15 for 2015: The Year in Research News at Caltech

The year 2015 proved to be another groundbreaking year for research at Caltech. From seeing quantum motion, to reconfiguring jellyfish limbs, to measuring stellar magnetic fields, researchers continued to ask and answer the deepest scientific questions.

In case you missed any of them, here are 15 stories highlighting a few of the discoveries, methods, and technologies that came to life at Caltech in 2015.

 

 

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Here are 15 stories highlighting a few of the discoveries, methods, and technologies that came to life at Caltech in 2015.

15 for 2015: The Year in Research News at Caltech

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Credit: K.Batygin/Caltech

New Research Suggests Solar System May Have Once Harbored Super-Earths

Thanks to recent surveys of exoplanets—planets in solar systems other than our own—we know that most planetary systems typically have one or more super-Earths (planets that are substantially more massive than Earth but less massive than Neptune) orbiting closer to their suns than Mercury does. In March, researchers showed that our own solar system may have once had these super-Earths, but they were destroyed by Jupiter's inward and outward migration through the solar system. This migration would have gravitationally flung small planetesimals through the solar system, setting off chains of collisions that would push any interior planets into the sun.
Credit: Lance Hayashida/Caltech and the Hoelz Laboratory/Caltech

Caltech Biochemists Shed Light on Cellular Mystery

The nuclear pore complex (NPC) is an intricate portal linking the cytoplasm of a cell to its nucleus. It is made up of many copies of about 34 different proteins. Around 2,000 NPCs are embedded in the nuclear envelope of a single human cell and each NPC shuttles hundreds of macromolecules of different shapes and sizes between the cytoplasm and nucleus. In February, Caltech biochemists determined the structure of a significant portion of the NPC called the outer rings; in August, the same group solved the structure of the pore's inner ring. Understanding the structure of the NPC could lead to new classes of cancer drugs as well as antiviral medicines.
Credit: iStockphoto

Research Suggests Brain's Melatonin May Trigger Sleep

For decades, supplemental melatonin has been sold over the counter as a sleep aid despite the absence of scientific evidence proving its effectiveness. Few studies have investigated melatonin produced naturally in the human body. This March, Caltech researchers studying zebrafish—animals that, like humans, are awake during the day and asleep at night—determined that the melatonin hormone does help the body fall asleep and stay asleep. Specifically, they found that zebrafish larvae that could not produce melatonin slept for only half as long as normal larvae.
Credit: Gregg Hallinan/Caltech

Advances in Radio Astronomy

In May, a new radio telescope array called the Owens Valley Long Wavelength Array (OV-LWA) saw its first light. Developed by a consortium led by Caltech, the OV-LWA has the ability to image simultaneously the entire sky at radio wavelengths with unmatched speed, helping astronomers to search for objects and phenomena that pulse, flicker, flare, or explode.

In July, Caltech researchers used both radio and optical telescopes to observe a brown dwarf located 20 light-years away and found that these so-called failed stars host powerful auroras near their magnetic poles.
Credit: Michael Abrams and Ty Basinger

Injured Jellyfish Seek to Regain Symmetry

Some kinds of animals can regrow lost limbs and body parts, but moon jellyfish have a different strategy. In June, Caltech researchers reported that the star-shaped eight-armed moon jellyfish rearranges itself when injured to maintain symmetry. It is hypothesized that the rearrangement helps to preserve the jellyfish's propulsion mechanism.
Credit: NASA/JPL-Caltech

Geologists Characterize Nepal Earthquake

In April, a magnitude 7.8 earthquake rocked Nepal. While the damage was extensive, it was not as severe as many geologists predicted. This year, a Caltech team of geologists used satellite radar imaging data and measurements from seismic instruments in Nepal to create models of fault rupture and ground movement. They found that the quake ruptured only a small fraction of the "locked" tectonic plate and that there is still the potential for the locked portion to produce a large earthquake.
Credit: Caltech/JPL

New Polymer Creates Safer Fuels

Plane crashes cause devastating damage, but this damage is often exacerbated by the highly explosive nature of jet fuel. This October, researchers at Caltech and JPL discovered a polymeric fuel additive that can reduce the intensity of postimpact explosions that occur during accidents and crashes. Preliminary results show that the additive can provide this benefit without adversely affecting fuel performance. The polymer works by inhibiting "misting"—the process that causes fuel to rapidly disperse and easily catch fire—under crash conditions.
Credit: Spencer Kellis/Caltech

Controlling a Robotic Arm with a Patient's Intentions

When you reach for a glass of water, you do not consciously think about moving your arm muscles or grasping with your fingers—you think about the goal of the movement. This May, by implanting neural prosthetic devices into the posterior parietal cortex (PCC)—the region of the brain that governs intentions for movement—rather than the motor cortex, which controls movement, Caltech researchers enabled a paralyzed patient to more smoothly and naturally control a prosthetic limb. In November, the researchers showed that there are individual neurons in the PPC that encode for entire hand shapes, such as those used for grasping or gesturing.

 

Caltech Scientists Develop Cool Process to Make Better Graphene

Graphene is an ultrastrong and conductive material made of a single layer of carbon atoms. While it is a promising material for scientific and engineering advances, manufacturing it on an industrially relevant scale has proven to be impractical, requiring temperatures of around 1,800 degrees Fahrenheit and long periods of time. A new technique invented at Caltech allows the speedy production of graphene—in just a few minutes—at room temperatures. The technique also produces graphene that is stronger, smoother, and more electrically conductive than normally produced synthetic graphene.
Credit: Rafael A. García (SAp CEA), Kyle Augustson (HAO), Jim Fuller (Caltech) & Gabriel Pérez (SMM, IAC), Photograph from AIA/SDO

Astronomers Peer Inside Stars, Finding Giant Magnets

Before this October, astronomers have only been able to study the magnetic fields of stars on the stellar surfaces. Now, using a technique called asteroseismology, scientists were able to probe the fusion-powered hearts of dozens of red giants (stars that are evolved versions of our sun) to calculate the magnetic field strengths inside those stars. They found that the internal magnetic fields of the red giants were as much as 10 million times stronger than Earth's magnetic field. Magnetic fields play a key role in the interior rotation rate of stars, which has a dramatic effect on how the stars evolve.
Credit: Chan Lei and Keith Schwab/Caltech

Seeing Quantum Motion

To the casual observer, an object at rest is just that—at rest, motionless. But on the subatomic scale, the object is most certainly in motion—quantum mechanical motion. Quantum motion, or noise, is ever-present in nature, and in August, Caltech researchers discovered how to observe and manipulate that motion in a small device. By creating what they called a "quantum squeezed state," they were able to periodically reduce the quantum fluctuations of the device. The ability to control quantum noise could one day be used to improve the precision of very sensitive measurements.
Credit: Ali Hajimiri/Caltech

New Camera Chip Provides Superfine 3-D Resolution

3-D printing can produce a wide array of objects in relatively little time, but first the printer needs to have a blueprint of what to print. The blueprints are provided by 3-D cameras, which scan objects and create models for the printer. Caltech researchers have now developed a 3-D camera that produces the highest depth-measurement accuracy of any similar device, allowing it to deliver replicas of an object to be 3-D printed within microns of similarity to the original object. In addition, the camera, known as a nanophotonic coherent imager, is inexpensive and small.
Credit: Image provided courtesy of Joint Center for Artificial Photosynthesis; artwork by Darius Siwek.

One Step Closer to Artificial Photosynthesis and 'Solar Fuels'

Plants are masters of photosynthesis—the process of turning carbon dioxide, sunlight, and water into oxygen and sugar. Inspired by this natural and energy-efficient process, Caltech researchers have created an "artificial leaf" that takes in CO2, sunlight, and water to produce hydrogen fuels. This solar-powered system, one researcher says, shatters all of the combined safety, performance, and stability records for artificial leaf technology by factors of 5 to 10 or more.
Credit: Santiago Lombeyda and Robin Betz

Potassium Salt Outperforms Precious Metals As a Catalyst

Rare precious metals have been the standard catalyst for the formation of carbon-silicon bonds, a process crucial to the synthesis of a host of products from new medicines to advanced materials. However, they are expensive, inefficient, and produce toxic waste byproducts. This February, Caltech researchers discovered a much more sustainable catalyst in the form of a simple potassium salt that is one of the most abundant metals on Earth and thousands of times less expensive than other commonly used catalysts. In addition, the potassium salt is much more effective at running challenging chemical reactions than state-of-the-art precious metal complexes.
Credit: Qi Zhao/National University of Singapore

Probing the Mysterious Perceptual World of Autism

The way in which people with autism spectrum disorder (ASD) perceive the world is unique. It has been a long-standing belief that people with ASD often miss facial cues, contributing to impaired social interaction. In a study published in October, Caltech researchers showed 700 images to 39 subjects and found that people with ASD pay closer attention to simple edges and patterns in images than to the faces of people. The study also found that subjects were strongly attracted to the center of images—regardless of what was placed there—and to differences in color and contrast rather than facial features. These findings may help doctors diagnose and more effectively treat the different forms of autism.
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The year 2015 proved to be another groundbreaking year for research at Caltech. From seeing quantum motion, to reconfiguring jellyfish limbs, to measuring stellar magnetic fields, researchers continued to ask and answer the deepest scientific questions.

In case you missed any of them, here are 15 stories highlighting a few of the discoveries, methods, and technologies that came to life at Caltech in 2015.

Written by Lori Dajose

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Unlocking the Chemistry of Life

In just the span of an average lifetime, science has made leaps and bounds in our understanding of the human genome and its role in heredity and health—from the first insights about DNA structure in the 1950s to the rapid, inexpensive sequencing technologies of today. However, the 20,000 genes of the human genome are more than DNA; they also encode proteins to carry out the countless functions that are key to our existence. And we know much less about how this collection of proteins supports the essential functions of life.

In order to understand the role each of these proteins plays in human health—and what goes wrong when disease occurs—biologists need to figure out what these proteins are and how they function. Several decades ago, biologists realized that to answer these questions on the scale of the thousands of proteins in the human body, they would have to leave the comfort of their own discipline to get some help from a standard analytical-chemistry technique: mass spectrometry. Since 2006, Caltech's Proteome Exploration Laboratory (PEL) has been building on this approach to bridge the gap between biology and chemistry, in the process unlocking important insights about how the human body works.

Scientists can easily sequence an entire genome in just a day or two, but sequencing a proteome—all of the proteins encoded by a genome—is a much greater challenge says Ray Deshaies, protein biologist and founder of the PEL. "One challenge is the amount of protein. If you want to sequence a person's DNA from a few of their cheek cells, you first amplify—or make copies of—the DNA so that you'll have a lot of it to analyze. However, there is no such thing as protein amplification," Deshaies says. "The number of protein molecules in the cells that you have is the number that you have, so you must use a very sensitive technique to identify those very few molecules."

The best means available for doing this today is called shotgun mass spectrometry, Deshaies says. In general, mass spectrometry allows researchers to identify the amount and types of molecules that are present in a biological sample by separating and analyzing the molecules as gas ions, based on mass and charge; shotgun mass spectrometry—a combination of several techniques—applies this separation process specifically to digested, broken-down proteins, allowing researchers to identify the types and amounts of proteins that are present in a heterogeneous mixture.

"Up until this technique was invented, people had to take a mixture of proteins, run a current through a polyacrylamide gel to separate the proteins by size, stain the proteins, and then physically cut the stained bands out of the gel to have each individual protein species sequenced," says Deshaies. "But mass spectrometry technology has gotten so good that we can now cast a broader net by sequencing everything, then use data analysis to figure out what specific information is of interest after the dust settles down."

For more about the PEL, visit E&S+.

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Caltech has an advantage in the quest to decipher details of the human proteome—the proteins encoded by the human genome.
Tuesday, December 15, 2015
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New Horizons in Developmental Biology

Popping Microbubbles Help Focus Light Inside the Body

A new technique developed at Caltech that uses gas-filled microbubbles for focusing light inside tissue could one day provide doctors with a minimally invasive way of destroying tumors with lasers, and lead to improved diagnostic medical imaging.

The primary challenge with focusing light inside the body is that biological tissue is optically opaque. Unlike transparent glass, the cells and proteins that make up tissue scatter and absorb light. "Our tissues behave very much like dense fog as far as light is concerned," says Changhuei Yang, professor of electrical engineering, bioengineering, and medical engineering. "Just like we cannot focus a car's headlight through fog, scientists have always had difficulty focusing light through tissues."

To get around this problem, Yang and his team turned to microbubbles, commonly used in medicine to enhance contrast in ultrasound imaging.

The gas-filled microbubbles are encapsulated by thin protein shells and have an acoustic refractive index—a property that affects how sound waves propagate through a medium—different from that of living tissue. As a result, they respond differently to sound waves. "You can use ultrasound to make microbubbles rapidly contract and expand, and this vibration helps distinguish them from surrounding tissue because it causes them to reflect sound waves more effectively than biological tissue," says Haowen Ruan, a postdoctoral scholar in Yang's lab.

In addition, the optical refractive index of microbubbles is not the same as that of biological tissue. The optical refractive index is a measure of how much light rays bend when transitioning from one medium (a liquid, for example) to another (a gas).

Yang, Ruan, and graduate student Mooseok Jang developed a novel technique called time-reversed ultrasound microbubble encoded (TRUME) optical focusing that utilizes the mismatch between the acoustic and optical refractive indexes of microbubbles and tissue to focus light inside the body. First, microbubbles injected into tissue are ruptured with ultrasound waves. By measuring the difference in light transmission before and after such an event, the Caltech researchers can modify the wavefront of a laser beam so that it is focuses on the original locations of the microbubbles. The result, Yang explains, "is as if you're searching for someone in a dark field, and suddenly the person lets off a flare. For a brief moment, the person is illuminated and you can home in on their location."

In a new study, published online November 24, 2015, in the journal Nature Communications, the team showed that their TRUME technique could be used as an effective "guidestar" to focus laser beams on specific locations in a biological tissue. A single, well-placed microbubble was enough to successfully focus the laser; multiple popping bubbles located within the general vicinity of a target functioned as a map for the light.

"Each popping event serves as a road map for the twisting light trajectories through the tissue," Yang says. "We can use that road map to shape light in such a way that it will converge where the bubbles burst."

If TRUME is shown to work effectively inside living tissue—without, for example, any negative effects from the bursting microbubbles—it could enable a range of research and medical applications. For example, by combining the microbubbles with an antibody probe engineered to seek out biomarkers associated with cancer, doctors could target and then destroy tumors deep inside the body or detect malignant growths much sooner.

"Ultrasound and X-ray techniques can only detect cancer after it forms a mass," Yang says. "But with optical focusing, you could catch cancerous cells while they are undergoing biochemical changes but before they undergo morphological changes."

The technique could take the place of other of diagnostic screening methods. For instance, it could be used to measure the concentrations of a protein called bilirubin in infants to determine their risk for jaundice. "Currently, this procedure requires a blood draw, but with TRUME, we could shine a light into an infant's body and look for the unique absorption signature of the bilirubin molecule," Ruan says.

In combination with existing techniques that allow scientists to activate individual neurons in lab animals using light, TRUME could help neuroscientists better understand how the brain works. "Currently, neuroscientists are confined to superficial layers of the brain," Yang says. "But our method of optical focusing could allow for a minimally invasive way of probing deeper regions of the brain."

The paper is entitled "Optical focusing inside scattering media with time-reversed ultrasound microbubble encoded (TRUME) light." Support for the research was provided by the National Institutes of Health, the National Institutes of Health BRAIN Initiative, and a GIST-Caltech Collaborative Research Proposal.

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A new technique could one day provide doctors with a minimally invasive way of destroying tumors with lasers, and lead to improved diagnostic medical imaging.

Two Caltech Faculty Inducted into the AAAS

Erik Winfree (PhD '98) and Jay R. Winkler (PhD '84) have been elected as Fellows of the American Association for the Advancement of Science (AAAS). Winfree, a professor of computer science, computation and neural systems, and bioengineering, was recognized by the AAAS for his "foundational contributions to biomolecular computing and molecular programming." Winkler is a faculty associate and lecturer in chemistry in the Division of Chemistry and Chemical Engineering, as well as the director of the Beckman Institute Laser Resource Center. He was elected for "distinguished contributions to the field of electron transfer chemistry and the development of its applications in biology, materials science, and solar energy."

Winfree's research with biological computing aims to "coax DNA into performing algorithmic tricks," he says. An algorithm is a collection of mechanistic rules—information—that directs the creation and organization of structure and behavior. In biology, information in DNA can be likened to an algorithm: it encodes instructions for biochemical networks, body plans, and brain architectures, and thus produces complex life. The Winfree group is developing molecular engineering methods that exploit the same principles as those used by biology: they study theoretical models of computation based on realistic molecular biochemistry, write software for molecular system design and analysis, and experimentally synthesize promising systems in the laboratory using DNA nanotechnology.

"We are seeking to create a kind of molecular programming language: a set of elementary components and methods for combining them into complex systems that involve self-assembled structures and dynamical behaviors," Winfree says. "DNA is capable of and can be rationally designed to perform a wide variety of tasks. We want to know if DNA is a sufficient building block for constructing arbitrarily complex and sophisticated molecular machines."

Winfree became an assistant professor at Caltech in 2000, an associate professor in 2006, and was named full professor in 2010. He was also named a MacArthur Fellow in 2000.

Winkler works on developing new methods for using laser spectroscopy to study chemical kinetics and the intermediate molecules that form during chemical reactions. In particular, his work involves experimental investigations of the factors that affect the rates of long-range electron-tunneling processes—the processes by which electrons are transported between atoms and molecules.

"Electron transfer reactions are fundamental processes in many chemical transformations, including electrochemical catalysis, solar energy conversion, and biological energy transduction," Winkler says. "In the Beckman Institute Laser Center, we have spent the past 25 years studying electron transfer reactions in small inorganic molecules and in metalloproteins"—proteins that contain metal atoms. "Our studies are aimed at experimentally elucidating the molecular factors that regulate the speed and efficiency of electron flow.

"I have been fortunate to work on these projects with many dedicated and talented students and postdoctoral scholars at Caltech. It is extremely gratifying to have this work recognized by the AAAS," he adds.

Following postdoctoral work at the Brookhaven National Laboratory, Winkler returned to Caltech as a Member of the Beckman Institute in 1990. He was first appointed as a lecturer in chemistry in 2002, and later a faculty associate in chemistry in 2008.

In addition to Winkler and Winfree, eight other Caltech alumni were named as AAAS Fellows: Edmund W. Bertschinger (BS '79), J. Edward Russo (BS '63), Mitchell Kronenberg (PhD '83), Donald P. Gaver III (BS '82), James W. Demmel II (BS '75), Jacqueline E. Dixon (PhD '92), Brian K. Lamb (PhD '78), and Shelly Sakiyama-Elbert (MS '98, PhD '00).

The AAAS is the world's largest general scientific society. This year, the AAAS awarded the distinction of Fellow to 347 of its members. New Fellows will be honored during the 2016 AAAS Annual Meeting in February.

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Viral Videos (and Bacterial Ones, Too)

Grant Jensen is a high-powered movie producer. You won't see his name on any of this fall's Hollywood blockbusters, but in the field of cell biology, he has revolutionized the view that researchers, and even the curious public, get of the insides of cells. He does this through the innovative use of a digital camera and specialized electron microscope, which together enable a field called cryo-electron microscopy, or cryo-EM.

Now, he's taking what he's learned over the past 13 years using cryo-EM and sharing it with the world through a series of online videos that serve as visual textbooks to teach to the world the skills and knowledge needed for cryo-EM studies.

Read the full story on the E&S website

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Grant Jensen has revolutionized the view that researchers, and even the curious public, get of the insides of cells.

Neurons Encoding Hand Shapes Identified in Human Brain

Neural prosthetic devices, which include small electrode arrays implanted in the brain, can allow paralyzed patients to control the movement of a robotic limb, whether that limb is attached to the individual or not. In May 2015, researchers at Caltech, USC, and Rancho Los Amigos National Rehabilitation Center reported the first successful clinical trial of such an implant in a part of the brain that translates intention—the goal to be accomplished through a movement (for example, "I want to reach to the water bottle for a drink")—into the smooth and fluid motions of a robotic limb. Now, the researchers, led by Richard Andersen, the James G. Boswell Professor of Neuroscience, report that individual neurons in that brain region, known as the posterior parietal cortex (PPC), encode entire hand shapes which can be used for grasping—as when shaking someone's hand—and hand shapes not directly related to grasping, such as the gestures people make when speaking.

Most neuroprostheses are implanted in the motor cortex, the part of the brain controlling limb motion. But the movement of these robotic arms are jerky, probably due to the complicated mechanics for controlling muscle movement. Having eliminated that problem by implanting the device in the PPC, the brain region that encodes the intent, led Andersen and colleagues to further investigate the role specific neurons play in this part of the brain.

The research appears in the November 18 issue of the Journal of Neuroscience.

"The human hand has the ability to do numerous complex operations beyond just grasping," says Christian Klaes, a postdoctoral fellow at Caltech and first author of the paper. "We gesture when we speak, we manipulate objects, we use sign language to communicate with the hearing impaired. Tetraplegic patients rate hand and arm function to be of the highest importance to have better control over their environment. So our ultimate goal is to improve the range of neuroprostheses using control signals from the PPC.

"The more precisely we can identify individual neurons involved with hand movements, the better the capability these robotic devices will provide. Ultimately, we hope to mimic in a robotic hand the same freedom of movement of the human hand."

In the study, the researchers used the rock-paper-scissors game and a variation, rock-paper-scissors-lizard-Spock. The game, says Andersen, is "perfect" for this kind of research. "The addition of a lizard, depicted as a cartoon image of a lizard, and Spock—a picture of Leonard Nimoy in character—was to increase the repertoire of possible hand shapes available to our tetraplegic participant, Erik G. Sorto, whose limbs are completely paralyzed. We assigned a pinch gesture for the lizard and a spherical shape for Mr. Spock."

The game was played in two phases, first rock-paper-scissors and then the expanded game with the lizard and Spock. In the task, Sorto was briefly shown an object on a screen that corresponded to one of the hand shapes—for example, a picture of a rock or Mr. Spock. The image was followed by a blank screen, and then text appeared instructing Sorto to imagine making the corresponding hand shape with his right hand—a fist for the rock, an open hand for paper, a scissors gesture for scissors, a pinch for the lizard, and a spherical shape (loosely analogous to the Vulcan salute) for Spock—and to say which visual image he had seen, as the neuroprosthetic device recorded the activity of neurons in the PPC.

The researchers were able to identify single neurons in the PPC that fired when Sorto was presented with an image of an object to be grasped—a rock, say—and identified a nearly completely separate class of neurons that responded when Sorto engaged in motor imagery (the mental planning and imagined execution of a movement without the subject actually trying to move the limb).

"We found two mostly separate populations of neurons in the PPC that show either visual responses or motor-imagery responses during the task, the former when Erik identified a cue and the latter when he imagined performing a corresponding hand shape," says Andersen.

The researchers discovered that individual neurons in the PPC also responded to hand shapes that did not directly correspond to a grasp-related visual stimulus. The paper shape can be related to the initial opening of the hand to grasp a paper, and the rock closing the hand to grasp a rock—and in fact, these imagined hand shapes were used by Sorto to imagine opening a robotic hand by imagining paper and closing the robotic hand around an object by imagining rock. However, scissors, lizard, and Spock call for imagining hand gestures that are more abstract and iconic than those needed to grasp the visual objects, and suggests, says Andersen, that this area of the brain may also be involved in more general hand gestures, such as ones we use when talking, or for sign language.

The results of the trial were published in a paper titled, "Hand Shape Representations in the Human Posterior Parietal Cortex." In addition to Andersen and Klaes, other authors on the study are Spencer Kellis, Tyson Aflalo, and Kelsie Pejsa from Caltech; Brian Lee, Christi Heck, and Charles Liu from USC; and Kathleen Shanfield, Stephanie Hayes-Jackson, and Mindy Aisen from Rancho Los Amigos National Rehabilitation Center.

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The neurons, identified through brain studies using the game rock-paper- scissors-lizard-Spock, may lead to improved prosthetic devices.

Choosing the T-Cell Profession: Higher Education for Stem Cells

Watson Lecture Preview

Your body is continuously making new blood cells from a reservoir of "starter" cells called stem cells. Blood cells come in many types, including the highly versatile T cells that play a number of key roles in the immune system. All stem cells are alike, and all the T cells that come from them start out alike before choosing specific careers in response to signals from their environment.

On Wednesday, November 18 at 8 p.m. in Caltech's Beckman Auditorium, Ellen Rothenberg, Caltech's Albert Billings Ruddock Professor of Biology, will lead us along the paths that T cells follow and show how her lab has mapped their journeys. Admission is free.

What do you do?

I'm interested in how cells choose their identities through reading out information stored in the genome, which is the entire collection of DNA that makes a creature what it is, and how a cell that begins with one identity can spawn descendants with very different, very durable new identities.

We study T cells, a large family of white blood cells that form a major part of your immune system. T cells have an extremely long and varied life. They come from so-called stem cells, which have the ability to become many, many different kinds of cells. We want to learn how a "blank slate" of a stem cell develops to achieve a rock-solid identity as a T cell—especially because a T cell has an irreversibly defined "T-cell-ness" at its core, yet it remains very dynamic in using genomic information to decide what kind of T cell it will be.

Generating T cells is a three-step process. First, a stem cell develops into a T cell. Second, the T cell circulates around the body, waiting to see how it will first be used by the body to fight an actual infection. And then third, once it has evolved a specialization, it will continue to go around the body for months, years, or even decades in humans, spawning descendants that are also specialized with the same specific type of cellular function the original T cell had when it was activated—as helper T cells, or killer T cells, or whatever other type of T cell was needed. And they may pick a subspecialty—for example, for every infectious agent you encounter, you develop a specific memory cell to recognize that particular bug so that if it comes around again you are ready for it.

Once made, the decisions are locked in. All the T cell's progeny will generally stay in "the family business." However, it sometimes happens that once a T cell has chosen its profession, a particularly strong environmental signal can drive it to change into a different type of T cell. But even so, it will never, ever go back to being a stem cell. My lab is trying to figure out the molecular control mechanisms that allow the former stem cell to achieve a new rock-solid identity as a T cell, yet maintain a level of flexibility within that T-cell-ness.

Why is this important?

I study biology for the same reason that astronomers study the universe. I believe that there are deep biological principles to be learned from T cells, whose import goes way beyond curing a particular disease. I'm ecstatic when things we do are picked up by clinicians, who do make a profession of helping people, but I do basic science.

There are two main branches to the developmental biology of multicellular organisms. The first goes from the fertilized egg through the embryo, and that's the process that makes your body in the first place. It follows well-known rules worked out by people like my late colleague Eric Davidson [Caltech's Norman Chandler Professor of Cell Biology].

I study a second form of development that begins when an embryo sets aside a bunch of cells and programs them to become stem cells. Stem cells do not differentiate further right away; they just make more copies of themselves. Then, whenever you need to make new blood cells or repair a tissue later in life, those cells are called into action. For example, red blood cells only last about three or four months, so the blood circulating in your body today is coming from stem cells, and those stem cells were "set aside" when you were a fetus. This means there's an additional set of rules, going well beyond embryonic development, for making new blood cells in the right balance and at the right time.

The new cells do have some wear and tear from the consequences of your adventures throughout your life, but to a first approximation they're the same. They're getting primed to do the same job. They have to set up all the molecular circuitry needed to retain their identity and maintain a clear one-directional flow from stem-ness to differentiation. The process has to be as accurate at our advanced ages as it was when we were fetuses. That's the genius of stem-cell-based developmental biology. In my view, the collection of stem-cell development mechanisms ranks right up there with the more established mechanisms of embryonic development.

How did you get into this line of work?

I've always been interested in science. The question when I was young was whether I wanted to be a physicist or a biologist, but then I fell completely in love with biochemistry when I was in high school. When I went off to Harvard I didn't know specifically what I was interested in, but I loved what was known about the genome. I thought it would be fantastic to understand how the genome works at a molecular, mechanistic level.

I had the great good fortune to have microbiologist Boris Magasanik as my undergraduate tutor and mentor. He was the head of MIT's biology department, but he had a relationship with Harvard and he liked teaching undergrads. Boris was an extraordinary intellectual. He was studying metabolic pathways in bacteria at the systems-biology level way before it was normal. He was drawing prototype diagrams of gene-regulatory networks back in the early '70s.

A lot of technology had to be invented before we could explain gene regulation on the molecular level, but when I became a graduate student in [Nobel Laureate] David Baltimore's lab at MIT in 1972, he was already doing incredible work on viral genomes. [Baltimore came to Caltech in 1997 and is currently the Robert Andrews Millikan Professor of Biology.] We were pushing the frontiers of knowledge outward on a daily basis, and it was exceptionally exciting.

However, the development of multicelled organisms was still extremely hard to understand back then. It seemed all anecdotal, as if every organism did things in a fundamentally different way. But by the late '70s, Eric Davidson here at Caltech was making it possible to make sense out of developmental systems. His views integrated Boris Magasanik's systems-level view with David Baltimore's molecular-level finesse, and his work was revealing general mechanisms of development in multicellular organisms. I owe a great deal to the conceptual and mechanistic perspectives that I have gotten from these three people.

Also, Caltech's smallness has been fantastic. Most of the people I know who work with T cells are in immunology departments, and most immunologists do the same kinds of things, more or less. The joy for me at Caltech has been doing things that nobody else is doing. Often when my colleagues here solve their problems, I can use those approaches to break new ground in my field. It's been extraordinarily fun, and a tremendous advantage. Science as it should be done.

Long ago at MIT, my labmates and I were studying a retrovirus that caused early T-cell leukemia in mice. Lots of retroviruses cause cancer by putting a gene responsible for normal cell growth into the host cell and then turning the gene on under the wrong conditions. But our retrovirus didn't cause cancer in other cell types, so we wondered why it affected early T cells. I realized that the T-cell development process itself must be an especially sensitive target. The retrovirus nudged the future T cells toward being cancerous, possibly by accident, and then a little push farther down the line would send them over the edge.

That's when I became interested in T-cell development and this question of what controlled the switchover between growth and differentiation. We've found in the last 10 years or so that there are actually two bursts of proliferation during T-cell development. My lab has focused on the first one, which we now know is the transition between stem-cell-ness and T-cell-ness, when the cell commits to becoming a T cell. And it turns out that if a stem-cell regulatory gene stays on during the process, you get an abnormal persistence of stem-cell-like growth and sometimes leukemia. It's ironic that it's taken me, gosh, 40 years to get back to that, but it has been an incredibly satisfying journey.

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T Cells Get Schooled
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Choosing the T-Cell Profession: Higher Education for Stem Cells
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Choosing the T-Cell Profession
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The road to becoming a T cell is fraught with choices, false starts, and dead ends, where a regulatory tug-of-war brings cells close to the border of leukemia.

Yuki Oka Awarded Mallinckrodt Grant

Yuki Oka, an assistant professor of biology, has been awarded a grant from the Edward Mallinckrodt, Jr. Foundation, given to "support early stage investigators engaged in biomedical research that has the potential to significantly advance the understanding, diagnosis, or treatment of disease," according to the foundation website. The grant will provide $60,000 per year for three years.

"I'm thrilled by being selected for the 2015 Mallinckrodt Grant," says Oka, whose lab uses thirst and water-drinking behavior as a simple model system to study how the brain monitors internal water balance and generates signals that drive appetitive behaviors. The long-term goal of the work is to understand how the brain integrates information about the internal body state and external sensory information to maintain homeostasis (a state of internal equilibrium). The research, he notes, will provide a framework for studying the mechanisms that govern innate behaviors such as eating and drinking. Currently, an estimated 30 million people in the U.S. suffer from appetite disorders including polydipsia and bulimia, characterized by excessive water and food intake, respectively. Identifying neural circuits underlying appetite may offer insights into safe treatments for associated disorders, he says.

Oka received his PhD from the University of Tokyo and was a postdoctoral researcher at UC San Diego and Columbia University before joining the Caltech faculty in 2014. He was named a Searle Scholar in April 2015.

Past Mallinckrodt grantees from Caltech include Sarkis Mazmanian, the Luis B. and Nelly Soux Professor of Microbiology; David Prober, assistant professor of biology; Mitchell Guttman, assistant professor of biology; and Viviana Gradinaru, assistant professor of biology and biological engineering.

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Yuki Oka Awarded Mallinckrodt Grant
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Yuki Oka, an assistant professor of biology, has been awarded a grant from the Edward Mallinckrodt, Jr. Foundation.

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