A Breakthrough Prize for Life Sciences

In the spring issue of E&S, we talked to Caltech physicists John Schwarz and Alexei Kitaev about the Breakthrough Prize in Fundamental Physics in our article, “Glitz and Qubits.” Alexander Varshavsky, Caltech’s Howard and Gwen Laurie Smits Professor of Cell Biology, is also a Breakthrough Prize winner; he was awarded one of the six 2014 Breakthrough Prizes in Life Sciences for “his discovery of the critical molecular determinants and biological functions of intracellular protein degradation,” according to the award citation.

Each of the laureates received $3 million, making the award one of the largest academic prizes in the world. The Breakthrough Prize in Life Sciences was instituted to recognize “excellence in research aimed at curing intractable diseases and extending human life,” according to the Breakthrough Prize in Life Sciences Foundation website.

Varshavsky was noted for the fundamental discovery, in the 1980s, of biological regulation by intracellular protein degradation and its central importance in cellular physiology. “Studies by my laboratory, at first at the Massachusetts Institute of Technology and later at Caltech, focused on the understanding of how and why cells destroy their own proteins to withstand stress, to grow and divide, to differentiate into new kinds of cells, and to do countless other things that make living organisms so astonishing and fascinating,” Varshavsky said.

His work focuses on the design and biological functions of the ubiquitin system, a major proteolytic circuit in living cells. Ubiquitin is a small protein that is present in cells either as a free protein or as a part of tight (covalent) complexes with many other proteins. The association of ubiquitin with cellular proteins marks them for degradation or other metabolic fates. Through its ability to destroy specific proteins, the ubiquitin system plays a major role in cell growth and differentiation, DNA repair, regulation of gene expression, and many other biological processes.

“The field of ubiquitin has been expanding at an amazing pace and is now one of the largest arenas in biomedical science,” Varshavsky said. “Both earlier and recent discoveries illuminate the ubiquitin system and protein degradation from many different angles and continue to foster our ability to tackle human diseases, from cancer, infections and cardiovascular illnesses to neurodegenerative syndromes and aging itself. I feel privileged having been able to contribute to the birth of this field and to partake in its later development.

“The Breakthrough Prize in Life Sciences recognized Alex’s truly pioneering discovery of ubiquitin-mediated protein degradation and its central role in both cellular function and dysfunction. His work has opened up completely new approaches to understanding and treating human disease,” said Stephen Mayo, Bren Professor of Biology and Chemistry and the William K. Bowes Jr. Leadership Chair of the Division of Biology and Biological Engineering.

Varshavsky earned his BS from Moscow State University in 1970 and his PhD from the Institute of Molecular Biology in 1973. He has been Smits Professor at Caltech since 1992.

A member of the National Academy of Sciences, the American Academy of Arts and Sciences, the American Philosophical Society, and the Academia Europaea, Varshavsky has received many international prizes in biology and medicine, including the 2014 Albany Medical Center Prize in Medicine and Biomedical Research; 2012 King Faisal International Prize for Science (Saudi Arabia); the 2011 Otto Warburg Prize (Germany); the 2008 Gotham Prize in Cancer Research; the 2006 Gagna Prize (Belgium); the 2006 Griffuel Prize (France); the 2005 Stein and Moore Award; the 2001 Horwitz Prize; the 2001 Merck Award; the 2001 Wolf Prize in Medicine (Israel); the 2000 Lasker Award in Basic Medical Research; and the 1999 Gairdner International Award (Canada).

Written by Kathy Svitil
Photograph courtesy of the Breakthrough Prize

Student-Faculty Colloquium Seeks to Improve Diversity, Climate at Caltech (+)

The Graduate Student Council recently hosted a forum designed to bring graduate students, faculty, and the administration together to discuss important campus issues. The Student-Faculty Colloquium (SFC) featured a keynote address by Caltech president Thomas Rosenbaum, followed by presentations on campus culture, mentoring, diversity, and work-life balance.

The forum, held February 11, included four sessions, each led by two graduate student cochairs and at least one faculty cochair. “The overwhelming enthusiasm and support of everyone we talk to—the faculty, the administration—speaks volumes to how important people at Caltech think these issues are,” says SFC organizer Allison Strom, a grad student.

“What I’m most proud of is that the graduate students have involved faculty in the panels and discussions. They’ve made it a joint effort. It’s not just the graduate students talking to the faculty; it’s a dialogue,” says Felicia Hunt, GSC advisor, assistant vice president for equity, accessibility, and inclusion initiatives, and Title IX coordinator. “We don’t have a class on planning a conference. To be able to pick it up and run with it takes an incredible amount of initiative.”

All sessions centered on discussions for the “sharing of ideas across departments, which goes with Caltech’s identity as a collaborative institution,” says grad student Natalie Higgins, cochair of the session “Supporting Students through Mentoring Networks.”

Grad student Emily Blythe, cochair of the session “Admissions and Recruitment,” agrees. “We see the SFC as a really good way to get everyone from different options in a room together. Certainly, options are doing great things the others don’t know about.”

Students in different departments may also be facing similar problems, as “many of the issues graduate students face transcend departments,” says Strom. “The challenges of being a scientist or engineer are pretty universal.”

The SFC aims to address these matters by facilitating conversation and opening lines of communication among students and faculty “to create a network of people you can talk to for advice,” says Higgins.

The main goals of the discussion in the mentoring networks session include making students and faculty aware of the issues that grad students face and of available resources for dealing with these issues, and attempting to fill any gaps in this system. The session will also provide information about “nonresearch mentoring—mentoring for other aspects of life,” says grad student Henry Ngo, Higgins’s cochair. “We’re not just researchers; there are different worlds we need to seek out.”

Similarly, Blythe hopes “to get a sort of best practices guide out of this to make sure everyone feels welcome at Caltech.”

The admissions and recruitment session, says grad student Sofia Quinodoz, Blythe’s cochair, offered a good opportunity to discuss “how each option can recruit the best people.” She said  grad students sharing their experiences with professors could “show them how they can help with recruitment” by letting them know what has and has not worked at Caltech.

The session “Professional and Career Development,” cochaired by grad students Parham Noorzad and Andrew Robbins, addressed the development of skills necessary for navigating graduate school and future work and the preparation required to navigate the job market. These discussions were important, especially for grad students, since “just finishing your thesis is not enough to get a job; you need presentation and interview skills,” says Noorzad.

Faculty at the professional and career development session offered “perspective on preparing students for different careers and to share their experiences with students, whether they have gone on to industry or academia,” says Robbins.

One challenge of the GSC was “getting people who aren’t interested in being student leaders involved in conversations,” says Strom. “They don’t have to be involved in student government to have their voices heard, so the SFC hopefully provided them with an opportunity to do that.”

Grad students Gina Duggan and Alicia Lanz organizinged a panel of students and faculty for the session “Advisor-Advisee Relationships” to address concerns identified from the Graduate Exit Survey and to answer questions about advisor/advisee styles, methods of communication, and expectations. “As graduate dean,” says Doug Rees, Roscoe Gilkey Dickinson Professor of Chemistry and dean of graduate studies, “one thing I’ve learned is that each lab and option has its own ways of doing things. We won’t find just one solution, but we’ll find what the basic elements are for a happy and productive relationship.”

“I was excited to hear what members of the faculty think about these issues,” says Duggan, one of the student panelists. “They’ve all been grad students also.”

Engaging students and faculty in this discussion was one of the main points of the SFC. “Now is a good time for departments; they seem more receptive and open to change,” says Lanz, the panel moderator.

Strom says the day was designed “to give students the confidence to be able to advocate for themselves. With more information, they can be more confident with their identities as scientists and people and figure out what they want to do in the future.”

For more about graduate student life, see our Winter 2015 article “Seeking a Balanced Equation.” 

Written by Nehaly Shah

A Bold Enterprise (+)

Our Winter 2015 article “Seeking a Balanced Equation” referenced the Star Trek musical parody Boldly Go!, which was written by Caltech grad student Grant Remmen and his brother, Cole. 

• • •

Grant Remmen, a graduate student in theoretical physics at Caltech, and his younger brother, Cole, who majors in theater arts at the University of Minnesota, have long shared a passion for musical theater. For years, they had discussed creating their own work, including songs, lyrics, and script.

Seeking inspiration, Grant, whose work at Caltech involves high-energy physics related to gravity, turned to space. What he found, besides the actual universe, was a version represented by the Star Trek television series of the 1960s.

“The topic of Star Trek was natural for us,” explains Grant. “We always loved the show.” The result, entitled Boldly Go!, will have its world premiere at Ramo Auditorium on the Caltech campus February 26–28 and March 3–5, 2016. Brian Brophy, a lecturer in theater at Caltech, will direct.

The production features 19 original songs and 20 scenes. Grant describes it as a “loving parody,” which he says combines affection for the material with moments of sheer irreverence. Many of the popular characters are included, such as Captain Kirk, Spock, Doctor McCoy, Sulu, Uhura, and Chekov, plus new ones as well.

By design, Grant says, Boldly Go! features a variety of musical styles, “including classic musical theater, gospel, tango, indie rock, ragtime power ballad, patter song, and more.”

“We did this in order to parody musical theater itself, a genre that we enjoy and with which we are very familiar,” he adds.

Song titles include “Klingons are Misunderstood,” “The Vulcan Way,” “Dammit Jim, I’m a Doctor,” and “Live Long and Prosper.”

Since September 2013, when work commenced on the musical, Grant has cowritten all facets while pursuing his doctorate at Caltech under faculty advisors Clifford Cheung, assistant professor of theoretical physics, and Sean Carroll, research professor of physics.

“I’m excited about my work because understanding the high-energy behavior of gravity and the nature of space-time is arguably the ultimate question in physics,” he says.

Grant remains “first, foremost, and always a scientist,” and spends most of his days doing research exclusively. During the time he spent developing the musical, he allowed himself small breaks to work on the production, writing bits of dialogue and lyrics whenever possible, which he then sent to his brother for suggestions and edits. Cole did the same in return.

Over the Thanksgiving and Christmas holidays in 2013 and 2014, while the brothers stayed at the family home in Minnesota, they spent hours each day alone together in a room, composing melodies like veteran Broadway composers.

The work on Boldly Go! also included what would be a leisure-time activity under different circumstances. To better understand the nuances of the characters, Grant viewed an estimated 500 hours of Star Trek programming, both film and television.

Watching Star Trek has been popular at Caltech since the 1960s. In January 1968, when NBC was threatening to cancel the program, a group of Caltech students protested the planned move. According to a story about the protest that appeared in the Los Angeles Times, “200 chanting, banner-waving Caltech scholars conducted a torchlight procession through the streets of Burbank to carry a protest to the steps of the National Broadcasting Company.”

A national campaign succeeded; NBC renewed the series for 1968–69, before canceling it permanently.

In the spring of 2015, Brophy and Grant conducted a five-week rehearsal of Boldly Go!, which culminated in a staged reading at the Cahill Center for Astronomy and Astrophysics. Many audience members at the event, which was sold out, wore Star Trek T-shirts. “I was overwhelmed by the reaction,” says Kelvin Bates, who is playing the role of Captain Kirk.

“At its core,” Grant says, “Boldly Go! is a story about being true to oneself and one’s convictions, about friendship and love, about discovery and wonder, about the triumph of the individual over adversity, and about the joy of sharing with each other this vast and mysterious universe.”

Written by Tom Waldman

CALTECH GRADS LEAD KEY U.S. RESEARCH AGENCIES (+)

Today’s graduate students, like those showcased in our Winter 2015 issue, often become tomorrow’s scientific leaders. The careers of France Córdova (PhD ’79), Arati Prabhakar (MS ’80, PhD ’85), and Ellen Williams (PhD ’81), offer dramatic examples of how true that can be.

These women now lead three of the nation’s top science, technology, and research agencies: the National Science Foundation (NSF), the Defense Advanced Research Projects Agency (DARPA), and the Advanced Research Projects Agency-Energy (ARPA-E).

France Córdova

France Córdova
France Córdova

Since 2014, Córdova has led the NSF, a $7 billion-a-year federal agency that supports fundamental research and education in all the nonmedical fields of science and engineering.

Córdova studied physics as a graduate student at Caltech, working on X-ray astronomy. It was a time she remembered in a recent interview in the Caltech Alumni Association’s publication, Techer, as “rigorous, collaborative, and fun. … As graduate students, you were able to learn from and work right alongside all of these incredible minds, like theoretical physicists Murray Gell-Mann and Richard Feynman.”

After Caltech, Córdova built an impressive resume that included working for a decade at Los Alamos National Laboratory; leading the department of astronomy and astrophysics at Pennsylvania State University; and becoming the youngest person and first woman to hold the position of NASA chief scientist. Over those and subsequent years, the positions she held shifted from those focused primarily on research to more administrative roles, eventually including vice chancellor for research at UC Santa Barbara, chancellor of UC Riverside, president of Purdue University, and chair of the Board of Regents of the Smithsonian Institution before being named as the NSF’s director.

Arati Prabhakar

Arati Prabhakar
Arati Prabhakar

Prabhakar serves as director of DARPA—an agency of the U.S. Department of Defense that develops emerging technologies for use by the military and whose achievements include the creation of ARPANET, the precursor to the Internet.

Prabhakar first joined DARPA in 1986 after receiving her doctorate in applied physics from Caltech. Her initial job with the agency was to manage programs in advanced semiconductor technology and flexible manufacturing, and to manage demonstration projects to insert new semiconductor technologies into military systems.

She discussed how Caltech prepared her for that role in a 2011 interview with ENGenious, a publication of the Division of Engineering and Applied Science. In that interview, she said that “having a very solid technical foundation really helped with judgments I had to make in my career. … I was investing in people that I thought were going to make big leaps forward in technology. I wasn’t in the lab doing the work, but I was trying to exercise good judgment about where real breakthroughs might come from. That wouldn’t have been possible without the solid technical foundation I received at Caltech.”

In 1993, President Bill Clinton named Prabhakar director of the National Institute of Standards and Technology, a post she held until 1997, when she stepped down to pursue entrepreneurial interests in the Silicon Valley, funding and managing engineers and scientists to create new technologies and businesses. She returned to DARPA, this time as its director, in 2012.

Prabhakar appears in a 2015 video describing DARPA’s mission here.

Ellen Williams

Ellen Williams
Ellen Williams

Since 2014, Williams has served as director of the Advanced Research Projects Agency-Energy (ARPA-E), a federal agency modeled after DARPA and tasked with promoting and funding research and development of advanced energy technologies.

In 2014, as part of the kickoff to President Thomas F. Rosenbaum’s inauguration, she participated in a panel discussion at Caltech on “Science and the University-Government Partnership,” in which she described ARPA-E’s job as similar to that of a stockbroker, putting money into investments—in this case technologies—that will perform solidly but also rounding out the portfolio with riskier investments that nonetheless “have the potential to really win big.”

She said, “We have to take some risks [because] traditionally something like 20 percent of the initial investment of a technology portfolio will give 80 percent of the benefits—you just don’t know which are the 20 percent.”

Prior to joining ARPA-E, Williams served as the senior adviser to the United States Secretary of Energy and as the chief scientist for BP, where she was responsible for the company’s long-range scientific plans and activities as well as its major university research programs around the world.

Before working in industry and for the federal government, Williams built a 30-year career in academia, conducting research in nanoscience. She joined the faculty at the University of Maryland shortly after receiving her doctorate in chemistry from Caltech in 1981 and is currently on leave from her position of Distinguished University Professor in the Department of Physics and the Institute of Physical Science and Technology there.

CALTECH’S FIRST GRAD STUDENTS (+)

Our Winter 2015 issue highlighted PhD students’ efforts to navigate copious amounts of coursework, lab work, and teaching duties as well as their personal lives. Here we look at two of Caltech’s pioneering graduate students: Roscoe Dickinson, who earned the Institute’s first PhD, and Dorothy Ann Semenow, the first female graduate student at Caltech.

Roscoe Dickinson

Roscoe Dickinson in 1923
Roscoe Dickinson in 1923

Dickinson joined Caltech in 1917 after completing his undergraduate education at MIT. According to Judith Goodstein’s history of the Institute, Millikan’s School, Dickinson began working with Arthur Amos Noyes, the founder and first director of the Gates Chemical Laboratory on a then-pioneering technology: X-ray crystallography, a technique to help determine the atomic configurations of crystals.

Dickinson went on to receive a doctorate in chemistry as Caltech’s first PhD recipient in 1920, shortly after the school changed its name from the Throop College of Technology to its current title. He then joined the faculty as a professor of chemistry, mentoring promising graduate students including Linus Pauling (PhD ’25), who went on to become a two-time Nobel laureate, and Arnold O. Beckman (PhD ’28), who later invented the pH meter and was a longtime trustee and benefactor of Caltech.

Dorothy Ann Semenow

Dorothy Ann Semenow in photo from a 1953 article in E&S magazine.
Dorothy Ann Semenow in photo from a 1953 article in E&S magazine.

After getting her chemistry degree at Mount Holyoke and studying at MIT, Semenow joined Caltech as its sole female student at the invitation of John D. Roberts, Institute Professor of Chemistry (now emeritus). On arrival, she pursued research in theoretical organic chemistry, earning a PhD in chemistry and biology in 1955.

Roberts, who in a 1985 interview described Semenow as “a superb student … an excellent perseverer, a very sharp mind [and] a very good experimentalist,” said that, with her in mind, he worked with Linus Pauling to persuade the Institute administration to rescind the rule, then in force, prohibiting women from enrolling.

A July 2, 1955, article in the Pittsburgh Post-Gazette noted that she was permitted to enroll once “the school let down the barrier against her sex in favor of ‘women who give promise of great scientific contributions.’”

It also noted that by earning her PhD at Caltech, Semenow, then 25, had “cracked a male fortress.”

—Written by Jon Nalick

Endnotes (+)

In our Fall 2015 issue, we asked alumni to share what they would do if they had no limits. We printed only a few of the responses we received. Here are several more, some of which were edited for grammar, spelling, length, and clarity.

If you had no limits, what would you do, build, or explore?

Universecolor_300

Build a faster-than-light spacecraft and explore the universe.

Establish a settlement on the moon.

I would want to unify physics, biology, and psychology to answer the three biggest questions about our world: 1. How did the universe arise? 2. How did life arise? 3. How did consciousness arise?

I would build a public college or university where talented students could attend without paying tuition or fees.

Build a diagnostic tool to determine what mental illness a person has, whether a person is getting better or worse, and whether treatment is effective.

Go back_otl_hex

Since 1984, my dream has been to work on the development of the first-generation artificial intelligence system capable of guiding the development of a second-generation AI system that exceeds the capabilities of humans.

peace2I would end all wars, fighting, terrorism, crime, poverty and suffering—forever. I would change people so they accept other people as they are without trying to convert them to their beliefs.

I would expand to fill the universe.

A PASSION FOR PHYSICS—AND FASHION (+)

As we noted in the Fall 2015 issue, the tiny hairs on gecko feet exploit intermolecular, electrostatic attractive forces—called van der Waals forces—to allow the reptiles to defy gravity. Using a technology based on the same mechanism, one enterprising alumnus has found a way to meld physics with fashion.

Probably no one in history has ever needed to write a sentence that contained the words “gecko feet,” “van der Waals forces,” and “strapless bras.”

Until now.

That’s because Caltech alum Tony Roy (PhD, ’10) made an unlikely connection between the three, all in an effort to solve his wife’s dilemma of finding a strapless bra that would not slip over the course of an evening. His novel solution—which mixes physics, biomimicry, and fashion—spurred the creation of a new apparel company, Kellie K Apparel, named for his wife.

Roy’s insight was to incorporate into strapless bras a material that uses the same van der Waals forces that allow geckos to stick to walls and ceilings to deter the bras’ annoying tendency to slip. Specifically, he used a biocompatible, silicone-based material he designed, called GeckTech, as the crucial adhesive. (You can learn more about how GeckTech works on this webpage, which includes a video of Roy—with his friend and fellow Caltech alum, chemist Jessica Pfeilsticker (PhD ’14)—discussing the science behind the adhesive.)

Kellie K secured $27,000 in Kickstarter funding on November 12—the second round of funding it has received from Kickstarter—that will enable it to refine its bra designs based on customer feedback received over the past two years.

Before starting the company, Roy designed prototypes for various multimillion dollar startups as a research engineer at Idealab. He received his BS and MS degrees from the Ohio State University and his PhD from Caltech, all in mechanical engineering.

Roy said engineering the gecko-inspired bra was unusual in that it lacked the kinds of set objective parameters he was used to, needing instead to satisfy subjective requirements such as fit, aesthetics, and comfort. But regardless of the engineering challenges, he says he suspected the concept for the bra was solid pretty early on. “I thought the first one I made for my wife would be marginally better than a conventional strapless at best,” he notes. “But I knew I had made something special when she grabbed it the next time she needed to wear a strapless bra.”

—Written by Jon Nalick

How an RNA Gene Silences a Whole Chromosome (+)

 

Our Fall 2015 article “Unlocking the Chemistry of Life” noted how Caltech’s Proteome Exploration Laboratory has helped researchers like biologist Mitch Guttman decipher details of the human proteome—the proteins encoded by the human genome. Here we dive deeper into Guttman’s exploration of a class of RNA genes called long non-coding RNAs.

Researchers at Caltech have discovered how an abundant class of RNA genes, called long non-coding RNAs (lncRNAs, pronounced link RNAs) can regulate key genes. By studying an important lncRNA, called Xist, the scientists identified how this RNA gathers a group of proteins and ultimately prevents women from having an extra functional X-chromosome—a condition in female embryos that leads to death in early development. These findings mark the first time that researchers have uncovered the detailed mechanism of action for lncRNA genes.

“For years, we thought about genes as just DNA sequences that encode proteins, but those genes only make up about 1 percent of the genome. Mammalian genomes also encode many thousands of lncRNAs,” says Assistant Professor of Biology Mitch Guttman, who led the study published online in the April 27 issue of the journal Nature. These lncRNAs such as Xist play a structural role, acting to scaffold—or bring together and organize—the key proteins involved in cellular and molecular processes, such as gene expression and stem cell differentiation.

Guttman, who helped to discover an entire class of lncRNAs as a graduate student at MIT in 2009, says that although most of these genes encoded in our genomes have only recently been appreciated, there are several specific examples of lncRNA genes that have been known for decades. One well-studied example is Xist, which is important for a process called X chromosome inactivation.

All females are born with two X chromosomes in every cell, one inherited from their mother and one from their father. In contrast, males only contain one X chromosome (along with a Y chromosome). However, like males, females only need one copy of each X-chromosome gene—having two copies is an abnormality that will lead to death early during development. The genome skirts these problems by essentially “turning off” one X chromosome in every cell.

Previous research showed that Xist is essential to this process and does this by somehow preventing transcription, the initial step of the expression of genes on the X chromosome. However, because Xist is not a traditional protein-coding gene, until now researchers have had trouble figuring out exactly how Xist stops transcription and shuts down an entire chromosome.

“To start to make sense of what makes lncRNAs special and how they can control all of these different cellular processes, we need to be able to understand the mechanism of how any lncRNA gene can work. Because Xist is such an important molecule and because so much is known about what it does, it seemed like a great system to try to dissect the mechanisms of how it and other lncRNAs work,” Guttman says.

lncRNAs are known to corral and organize the proteins that are necessary for cellular processes, so Guttman and his colleagues began their study of the function of Xist by first developing a technique to find out what proteins it naturally interacts with in the cell. With a new method, called RNA antisense purification with mass spectrometry (RAP-MS), the researchers extracted and purified Xist lncRNA molecules, as well as the proteins that directly interact with Xist, from mouse embryonic stem cells. Then, collaborators at the Proteome Exploration Laboratory at Caltech applied a technique called quantitative mass spectrometry to identify those interacting proteins.

“RNA usually only obeys one rule: binding to proteins. RAP-MS is like a molecular microscope into identifying RNA-protein interactions,” says John Rinn, associate professor of stem cell and regenerative biology at Harvard University, who was not involved in the study. “RAP-MS will provide critically needed insights into how lncRNAs function to organize proteins and in turn regulate gene expression.”

Applying this to Xist uncovered 10 specific proteins that interact with Xist. Of these, three—SAF-A (Scaffold attachment factor-A), LBR (Lamin B Receptor), and SHARP (SMRT and HDAC associated repressor protein)—are essential for X chromosome inactivation. “Before this experiment,” Guttman says, “no one knew a single protein that was required by Xist for silencing transcription on the X chromosome, but with this method we immediately found three that are essential. If you lose any one of them, Xist doesn’t work—it will not silence the X chromosome during development.”

The new findings provide the first detailed picture of how lncRNAs work within a cellular process. Through further analysis, the researchers found that these three proteins performed three distinct, but essential, roles. SAF-A helps to tether Xist and all of its hitchhiking proteins to the DNA of the X chromosome, at which point LBR remodels the chromosome so that it is less likely to be expressed. The actual “silencing,” Guttman and his colleagues discovered, is done by the third protein of the trio: SHARP.

To produce functional proteins from the DNA (genes) of a chromosome, the genes must first be transcribed into RNA by an enzyme called RNA polymerase II. Guttman and his team found that SHARP leads to the exclusion of polymerase from the DNA, thus preventing transcription and gene expression.

This information soon may have clinical applications. The Xist lncRNA silences the X chromosome simply because it is located on the X chromosome. However, previous studies have demonstrated that this RNA and its silencing machinery can be used to inactivate other chromosomes—for example, the third copy of chromosome 21 that is present in individuals with Downs’ syndrome.

“We are starting to pick apart how lncRNAs work. We now know, for example, how Xist localizes to sites on X, how it silences transcription, and how it can change DNA structure,” Guttman says. “One of the things that is really exciting for me is that we can potentially leverage the principles used by lncRNAs, move them around in the genome, and use them as therapeutic agents to target specific defective pathways in disease.”

“But I think the real reason why this is so important for our field and even beyond is because this is a different type of regulation than we’ve seen before in the cell—it is a vast world that we previously knew nothing about,” he adds.

This work was published in a paper titled: “The Xist lncRNA interacts directly with SHARP to silence transcription through HDAC3.” The co-first authors of the paper are Caltech postdoctoral scholar Colleen A. McHugh and graduate student Chun-Kan Chen. Other coauthors from Caltech are Amy Chow, Christine F. Surka, Christina Tran, Mario Blanco, Christina Burghard, Annie Moradian, Alexander A. Shishkin, Julia Su, Michael J. Sweredoski, and Sonja Hess from the Proteome Exploration Laboratory. Additional authors include Amy Pandya-Jones and Kathrin Plath from UCLA and Patrick McDonel from MIT.

The study was supported by funding from the Gordon and Betty Moore Foundation, the Beckman Institute, the National Institutes of Health, the Rose Hills Foundation, the Edward Mallinckrodt Foundation, the Sontag Foundation, and the Searle Scholars Program.

Written by Jessica Stoller-Conrad

 

Image: Artist’s illustration of an X-chromosome. Caltech scientists developed a “molecular microscope” to study a new class of RNA gene and uncovered how an RNA can orchestrate the silencing of all genes across an entire chromosome. (Credit: Lance Hayashida/Caltech Office of Strategic Communications)

A Passion for Entanglement (+)

Our Fall 2015 article “Full Circle Physics” highlighted Caltech’s Institute for Quantum Information and Matter (IQIM) and its researchers who are exploring the frontiers of quantum science. We revisit the topic here from the viewpoint of SURF participant Patrick Rall, a senior who spent the summer there doing cutting-edge science.

For senior Patrick Rall, a native of Munich, Germany, the summer offers one of the year’s few chances to visit home. But for the last two summers, Rall, a Caltech physics major, has been spending his summers on campus, drawn by another opportunity—the chance to conduct cutting-edge research while being mentored by John Preskill, the Richard P. Feynman Professor of Theoretical Physics, as part of the Institute’s Summer Undergraduate Research Fellowships (SURF) program. Last year, Rall worked in the laser lab of Assistant Professor of Physics David Hsieh on a condensed matter physics experiment. This summer, he switched his attention to quantum information science, a new field that seeks to exploit quantum mechanical effects to create next-generation computers that will be faster and more secure than those currently available.

A key idea in quantum mechanics is superposition of states. Subatomic particles like electrons can be described as having multiple positions, or more than one speed or energy level. This is illustrated by the thought experiment developed in 1935 by Austrian physicist Edwin Schrödinger. In it, a cat is placed into an imaginary box containing a bottle of poison, radioactive material, and a radiation detector. If a radioactive particle decays and radiation is detected inside the box, the poison is released and the cat is killed. But according to quantum mechanics, the cat could be simultaneously alive and dead. Yet if one were to open the lid of the box, the cat would become alive or dead. By opening the box, we have destroyed the quantum nature of the state; that is to say, the observation itself affects the outcome, and yet that outcome is randomly determined.

“Where this gets really interesting is when more than one cat gets involved,” Rall says. “Then we can have states where looking at one cat determines the outcome of looking at the other, even if they are on different continents or even different planets. For example, I cannot know if I will see a live or a dead cat upon opening either box, but I can know that the cats are either both alive or both dead.”

This “spooky action at a distance”—as Einstein phrased it—is called entanglement, and an entangled state, physicists say, can store information. “When looking at systems with many cats, the amount of entanglement information is much larger than what I can obtain by looking at the cats individually,” Rall says. “To harness the sheer quantity of information stored in these so-called many-body systems, we must better understand the structure of these spooky correlations. This is what I worked on this summer.”

Quantum many-body systems are difficult to simulate on a computer, but by looking at small-enough systems and using mathematical tools, researchers can study complex entangled quantum states. Physicists have been studying many-body entanglement for a long time because of its importance in understanding certain semiconductors.

“This summer, I had the privilege to work under Professor Preskill, and that was an incredible experience,” Rall says. A central interest of Preskill’s lab is to design schemes for quantum computation. Modern computers use classical bits—ones and zeroes—to store data. A quantum computer would use quantum bits—or qubits—and use their superposition and entanglement to perform computation. Quantum computers, while still in the experimental stage (with heavy investment from companies like IBM, Microsoft, and Google), have been touted for their potential to generate unbreakable codes and to efficiently simulate many complex systems, with implications for computational chemistry and biology.

“The most interesting thing about the quantum computer is that we have no idea what it could be capable of,” says Rall. “We know some quantum algorithms that are faster than the best-known classical algorithms. But what are the limits? Nobody knows.”

Written by Rod Pyle

 

Photo: Caltech undergraduate Patrick Rall worked on quantum information science during last summer’s SURF program (Credit: Seth Hansen)

Cryo-EM: The Next Generation (+)

As noted in our Fall 2015 article “Viral Videos (And Bacterial Ones, Too)”, Grant Jensen, professor of biophysics and biology, has trained 11 researchers over the last decade in the use of cryo-electron microscopy (cryo-EM); many of them have gone on to build and run cryo-EM labs of their own in various corners of the globe. Here, we talk to a few of those he has trained about their time in the Jensen lab. #ViralVideos

 

Ariane Briegel

“I joined the laboratory of Grant Jensen in 2005. At the time, electron cryotomography was still largely unknown in the field of microbiology, but during my time at Caltech, I witnessed the dramatic change in the cryo-EM field as it became the method of choice for many structural biology questions.

“I also experienced the growth of the Jensen group from the small lab of an assistant professor to the large and established lab that Grant is running today. Also during my time here, I closely followed all the steps of his developing career, from his first grant applications, his preparation for tenure, and finally becoming an HHMI investigator and a full professor.”

This month, Briegel—who was a research scientist in the Jensen lab—will be starting a tenured professorship at Leiden University in the Netherlands.

 

Elitza Tocheva

Assistant professor at Université de Montréal

“I worked alongside world-class scientists in an exciting research environment during my time at Caltech. The opportunities in Grant Jensen’s lab were endless, and I got to explore novel areas of microbiology and develop my own scientific ideas. It is that freedom and independence that were the best schooling for becoming a principal investigator.”

 

Lu Gan

Assistant professor of biological sciences at the National University of Singapore

“Grant not only prepared me to run a lab but also to secure a faculty position. He provided intensive training and clear communication in how to identify, think about, and focus on the most important questions in biology. These skills are critical, because there are too many interesting questions for a junior faculty member to pursue; only a few of them can bear the ripest fruit. Also, given how much our research depends on high-end instrumentation, I also find it valuable to reflect on how Grant dealt with the usage and allocation of instrument time. Currently, we are in a shared-usage cryo-EM facility that is managed by Jian Shi, who is also a Jensen-lab alum. He runs this facility similar to how Grant did, so I think our new high-end instruments are being used effectively.”

 

Morgan Beeby

Lecturer in structural biology at Imperial College in London

“I felt really privileged and excited to join Grant’s lab in 2008, just as the cryo-EM field began to explode. Grant’s enthusiasm and focus were infectious and really inspired me to start my own lab at Imperial College in London. I still have fond memories of the Caltech environment and enjoying the fantastic panorama of the San Gabriel Mountains from campus. I also fondly recall Grant’s exclamation of ‘hot dog!’ You really knew you’d caught his attention if your results elicited that!”

Taking Dinosaur Temperatures with Eggshells (+)

Caltech geochemist John Eiler has a knack for finding novel scientific niches to investigate, as we reported in our Fall 2015 article “Ready, Set, Explore.”

Now, he and Rob Eagle, a former Caltech postdoctoral scholar now at UCLA, have measured the body temperatures of a wide range of dinosaurs, providing insight into how the animals may have regulated their internal heat.

In the October 13, 2015, issue of the journal Nature Communications, the pair described how they used the analysis of isotopic ratios to reveal the way in which sauropods—a group that includes some of the biggest dinosaurs ever to live—performed the basic task of balancing their energy intake and output.

Read on to learn more about how they examined dinosaurs’ metabolisms and uncovered one of the dinosaurs’ biggest secrets.

Featured image: A large clutch of titanosaur eggs that has been cleaned for research.
Credit: Luis Chiappe, LA County Natural History Museum

LIGO’s SURF Students Look for the Perfect Wave (+)

Above, LIGO SURF students, class of 2015, in the control room at the LIGO facility in Livingston, Louisiana. The large monitor over their heads displays incoming data in real time. Credit: LIGO/LLO/Caltech

As noted in our Fall 2015 Random Walk article, “An Advanced Look,” Caltech president Thomas Rosenbaum spent a few hours in May touring the Laser Interferometer Gravitational-wave Observatory (LIGO) in Hanford, Washington.

Over the following summer, 27 students in Caltech’s Summer Undergraduate Research Fellowships (SURF) program got an even more intimate look at LIGO: they became full partners in one of the biggest, most complex physics experiments ever. Their contributions ranged from creating hardware and software for LIGO’s current upgrade to helping design the next generation of upgrades.

Thanks to SURF, students have been part of LIGO since the 1990s—more than 350 of them. Some have gone on to careers with LIGO, and some are now mentoring students themselves.

Read more about LIGO and what this year’s SURFers got up to.