, eating more eels—was a mystery, as was the appearance of the occasional redhead in a dark-haired family.

A monk named Gregor Mendel in an abbey in what is now the Czech Republic had in fact divined the secret in the mid-1800s, but his "Experiments on Plant Hybridization," published in 1866 in the Proceedings of the Natural History Society of Brno, did not exactly make a splash in scientific circles. Patiently crossbreeding various strains of pea plants, Mendel had compiled pedigrees for such traits as green pods versus yellow pods as they appeared in some 29,000 plants grown over several generations. He concluded that these characteristics were represented by "factors" that were somehow passed down from each individual to its offspring.

Mendel had trained as a physicist before entering the priesthood, and, as they say, he did the math. Working backward from his tallies of how often each individual trait appeared in every generation, he concluded that every plant carried not one but two copies of each factor, and that they need not be identical. Some factors were dominant—for example, any plant having even a single copy of the green factor would have green pods. Others were recessive—only pea plants with two copies of the yellow factor had yellow pods.

The act of pollination shuffled the factors: each parent contributed only one of its two copies, and there was a 50-50 chance as to which copy it would be. Thus the seeds coming from a pair of plants carrying one green-pod factor and one yellow would contain, in equal number, green-green (resulting in green pods), green-yellow (also resulting in green pods), yellow-green (ditto) and yellow-yellow—a three-to-one ratio of green pods to yellow ones. Mendel also concluded that every factor was inherited independently—whether a pod was yellow or green had no bearing on whether it was lumpy or smooth. The calculations got trickier with each additional factor and successive generation, but the ratios between all the possible outcomes still reduced to simple whole numbers.

Mendel's work was rediscovered at the turn of the 20th century. By then it was known that chromosomes always came in pairs of equal length in body cells. Furthermore, egg cells and sperm cells had only half the usual number of chromosomes—and unpairable ones at that. The potential connection between chromosome counts and Mendel's math dawned on several people—not including Morgan, who was skeptical not only of Mendel but of Darwin and the entire notion of natural selection. "Nature," Morgan wrote in Popular Science Monthly in 1905, "makes new species outright."

Morgan began to change his mind after he started breeding fruit flies in 1909. Their short lives (10 days from egg to adult) and incredible fecundity (you could breed them by the millions, and he did) made them an ideal lab animal for experimental zoology—the recently coined term "genetics" had yet to catch on—and the fact that they took up very little lab space didn't hurt. He kept hundreds of strains, each in its own quart-sized milk bottle stoppered with a sponge to let fresh air in. And, as he was about to discover, it was going to be very handy that the genus Drosophila has only four pairs of chromosomes, versus 23 for humans.

One of these four pairs determined the fly's sex. It was known by then that female flies had two so-called X chromosomes, paired in the usual way. Male flies had only one X chromosome, mismatched with a much shorter Y. Fruit flies normally have red eyes, but in 1910 Morgan discovered a mutant in which the males, and only the males, had white eyes. This could only happen, he reasoned, if the alteration had occurred in the sex chromosome; and if this one trait was physically associated with a specific chromosome, the same was probably true for others.

But as more and more mutations were discovered, it became apparent that Mendel's math wasn't working. Rather than every trait being inherited independently, some of them, such as eye color and body color, tended to get passed down together—but not consistently. In 1911, Morgan proposed that any collection of traits apparently linked to one another must reside on the same chromosome, along which they were arrayed like stations on a railroad line. Chromosome pairs had been observed to twist together during the early stages of egg- and sperm-cell formation, and it was conceivable that pieces of each chromosome might break off and trade places during this intimate embrace. If the breaks occurred at random, the odds of two traits crossing over would be much higher if they lay close to each other.

Which brings us, at long last, to Morgan's grad student Alfred Sturtevant. Sturtevant realized that if a given chromosome was the same length in all flies, and if genes had specific physical locations on it, the "distance" between any two genes should be a fixed number—and one that he could measure by how often they were inherited together. In other words, no matter which milk bottle a batch of flies came from, any pair of mutations would show a consistent crossover percentage from generation to generation. Furthermore, if these "distances" were real, he could use them to work out the genes' relative locations—if the distance between genes A and C was exactly equal to the distances from A to B and B to C, clearly gene B lay between A and C.

Sturtevant was so excited by his idea that, in archetypal Techer fashion, he blew off his homework that night to explore it. With data from tens of thousands of flies at his disposal, he counted how often various traits—as many as three at a time—were inherited together, and calculated the percentages for each batch of flies.  Then, since nobody knew how long a chromosome actually was, he took each 1 percent decline in crossover frequency as equivalent to inserting one unit of distance between the pair of genes in question. He showed his "map" to Morgan the following morning; the impressed professor saw to its prompt publication.

Sturtevant got his PhD the following year and stayed on in what was now known around the world as "the fly room." Morgan moved the lab lock, stock, and milk bottles from Columbia to Caltech in 1928, and in 1933 he became the Institute's second Nobel laureate. Sturtevant came with Morgan as part of the deal, and his maps of genetic linkages remain the gold standard today—although the unit of measure he invented is now, ironically, called the centimorgan. Both men spent the balance of their careers here, ushering in the first golden era of molecular biology.

Douglas Smith
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Mayo Appointed to National Science Board

President Barack Obama has appointed Stephen Mayo, Caltech's William K. Bowes Jr. Foundation Chair of the Division of Biology and Bren Professor of Biology and Chemistry, to the National Science Board, the governing body of the National Science Foundation.

"I'm truly delighted to serve the Obama administration in this capacity and look forward to engaging with the board and the foundation, which play such a critical role in our nation's support of research and education in science and engineering," says Mayo.

Mayo earned his PhD at Caltech in 1987 and has been a member of the faculty since 1991. He served as Caltech's vice provost for research from 2007 to 2010 and has served on the board of directors of the American Association for the Advancement of Science since 2010. Mayo's research focuses on the development of computational approaches to protein engineering—a field that has broad applications ranging from advanced biofuels to human medical therapeutics. His pioneering role in the development of computational protein-design methods was recognized with his election to the National Academy of Sciences in 2004.

The National Science Board is the 25-member policymaking body for the National Science Foundation and advisory body to the president and Congress on science and engineering issues. Anneila Sargent, vice president for student affairs and the Benjamin M. Rosen Professor of Astronomy at Caltech, currently serves as a member of the board, which she joined in 2011. Previous members from Caltech are Barry Barish, the Ronald and Maxine Linde Professor of Physics, Emeritus; the late Lee DuBridge, physicist, former Caltech president, and science advisor to Presidents Harry Truman and Richard Nixon; and the late William Fowler, astrophysicist and Nobel laureate.

Katie Neith
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Sorting Out Stroking Sensations

Caltech biologists find individual neurons in the skin that react to massage

PASADENA, Calif.—The skin is a human being's largest sensory organ, helping to distinguish between a pleasant contact, like a caress, and a negative sensation, like a pinch or a burn. Previous studies have shown that these sensations are carried to the brain by different types of sensory neurons that have nerve endings in the skin. Only a few of those neuron types have been identified, however, and most of those detect painful stimuli. Now biologists at the California Institute of Technology (Caltech) have identified in mice a specific class of skin sensory neurons that reacts to an apparently pleasurable stimulus.

More specifically, the team, led by David J. Anderson, Seymour Benzer Professor of Biology at Caltech, was able to pinpoint individual neurons that were activated by massage-like stroking of the skin. The team's results are outlined in the January 31 issue of the journal Nature.

"We've known a lot about the neurons that detect things that make us hurt or feel pain, but we've known much less about the identity of the neurons that make us feel good when they are stimulated," says Anderson, who is also an investigator with the Howard Hughes Medical Institute. "Generally it's a lot easier to study things that are painful because animals have evolved to become much more sensitive to things that hurt or are fearful than to things that feel good. Showing a positive influence of something on an animal model is not that easy."

In fact, the researchers had to develop new methods and technologies to get their results. First, Sophia Vrontou, a postdoctoral fellow in Anderson's lab and the lead author of the study, developed a line of genetically modified mice that had tags, or molecular markers, on the neurons that the team wanted to study. Then she placed a molecule in this specific population of neurons that fluoresced, or lit up, when the neurons were activated.

"The next step was to figure out a way of recording those flashes of light in those neurons in an intact mouse while stroking and poking its body," says Anderson. "We took advantage of the fact that these sensory neurons are bipolar in the sense that they send one branch into the skin that detects stimuli, and another branch into the spinal cord to relay the message detected in the skin to the brain."

The team obtained the needed data by placing the mouse under a special microscope with very high magnification and recording the level of fluorescent light in the fibers of neurons in the spinal cord as the animal was stroked, poked, tickled, and pinched. Through a painstaking process of applying stimuli to one tiny area of the animal's body at a time, they were able to confirm that certain neurons lit up only when stroked. A different class of neurons, by contrast, was activated by poking or pinching the skin, but not by stroking.

"Massage-like stroking is a stimulus that, if were we to experience it, would feel good to us, but as scientists we can't just assume that because something feels good to us, it has to also feel good to an animal," says Anderson. "So we then had to design an experiment to show that artificially activating just these neurons—without actually stroking the mouse—felt good to the mouse."

The researchers did this by creating a box that contained left, right, and center rooms connected by little doors. The left and right rooms were different enough that a mouse could distinguish them through smell, sight, and touch. In the left room, the mouse received an injection of a drug that selectively activated the neurons shown to detect massage-like stroking. In the room on the right, the mouse received a control injection of saline. After a few sessions in each outer room, the animal was placed in the center, with the doors open to see which room it preferred. It clearly favored the room where the massage-sensitive neurons were activated. According to Anderson, this was the first time anyone has used this type of conditioned place-preference experiment to show that activating a specific population of neurons in the skin can actually make an animal experience a pleasurable or rewarding state—in effect, to "feel good."

The team's findings are significant for several reasons, he says. First, the methods that they developed give scientists who have discovered a new kind of neuron a way to find out what activates that neuron in the skin.

"Since there are probably dozens of different kinds of neurons that innervate the skin, we hope this will advance the field by making it possible to figure out all of the different kinds of neurons that detect various types of stimuli," explains Anderson. The second reason the results are important, he says, "is that now that we know these neurons detect massage-like stimuli, the results raise new sets of questions about which molecules in those neurons help the animal detect stroking but not poking."

The other benefit of their new methods, Anderson says, is that they will allow researchers to, in principle, trace the circuitry from those neurons up into the brain to ask why and how activating these neurons makes the animal feel good, whereas activating other neurons that are literally right next to them in the skin makes the animal feel bad.

"We are now most interested in how these neurons communicate to the brain through circuits," says Anderson. "In other words, what part of the circuit in the brain is responsible for the good feeling that is apparently produced by activating these neurons? It may seem frivolous to be identifying massage neurons in a mouse, but it could be that some good might come out of this down the road."

Allan M. Wong, a senior research fellow in biology at Caltech, and Kristofer K. Rau and Richard Koerber from the University of Pittsburgh were also coauthors on the Nature paper, "Genetic identification of C fibers that detect massage-like stroking of hairy skin in vivo." Funding for this research was provided by the National Institutes of Health, the Human Frontiers Science Program, and the Helen Hay Whitney Foundation.

Katie Neith
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Friday, January 25, 2013

Course Ombudspeople Lunch