The Law of Moore

This year, as Moore’s Law turned 50, many people turned to look at what it has meant for not just the computer industry, but for our world. In May, the New York Times columnist and Pulitzer Prize winning author Thomas Friedman talked about the Law with Gordon Moore himself, at San Francisco’s Exploratorium at an event hosted by Intel (the company Moore co-founded in 1968) and the Gordon and Betty Moore Foundation.


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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?


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.

The Science of Economics

John Ledyard is an economist, but when he talks about the work that he and his colleagues who study socioeconomic systems at Caltech have completed over the last decade with the support of the Gordon and Betty Moore Foundation, he looks to astronomy for an appropriate metaphor. He’s trying to find a way to explain the importance and utility of a suite of software they have developed.

“It’s kind of like building a new, powerful telescope,” Ledyard says. “It’s not that all of the astronomers using that telescope are working on the same thing, but because of the larger telescope, they can all do a lot more, different work. What the Moore Foundation grant enabled us to do was to build a bigger measurement device.”

The new software, along with funding, has enabled researchers to create and run experiments in the lab to test all sorts of market systems involving social interactions—everything from the effect of inequality on tax rates to the best way for the United Nations to auction off pallets of natural rubber in Vietnam.

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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

Full Circle Physics

With the help of interviews conducted by IQIM communications coordinator Crystal Dilworth (PhD ’14) and filmmaker Iram Parveen Bilal (BS ’04), E&S has delved into the thinking of several IQIM scientists about the frontiers of quantum science, the role IQIM plays in exploring that frontier, and the question oft thought but rarely spoken: Why should we care? Here—in a “conversation” assembled from separate interviews—are some of their insights into what makes the world of the tiny such a big deal.

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Unlocking the Chemistry of Life

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.

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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)

Viral Videos (And Bacterial Ones, Too)

Grant Jensen is 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.

“The nature of our work is very visual,” says Jensen, a biologist who is one of just a handful of experts in this growing field, in which the electron imaging of cryogenic samples allows scientists to image biological specimens in as close to a natural, or native, state as possible.

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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)

Ready, Set, Explore

In recent years, John Eiler has partnered with colleagues in disparate scientific fields to make discoveries in paleontology, archaeobiology, atmospheric chemistry, climatology, martian geology, and more. Along the way, he has helped develop and refine instruments that reveal previously hidden facets of chemistry, and opened up new areas for scientific exploration.

“My inclination is to be constantly in motion and working in a segment of the scientific community where I can create something that really feels new to me,” Eiler says.

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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!”

Origins: Birth of the pH Meter

Arnold O. Beckman was a Caltech alumnus (PhD ‘28), former faculty member, and trustee. He was also the founder of Beckman Instruments (now Beckman Coulter), a company that began with Beckman’s invention of the pH meter, now one of the most widely used pieces of laboratory equipment in the world.

The pH meter’s story started in 1934, when one of Beckman’s undergrad classmates from the University of Illinois at Urbana, Glen Joseph—who was then working for the California Fruit Growers Exchange—came to Beckman’s Caltech office with a lemon problem. Here is how Beckman recalled that encounter during a 1978 interview with Mary Terrall for the Caltech Oral Histories Project.

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