The Next Big Thing

To get a glimpse into the future, what better place is there to look than the minds of those about to become Caltech's newest alumni? After all, our 2016 graduates have been at the forefront of research in vastly different fields for the past few years. Their unique perspectives have informed their ideas of the future, and their work will reach far beyond the confines of a lab.

With that in mind, in the Summer 2016 issue of E&S magazine, we talked to a handful of undergraduate and graduate students prior to commencement to find out what they think will be the next big thing in science and engineering and how their plans after graduation reflect those ideas.

 

I believe that the future of science, technology, engineering, and mathematics (STEM) will place a greater emphasis on implementation and impact of research. While rapid economic growth and globalization have introduced numerous difficult challenges, society has acquired powerful new tools and technology to develop and implement solutions for these issues.

I will be working as a management consultant after graduating to expose myself to business and strategy. That way, I can perhaps one day help new discoveries and ideas produce a tangible impact on people's lives."

Aditya Bhagavathi
BS in Computer Science

 

I believe the future of planetary and space exploration will follow two paths—one, the search for life beyond Earth within the solar system, and two, the characterization of exoplanets.

For the solar system, the initial survey of its major worlds was just completed with the New Horizons flyby of Pluto, and therefore a new focus will likely emerge. That initial survey has revealed several worlds to be potentially habitable, including Mars, Europa, and Enceladus, with the former two already targets for future missions. These new missions will not only reveal more about these worlds but also force us to reevaluate what life is, how it arises, and how it endures.

For exoplanets, the diversity of worlds is immense. From giant planets that orbit their host stars in less than a day to habitable planets with permanent daysides and nightsides, exoplanets offer a tremendous opportunity to understand the planets in our own solar system. With the rapid development of technologies, instruments, and observing techniques, the flood of data regarding exoplanets will only continue. I plan to be among the scientists who will analyze this data and combine their results with theoretical models to investigate what these distant worlds are like. By doing this, we will be exploring our place in the universe and whether we are alone within it."

Peter Gao
PhD in Planetary Science

 

When asked what he would do with his degree in philosophy during a routine dentist appointment, David Silbersweig, MD at Brigham and Women's Hospital and Academic Dean at Harvard Medical School, responded with a single word that spoke volumes: 'Think.' Simply put, I too want to think.

I want to learn how to think at a complex level such that my ability to think and subsequently solve problems allows me to change lives. The history and philosophy of science degree at Caltech has given me exactly this. According to Silbersweig, 'If you can get through a one-sentence paragraph of Kant, holding all of its ideas and clauses in juxtaposition in your mind, you can think through most anything.' In my first History and Philosophy of Science class, I read Kant. I also find immense happiness in working with and helping other individuals, a sense of euphoria matched by little else in life. I learned this lesson through tutoring students and coaching younger athletes. And finally, as a collegiate athlete myself, I have undergone multiple orthopedic surgeries that ignited an interest in the musculoskeletal system and its ability to suffer injury yet recover remarkably. Together, these three aspects of life are central to my vision of the future. Becoming an orthopedic surgeon is the perfect combination—the career that will give me these components and a lot more.

One of the major developments in medicine will be 3-D printing, primarily in order to provide individuals with replacement bones and organs. Combining new progress in computer science will facilitate immense progress in 3-D printing, which also aligns well with the use of robotics in surgery. As an athlete who has torn my ACL and had bone spurs in the past year, I'm excited to be a part of this field in the future and hopefully help other athletes succeed in pursuing their passions."

Harinee Maiyuran
BS in History and Philosophy of Science

 

My personal hunch, and perhaps a somewhat common one, is that all disciplines—and not just STEM ones—are moving toward being increasingly data driven, a phenomenon rooted in freer dissemination and greater influx of research data. Correspondingly, computers and programming drive data processing in all disciplines; a common joke is that every scientist is automatically a software engineer. Statistical and machine learning techniques that are designed to tackle vast quantities of data are increasingly common in academic papers and will probably continue to climb in popularity.

I am planning to go into computational astrophysics research because I believe that the recent influx of data from new detectors will drive a huge surge of research questions to be investigated. And as a physics/computerscience double major, I'm uniquely equipped to analyze big data and extract scientific meaning from it."

Yubo Su
BS in Physics and Computer Science

 

Many aspects about future climate are unclear, such as how cloudiness, precipitation, and extreme events will change under global warming. But recent progress in observational and computational technology has provided great potential for clarifying these uncertainties. I plan to continue my research and utilize new data and models to develop theoretical understanding of these problems. I hope that such new insight will be helpful for assessing climate change impacts and designing effective adaptation and mitigation strategies."

Zhihong Tan
PhD in Environmental Science and Engineering

 

The future of science and engineering depends on closing the huge gap between the general public and scientists and engineers. I think this stems from a good deal of ignorance about what it is we do and hope to achieve, which leads to misconceptions about our work and community, and the separation between 'us' and 'them.' But if we're trying to understand and solve problems that affect everyone, shouldn't everyone be more involved?

When I graduate, I'm going to take a year off to try and bridge this gap in my own life. I don't know what I'll do yet, but it will be decidedly nonacademic. I want to travel, work odd jobs, and pursue hobbies I've set aside to finish my education. If I want to help people understand why I do what I do, I need to be certain that I understand first. After only four years surrounded almost exclusively by scientists and engineers, I want to get away a little. That way, when I inevitably return, I'll have a bit more perspective."

Valerie Pietrasz
BS in Mechanical Engineering and Planetary Science

 

Driven by the goal of reducing fossil fuel use and pollution, clean energy research plays and will play a pivotal role in America's energy future. Clean energy research spans disciplines such as biological and environmental sciences, advanced materials, nuclear sciences, and chemistry. Therefore, multidisciplinary efforts are not only necessary but also crucial to develop and deploy real-world solutions for energy security and protecting the environment.

As a graduate student, I have focused on understanding nanoscale energy transport in novel energy-efficient materials. In the future, I plan to further advance and apply my expertise to solve real-world problems in an integrated and multidisciplinary approach. I hope this effort will eventually lead to developing advanced clean energy technologies that could not only ease today's energy crisis but also improve our quality of life."

Chengyun Hua
PhD in Mechanical Engineering

 

I believe that in the next decade, the behavioral and computational subfields of neuroscience will work together seamlessly. I think this change will be primarily fueled by the development of new tools that allow us to measure the activity of large populations of neurons more precisely.

A prominent behavioral method of research, in mice at least, is to activate large structures in the brain and observe the aggregate behavioral effect. However, it is unlikely that all of these neurons are responsible for the same signal, so this approach may be too crude. I think new measurement techniques will enable behavioralists to collect large-scale population activity that computationalists can use in order to find subtle differences of function within these structures. Hopefully this collaboration will lead to generating and validating fundamental theories underlying how the brain works.

Currently, I am in the process of developing a method to measure the activity from over 10,000 neurons simultaneously. I hope to validate this technique before I graduate and then apply it to studying large-scale population activity during various behaviors. My future aim is to work closely with computationalists with the hope of discovering fundamental theories of brain function."

Gregory Stevens
BS in Biology

 

I think the future of planetary science is to discover and characterize more and more extra-solar planets, including their orbital configurations, atmospheres, and habitability. This is a challenging task because it requires a solid understanding of how chemistry and physics work on a planetary scale. Learning more about the planets closest to us paves a way toward the understanding of exoplanets that are far beyond our reach, since we can send missions to them. So after graduation, I will join the team for Juno—the spacecraft that will arrive at Jupiter in summer 2016—at JPL. New discoveries about Jupiter will also tell us more about what other planets beyond our solar system could look like."

Cheng Li
PhD in Planetary Science

 

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The Next Big Thing
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We hear from a handful of graduating students to learn what they think will be the next big thing in science and engineering and how their plans reflect those ideas.

Solving Molecular Structures

Determining the chemical formula of a protein is fairly straightforward, because all proteins are essentially long chains of molecules called amino acids. Each chain, however, folds into a unique three-dimensional shape that helps produce the characteristic properties and function of the protein. These shapes are more difficult to determine (or "solve"); scientists traditionally do so using a technique called X-ray crystallography, in which X-rays are shot through a crystallized sample and scatter off the atoms in a distinctive pattern.

This spring, Caltech students had the opportunity to use the technique to solve protein structures themselves in a new course taught by Professor of Chemistry André Hoelz.

Although the Institute has a long history in the fields of structural biology and X-ray crystallography, the chance to get hands-on experience with the technique is rare at most universities, Caltech included. Indeed, the method is more commonly performed at specialized facilities with high-energy X-ray beam lines, including the Stanford Synchrotron Radiation Laboratory (SSRL). However, in 2007, thanks to a gift from the Gordon and Betty Moore Foundation, Caltech opened the Molecular Observatory—a dedicated, completely automated radiation beam line at SSRL.

"The Molecular Observatory gives us lots of beam time," notes Hoelz. "Recently, I also received a grant from the Innovation in Education Fund from the Provost's Office that was matched by the Division of Chemistry and Chemical Engineering, and this allowed me the opportunity to develop this course and train students in a way not commonly found at universities."

In the new course, "Macromolecular Structure Determination with Modern X-ray Crystallography Methods" (BMB/Ch 230), Hoelz's students have been using the Molecular Observatory and other on-campus crystallization resources to solve the structures of various proteins, in particular, variants of green fluorescent proteins (GFPs)—proteins that exhibit bright green fluorescence under certain wavelengths of light. "These proteins are crucial tools in biology because they can be visualized by fluorescence techniques. It's important to know their physical structure, because it affects the intensity and wavelength at which the protein fluoresces," says Anders Knight, a first-year graduate student studying protein engineering with Frances Arnold, the Dick and Barbara Dickinson Professor of Chemical Engineering, Bioengineering and Biochemistry, and one of nine students—including two undergraduates—in the inaugural class.

During the first few weeks of the course, students determined the proper conditions—the pH levels and the mix of salts and buffer solutions—that are required to get a protein to crystallize. These conditions vary from protein to protein, making it tricky to "grow" perfect single crystals of the proteins. "Most of the ones we are working with have known 3-D structures, and they crystallize relatively easily, so they are a great place to start learning about the technique of X-ray crystallography," Knight says. "But some of us were also given protein variants that had never been crystallized before."

Once the students crystallized their proteins, single crystals were mounted in tiny nylon loops that are attached to small metal bases, frozen in liquid nitrogen, and loaded into pucks that were shipped to SSRL. There, the pucks were loaded into a robotic machine—remotely controllable from Caltech and operated by the students—that placed them, one by one, into a powerful X-ray beam. X-rays are scattered at characteristic angles by the electrons within the crystallized samples, generating a diffraction pattern that can be converted into a so-called electron-density map, which is then used to determine the 3-D location of all of the atoms.

"The electron density map doesn't exactly show you what the protein's structure is," Knight says. "You do have to correctly interpret the electron density map to determine where the protein's atoms will go. It's difficult, but this class is designed to give us practice doing that. Collecting data at SSRL was a great learning experience. It was interesting to be able to accurately mount and position the crystals—each smaller than a millimeter—on the beamline from hundreds of miles away. The data collection went fairly quickly, taking around eight minutes."

For their final assignment, students will write a mock journal paper about their methods and the final protein structure. Most of the structures had been determined previously, but one student did solve a previously unknown GFP structure, a bright red fluorescent protein called dTomato.

"dTomato is a product of directed evolution in protein engineering, created by subjecting its parent, DsRed, through several rounds of random genetic mutations," says Phong Nguyen, a graduate student in the lab of Doug Rees, Roscoe Gilkey Dickinson Professor of Chemistry and Howard Hughes Medical Institute Investigator, and the student who solved the structure of dTomato in Hoelz's class. "By solving its structure, we can see how directed evolution—a method developed by Frances Arnold to create new proteins using the principles of evolution—changed the protein from its parent. Specifically, we are able to explain how individual mutations contributed to the structural outcome of the protein and consequently to differing chemical and physical properties from the parent. We all are so excited to solve a new structure and contribute knowledge to the field of GFP protein engineering."

"Having the Molecular Observatory at Caltech allows us to train students with very sophisticated technology," says Hoelz, who is now envisioning a second, related course. "Students would learn recombinant protein expression and purification, directly prior to this course, so they can purify the proteins themselves with cutting-edge technology and then go on to determine their 3D structure by X-ray crystallography," he says.

"In my opinion, learning by doing is the best way to master how to determine crystal structures and this new course will solidify the strong roots Caltech has in X-ray crystallography," Hoelz adds. "Not only will this new course accelerate the otherwise slow learning process for this technique, but it will also allow non-structural biology laboratories on campus to determine crystal structures of their favorite proteins using Molecular Observatory, a unique and spectacular facility at Caltech."

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At Caltech, students have the opportunity to learn X‑ray crystallography, a technique that reveals the three-dimensional structure of molecules like proteins.

Gilmartin Named Dean of Undergraduate Students

On July 1, 2016, Kevin Gilmartin, professor of English, will begin serving as Caltech's dean of undergraduate students.

In announcing Gilmartin's appointment, Joseph E. Shepherd, vice president for student affairs and the C. L. Kelly Johnson Professor of Aeronautics and Mechanical Engineering, described him as "an accomplished scholar and author who brings to this position twenty-five years of experience in teaching and mentoring our students, and who has shown a keen interest in the welfare of our undergraduate students in and outside of the classroom."

In his new role as dean of undergraduate students, Gilmartin will work on fostering academic and personal growth through counseling and support for student activities as well as acting as a liaison between students and faculty, says Shepherd.

A recipient the Feynman Prize, Caltech's highest teaching award, Gilmartin says he was attracted to the job of dean because "I have always found our students to be so interesting, and engaging. They are extraordinarily optimistic. They seem to have a positive attitude toward the world—they're curious, and they're open to new things. What more could you ask for?"

He says he sees his role as helping undergraduates develop and thrive. "I'm excited to work with students to help foster their intellectual and academic growth and their development as individuals," he says. "Our students are remarkably diverse and they have diverse interests. The Caltech curriculum is demanding, and focused, no doubt. But within it, and through it, our students do find so many opportunities."

He adds, "The dean's office provides essential support. But we can also encourage our students to do more than they are inclined to do, to challenge themselves, to try new things."

Gilmartin received his undergraduate degree in English from Oberlin College in 1985. He received both his MS ('86) and PhD ('91) in English from the University of Chicago, joining the faculty of Caltech in 1991.

Barbara Green, who has served as the interim dean over the past year will return to her regular position as associate dean in July. In his announcement, Shepherd thanked Green "for her work with our students and service to the Institute [and for] being so willing and committed to the success of our undergraduate student body."

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On July 1, 2016, Kevin Gilmartin, professor of English, will begin serving as Caltech's dean of undergraduate students.

Ditch Day? It’s Today, Frosh!

Today we celebrate Ditch Day, one of Caltech's oldest traditions. During this annual spring rite—the timing of which is kept secret until the last minute—seniors ditch their classes and vanish from campus. Before they go, however, they leave behind complex, carefully planned out puzzles and challenges—known as "stacks"—designed to occupy the underclassmen and prevent them from wreaking havoc on the seniors' unoccupied rooms.

Follow the action on Caltech's Facebook, Twitter, and Instagram pages as the undergraduates tackle the puzzles left for them to solve around campus. Join the conversation by sharing your favorite Ditch Day memories and using #CaltechDitchDay in your tweets and postings.

          

 

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Oka Receives McKnight Award

Yuki Oka, assistant professor of biology, has been named one of six recipients of the 2016 McKnight Scholars Award. The McKnight Endowment Fund for Neuroscience awards $75,000 per year for three years to support young scientists who are establishing their own laboratories and research centers. The award is only available to researchers in the first four years of a tenure-track faculty position.

 

"A McKnight Scholar Award is one of the most prestigious early-career honors that a young neuroscientist can receive," said Anthony Movshon, chair of the awards committee and professor at New York University, in a press release. "This year's Scholars are a superbly talented group, with as much promise as any selected in the past. … Their work will help us to understand the brain's function in health and in disease, and will shape the neuroscience of the future."

 

Oka studies the neural mechanisms controlling thirst. These mechanisms help the body maintain a healthy balance of water and salt. He is attempting to isolate exactly which circuits in the brain regulate thirst and to determine how those circuits are triggered by external signals. Understanding these key brain functions may lead to new treatments for appetite-related disorders.

 

The McKnight Foundation of Minneapolis, Minnesota has supported neuroscience research since 1977. It created the Endowment Fund in 1986 in honor of William L. McKnight, an early leader of the 3M Company who had a personal interest in neurological diseases and wanted his legacy to help find cures. Previous awardees from Caltech include Athanossios Siapas, professor of computation and neural systems, and Kai Zinn, professor of biology.

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A Feeling Touch

Using funding from the BRAIN Initiative, Caltech biologists are developing neuroprosthetics to bring tactile sensations to the users of robotic arms.

Caltech biologist Richard Andersen is working to incorporate a sense of touch into the neural prosthetics he has been helping develop for years—devices implanted in the brain that allow a paralyzed patient to manipulate a robotic arm.

Andersen and colleagues first reported success of their original implant in early 2015. The team, led by Andersen, placed their prosthesis in the posterior parietal cortex, an area that controls the intent to move rather than controlling movement directly as previous experiments had done. This allowed Erik Sorto, a 35-year-old man who has been paralyzed from the neck down for more than 10 years, to use a robotic arm placed next to his body to perform a fluid hand-shaking gesture, play rock-paper-scissors, and even grasp a bottle of beer and bring it to his mouth for a sip—something he had long dreamed of doing.

This research on how to make a robotic arm move resulted in a 2015 National Science Foundation grant to Andersen from President Obama's Brain Research through Advancing Innovative Neurotechnology—or BRAIN—Initiative, as well as seed money from the California Blueprint for Research to Advance Innovations in Neuroscience (Cal-BRAIN) program, the California complement to the federal initiative, which gave out its first-ever monetary awards last year to a group of researchers that included Andersen.

Andersen is now using those Cal-BRAIN funds—designed to bring together interdisciplinary teams of scientists and engineers from diverse fields for fundamental brain research—to take his team's work to the next level. His hope is to enable people using robotic arms to literally regain their sense of touch—their ability to feel an object in their "hands."

For more on Andersen's work, read A Feeling Touch on E&S+

 

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Caltech biologists are developing neuroprosthetics to bring tactile sensations to the users of robotic arms.

DNA Origami: Folded DNA as a Building Material for Molecular Devices

Living things use DNA to store the genetic information that makes each plant, bacterium, and human being unique. The reproduction of this information is made possible because DNA's nucleotides—A's and T's, G's and C's—fit together perfectly, like matching jigsaw puzzle pieces. Engineers can take advantage of the matching between long strands of DNA nucleotides to use DNA as a kind of molecular origami, folding it into everything from nanoscale smiley face artwork to serious drug-delivery devices.

On Wednesday, May 25, at 8 p.m. in Beckman Auditorium, Paul Rothemund (BS '94), the inventor of the DNA origami technique, will explain how his group and groups around the world are using DNA origami in applications ranging from potential cancer treatments to devices for computing. Rothemund is research professor of bioengineering, computing and mathematical sciences, and computation and neural systems in the Division of Engineering and Applied Science at Caltech. Admission is free.

What do you do?

I use DNA and RNA as building materials to create shapes and patterns with a resolution of just a few nanometers. The smallest features in the DNA structures we make are about 20,000 times smaller than the pixels in the fanciest computer displays, which are each about 80 microns across. A large part of our work over the last 20 years has been just figuring out how to get DNA or RNA strands to fold themselves into a desired computer-designed shape. As we've mastered the ability to make whatever shape or pattern we desire, we've moved on to using these shapes as "pegboards" for arranging other nano-sized objects, such as protein enzymes, carbon-nanotube transistors, and fluorescent molecules.

Why is this important?

Every task in your body, from digesting food to moving your muscles to sensing light, is powered by tiny nanometer-scale biological machines, all built from the "bottom up" via the self-folding of molecules such as proteins and RNAs. The billions of transistors that make up the chips in our cell phones and computers are tens of nanometers in size, but they are built in a "top down" fashion using fancy printing processes in billion-dollar factories. Our goal is to learn how to build complex artificial devices the way biology builds natural ones—that is, starting from self-folding molecules that assemble together into larger more complex structures. In addition to vastly cheaper devices, this will enable completely new applications, such as man-made molecular machines that can make complex therapeutic decisions and apply drugs only where needed.

How did you get into this line of work?

As an undergraduate at Caltech, I had great difficulty trying to decide how to combine my diverse interests in computer science, chemistry, and biology. Fortunately, the late Jan L. A. van de Snepscheut introduced his computer science class to the hypothetical idea of building a DNA Turing machine—a very simple machine which can nevertheless run every possible computer program. He challenged us, suggesting that someone who knew about both biochemistry and computer science could come up with a concrete way to build such a DNA computer. For a project class in information theory with Yaser Abu-Mostafa, a professor of electrical engineering and computer science, I came up with a pretty inefficient, yet possible, way to do this. At the time, I couldn't interest any Caltech professors in building my DNA computer, but shortly after, USC professor Len Adleman published a paper on a more practical DNA computer in Science. I joined Adleman's lab at USC as a graduate student, and I've been trying to use DNA to build computers or other complex devices ever since. I returned to Caltech as a postdoc in 2001 and became a research professor in 2008.

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A preview of Paul Rothemund's upcoming Watson Lecture.

Seven from Caltech Elected to National Academy of Sciences

Three Caltech professors and four Caltech alumni have been elected to the prestigious National Academy of Sciences (NAS). The announcement was made Tuesday, May 3.

Raymond Deshaies is a professor of biology, investigator at the Howard Hughes Medical Institute, and executive officer for molecular biology. Deshaies's work focuses on understanding the basic biology of protein homeostasis, the mechanisms that maintain a normal array of functional proteins within cells and organisms. He is the founder of Caltech's Proteome Exploration Laboratory to study and sequence proteomes, which are all of the proteins encoded by a genome.

John Eiler is the Robert P. Sharp Professor of Geology and professor of geochemistry, as well as the director of the Caltech Microanalysis Center. Eiler uses geochemistry to study the origin and evolution of meteorites and the earth's rocks, atmosphere, and interior. Recently, his team published a paper detailing how dinosaurs' body temperatures can be deduced from isotopic measurements of their eggshells.

Ares Rosakis is the Theodore von Kármán Professor of Aeronautics and Mechanical Engineering in the Division of Engineering and Applied Science. His research interests span a wide spectrum of length and time scales and range from the mechanics of earthquake seismology, to the physical processes involved in the catastrophic failure of aerospace materials, to the reliability of micro-electronic and opto-electronic structures and devices.

Deshaies, Eiler, and Rosakis join 70 current Caltech faculty and three trustees as members of the NAS. Also included in this year's new members are four alumni: Ian Agol (BS '92), Melanie S. Sanford (PhD '01), Frederick J. Sigworth (BS '74), and Arthur B. McDonald (PhD '70).

The National Academy of Sciences is a private, nonprofit organization of scientists and engineers dedicated to the furtherance of science and its use for the general welfare. It was established in 1863 by a congressional act of incorporation signed by Abraham Lincoln that calls on the academy to act as an official adviser to the federal government, upon request, in any matter of science or technology.

A full list of new members is available on the academy website at: http://www.nasonline.org/news-and-multimedia/news/may-3-2016-NAS-Electio...

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Three faculty members and four alumni have been elected to the National Academy of Sciences.

When Beneficial Bacteria Knock But No One is Home

The community of beneficial bacteria that live in our intestines, known as the gut microbiome, are important for the development and function of the immune system. There has been growing evidence that certain probiotics—therapies that introduce beneficial bacteria into the gut—may help alleviate some of the symptoms of intestinal disorders such as Crohn's disease. By studying the interplay between genetic risk factors for Crohn's and the bacteria that populate the gut, researchers at Caltech have discovered a new potential cause for this disorder in some patients—information that may lead to advances in probiotic therapies and personalized medicine.

The results were published online in the May 5 edition of the journal Science.

Previously, scientists had found that patients with Crohn's disease often exhibit alterations in both their genome and their gut microbiome—the diverse collection of bacteria that reside in the intestine. More than 200 genes have been implicated as having a role in the susceptibility to Crohn's. For years, researchers in the field have believed that these are genes that normally function by sensing pathogenic bacteria and deploying an immune response to kill the unwanted microbes; when these genes are defective, the pathogenic bacteria survive, multiply in the gut, and lead to disease.

"While we believe that all of that is true, in this study we were curious to see if some of the genes that are important in sensing pathogenic bacteria may also be important in sensing beneficial bacteria to promote immune health," says the study's first author, Hiutung Chu, a postdoctoral scholar in biology and biological engineering at Caltech. "Typically, the signals from these beneficial commensal microbes promote anti-inflammatory responses that dampen inflammation in the gut. However, mutations in genes that sense and respond to pathogenic bacteria would also impair the response to the beneficial ones. So it's kind of a new spin on the existing dogma."

To figure this out, Chu and her colleagues in the laboratory of Sarkis Mazmanian, the Luis B. and Nelly Soux Professor of Microbiology, designed several experiments to study how genetic mutations might interrupt the immune-enhancing effects of a known beneficial bacterium, Bacteroides fragilis. The researchers tested their new theory by using B. fragilis to treat mice that had nonfunctional versions of two genes known to play a role in Crohn's disease risk, called ATG16L1 and NOD2.

The researchers found that if just one of these two genes was absent, the mice were unable to develop disease-protective immune cells called regulatory T cells in response to B. fragilis—and that even after treatment with B. fragilis, symptoms in an ATG16L1-deficient mouse model of intestinal disease remained unchanged.

Chu and Mazmanian then obtained blood samples from both healthy patients and patients with Crohn's disease at the Cedars-Sinai Medical Center in Los Angeles. "We could see that certain patients' immune cells responded to Bacteroides fragilis, while immune cells from other patients didn't respond at all," Chu says. "Because the cells from Cedars had already been genotyped, we were able to match up our results with the patients' genotypes: immune cells from individuals with the protective version of ATG16L1 responded to the treatment, but cells from patients who had the mutated version of the gene showed no anti-inflammatory response to B. fragilis."

Mazmanian says the results suggest that the faulty versions of these genes may cause Crohn's disease in two different ways: by being unable to assist in destroying pathogenic bacteria and by preventing the beneficial immune signals usually elicited by "good" bacteria. "What Hiutung has shown is that there are specific bacteria in the human microbiome that appear to utilize the pathways that are encoded by these genes—genes normally involved in killing bacteria—to send beneficial signals to the host," he says.

This work reveals the important relationship between the genome and the microbiome—and it may also one day be used to improve the use of probiotics in clinical trials, Mazmanian says. "For example, our previous work has suggested using B. fragilis as a probiotic treatment for certain disorders. What this new study suggests is that there are certain populations that wouldn't benefit from this treatment because they have this genetic predisposition," he notes. "Right now, clinical trials don't do a good job of identifying which patients might respond best to treatment, but our experiments in mouse models suggest that, conceptually, you could design clinical trials that are more effective."

The research described in the paper, "Gene-Microbiota Interactions Contribute to the Pathogenesis of Inflammatory Bowel Disease," was funded by the National Institutes of Health, the Cedars-Sinai F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, the Lupus Research Institute, the European Union, the Crohn's and Colitis Foundation of America, the Leona M. and Harry B. Helmsley Charitable Trust, and the Heritage Medical Research Institute.

In addition to Chu and Mazmanian, other Caltech coauthors include former graduate students Arya Khosravi (PhD '14) and Yue Shen (PhD '12); research technician assistants Indah Kusumawardhani and Alice Kwon; and Wei-Li Wu, a postdoctoral scholar in biology and biological engineering. Coauthors from other institutions include: Anilton Vasconcelos and Peter Ernst from UC San Diego; Larissa Cunha and Douglas Green from St. Jude Children's Research Hospital in Memphis; Anne Mayer, Amal Kambal, and Herbert Virgin from the Washington University School of Medicine in St. Louis; Stephan Targan and Dermot McGovern from Cedars-Sinai Medical Center; and Ramnik Xavier from Harvard Medical School.

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Wednesday, May 11, 2016
Noyes 147 (J. Holmes Sturdivant Lecture Hall) – Arthur Amos Noyes Laboratory of Chemical Physics

Administrative Contact Information Session

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