Making Nanowires from Protein and DNA

The ability to custom design biological materials such as protein and DNA opens up technological possibilities that were unimaginable just a few decades ago. For example, synthetic structures made of DNA could one day be used to deliver cancer drugs directly to tumor cells, and customized proteins could be designed to specifically attack a certain kind of virus. Although researchers have already made such structures out of DNA or protein alone, a Caltech team recently created—for the first time—a synthetic structure made of both protein and DNA. Combining the two molecule types into one biomaterial opens the door to numerous applications.

A paper describing the so-called hybridized, or multiple component, materials appears in the September 2 issue of the journal Nature.

There are many advantages to multiple component materials, says Yun (Kurt) Mou (PhD '15), first author of the Nature study. "If your material is made up of several different kinds of components, it can have more functionality. For example, protein is very versatile; it can be used for many things, such as protein–protein interactions or as an enzyme to speed up a reaction. And DNA is easily programmed into nanostructures of a variety of sizes and shapes."

But how do you begin to create something like a protein–DNA nanowire—a material that no one has seen before?

Mou and his colleagues in the laboratory of Stephen Mayo, Bren Professor of Biology and Chemistry and the William K. Bowes Jr. Leadership Chair of Caltech's Division of Biology and Biological Engineering, began with a computer program to design the type of protein and DNA that would work best as part of their hybrid material. "Materials can be formed using just a trial-and-error method of combining things to see what results, but it's better and more efficient if you can first predict what the structure is like and then design a protein to form that kind of material," he says.

The researchers entered the properties of the protein–DNA nanowire they wanted into a computer program developed in the lab; the program then generated a sequence of amino acids (protein building blocks) and nitrogenous bases (DNA building blocks) that would produce the desired material.

However, successfully making a hybrid material is not as simple as just plugging some properties into a computer program, Mou says. Although the computer model provides a sequence, the researcher must thoroughly check the model to be sure that the sequence produced makes sense; if not, the researcher must provide the computer with information that can be used to correct the model. "So in the end, you choose the sequence that you and the computer both agree on. Then, you can physically mix the prescribed amino acids and DNA bases to form the nanowire."

The resulting sequence was an artificial version of a protein–DNA coupling that occurs in nature. In the initial stage of gene expression, called transcription, a sequence of DNA is first converted into RNA. To pull in the enzyme that actually transcribes the DNA into RNA, proteins called transcription factors must first bind certain regions of the DNA sequence called protein-binding domains.

Using the computer program, the researchers engineered a sequence of DNA that contained many of these protein-binding domains at regular intervals. They then selected the transcription factor that naturally binds to this particular protein-binding site—the transcription factor called Engrailed from the fruit fly Drosophila. However, in nature, Engrailed only attaches itself to the protein-binding site on the DNA. To create a long nanowire made of a continuous strand of protein attached to a continuous strand of DNA, the researchers had to modify the transcription factor to include a site that would allow Engrailed also to bind to the next protein in line.

"Essentially, it's like giving this protein two hands instead of just one," Mou explains. "The hand that holds the DNA is easy because it is provided by nature, but the other hand needs to be added there to hold onto another protein."

Another unique attribute of this new protein–DNA nanowire is that it employs coassembly—meaning that the material will not form until both the protein components and the DNA components have been added to the solution. Although materials previously could be made out of DNA with protein added later, the use of coassembly to make the hybrid material was a first. This attribute is important for the material's future use in medicine or industry, Mou says, as the two sets of components can be provided separately and then combined to make the nanowire whenever and wherever it is needed.

This finding builds on earlier work in the Mayo lab, which, in 1997, created one of the first artificial proteins, thus launching the field of computational protein design. The ability to create synthetic proteins allows researchers to develop proteins with new capabilities and functions, such as therapeutic proteins that target cancer. The creation of a coassembled protein–DNA nanowire is another milestone in this field.

"Our earlier work focused primarily on designing soluble, protein-only systems. The work reported here represents a significant expansion of our activities into the realm of nanoscale mixed biomaterials," Mayo says.

Although the development of this new biomaterial is in the very early stages, the method, Mou says, has many promising applications that could change research and clinical practices in the future.

"Our next step will be to explore the many potential applications of our new biomaterial," Mou says. "It could be incorporated into methods to deliver drugs into cells—to create targeted therapies that only bind to a certain biomarker on a certain cell type, such as cancer cells. We could also expand the idea of protein–DNA nanowires to protein–RNA nanowires that could be used for gene therapy applications. And because this material is brand-new, there are probably many more applications that we haven't even considered yet."  

The work was published in a paper titled, "Computational design of co-assembling protein-DNA nanowires." In addition to Mou and Mayo, other Caltech coauthors include former graduate students Jiun-Yann Yu (PhD '14) and Timothy M. Wannier (PhD '15), as well as Chin-Lin Guo from Academia Sinica in Taiwan. The work was funded by the Defense Advanced Research Projects Agency Protein Design Processes Program, a National Security Science and Engineering Faculty Fellowship, and the Caltech Programmable Molecular Technology Initiative funded by the Gordon and Betty Moore Foundation.

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Student Biosciences Innovator Named International Research Fellow

Graduate student Nathan Belliveau has been selected as a Howard Hughes Medical Institute International Student Research Fellow. Awardees are graduate students in the sciences and will receive $43,000 annually through their third, fourth, and fifth years of predoctoral study. This year, HHMI selected 45 new fellows from 329 applications.

Belliveau applies techniques from DNA sequencing as well as ideas from information theory to the study of gene regulation, the processes by which cells trigger or inhibit the production of RNA and proteins. "I'm examining several bacterial genes that have been implicated in antibiotic resistance," he says. "In the future I hope to continue studying aspects of regulation, but with a focus on understanding how these details support interactions between microbes and other organisms."

"I have been astonished at the rate at which he has brought new technologies, such as the routine use of mass spectrometry and genome editing with CRISPR, into my group," says Rob Phillips, the Fred and Nancy Morris Professor of Biophysics and Biology, and Belliveau's advisor. "Each time he introduces one of these techniques, it brings us that much closer to our ambition of being able to read the regulatory logic of genomes at will."

Belliveau completed his undergraduate degree at the University of Waterloo in Canada before coming to Caltech. "When I applied for the HHMI award I was forced to thoroughly consider my proposed research direction, and it has provided me with a boost of confidence knowing that those examining the applications agree with its importance," Belliveau says. "I was very happy to hear I was awarded this funding."

"Nathan is a truly outstanding student who surprises me nearly every time I talk to him by his experimental talent, his creative thinking, and how fast he gets things done," Phillips says. "He is one of those exceptional people who has a Midas touch. I have so far not seen him touch a single thing that doesn't turn out way better than I had imagined."

Lori Dajose
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High School Students Visit for Women in STEM Preview Day

On Friday, August 7, 104 female high school seniors and their families visited Caltech for the fourth annual Women in STEM (WiSTEM) Preview Day, hosted by the undergraduate admissions office. The event was designed to explore the accomplishments and continued contributions of Caltech women in the disciplines of science, technology, engineering, and mathematics (STEM).

The day opened with a keynote address by Marianne Bronner, the Albert Billings Ruddock Professor of Biology and executive officer for neurobiology. Bronner, who studies the development of the central nervous system, spoke about her experiences in science and at Caltech.

"Caltech is an exciting place to be. It's a place where you can be creative and think outside the box," she said. "My advice to you would be to try different things, play around, and do what makes you happy." Bronner ended her address by noting the pleasure she takes in mentoring young scientists, and especially young women. "I was just like you," she said.

Over the course of the day, students and their families attended panels on undergraduate research opportunities and participated in social events where current students shared their experiences of Caltech life. They also listened to presentations from female scientists and engineers of the Jet Propulsion Laboratory.

"I really love science, and it's so exciting to be around all of these other people who share that," says Sydney Feldman, a senior from Maryland. "I switched around my whole summer visit schedule to come to this event and I'm having such a great time."

The annual event began four years ago with the goal of encouraging interest in STEM in high school women and ultimately increasing applications to Caltech by female candidates. In 2009, a U.S. Department of Commerce study showed that women make up 24 percent of the STEM workforce and hold a disproportionately low share of undergraduate degrees in STEM fields.

"Women are seriously underrepresented in these fields," says Caltech admissions counselor and WiSTEM coordinator Abeni Tinubu. "Our event really puts emphasis on how Caltech supports women on campus, and we want to show prospective students that."

This year, the incoming freshman class is a record 47 percent female students. "This is hugely exciting," says Jarrid Whitney, the executive director of admissions and financial aid. "We've been working hard toward our goal of 50 percent women, and it is clearly paying off thanks to the support of President Rosenbaum and the overall Caltech community."

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NSF BRAIN Funding Awarded to Caltech Neuroscientist

On August 12, in support of President Obama's Brain Research through Advancing Innovative Neurotechnology—or BRAIN—Initiative, the National Science Foundation (NSF) announced 16 new grants for fundamental brain research. A cognitive neuroengineering project co-led by Richard Andersen, the James G. Boswell Professor of Neuroscience, was selected as a recipient for one of these grants.

Designed to bring together interdisciplinary teams of scientists and engineers from diverse fields, the grants represent two themes: neuroengineering and brain-inspired concepts and designs, and individuality and variation. Each grants provides up to $1 million in funding over two to four years.

Andersen, whose work falls under the first theme, plans to use his grant to improve the functionality of neural prosthetic devices—devices that, when implanted in the brain, can allow patients with amputations or paralysis to control the movement of a robotic limb. The work is a collaboration with Charles Y. Liu, of Keck Medicine of USC, and Kapil Katyal of Johns Hopkins University.

In a clinical trial earlier this year, Andersen showed that a neural prosthetic device implanted in the brain's center for intentions—the posterior parietal cortex—could allow a tetraplegic patient to control a robotic arm with only his thoughts. The new work will build on this idea, Andersen says. "We are developing a shared control system in which we can record the intent of a tetraplegic patient and immediately communicate that intent to a smart robotic limb that can handle the details of the movement. This enables more effortless control by the patients," he says.

The grants are funded by the NSF Integrative Strategies of Understanding Neural and Cognitive Systems program and the NSF Computer & Information Science & Engineering Directorate. The NSF Directorates for Engineering and for Education and Human Resources also support the grants.

Andersen, who also received a grant from the state-funded Cal-BRAIN program for work in improving neural prosthetics, joins six other Caltech projects associated with the BRAIN Initiative that were funded by the National Institutes of Health last fall.

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Science for the Community

On the grounds of San Marino's Huntington Library, Art Collections, and Botanical Gardens—to the north of the Chinese Gardens, in the private, half-acre Huntington Ranch area—nearly two dozen middle- and high-school students have been spending this summer measuring the levels of nitrogen in the soils around them to help the ranch determine whether its soil is up to the challenge of growing an urban garden.

This hands-on research experience is part of the Community Science Academy @ Caltech, which is affiliated with Caltech's Center for Teaching, Learning, and Outreach (CTLO). The 23 first-timers in what is called CSA 1 are studying biological systems at the ranch; a similar number of continuing students, in CSA 2, are studying engineering and programming, and are building their own scientific instruments.

The program runs three days a week for six weeks. For CSA 1 students, it began on June 15 with soil sampling; by July 24, when it ends, students will have designed and performed their own experiments.

CSA@Caltech is now in its second year. It initially was funded with support from a National Institutes of Health Director's Pioneer Award to Caltech Professor of Biology Bruce Hay. In addition, the Pasadena Educational Foundation and the Siemens Foundation currently provide support for scholarships that allow all students from the Pasadena Unified School District to attend the program free of charge.

The students start most days with lectures by members of the Caltech staff. Every student is issued an iPad and keyboard for note taking and fieldwork. This technology allows the lectures to become interactive presentations using software that allows constant feedback between teacher and student. They spend much of their time at the CTLO on the Caltech campus, for talks on topics including soil and water quality, pest control, environmental monitoring, and remote sensing. They also work in the undergraduate teaching labs in Caltech's Divisions of Chemistry and Chemical Engineering and Biology and Biological Engineering for lessons on plant processing and bacterial detection, respectively.

At the Huntington Library, students apply in an outdoor setting what they have learned and practiced in Caltech classrooms and labs. For example, they gather soil samples from gardens and water samples from lily ponds for nitrate and ammonia testing; they conduct experiments on ant behavior; and they design and build sensor-carrying remote-controlled powered kites, which they fly over the Library grounds.

"These hands-on methods are critical for teaching students about the collaborative nature of science, the system of trial and error, and the importance of following protocols in scientific experimentation and analysis," says James Maloney (MS '06), one of the two codirectors of the CSA@Caltech program. Even while the students are getting what may well be their first exposure to research, they are also making a serious contribution to the Huntington's understanding of the ranch's viability as an urban garden. The ranch was originally a gravel parking lot, notes ranch coordinator Kyra Saegusa. It took six years for the soil to be rebuilt with sheets of mulch. The question now is whether it is ready for growing fruits and vegetables.

If the shouts of "I got a worm!" from one 13-year-old field worker are any indication, the soil restoration is certainly moving in the right direction.

The ultimate goal of CSA@Caltech—to promote STEM (science, technology, engineering, and mathematics) in secondary education and to help create the next generation of scientists—is further buttressed by tours of Caltech labs, where researchers such as Sarah Reisman, professor of chemistry, talked to the CSA@Caltech students about life as a scientist. Some of the students have already chosen areas in which they think they would like to specialize: for instance, Eris, a ninth grader from Blair High School in CSA 2, wants to study engineering and chemistry; Brandon, a CSA 2 ninth grader from Pasadena High School, wants to go into theoretical physics; and CSA 1 student Connor, an eighth grader from Sierra Madre Middle School, wants to be an aerospace engineer.

Building on this success, CSA@Caltech plans to add a third year of study next summer and continue their development of new educational technologies. "Our goal is to make high-quality science accessible to all," says CSA@Caltech codirector Julius Su (BS '98, BS '99, PhD '07).

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$100 Million Gift from Gordon and Betty Moore Will Bolster Graduate Fellowships

Trustees Gordon (PhD '54) and Betty Moore have pledged $100 million to Caltech, the second-largest single contribution in the Institute's history. With this gift, they have created a permanent endowment and entrusted the choice of how to direct the funds to the Institute's leadership—providing lasting resources coupled with uncommon freedom.

"Those within the Institute have a much better view of what the highest priorities are than we could have," Intel Corporation cofounder Gordon Moore explains. "We'd rather turn the job of deciding where to use resources over to Caltech than try to dictate it from outside."

Applying the Moores' donation in a way that will strengthen the Institute for generations to come, Caltech's president and provost have decided to dedicate the funds to fellowships for graduate students.

"Gordon and Betty Moore's incredibly generous gift will have a transformative effect on Caltech," says President Thomas F. Rosenbaum, holder of the Institute's Sonja and William Davidow Presidential Chair and professor of physics. "Our ultimate goal is to provide fellowships for every graduate student at Caltech, to free these remarkable young scholars to pursue their interests wherever they may lead, independent of the vicissitudes of federal funding. The fellowships created by the Moores' gift will help make the Institute the destination of choice for the most original and creative scholars, students and faculty members alike."

Further multiplying the impact of the Moores' contribution, the Institute has established a program that will inspire others to contribute as well. The Gordon and Betty Moore Graduate Fellowship Match will provide one additional dollar for every two dollars pledged to endow Institute-wide fellowships. In this way, the Moores' $100 million commitment will increase fellowship support for Caltech by a total of $300 million.

Says Provost Edward M. Stolper, the Carl and Shirley Larson Provostial Chair and William E. Leonhard Professor of Geology: "Investigators across campus work with outstanding graduate students to advance discovery and to train the next generation of teachers and researchers. By supporting these students, the Moore Match will stimulate creativity and excellence in perpetuity all across Caltech. We are grateful to Gordon and Betty for allowing us the flexibility to devote their gift to this crucial priority."

The Moores describe Caltech as a one-of-a-kind institution in its ability to train budding scientists and engineers and conduct high-risk research with world-changing results—and they are committed to helping the Institute maintain that ability far into the future.

"We appreciate being able to support the best science," Gordon Moore says, "and that's something that supporting Caltech lets us do."

The couple's extraordinary philanthropy already has motivated other benefactors to follow their example, notes David L. Lee, chair of the Caltech Board of Trustees.

"The decision that Gordon and Betty made—to give such a remarkable gift, to make it perpetual through an endowment, and to remove any restrictions as to how it can be used—creates a tremendous ripple effect," Lee says. "Others have seen the Moores' confidence in Caltech and have made commitments of their own. We thank the Moores for their leadership."

The Moores consider their gift a high-leverage way of fostering scientific research at a place that is close to their hearts. Before he went on to cofound Intel, Gordon Moore earned a PhD in chemistry from Caltech.

"It's been a long-term association that has served me well," he says.

Joining him in Pasadena just a day after the two were married, Betty Moore became active in the campus community as well. A graduate of San Jose State College's journalism program, she secured a job at the Ford Foundation's new Pasadena headquarters and also made time to come to campus to participate in community activities, including the Chem Wives social club.

"We started out at Caltech," she recalls. "I had a feeling that it was home away from home. It gives you a down-home feeling when you're young and just taking off from family. You need that connection somehow."

After earning his PhD from Caltech in 1954, Gordon Moore took a position conducting basic research at the Applied Physics Laboratory at Johns Hopkins University. Fourteen years and two jobs later, he and his colleague Robert Noyce cofounded Intel Corp. Moore served as executive vice president of the company until 1975, when he took the helm. Under his leadership—as chief executive officer (1975 to 1987) and chairman of the board (1987 to 1997)—Intel grew from a Mountain View-based startup to a giant of Silicon Valley, worth more than $140 billion today.

Moore is widely known for "Moore's Law," his 1965 prediction that the number of transistors that can fit on a chip would double every year. Still relevant 50 years later, this principle pushed Moore and his company—and the tech industry as a whole—to produce continually more powerful and cheaper semiconductor chips.

Gordon Moore joined the Caltech Board of Trustees in 1983 and served as chair from 1993 to 2000. That same year, he and his wife established the Gordon and Betty Moore Foundation, an organization dedicated to creating positive outcomes for future generations in the San Francisco Bay Area and around the world.

Among numerous other honors, Gordon Moore is a member of the National Academy of Engineering, a fellow of the Institute of Electrical and Electronics Engineers, and a recipient of the National Medal of Technology and the Presidential Medal of Freedom. 

The Gordon and Betty Moore Graduate Fellowship Match is available for new gifts and pledges to endow graduate fellowships. For more information about the match and how to support graduate education at Caltech, please contact Jon Paparsenos, executive director of development, at (626) 395-3088 or

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Mosquitoes Use Smell to See Their Hosts

On summer evenings, we try our best to avoid mosquito bites by dousing our skin with bug repellents and lighting citronella candles. These efforts may keep the mosquitoes at bay for a while, but no solution is perfect because the pests have evolved to use a triple threat of visual, olfactory, and thermal cues to home in on their human targets, a new Caltech study suggests.

The study, published by researchers in the laboratory of Michael Dickinson, the Esther M. and Abe M. Zarem Professor of Bioengineering, appears in the July 17 online version of the journal Current Biology.

When an adult female mosquito needs a blood meal to feed her young, she searches for a host—often a human. Many insects, mosquitoes included, are attracted by the odor of the carbon dioxide (CO2) gas that humans and other animals naturally exhale. However, mosquitoes can also pick up other cues that signal a human is nearby. They use their vision to spot a host and thermal sensory information to detect body heat.

But how do the mosquitoes combine this information to map out the path to their next meal?

To find out how and when the mosquitoes use each type of sensory information, the researchers released hungry, mated female mosquitoes into a wind tunnel in which different sensory cues could be independently controlled. In one set of experiments, a high-concentration CO2 plume was injected into the tunnel, mimicking the signal created by the breath of a human. In control experiments, the researchers introduced a plume consisting of background air with a low concentration of CO2. For each experiment, researchers released 20 mosquitoes into the wind tunnel and used video cameras and 3-D tracking software to follow their paths.

When a concentrated CO2 plume was present, the mosquitos followed it within the tunnel as expected, whereas they showed no interest in a control plume consisting of background air.

"In a previous experiment with fruit flies, we found that exposure to an attractive odor led the animals to be more attracted to visual features," says Floris van Breugel, a postdoctoral scholar in Dickinson's lab and first author of the study. "This was a new finding for flies, and we suspected that mosquitoes would exhibit a similar behavior. That is, we predicted that when the mosquitoes were exposed to CO2, which is an indicator of a nearby host, they would also spend a lot of time hovering near high-contrast objects, such as a black object on a neutral background."

To test this hypothesis, van Breugel and his colleagues did the same CO2 plume experiment, but this time they provided a dark object on the floor of the wind tunnel. They found that in the presence of the carbon dioxide plumes, the mosquitoes were attracted to the dark high-contrast object. In the wind tunnel with no CO2 plume, the insects ignored the dark object entirely.

While it was no surprise to see the mosquitoes tracking a CO2 plume, "the new part that we found is that the CO2 plume increases the likelihood that they'll fly toward an object. This is particularly interesting because there's no CO2 down near that object—it's about 10 centimeters away," van Breugel says. "That means that they smell the CO2, then they leave the plume, and several seconds later they continue flying toward this little object. So you could think of it as a type of memory or lasting effect."

Next, the researchers wanted to see how a mosquito factors thermal information into its flight path. It is difficult to test, van Breugel says. "Obviously, we know that if you have an object in the presence of a CO2 plume—warm or cold—they will fly toward it because they see it," he says. "So we had to find a way to separate the visual attraction from the thermal attraction."

To do this, the researchers constructed two glass objects that were coated with a clear chemical substance that made it possible to heat them to any desired temperature. They heated one object to 37 degrees Celsius (approximately human body temperature) and allowed one to remain at room temperature, and then placed them on the floor of the wind tunnel with and without CO2 plumes, and observed mosquito behavior. They found that mosquitoes showed a preference for the warm object. But contrary to the mosquitoes' visual attraction to objects, the preference for warmth was not dependent on the presence of CO2.

"These experiments show that the attraction to a visual feature and the attraction to a warm object are separate. They are independent, and they don't have to happen in order, but they do often happen in this particular order because of the spatial arrangement of the stimuli: a mosquito can see a visual feature from much further away, so that happens first. Only when the mosquito gets closer does it detect an object's thermal signature," van Breugel says.

Information gathered from all of these experiments enabled the researchers to create a model of how the mosquito finds its host over different distances. They hypothesize that from 10 to 50 meters away, a mosquito smells a host's CO2 plume. As it flies closer—to within 5 to 15 meters—it begins to see the host. Then, guided by visual cues that draw it even closer, the mosquito can sense the host's body heat. This occurs at a distance of less than a meter.

"Understanding how brains combine information from different senses to make appropriate decisions is one of the central challenges in neuroscience," says Dickinson, the principal investigator of the study. "Our experiments suggest that female mosquitoes do this in a rather elegant way when searching for food. They only pay attention to visual features after they detect an odor that indicates the presence of a host nearby. This helps ensure that they don't waste their time investigating false targets like rocks and vegetation. Our next challenge is to uncover the circuits in the brain that allow an odor to so profoundly change the way they respond to a visual image."

The work provides researchers with exciting new information about insect behavior and may even help companies design better mosquito traps in the future. But it also paints a bleak picture for those hoping to avoid mosquito bites.

"Even if it were possible to hold one's breath indefinitely," the authors note toward the end of the paper, "another human breathing nearby, or several meters upwind, would create a CO2 plume that could lead mosquitoes close enough to you that they may lock on to your visual signature. The strongest defense is therefore to become invisible, or at least visually camouflaged. Even in this case, however, mosquitoes could still locate you by tracking the heat signature of your body . . . The independent and iterative nature of the sensory-motor reflexes renders mosquitoes' host seeking strategy annoyingly robust."

These results were published in a paper titled "Mosquitoes use vision to associate odor plumes with thermal targets." In addition to Dickinson and van Breugel, the other authors are Jeff Riffell and Adrienne Fairhall from the University of Washington. The work was funded by a grant from the National Institutes of Health.

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Sniffing Out Answers: A Conversation with Markus Meister

Blindfolded and asked to distinguish between a rose and, say, smoke from a burning candle, most people would find the task easy. Even differentiating between two rose varieties can be a snap because the human olfactory system—made up of the nerve cells in our noses and everything that allows the brain to process smell—is quite adept. But just how sensitive is it to different smells?

In 2014, a team of scientists from the Rockefeller University published a paper in the journal Science, arguing that humans can discriminate at least 1 trillion odors. Now Markus Meister, the Anne P. and Benjamin F. Biaggini Professor of Biological Sciences at Caltech, has published a paper in the open-access journal eLife, in which he disputes the 2014 claim, saying that the science is not yet in a place where such a number can be determined.

We recently spoke with Meister about his new paper and what it says about the claim that we can distinguish a trillion smells.


What was the goal of the 2014 paper, and why do you take issue with it?

The overt question the authors asked was: How many different smells can humans distinguish? That is a naturally interesting question, in part because in other fields of sensory biology, similar questions have already been answered. People quibble about the exact numbers, but in general scientists agree that humans can distinguish about 1 to 2 million colors and something on the order of 100,000 pure tones.

But as interesting as the question is, I argue that we, as a field, are not yet prepared to address it. First we need to know how many dimensions span the perceptual space of odors. And by that I mean: how many olfactory variables are needed to fully describe all of the odors that humans can experience?

In the case of human vision, we say that the perceptual space for colors has three dimensions, which means that every physical light can be described by three numbers—how it activates the red, green, and blue cone photoreceptors in the retina.

As long as we don't know the dimensionality of odor space, we don't know how to even start interpreting measurements. Once we know the dimensionality, we can start probing the space systematically and ask how many different odors fit into it in the same way that we've looked at how many different colors fit into the three-dimensional space of colors.

The fundamental conceptual mistake that the authors of the Science paper made was to assume that the space of odor perception has 128 dimensions or more and then interpret the data as though that was the case . . . even though there is absolutely no evidence to suggest that the odor space has such high dimensionality.


What makes it so hard to determine the dimensionality of odor?

Well, there are a couple of things. First, there is no natural coordinate system in which olfactory stimuli exist. This stands in contrast with visual and auditory stimuli. For example, pure (monochromatic) lights or tones can be represented nicely as sinusoidal waves with just two variables, the frequency and the amplitude of the wave. We can easily control those two variables, and they correspond nicely to things we perceive. For pure tones, the amplitude of the sine wave corresponds to loudness and the frequency corresponds to perceived pitch. For a pure light, the frequency determines your perception of the color; if you change the intensity of the light, that alters your perception of the brightness. These simple physical parameters of the stimulus allow us to explore those spaces more easily.

In the case of odors, there are probably several hundred thousand substances that have a smell that can be perceived. But they all have different structures. There is no intuitive way to organize the stimuli. There has been some recent progress in this area, but in general we have not been successful in isolating a few physical variables that can account for a lot of what we smell.

Another aspect of olfaction that has complicated people's thinking is that humans have about 400 types of primary smell receptors. These are the actual neurons in the lining of the nasal cavity that detect odorants. So at the very input to the nervous system, every smell is characterized by the action it has on those 400 different sensors. Based on that, you might assume that smell lives in a much larger space than color vision—one with as many as 400 dimensions.

But can we perceive all of those 400 dimensions? Just because two odors cause a different pattern of activation of nerve cells in the nose doesn't mean you can actually tell them apart. Think about our sense of touch. Every one of our hairs has at its root several mechanoreceptors. If you run a comb through the hair on your head, you activate a hundred thousand mechanoreceptors in a particular pattern. If you repeat the action, you activate a different pattern of receptors, but you will be unable to perceive a difference. Similarly, I argue, there's no reason to think that we can perceive a difference between all the different patterns of activation of nerve cells in the nasal cavity. So the number of dimensions could, in fact, be much lower than 400. In fact, some recent studies have suggested that odor lives in a space with 10 or fewer perceptual dimensions.


In your work you describe a couple of basic experimental design failures of the 2014 paper. Can you walk us through those?

Basically, two scientific errors were made in the original study. They have to do with the concept of a positive-control experiment and the concept of testing alternative hypotheses.

In science, when we come up with a new way of analyzing things, we need to perform a test—called a positive control—that gives us confidence that the new analysis can find the right answer in a case where we already know what the answer is. So, for example, if you have devised a new way of weighing things, you will want to test it by weighing something whose weight you already know very well based on some accepted procedure. If the new procedure gives a different answer, we say it failed the positive control.

The 2014 paper did not include a positive-control test. In my paper, I provide two; applying the system that the authors propose to a very simple model microbe and to the human color-vision system. In both cases, the answers come out wrong by huge factors.

The other failure of the 2014 paper is a failure to consider alternate hypotheses. When scientists interpret the outcome of an experiment, we need to seriously analyze alternate hypotheses to the ones we believe are most likely and show why they are not reasonable explanations for what we are seeing.

In my paper, I show that an alternate model that is clearly absurd—that humans can only discriminate 10 odors—explains the data just as well as the very complicated explanation that the authors propose, which involves 400 dimensions and 1 trillion odor percepts. What this really means is that the experiment was poorly designed, in the sense that it didn't constrain the answer to the question.

By the way, there is an accompanying paper by Gerkin and Castro in the same issue of eLife that critiques the experimental design from an entirely different angle, regarding the use of statistics. I found this article very instructive, and have used it already in teaching.


How do you suggest scientists go about determining the dimensionality of the odor space?

One concrete idea is to try to figure out what the number of dimensions is in the vicinity of a particular point in that space. If you did that with color, you would arrive at the number three from the vast majority of points. So I suggest we start at some arbitrary point in odor space—say a 50 percent mixture of 30 different odors—and systematically go in each of the directions from there and ask: can humans actually distinguish the odor when you change the concentration a little bit up or down from there? If you do that in 30 different dimensions you might find that maybe only five of those dimensions contribute to changing the perceived odor and that along the other dimensions there is very little change. So let's figure out the dimensionality that comes out of a study like that. Is it two? Probably not. I would guess for something like 10 or 20.

Once we know that, we can start to ask how many odors fit into that space.


Why does all of this matter? Why do we need to know how many odors we can smell?

The question of how many smells we can discriminate has fascinated people for at least a century, and the whole industry of flavors and fragrances has been very interested in finding out whether there is a systematic set of rules by which one could mix together some small number of primary odors in order to produce any target smell.

In the field of color vision, that problem has been solved. As a result, we all use color monitors that only have three types of lights—red, green, and blue. And yet by mixing them together, they can make just about every color impression that you might care about. So there's a real technological incentive to figuring out how you can mix together primary stimuli to make any kind of perceived smell.


What is the big lesson you would like people to take away from this scientific exchange?

One lesson I try to convey to my students is the value of a simple simulation—to ask, "Could this idea work even in principle? Let's try it in the simplest case we can imagine." That sort of triage can often keep you from walking down an unproductive path.

On a more general note, people should remain skeptical of spectacular claims. This is particularly important when we referee for the high-glamour journals, where the editors have a predilection for unexpected results. As a community we should let things simmer a bit before allowing a spectacular claim to become the conventional wisdom. Maybe we all need to stop and smell the roses.

Kimm Fesenmaier
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New VP for Student Affairs Named

Joseph Shepherd (PhD '81), the C. L. "Kelly" Johnson Professor of Aeronautics and professor of mechanical engineering, is leaving his post as dean of graduate studies to succeed Anneila Sargent (MS '67, PhD '78), the Ira S. Bowen Professor of Astronomy, as vice president for student affairs. Shepherd's new role is effective September 15.

Sargent, who served the campus as the leader of student affairs the last eight years, announced in March that she was leaving the post to return to research and teaching full time. Shepherd, who joined the Caltech faculty in 1993, has served the last six years as the dean of graduate studies.

We recently sat down with Shepherd to talk about his past role and his new one, his strengths and goals, and his experience at Caltech.


Q: What does the vice president for student affairs do?

A: Student Affairs includes the offices of the undergraduate and graduate deans as well as obvious things like the registrar, undergraduate admissions, fellowships and study abroad, the career center, the health center, and the counseling center. It also includes things you might not think of—athletics; performing and visual arts, which includes the music programs, the theater program, the various arts programs, and all of the faculty and instructors that make these programs possible; and a whole group of organizations lumped under "auxiliaries."

The term "auxiliaries" is misleading, because they're central to student life. Housing and dining are the biggest parts, but there are services like the C-Store, the Red Door Café, the Caltech Store and Wired.


Q: What makes this role exciting for you?

A:  People speculate about what it is that makes Caltech a great school. A lot of folks say, "Well, it's because it's so small." But I think it's also because we work with people instead of creating some bureaucratic mechanism to solve problems. We say, "All right, what's the issue here? How can we resolve this?" instead of, "We need to create a rule. And then we need to create a group to enforce the rule." My approach is to ask, "What do we want the outcome to be?" In Student Affairs, you want the outcome to be something that supports the students, supports the faculty, and then you make sure that it's not going to adversely affect the Institute.


Q: Are there any changes coming, any initiatives you want to establish?

A: We need to think about how we build on the strengths we have and improve the things that we're weakest at. Before you make any changes to an organization, you need to understand those two things. There are a lot of parts to Student Affairs, so I need to understand the strong points of those organizations, and then get them to help me formulate what's important to do.

You always have to be careful of unintended consequences. As they say in chess, you want to think several moves deep. All right, suppose we do that. What will it mean for different parts of our population? Do we make this choice based on the data we have, or do we need more data? Will there be effects on people we haven't thought about? Maybe we need to go talk to those people.

When you have the authority to change things, you also have the responsibility to ask, "Are these the right changes?" Nothing happens in isolation. Anything you do is invariably going to wind up touching quite a few people.


Q: You've been dean of graduate studies since 2009. Did you consider taking a breather before jumping into this?

A: Well, much to my surprise, I found that being the dean of graduate studies was rewarding in many different ways. Sometimes you had to do some difficult things, but I actually liked being the dean. I was able, to some extent, to continue my research. I did some teaching—although last year I taught a major course all three terms, and I had my research group—and I was the dean of graduate studies. That taught me a lesson: a man's got to know his limitations.

So when I was asked if I would take this position, I did think about taking a break and not doing it. I enjoy my research and I enjoy teaching. I enjoy working with students, but I also enjoy trying to help the Institute as a whole. Here at Caltech, we pride ourselves on the notion that we have this very special environment. We have this small school, and we have dedicated professionals that work together with faculty to nurture that environment—having faculty who are invested in participating in the key administrative roles is essential.

When I was a graduate student here, my adviser was Brad Sturtevant [MS '56, PhD '60, and a lifelong faculty member thereafter]. Brad was the executive officer for aeronautics [1972-76]. He was in charge of the committee that built the Sherman Fairchild Library and he was on the faculty board. He emphasized to me that being involved in administration was just as valuable as all the other aspects of being a faculty member. He was a dedicated researcher, but he also felt strongly that you should be a good citizen. You should contribute.


Q: It seems like this is more than just a duty to you, though.

A: I'm looking forward to it. I'm also very conscious of the responsibility. I think it's going to be important for us all to think about how we maintain the excellence of the Institute and that we imagine how this place is going to evolve. As society evolves around us, we will naturally wind up changing. We need to do that in a thoughtful way so that we continue to be the special organization that we are.

At the end of the day, I'm counting on help from the faculty and staff. Caltech works because of the committed individuals within our organizations, the personal connections we form as we work together and the cooperation across the campus that these connections enable.  It's a collective enterprise.

I think administration is not something that's done to people. It's being responsible for making sure that folks have the right work environment, the right job assignments, and the right resources. It's making sure we're doing the right things with the finite resources we have. One of our former presidents said something that's always stuck with me: an administrator's goals are not about their own career so much as helping the careers of others. You need to think about how you're helping the people working for you, because they have goals and aspirations. That's where you take your satisfaction.

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Thursday, September 24, 2015
Beckman Institute, Glanville Courtyard – Beckman Institute

3rd Annual Caltech Teaching Conference


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