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

Research Update: Wordy Worms and Their Eavesdropping Predators

For over 25 years, Paul Sternberg has been studying worms—how they develop, why they sleep, and, more recently, how they communicate. Now, he has flipped the script a bit by taking a closer look at how predatory fungi may be tapping into worm conversations to gain clues about their whereabouts.

Nematodes, Sternberg's primary worm interest, are found in nearly every corner of the world and are one of the most abundant animals on the planet. Unsurprisingly, they have natural enemies, including numerous types of carnivorous fungi that build traps to catch their prey. Curious to see how nematophagous fungi might sense that a meal is present without the sensory organs—like eyes or noses—that most predators use, Sternberg and Yen-Ping Hsueh, a postdoctoral scholar in biology at Caltech, started with a familiar tool: ascarosides. These are the chemical cues that nematodes use to "talk" to one another.

"If we think about it from an evolutionary perspective, whatever the worms are making that can be sensed by the nematophagous fungi must be very important to the worm—otherwise, it's not worth the risk," explains Hsueh. "I thought that ascarosides perfectly fit this hypothesis."

In order to test their idea, the team first evaluated whether different ascarosides caused one of the most common nematode-trapping fungi species to start making a trap. Indeed, it responded by building sticky, web-like nets called adhesive networks, but only when it was nutrient-deprived. It takes a lot of energy for the fungi to build a trap, so they'll only do it if they are hungry and they sense that prey is nearby. Moreover, this ascaroside-induced response is conserved in three other closely related species. But, the researchers say, each of the four fungal species responded to different sets of ascarosides.

"This fits with the idea that different types of predators might encounter different types of prey in nature, and also raises the possibility that fungi could 'read' the different dialects of each worm type," says Sternberg. "What's cool is that we've shown the ability for a predator to eavesdrop on essential prey communication. The worms have to talk to each other using these chemicals, and the predator is listening in on it—that's how it knows the worms are there."

Sternberg and Hsueh also tested a second type of fungus that uses a constricting ring to trap the worms, but it did not respond to the ascarosides. However, the team says that because they only tested a handful of the chemical cues, it's possible that they simply did not test the right ones for that type of fungus.

"Next, the focus is to really study the molecular mechanism in the fungi—how does a fungus sense the ascarosides, and what are the downstream pathways that induce the trap formation," says Hsueh. "We are also interested in evolutionary question of why we see this ascaroside sensing in some types of fungi but not others."  

In the long run, their findings may help improve methods for pest management. Some of these fungi are used for biocontrol to try and keep nematodes away from certain plant roots. Knowing more about what stimulates the organisms to make traps might allow for the development of better biocontrol preparations, says Sternberg.

The full results of Sternberg and Hsueh's study can be found in the paper, "Nematode-trapping fungi eavesdrop on nematode pheromones," published in the journal Current Biology

Katie Neith
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Social Synchronicity

New Caltech-led research finds a connection between bonding and matched movements

PASADENA, Calif.—Humans have a tendency to spontaneously synchronize their movements. For example, the footsteps of two friends walking together may synchronize, although neither individual is consciously aware that it is happening. Similarly, the clapping hands of an audience will naturally fall into synch. Although this type of synchronous body movement has been observed widely, its neurological mechanism and its role in social interactions remain obscure. In a new study, led by cognitive neuroscientists at the California Institute of Technology (Caltech), researchers found that body-movement synchronization between two participants increases following a short session of cooperative training, suggesting that our ability to synchronize body movements is a measurable indicator of social interaction.

"Our findings may provide a powerful tool for identifying the neural underpinnings of both normal social interactions and impaired social interactions, such as the deficits that are often associated with autism," says Shinsuke Shimojo, Gertrude Baltimore Professor of Experimental Psychology at Caltech and senior author of the study.

Shimojo, along with former postdoctoral scholar Kyongsik Yun, and Katsumi Watanabe, an associate professor at the University of Tokyo, presented their work in a paper published December 11 in Scientific Reports, an online and open-access journal from the Nature Publishing Group.

For their study, the team evaluated the hypothesis that synchronous body movement is the basis for more explicit social interaction by measuring the amount of fingertip movement between two participants who were instructed to extend their arms and point their index fingers toward one another—much like the famous scene in E.T. between the alien and Elliott. They were explicitly instructed to keep their own fingers as stationary as possible while keeping their eyes open. The researchers simultaneously recorded the neuronal activity of each participant using electroencephalography, or EEG, recordings. Their finger positions in space were recorded by a motion-capture system.

The participants repeated the task eight times; the first two rounds were called pretraining sessions and the last two were posttraining sessions. The four sessions in between were the cooperative training sessions, in which one person—a randomly chosen leader—made a sequence of large finger movements, and the other participant was instructed to follow the movements. In the posttraining sessions, finger-movement correlation between the two participants was significantly higher compared to that in the pretraining sessions. In addition, socially and sensorimotor-related brain areas were more synchronized between the brains, but not within the brain, in the posttraining sessions. According to the researchers, this experiment, while simple, is novel in that it allows two participants to interact subconsciously while the amount of movement that could potentially disrupt measurement of the neural signal is minimized.

"The most striking outcome of our study is that not only the body-body synchrony but also the brain-brain synchrony between the two participants increased after a short period of social interaction," says Yun. "This may open new vistas to study the brain-brain interface. It appears that when a cooperative relationship exists, two brains form a loose dynamic system."

The team says this information may be potentially useful for romantic or business partner selection.

"Because we can quantify implicit social bonding between two people using our experimental paradigm, we may be able to suggest a more socially compatible partnership in order to maximize matchmaking success rates, by preexamining body synchrony and its increase during a short cooperative session" explains Yun.

As part of the study, the team also surveyed the subjects to rank certain social personality traits, which they then compared to individual rates of increased body synchrony. For example, they found that the participants who expressed the most social anxiety showed the smallest increase in synchrony after cooperative training, while those who reported low levels of anxiety had the highest increases in synchrony. The researchers plan to further evaluate the nature of the direct causal relationship between synchronous body movement and social bonding. Further studies may explore whether a more complex social interaction, such as singing together or being teamed up in a group game, increases synchronous body movements among the participants.

"We may also apply our experimental protocol to better understand the nature and the neural correlates of social impairment in disorders where social deficits are a common symptom, as in schizophrenia or autism," says Shimojo.

The title of the Scientific Reports paper is "Interpersonal body and neural synchronization as a marker of implicit social interaction." Funding for this research was provided by the Japan Science and Technology Agency's CREST and the Tamagawa-Caltech gCOE (global Center Of Excellence) programs.

Katie Neith
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Social Synchronicity: A Connection Between Bonding and Matched Movements
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Top 12 in 2012

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Top 12 in 2012
Credit: Benjamin Deverman/Caltech

Gene therapy for boosting nerve-cell repair

Caltech scientists have developed a gene therapy that helps the brain replace its nerve-cell-protecting myelin sheaths—and the cells that produce those sheaths—when they are destroyed by diseases like multiple sclerosis and by spinal-cord injuries. Myelin ensures that nerve cells can send signals quickly and efficiently.

Credit: L. Moser and P. M. Bellan, Caltech

Understanding solar flares

By studying jets of plasma in the lab, Caltech researchers discovered a surprising phenomenon that may be important for understanding how solar flares occur and for developing nuclear fusion as an energy source. Solar flares are bursts of energy from the sun that launch chunks of plasma that can damage orbiting satellites and cause the northern and southern lights on Earth.

Coincidence—or physics?

Caltech planetary scientists provided a new explanation for why the "man in the moon" faces Earth. Their research indicates that the "man"—an illusion caused by dark-colored volcanic plains—faces us because of the rate at which the moon's spin rate slowed before becoming locked in its current orientation, even though the odds favored the moon's other, more mountainous side.

Choking when the stakes are high

In studying brain activity and behavior, Caltech biologists and social scientists learned that the more someone is afraid of loss, the worse they will perform on a given task—and that, the more loss-averse they are, the more likely it is that their performance will peak at a level far below their actual capacity.

Credit: NASA/JPL-Caltech

Eyeing the X-ray universe

NASA's NuSTAR telescope, a Caltech-led and -designed mission to explore the high-energy X-ray universe and to uncover the secrets of black holes, of remnants of dead stars, of energetic cosmic explosions, and even of the sun, was launched on June 13. The instrument is the most powerful high-energy X-ray telescope ever developed and will produce images that are 10 times sharper than any that have been taken before at these energies.

Credit: CERN

Uncovering the Higgs Boson

This summer's likely discovery of the long-sought and highly elusive Higgs boson, the fundamental particle that is thought to endow elementary particles with mass, was made possible in part by contributions from a large contingent of Caltech researchers. They have worked on this problem with colleagues around the globe for decades, building experiments, designing detectors to measure particles ever more precisely, and inventing communication systems and data storage and transfer networks to share information among thousands of physicists worldwide.

Credit: Peter Day

Amplifying research

Researchers at Caltech and NASA's Jet Propulsion Laboratory developed a new kind of amplifier that can be used for everything from exploring the cosmos to examining the quantum world. This new device operates at a frequency range more than 10 times wider than that of other similar kinds of devices, can amplify strong signals without distortion, and introduces the lowest amount of unavoidable noise.

Swims like a jellyfish

Caltech bioengineers partnered with researchers at Harvard University to build a freely moving artificial jellyfish from scratch. The researchers fashioned the jellyfish from silicon and muscle cells into what they've dubbed Medusoid; in the lab, the scientists were able to replicate some of the jellyfish's key mechanical functions, such as swimming and creating feeding currents. The work will help improve researchers' understanding of tissues and how they work, and may inform future efforts in tissue engineering and the design of pumps for the human heart.

Credit: NASA/JPL-Caltech

Touchdown confirmed

After more than eight years of planning, about 354 million miles of space travel, and seven minutes of terror, NASA's Mars Science Laboratory successfully landed on the Red Planet on August 5. The roving analytical laboratory, named Curiosity, is now using its 10 scientific instruments and 17 cameras to search Mars for environments that either were once—or are now—habitable.

Credit: Caltech/Michael Hoffmann

Powering toilets for the developing world

Caltech engineers built a solar-powered toilet that can safely dispose of human waste for just five cents per use per day. The toilet design, which won the Bill and Melinda Gates Foundation's Reinventing the Toilet Challenge, uses the sun to power a reactor that breaks down water and human waste into fertilizer and hydrogen. The hydrogen can be stored as energy in hydrogen fuel cells.

Credit: Caltech / Scott Kelberg and Michael Roukes

Weighing molecules

A Caltech-led team of physicists created the first-ever mechanical device that can measure the mass of an individual molecule. The tool could eventually help doctors to diagnose diseases, and will enable scientists to study viruses, examine the molecular machinery of cells, and better measure nanoparticles and air pollution.

Splitting water

This year, two separate Caltech research groups made key advances in the quest to extract hydrogen from water for energy use. In June, a team of chemical engineers devised a nontoxic, noncorrosive way to split water molecules at relatively low temperatures; this method may prove useful in the application of waste heat to hydrogen production. Then, in September, a group of Caltech chemists identified the mechanism by which some water-splitting catalysts work; their findings should light the way toward the development of cheaper and better catalysts.


In 2012, Caltech faculty and students pursued research into just about every aspect of our world and beyond—from understanding human behavior, to exploring other planets, to developing sustainable waste solutions for the developing world.

In other words, 2012 was another year of discovery at Caltech. Here are a dozen research stories, which were among the most widely read and shared articles from

Did we skip your favorite? Connect with Caltech on Facebook to share your pick.

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Brain Control with Light

Watson Lecture Preview

Viviana Gradinaru (BS '05) might one day be getting inside your head—but in a good way. An assistant professor of biology at Caltech, Gradinaru is trying to map out the brain's wiring diagrams. Gradinaru will discuss her work at 8:00 p.m. on Wednesday, December 5, in Caltech's Beckman Auditorium. Admission is free.


Q: What do you do?

A: I'm a neuroscientist. I'm trying to understand the brain by turning nerve cells in specific circuits on or off and seeing what the effects are. This is very difficult with conventional methods, one of which is to put in an electrode and pass a current that stimulates all the cells in the vicinity in a nondiscriminate fashion.

What we do instead is introduce modulators into well-defined sets of cells. These modulators are light-sensitive proteins called opsins, similar to the rhodopsin that's part of the visual system in your eye. Opsins form channels in the cell wall, and when they absorb light, they change shape and allow ions to flow into or out of the cell. So by using different opsins, we can either inhibit or excite neurons in a reversible fashion. Neurons are not naturally responsive to light, so when we light up the brain through a fiber-optic thread, we know exactly what cells we are affecting. We use genetic engineering to introduce our optical switches into different cell types. It's almost like giving ZIP codes to the opsins to tell them exactly where to go.


Q: How did you get into this line of work?

A: When I was an undergraduate here at Caltech, I did a very extensive research project in the lab of professor Paul Patterson. That was where I fell in love with neuroscience. It started as a SURF [Summer Undergraduate Research Fellowship] project, and I ended up staying in his lab until I graduated.

It so happens that I was working on a motor-disorder project—on Huntington's disorder—trying to understand what causes the disease. I was working on protein aggregation in cultured cells, because protein aggregation was a known phenomenon in degenerated nerve-cells in Huntington's disorder. However, I could see how remote it was from the real thing. Working in a dish. And I felt, "we should be doing this in the real thing." But the tools were not available.

When I moved to Stanford for my PhD work, there was this new lab just starting. Professor Deisseroth started the same year I did, and his lab developed this technology and also coined the name optogenetics for it. I wanted to look at the circuits involved in motor behavior, so I joined his lab to work on Parkinson's disorder. However, the technology was rather early, and I ended up spending a lot of time perfecting it before I could probe the circuits. But it was well worth it: I learned the value of making your own tools.


Q: What does this tell us that we can apply to people?

A: We can find out more about the circuitry underlying a defined disease, and by understanding the circuitry, we have a better chance to tackle the disease itself. Parkinson's is an interesting example. A very good therapy for Parkinson's after drug therapy stops working is to implant electrodes in the motor centers of the brain. Zapping those brain cells at 100 Hertz—a very high frequency—takes care of the tremor and lets people walk again, which is rather miraculous. It works very well, but we don't understand why it works, because electrical stimulation is nonspecific. We don't know what circuits are being affected. Optogenetics can help here, as a tool to generate information about both the healthy brain and the diseased brain.

Douglas Smith
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Watson Lecture: "Brain Control with Light"
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An Eye for Science: In the Lab of Markus Meister

Take one look around Markus Meister's new lab and office space on the top floor of the Beckman Behavioral Biology building, and you can tell that he has an eye for detail. Curving, luminescent walls change color every few seconds, wrapping around lab space and giving a warm glow to the open, airy offices that line the east wall. A giant picture of neurons serves as wallpaper, and a column is wrapped in an image from the inside of a retina. And while he may have picked up some tips from his architect wife to help direct the design of his lab, Meister is the true visionary—a biologist studying the details of the eye.

"Since we study the visual system, light is a natural interest for me," says Meister, of the lab he helped plan before joining the Caltech faculty in July. "The architecture team responded to this in so many creative ways. They even installed windows inside the lab space, so that researchers at the bench could see straight through the offices to the nature outside."

Exactly how our eyes process those images of the world around us forms the basis of Meister's research. In particular, he investigates the circuits of nerve cells in the retina—a light-sensitive tissue that lines the inner surface of your eyeball and essentially captures images as they come in through the cornea and lens at the front of your eye. A traditional view of the retina is that it acts like the film in a camera, simply absorbing light and then sending a signal directly to the brain about the image you are viewing.

But Meister, who earned his PhD at Caltech in 1987 and was the Tarr Professor of Molecular and Cellular Biology at Harvard before moving back west, sees things a bit differently.

"There is a lot of preprocessing that occurs in the retina, so the signal that gets sent to the brain ultimately is quite different from the raw image that is projected onto the retina by the lens in your eye," he says. "And it's not just one kind of processing. There are on the order of 20 different ways in which the retina manipulates a raw image and then sends those results onto the brain through the optic nerve. An ongoing puzzle is trying to figure out how that is possible with the limited circuitry that exists in the retina."

Meister and his lab are dedicated to finding new clues to help decode that puzzle. In a recent study, published in Nature Neuroscience, he and Hiroki Asari, a postdoctoral scholar in biology at Caltech, studied the connections between particular cells within the retina. Their specific discovery, he explains, has to do with the associations between bipolar cells, which are the neurons in the middle of the retina, and ganglion cells, which are the very last neurons in the retina that send signals to the brain. What they found is that the connections between these bipolar cells and ganglion cells are much more diverse than had been expected.

"Each upstream bipolar cell can make different neural circuits to do particular kinds of computations before it sends signals to ganglion cells," says Asari, who began his postdoctoral work at Harvard and moved to Caltech with the Meister lab.

The team was also able to show that in many cases, the processing of information in the retina involves amacrine cells, a type of cell in the eye that seems to be involved in fine-tuning the properties of individual bipolar cell actions.

"It's a little bit like electronics, where you have a transistor—one wire controlling the connection between two other wires—that is absolutely central to everything," says Meister. "In a way, this connection between the amacrine cells and the bipolar cell and the ganglion cell looks a little bit like a transistor, in that the amacrine cell can control how the signal flows from the bipolar to the ganglion cell. That's an analogy that I think will help us understand the intricacy of the signal flow in the retina. A goal that we have is to ultimately understand these neural circuits in the same way that we understand electronic circuits."

The next step in this particular line of research is to figure out exactly where the amacrine cells are making their impact on bipolar cells. They believe most of the action happens at the synapses, the connection points between the cells. Studying this area requires new technology to get a good look at the tiny connectors. Luckily, Meister's new lab includes an in-house shop room—complete with a milling machine, a band saw, and other power tools needed to build things like microscopes.

"In this lab, we're doing things on many levels—from the giant milling machine all the way down to measurements on the micron scale," says Meister.

He also plans to expand his research focus. The team has started to study the visual behavior of mice, evaluating, for example, the kinds of innate reactions—those that don't require any other knowledge about the environment—they have to certain visual stimuli. Ultimately, the researchers would like to know which of the pathways that come out of the retina control which behaviors, and if they can find a link between the processing of vision that occurs early in the eye and how the animal functions in its environment using its visual system.

"In my new lab at Caltech, I'm trying to branch out further into the visual system to leverage the understanding we have about the front end—namely processing in the retina—to better understand the different actions that occur in the brain, all the way to certain behaviors of the animal that are based on visual stimuli," he says.

Meister says that he's also excited to get back into an environment that's more focused on math, physics, and engineering—something he hopes to take advantage of at both the faculty/colleague level and the student level.

"Our research subject is one that I feel connects me with so many different areas of science—from molecular genetics to theoretical physics," he explains. "You can rely on a wide range of collaborators and people who are interested in different aspects of the subject. To me, that's been the most satisfying part of my career. I have collaborative projects with neurosurgeons, a theoretical physicist who develops models of visual processing, a particle physicist who builds miniature detector electronics, a molecular genetics expert. These interactions really keep you broadly connected."

And he's hoping to connect to even more people now that he's settled in his Beckman Behavioral Biology lab—even if it's just for a friendly visit.

"I know we're in a remote corner of the building at the north end of the top floor, but we try to keep our door open at all times," says Meister. "There are only five people in the lab right now, and it gets kind of lonely. We're going to build the group up, but in the meantime it would be nice if people came to visit us."

Katie Neith
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A Fresh Look at Psychiatric Drugs

Caltech researchers propose a new approach to understanding common treatments

Drugs for psychiatric disorders such as depression and schizophrenia often require weeks to take full effect. "What takes so long?" has formed one of psychiatry's most stubborn mysteries. Now a fresh look at previous research on quite a different drug—nicotine—is providing answers. The new ideas may point the way toward new generations of psychiatric drugs that work faster and better.

For several years, Henry Lester, Bren Professor of Biology at Caltech, and his colleagues have worked to understand nicotine addiction by repeatedly exposing nerve cells to the drug and studying the effects. At first glance, it's a simple story: nicotine binds to, and activates, specific nicotine receptors on the surface of nerve cells within a few seconds of being inhaled. But nicotine addiction develops over weeks or months; and so the Caltech team wanted to know what changes in the nerve cell during that time, hidden from view.

The story that developed is that nicotine infiltrates deep into the cell, entering a protein-making structure called the endoplasmic reticulum and increasing its output of the same nicotine receptors. These receptors then travel to the cell's surface. In other words, nicotine acts "inside out," directing actions that ultimately fuel and support the body's addiction to nicotine.

"That nicotine works 'inside out' was a surprise a few years ago," says Lester. "We originally thought that nicotine acted only from the outside in, and that a cascade of effects trickled down to the endoplasmic reticulum and the cell's nucleus, slowly changing their function."

In a new research review paper, published in Biological Psychiatry, Lester—along with senior research fellow Julie M. Miwa and postdoctoral scholar Rahul Srinivasan—proposes that psychiatric medications may work in the same "inside-out" fashion—and that this process explains how it takes weeks rather than hours or days for patients to feel the full effect of such drugs.

"We've known what happens within minutes and hours after a person takes Prozac, for example," explains Lester. "The drug binds to serotonin uptake proteins on the cell surface, and prevents the neurotransmitter serotonin from being reabsorbed by the cell. That's why we call Prozac a selective serotonin reuptake inhibitor, or SSRI." While the new hypothesis preserves that idea, it also presents several arguments for the idea that the drugs also enter into the bodies of the nerve cells themselves.

There, the drugs would enter the endoplasmic reticulum similarly to nicotine and then bind to the serotonin uptake proteins as they are being synthesized. The result, Lester hypothesizes, is a collection of events within neurons that his team calls "pharmacological chaperoning, matchmaking, escorting, and abduction." These actions—such as providing more stability for various proteins—could improve the function of those cells, leading to therapeutic effects in the patient. But those beneficial effects would occur only after the nerve cells have had time to make their intracellular changes and to transport those changes to the ends of axons and dendrites.

"These 'inside-out' hypotheses explain two previously mysterious actions," says Lester. "On the one hand, the ideas explain the long time required for the beneficial actions of SSRIs and antischizophrenic drugs. But on the other hand, newer, and very experimental, antidepressants act within hours. Binding within the endoplasmic reticulum of dendrites, rather than near the nucleus, might underlie those actions."

Lester and his colleagues first became interested in nicotine's effects on neural disorders because of a striking statistic: a long-term tobacco user has a roughly twofold lower chance of developing Parkinson's disease. Because there is no medical justification for using tobacco, Lester's group wanted more information about this inadvertent beneficial action of nicotine. They knew that stresses on the endoplasmic reticulum, if continued for years, could harm a cell. Earlier this year, they reported that nicotine's "inside-out" action appears to reduce endoplasmic reticulum stress, which could prevent or forestall the onset of Parkinson's disease.

Lester hopes to test the details of "inside-out" hypotheses for psychiatric medication. First steps would include investigating the extent to which psychiatric drugs enter cells and bind to their nascent receptors in the endoplasmic reticulum. The major challenge is to discover which other proteins and genes, in addition to the targets, participate in "matchmaking, escorting, and abduction."

"Present-day psychiatric drugs have a lot of room for improvement," says Lester. "Systematic research to produce better psychiatric drugs has been hampered by our ignorance of how they work. If the hypotheses are proven and the intermediate steps clarified, it may become possible to generate better medications."


Caltech Communications
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