The New York Academy of Sciences
The 2016 Blavatnik Science Symposium
Posted March 16, 2017
On July 18–19, 2016, the New York Academy of Sciences hosted the third annual Blavatnik Science Symposium, a gathering of 54 laureates, finalists, and alumnae of the Blavatnik Awards for Young Scientists. What began in 2007 as a regional program granting unrestricted funds to a small cohort of extraordinary young scientists has grown into a robust community nearly 200 strong.
The Blavatnik Science Symposium has become a vital component of the Blavatnik Awards community, bringing winners and finalists together for two days of research updates, panel discussions and networking among this interdisciplinary group of scientists.
Use the tabs above to find a meeting report and multimedia from this event.
Presentations available from:
David Charbonneau (Harvard University)
Matthew Disney, PhD (Scripps Florida)
Pieter Dorrestein and Rob Knight (University of California, San Diego)
Casey Dunn, PhD (Brown University)
Stuart Firestein (Columbia University)
Antonio Giraldez, PhD (Yale University)
Hani Goodarzi, PhD (University of California, San Francisco)
Jinzhong Lin, PhD (Yale University)
Arash Nikoubashman (Johannes Gutenberg University Mainz)
Amit Singer, PhD (Princeton University)
Edward Valeev (Virginia Polytechnic Institute and State University)
How to cite this eBriefing
The New York Academy of Sciences. The 2016 Blavatnik Science Symposium. Academy eBriefings. 2016. Available at: www.nyas.org/Blavatnik2016-eB
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Pieter Dorrestein and Rob Knight
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University of California, Berkeley
University of California, San Francisco
Transition Metal Signaling in the Brain and Beyond
The heart of the periodic table is home to the most flexible metals in chemistry—the transition metals. These have long held interest for chemists and engineers due to their high conductivity and ability to change valences, and, as 2015 Blavatnik National Laureate Chris Chang explained in the Symposium's opening presentation, the unique properties of transition metals also enable the most complex circuity on the planet—that of the human brain.
Chang's research probes the intersection of chemistry and biology, with a focus on how the brain's highly individualized chemistry both enables its remarkable abilities and makes it vulnerable to degeneration. In biology, metals come in two "flavors"—the redox-inactive metals like calcium and magnesium, which conduct charge and have a single oxidation state, and the redox-active transition metals, which can attain multiple oxidation states. Due to their high reactivity, redox-active metals were traditionally perceived as "too dangerous" to move freely in the body, and thought to be found only as bound, static cofactors. Both types of metals are utilized in trace amounts throughout the body. In the brain, however, huge metabolic demands result in metal levels 10–1000 times higher, putting the organ at high risk of oxidative stress and free radical damage. "Neurodegeneration, or the loss of brain cells, is intrinsically linked to the brain's unique chemistry," Chang said.
Chang explained the development of molecular imaging approaches to study the brain's underlying chemistry by tagging and dynamically tracking transition metals—copper in particular—without disturbing or stripping them from their cofactors. Specialized probes have visualized not only single neurons, but subcellular activity, making it possible to track the movement and location of metals within a cell at a given time.
The resulting findings overturned conventional wisdom about redox-active metals in the brain, showing that copper moves from cell body to synapse as a neuron transitions from a resting state to an active one. Copper, much like calcium, is released from an intracellular store and moves to the outer parts of the cell—and even in between cells—via copper ion channels distinct from those that transport calcium and other non-redox metals. And despite the fact that copper flows to the synapse, where communication occurs, it functions not to enhance that communication, but to end it. "It's almost like making a phone call, then sending the transition metal to hang up," Chang explained.
Networks throughout the brain rely on copper for such braking activity; mouse models show that knockout or inhibition of these networks results in uncontrollable signaling and seizures.
Beyond the Brain
As the gut is second only to the brain in metal levels, Chang delved into whether they also play a role in communication between the brain and peripheral tissues. Probing the notion of a "brain–fat" axis, he studied adipose tissues in the gut and their function in relation to metal status. Experiments showed that copper fluxes coincide with lipolysis fluxes, and further, that copper actually regulates lipolysis through its central messenger, cyclic adenosine monophosphate (cAMP). "More cAMP means more lipolysis, and more copper gives you more cAMP," Chang said. "If you don't have enough copper, you can't burn enough fat." This has been reinforced in in vivo models of Wilson's disease, where excess copper trapped in the liver results in a deficiency of copper in other tissues—including fat tissue— which leads to obesity.
Chang concluded with a reflection on the traditional beliefs about metals in biology, noting that his research rewrites the notion that redox-inactive metals are only for signaling, and redox-active restricted to being co-factors. "There's a continuum between the two—it's not like only some metals can perform some jobs and other perform other jobs. It depends on the time, the place and the amount."
The Human Speech Cortex
Speech and language are defining human abilities. While many species communicate with and respond to sound, no other species boasts the cognitive and signal processing systems that underlie human speech and language. As 2015 Blavatnik National Laureate Edward Chang explained, even as recently as five years ago, little was known about the workings of the highly specialized area of the cerebral cortex, Wernicke's area, that is the seat of human speech.
Wernicke's area is uniquely tuned to respond to speech sounds. Unlike the analogous region in a monkey's brain, which responds similarly to pure tone sounds and human speech, the human brain displays a strong preference for speech sounds. And despite the variety of languages spoken around the world, the brain processes only a set number of actual sounds, or phonemes, which in combination produce every possible sound and meaning in human language.
As a neurosurgeon working with epilepsy patients, Chang is afforded an unusual—and fortuitous—opportunity to study the mechanisms of language processing. Epilepsy patients seeking a surgical solution often submit to a weeklong hospital stay, during which time a subdural electrode array is implanted to record seizure activity. These electrodes can also provide exquisitely precise spatial and temporal information about speech production and processing. A high percentage of Chang's patients, awake and alert for a week in the hospital, readily agree to engage in listening or speaking exercises, the results of which have yielded the first maps of precisely where the brain processes the sounds of speech.
Chang was the first to visualize the brain's selectivity in mapping sounds according to their attributes. For example, fricative sounds such as f, v and z map to the same electrode. Plosive consonants, like p, b, g, and d, also map to the same location. "This part of the brain is not tuned to individual phonemes, but in fact it is going after these phonetic features—properties of groups of phonemes that have a shared acoustic attribute," Chang said.
Chang has also designed experiments to illuminate the mechanisms through which humans tune in specific sounds and drown out others—a skill that facilitates one-on-one conversation at a loud cocktail party, or allows an Air Force pilot to ignore radio instructions to other pilots and attend only to his own call sign. Chang's findings on the attentional mechanisms that allow the brain to differentiate stimuli and filter sound have applications in other industries, including wireless communications.
Chang also described his lab's translational efforts, which are focused on building brain-machine interfaces, with emphasis on creating a clinically viable speech neuroprosthesis. "Now that we have a code for all the phonemes in the English language, we want to be able to use this and apply it to patients who are disabled, particularly ones who cannot communicate," Chang said.
Ignorance, Failure, Doubt and Uncertainty: Why Science is So Successful
At the end of a day full of research presentations celebrating success, innovation, perseverance and triumph, Stuart Firestein delivered a keynote address applauding the exact opposite: ignorance, failure, doubt and uncertainty—the dark undercurrents that Firestein argues are crucial to all scientific endeavors.
A Black Cat in a Dark Room
"It's hard to find a black cat in a dark room, especially if there is no cat," said Firestein, quoting an old aphorism that he believes is an apt description of science. Rather than a scientific method, Firestein suggests that science follows a process—one that accounts for the fact that there is neither a recipe for success nor an expectation that a solution will be found. "You have a hunch, follow it, try some things, fail, try again, revise, fail again," he said.
He posits that most breakthroughs do not come from an intent to discover, but rather from a place of conscious ignorance, in which scientists learn, through failure, what they do not know. "It is precisely when things are most mysterious, when they are most uncertain, [that] we are the most creative in thinking what to do about them," Firestein said.
Acknowledging that uncertainty and doubt make poor fodder for grant applications, Firestein insists that research worth doing—and funding—must allow for elements of doubt and the potential for failure. "The rate of failure can be quite high and the endeavor can still be a success," he said. "If you keep hitting the bullseye, the target is just too damn close." Welcoming doubt and uncertainty requires two of the most unsung virtues of the lab—courage and patience. "Things in the lab can take a long time," he said. "None of this is cheap or easy."
University of Massachusetts Medical School
From the Molecular Rosetta Stone to Autism
Antonio Giraldez opened the first session of presentations from 2016 National Finalists by detailing the results of experiments using zebrafish to create an animal model of autism. Giraldez and his collaborators bred zebrafish with a gene mutation associated with autism, then observed the offspring from the larval stage through adulthood.
They noted that double-mutant zebrafish displayed nighttime hyperactivity and were more prone to seizures than their counterparts. They exposed the fish larvae to hundreds of psychoactive drugs to determine if any successfully altered or suppressed the phenotypic abnormalities of the mutant fish. Their results showed that phytoestrogens, which mimic human estrogens, acted as suppressors. Giraldez noted that while it is too early to extrapolate this information to humans, it is possible that estrogen is somehow protective against autism, which affects significantly more males than females.
The Search for Binary Supermassive Black Holes
Jenny Greene set the stage for a larger discussion about gravitational waves and black holes with an overview of her research on supermassive black holes. Found at the center of most known galaxies, these are largest black holes, boasting masses millions or billions of times that of the Sun. Studying this class of black holes poses numerous challenges, one of which is that the gravitational waves produced by the merger of supermassive black holes would be too low in frequency to be detected by even the most sensitive interferometers. Astronomers believe the best hope for detecting such mergers is through observing arrays of pulsars, spinning neutron stars with regular rotation periods measured in milliseconds. "These make excellent clocks," Greene said, "So if you see correlated changes in their timing, that can tell you that a gravitational wave has passed by them."
Since this type of observation has yet to occur, astronomers are working to predict the type of signal pattern they might expect of a supermassive black hole merger, as well as to determine the frequency of these mergers. Greene detailed two methods to search for supermassive black hole binaries, one of which involves searching for shifts in radial velocity that could indicate orbital motion between black holes, the other focusing on the changes in light that would occur in the accretion disk of a black hole if a second black hole was nearby.
Daddy Issues: Effects of Paternal Environment on Future Generations
Oliver Rando presented his research into epigenetic inheritance—the idea that offspring inherit not only a genome, but also epigenetic information that dictates gene expression. Rando is investigating how paternal environmental conditions can impact the phenotype of the next generation, exploring the mechanisms of transgenerational epigenetics through dietary paradigms.
Previous studies in mice have shown that diet and stress levels can alter offspring metabolism. Using a mouse model, Rando explained how brothers raised on different diets can mate with control females and produce offspring with dramatically different metabolic attributes. Male mice fed a low-protein diet produced offspring with elevated metabolic markers associated with obesity. Sperm analysis revealed that protein-deprived fathers had altered levels of a specific transfer RNA (tRNA) which is directly involved in metabolism and upregulates threefold in response to such dietary restriction. These tRNAs arise not in the testes, where sperm are made, but in the epididymis, where they are shifted to the sperm during maturation.
"The germ line has been defined as distinct from the soma for a hundred years," Rando said. "But what's interesting here is that we have an element of soma to germline communication." The notion that parents can pass along more than just their DNA—that experiences in the parents' lifetime can modify gene expression in heritable ways—was considered heretical until recently.
Cryo-Electron Microscopy: From Blob-ology to Atomic Resolution
Capturing atomic-scale resolution images of large macromolecules is notoriously difficult. Many structures, such as ribosomes, are dynamic and floppy, resisting all efforts to capture their structure through x-ray crystallography. Cryo-electron microscopy (Cryo-EM) has emerged as an alternative technique for visualizing these molecules. Amit Singer discussed how this method has evolved and its application in visualizing both large macromolecules as well as far smaller structures, including the Zika virus.
"Even five years ago, Cryo-EM was known as blob-ology," said Singer, referring to previous incarnations of the technique, which produced merely outlines of structures, devoid of detail. In Cryo-EM, single molecules are frozen in a very thin layer of ice. An electron beam shoots through the sample to a detector, which captures an image of the molecule. Recent improvements have sharpened the images obtained, yet they are still fairly noisy, leaving scientists with the daunting task of deriving a 3-D structure from tens or hundreds of thousands of noisy 2-D images of single molecules. "Every experiment generates terabytes of data that need to be processed and analyzed," said Singer. "Cryo-EM is definitely a Big Data problem."
Singer discussed how mathematicians are partnering with structural biologists to design software capable of single-particle reconstruction, using Cryo-EM images and a complex set of algorithms to reduce noise, analyze each molecule's potential orientation, and model the final structure.
Teaching Chemistry to Computers
In the 1920s, Paul Dirac famously commented on the complexity of applying the laws of chemistry, noting that they led to "equations much too complex to be soluble." Edward Valeev, with apologies to Dirac, acknowledged that such complex equations are an essential—and soluble—aspect of chemistry, and introduced his efforts to create computer models that can predict chemical phenomena.
Valeev joked that "nature is cruel, and in order to predict chemistry we have to work really hard." He shared several examples of his models that illustrate the complexity of computing the energy of complex systems with high accuracy. He also illustrated his advances in practical methods for numerically exact treatment of weakly coupled pairs of electrons.
Visualizing the Effects of Lifestyle on the Microbiome
Rob Knight and Pieter Dorrestein closed the first day of the Symposium with a deceptively simple question: "What do you see when you look in the mirror?" Acknowledging that most of us immediately think of faces, hair or skin, Knight and Dorrestein posed a different interpretation. Viewed through the lens of human microbiome research, each of us is at best 43 percent human, owing to the 39 trillion microbial cells that call our bodies home, versus 30 trillion native ones. From a genetic perspective, we are perhaps just 1 percent human, our 20,000 human genes dwarfed by between 2 and 20 million microbial genes. "If we just look at genes that are human, you neglect 99 percent of the system," Knight said, introducing the latest findings in his studies of the microbiome's connection to health and disease.
Knight commented on earlier work mapping the microbial communities of the body, which shows that such communities are so specific that analysis of microbiota on a person's hand and similar analysis of a computer keyboard can link a person to their keyboard 90 percent of the time.
Microbial communities also inhabit—and contribute to—unique chemical environments throughout the body. Dorrestein noted that early efforts to analyze the chemistry of the human microbiome in a petri dish lacked real-world context, a realization that led to experiments in mapping the microbiome spatially. Volunteers provided hundreds of body swabs, which Knight and Dorrestein subjected to mass spectrometry, in order to glean chemical signatures, and genetic sequencing, to read the bacteria themselves. Mapped back onto 3-D models, this was the first complete, in-situ representation of humans and their microbiomes.
These maps have since illuminated the effects of personal care habits and personal hygiene products on the microbiome, revealing that personal care products reduce microbial diversity, and that this reduction persists for days or weeks after discontinuation. It is also possible to visualize and correlate the chemical signatures of molecules like caffeine and certain medications with a particular person's microbiome, offering clues about their habits and even their health. Antibiotic activity in the presence of microbes can also be studied spatially, paving a path for a better understanding of resistant strains.
Knight and Dorrestein closed their session with a vision for a future where personal care will be based on dynamic, daily readings of an individual's microbiome and its attendant chemical signatures. "The idea is to show you where you are in relation to other healthy or unhealthy people," said Knight, "And if you're at risk for a particular condition, what you need to do to avoid it."
100 Years in the Making, Gravitational Waves Discovered
The search for gravitational waves was the quest to detect the unseen vibrations first predicted by Einstein's General Theory of Relativity one hundred years ago. It stated that the acceleration of massive objects, like binary black holes inspiraling toward each other, distorts space-time and sends gravitational waves rippling through the universe as they merge. The energy released during such an event would equal that of a billion trillion suns in a single second.
Humans have had eyes in the sky since the days of Galileo, but not even the most sophisticated optics can detect gravitational waves. As Szabolcs Marka explained, detecting the disturbance of a gravitational wave sweeping through space is like "detecting a millionth of a cent change in the national debt," an almost unimaginable subtlety.
Listening to the Universe
Enter LIGO, the Laser Interferometer Gravitational Wave Observatory, twin detectors more akin to seismometers than telescopes, employing the most sensitive technologies ever built for listening to the universe. In September 2015, for the first time, they heard something.
Marka recalled the first of LIGO's three gravitational wave discoveries, one that rocked the scientific community and proved Einstein right. LIGO registered the vibration from the birth of a black hole with the mass of roughly 60 suns resulting from the merger of two binary black holes. "When they merge, they send gravitational waves outward, then all is immediately still," Marka said, showing the LIGO signal plots and treating Symposium attendees to a recording of the "chirp" of the wave at the moment of detection. "We didn't just 'see' the hole," Marka said. "We saw how it was born, 1.3 billion years ago."
Frans Pretorius discussed the importance of modeling black hole collisions in interpreting LIGO data, explaining that because such collisions are point sources and don't emit over an extended region, it is difficult to interpret the observed signals without advance modeling.
Pretorius' models predicted the likely signal pattern of a black hole merger years before the first LIGO detection, a pattern he characterizes as "a runaway process as the holes eventually collide. The frequency decreases and the amplitude increases, and that's the unstable process predicted by relativity. As soon as the merger occurs, the signal dies completely and all that's left is noise."
Distinguishing signal from noise is a task for modeling techniques such as matched filtering, which Pretorius believes was crucial in detecting a second LIGO event in October 2015. "The first event was fortuitously loud and rose above the noise," he said. "The second was much quieter." He emphasized that efforts to simulate and predict the geometry of space and time associated with specific cosmic phenomena will help identify future events.
A New Chapter in Astrophysics
David Spergel offered a glimpse into what he deems a "new chapter in astrophysics," a time of not only black hole merger discovery, but new kinds of gravitational waves and perhaps novel collisions, like those of black holes and neutron stars. He noted that it may be possible to detect gravitational waves from the Big Bang, which would open a portal to studying the earliest stages of the universe. "Most things we've observed about the universe thus far are through photons, through light," Spergel said. "We are now hearing the universe for the first time, and the universe is playing Einstein's tune."
The panelists participated in a discussion about the potential discoveries that lie in wait. They noted that the body of knowledge to be gleaned from gravitational wave studies will grow quickly as LIGO detects more events, illuminating the process through which black holes form—including whether they form in binaries or globular clusters—as well as the role of supermassive black holes in galaxy formation. "We're looking for surprises, things that defy expectation," said Spergel. "For example, you can only spin a black hole so fast, and if we can detect one spinning at the extremal limit, it'll be extraordinary. It'll be the rare events that we really learn from."
Marka noted that attempts to build space-based, rather than land-based, interferometers are in early-stage testing. NASA launched the LISA Pathfinder mission in December 2015, paving the way for full-fledged space-based gravitational wave observatories in the next 20 years.
Developmental "Bet Hedging"
Leor Weinberger launched a panel discussion on infectious diseases with an overview of developmental 'bet-hedging'—the process through which biological systems generate variant phenotypes to preserve fitness in fluctuating environments.
Much as engineers discovered that signal processing and other inefficient systems can be improved through the introduction of small perturbations, or "dither," Weinberger argues that biology has innately tapped this principle for millions of years, using fluctuations in gene expression to drive decisions about cell fate. "If you look at a single cell over time, there are large protein fluctuations—or if you look at two identical sister cells, they can follow completely separate and different trajectories," he said. This cell-to-cell variability is biological dither, or "noise."
He illustrated the concept of noise as a driver of cell-fate decisions using a model of HIV, in which the virus takes one of two paths upon entering a T-cell: active replication or latency. Random fluctuations in the expression of a single HIV protein, Tat, drive this decision. Latency is the greatest barrier to curing HIV, and researchers have long pursued methods of influencing these cell-fate decisions and waking HIV out of latency. Weinberger reviewed the results of experiments showing that many compounds—including the common antihistamine cetirizine—can serve as noise enhancers, boosting the activation of the promoter that drives Tat expression and reactivating HIV from a latent state.
Decoding an Ancient Protein
Sinisa Urban began his presentation with what he deemed a naive question: wouldn't it be great if vastly different parasitic diseases had a common target for treatment? Showing images of the distinct activity of two parasites, one invasive and one phagocytic, he described how they may be vulnerable to a similar intervention—one that targets an ancient cell membrane enzyme present in bacteria, parasites, fungi, plants and humans: rhomboid.
Rhomboid proteases cut proteins, sometimes for the purpose of initiating communication between cells, and other times to enable movement into another cell, as in the case of malaria, which deploys rhomboid to enter and infect red blood cells.
Urban's efforts to understand the structure and stability of rhomboid and its role in malaria function led to the first blueprints of the enzyme and new insights into its role in malaria infection. Experiments targeting malarial rhomboid to impede invasion resulted in the development of a boronate engineered to bind to rhomboid, which researchers dubbed a RiBn (ribbon), or rhomboid-inhibiting boronate. Experiments show that RiBns prevent malarial invasion in a single dose, with no harm to human rhomboid. "You don't want to cause one disease while trying to cure another," Urban explained.
Lessons in Host Specificity
Xiang Gao turned the conversation to a uniquely toxic bacterium, Salmonella typhi. Unlike other forms of Salmonella, which infect a range of hosts and are a common cause of gastroenteritis, S. typhi only infects humans and causes a far more dangerous infection—typhoid fever.
S. typhi produces a factor called typhoid toxin, which Gao and a team of collaborators hypothesized was the key virulence factor in typhoid fever infection. When purified and injected into mice, the toxin produces symptoms similar to those of typhoid fever in humans. Yet in the wild, mice and all other animals—even great apes—are resistant to such infection.
Studies of typhoid toxin's structure and mechanism of infection reveal a strong binding preference to glycans that exist only on the surface of human cells—other mammals possess an enzyme that reconfigures these sugars in a way that inhibits typhoid binding. Yet this is not the only explanation for S. typhi's host specificity. When the bacterium enters a mouse or other non-human mammalian cell, a molecular courier, Rab32, mounts a vigorous defense and quickly dispatches it. In humans, Rab32 responds less effectively.
Matthew Evans also focused on an infectious agent with strong host specificity, the Hepatitis C virus (HCV). Some members of the flaviviridae family, such as dengue and Zika, infect a variety of hosts and tissues, yet HCV infects only humans and chimpanzees and is restricted to liver tissue. According to Evans, this highly selective tropism makes Hepatitis C an ideal research subject, as "it's easy to compare differences between cells it can infect and cells it can't."
Newly developed drugs can cure more than 90 percent of HCV cases, but high costs prohibit their widespread use, leading Evans and other researchers to focus on developing a vaccine. To do so, they must unravel the mechanisms that impact tropism in the virus, determining how the virus interacts with its host at each stage of the viral lifecycle and testing the limits of those interactions.
Evans identified tissue-and species-specific receptors that permit HCV to enter human and chimpanzee liver cells. By knocking out that receptor and passing HCV through those altered cells, strains of HCV that utilize different receptors emerged. Similarly, they evolved viral strains that can replicate in the absence of a microRNA found only in the liver, which was long thought to be crucial to viral replication. Researchers do not yet know if these evolved viruses can infect tissues outside the liver, or infect animals beyond humans and chimpanzees. Lamenting the lack of an animal model to test HCV vaccines, Evans said, "We're attempting to adapt the virus to use non-human versions of the receptors it needs to enter cells, and we have to face a block in the ability of the virus to evade immune responses."
Moderator Ruslan Medzhitov led the panel discussion. A dominant theme was the challenge of developing treatments for infectious agents that continuously evolve to evade detection. Medzhitov pointed out that immune evasion strategies are a direct consequence of the immune system challenging parasites, viruses and bacteria over time. Weinberger expressed doubt about the possibility of using of small molecules to ward off HIV, noting that nearly every primate in Africa is infected with its simian predecessor, SIV, and has been for tens of thousands of years. "If the immune system itself can't evade the virus over eons, we're probably not going to be able to do it with a static chemical," Weinberger said. "We have to think about building therapeutics that have the ability to do what pathogens do well—evolve and transmit." Urban mentioned that in the parasitic world, immune evasion is often a function of minimizing antigens on the organism's surface. "Malaria hides all its good stuff inside so the immune system doesn't react much," he said.
Kenneth Shepard was the first speaker in a panel discussion about nanotechnology. His work challenges the typical uses of CMOS technology for computation and communication, applying it instead to a new breed of nanoscale diagnostic devices.
Most molecular scale diagnostic technologies rely on ensemble—they require many molecules to make an identification—and typically use light-based approaches for detection. While accurate, this approach has major limitations, namely that samples require amplification and the labeling process is labor-intensive. Shepard noted that there is strong interest in moving the industry toward a single-molecule, electronic approach, and described a device that meets this demand.
Single-molecule diagnostics require no amplification. Rather, they rely on the intrinsic properties of the molecule for identification. "In our case, this is charge," said Shepard. "We need something that can transduce single-molecule presence or absence to an electronic signal with high gain and high spatial localization." A nanoscale transistor comprised of a functionalized carbon nanotube can accomplish this task. "We attach a molecule, and when another molecule comes in and binds, the signal changes. It's almost like digital detection," Shepard said, noting that information is contained in the temporal response of the platform—the binding and unbinding of a single molecule to a target molecule—and not in the amplitude of the response.
Shepard's startup company, Quicksilver Biosystems, is working toward a multiplexed system of 16 million nanotubes on an integrated circuit chip.
Better Communication Through Bioelectronics
George Malliaras reviewed the advantages of using organic materials in brain interface devices. Whether it's mapping the brain to source the site of epileptic seizures or applying deep brain stimulation to relieve the symptoms of Parkinson's disease, organic materials offer improvements at the brain/ interface site as well as in the quality of information that can be captured.
Organic electronics can be manufactured less expensively than their non-organic counterparts, and are better adapted to flexible substrates. They also transmit both electrons and ions, improving communication across the biotic/abiotic interface and resulting in stronger coupling. These electrodes are tunable through the use of side chains that either permit the flow of ions through the full volume of the film, or block them at the interface, allowing the device to function like a metal electrode.
Malliaras demonstrated several applications for organic electronics, including micro-conformable electrodes with impedance two orders of magnitude lower than a metal film of the same size. This allows researchers to scale the device down in size with no compromise in recording capability—in fact, such devices have recorded single neuron activity from the brain's surface with no penetration. He also described transistors for tracking epileptic activity that offer signal-to-noise ratios roughly ten times that of a traditional electrode.
Organic electronics also enable electrophoretic drug delivery pumps that can move a single molecule of drug through a solid film and deliver it to a precise location. "We're able to show that you can locally act on a neural circuit and stop hyperexcitablity," Malliaras said.
The Future of Electromechanics
Sergei Kalinin made the leap from the earliest days of electromechanics, when Luigi Galvani applied bias to a frog leg and produced a twitch, to the present, when it has become feasible to probe electromechanical activity of both organic and inorganic systems at the nanometer level. Scanning probe microscopy (SPM) is the most common tool for this task, yet these microscopes have a considerable drawback—they utilize only a single frequency for detection. Kalinin likens this limitation to "only having a single wavelength in our vision." His group has increased the sensitivity of SPM by exciting a band of frequencies, moving from single to parallel band detection. This approach has become an attractive model for studying biological systems as well as understanding and improving the functionality of electrochemical systems. Kalinin described a future of molecular electromagnetic machines that can be designed and controlled at the nanometer scale.
It has also precipitated transition from standard to what he described as "standard imaging to Big Data imaging." By coupling SPM with a high performance computer, Kalinin has captured an unprecedented flow of information, an advance that will be even more pronounced in electron microscopy. "Electron microscopes generate data on the order of the Large Hadron Collider, except the LHC data is analyzed and most data from microscopes is not," Kalinin said. Analysis of Big Data from SPM enables scientists to measure displacement on the order of picometers, revealing details a billion times smaller than what can be studied using previous detection methods.
Moderator Lynn Loo guided the panelists in a discussion that often returned to a theme of celebrating opportunities that have resulted from extending beyond one's original field of science. There was extensive discussion about the transformative impact that advances in electronics and electrochemical interfaces have had on the life sciences, a field which all panelists acknowledged being drawn to by both curiosity and an interest in doing broadly impactful work. Malliaras commented that he had long been working on traditional research in materials science when he was drawn to bioelectronics. "I had been working in displays, and if things went really well, you could make a better display," he said. "This was a way to have much more impact." Symposium attendees engaged in the discussion at several points, particularly regarding the challenge of ensuring biocompatibility in next-generation devices.
University of California, Berkeley
Bind, Degrade, Signal: The Story of Ubiquitin
Michael Rape introduced the aptly named protein ubiquitin, which exists in every cell and plays a crucial role in cell-fate decisions. Armed with three main commands—bind, degrade, and signal—ubiquitin acts in the earliest stages of cell-fate specification, attaching to proteins and altering their function. As ubiquitin is itself a protein, it can form polymeric chains that direct various tasks based on their structure and position in the amino acid sequence. Ubiquitin can also encode temporal information—one type of ubiquitin chain is formed at a key point in cellular division and directs the timing of the process, ensuring precise chromosomal distribution.
Rape explained that just as humans connect words to form complex sentences, ubiquitin chains can form branched structures to effect complex changes— for example, tagging a particularly difficult-to-degrade protein for degradation.
At least 600 of the 20,000 genes in the human genome encode for ubiquitin ligases, the enzymes that drive the ubiquitin code. These enzymes encode specificity on many levels, from substrate specificity—recruiting the right target protein at the right time—as well as site specificity, ensuring that ubiquitin is attached at the correct location to trigger the intended modification.
Impediments to or regulation errors in the ubiquitin code contribute to diseases including cancer, neurodegeneration, and developmental disorders. Rape illustrated the role of ubiquitylation in craniofacial disorders, explaining that neural crest development relies on a ubiquitin ligase targeting two proteins and attaching a single ubiquitin to bind the complex that drives cell specification. "Impairments to this pathway, or the loss of ubiquitylation, leads to loss of binding which leads to a disease that impacts facial development," he said. Conversely, too much ubiquitylation can also lead to disease—some cancers show overexpression of a ubiquitin ligase involved in controlling cell division.
Branched ubiquitin chains, which were recently visualized by Rape's lab, control protein folding in the cell and play a critical role in preventing neurodegeneration. When protein synthesis fails, a group of ubiquitin ligases modify the nascent protein with a complex ubiquitin chain, marking it for degradation and preventing aggregation in the cell. Ataxia, Huntington's disease, and ALS are likely rooted in a dysfunction of this quality control pathway.
The ubiquitin code was long considered undruggable, yet Rape described a bright future for therapeutics based on the system. His company, Nurix, has developed a small molecule capable of tethering an oncoprotein to a ubiquitin ligase, which then tags the mutant protein with a ubiquitin chain that triggers degradation. Rape predicts that all features of the ubiquitin code will soon be tapped for drug discovery. "Because you can select which ligase you're using, you can use every word of the ubiquitin code to your advantage. You can recruit a binding partner, you can degrade proteins ... suddenly, a lot of proteins and processes that were previously undruggable are accessible."
How to Find an Inhabited Exoplanet
If 10,000 years of space travel was a reasonable feat, David Charbonneau would have a clearer path to identifying Earth-like planets that may harbor life. "There are 200 billion stars in our galaxy ... and there could be an Earth-like planet around the closest star, there could be a group of scientists meeting right now, having this same conversation," Charbonneau joked. Unlike the hundreds of prior generations who have considered the skies and asked the question "are we alone?" with no real hope of an answer, Charbonneau believes that this generation will find one, and that the answer is less than a decade away.
Two methods are key in determining the size, mass and density of an exoplanet. The Doppler method analyzes spectral shifts from other stars to determine if planets are orbiting that star, and the transit method measures dips in the brightness of a star when an orbiting planet crosses in front of it. Studying transiting planets has an additional benefit, Charbonneau explained, as the technique offers information about a planet's atmosphere. "When the planet moves in front of the star, some of the light from that star filters through the planet's atmosphere," he said. "We can take spectra at that time and imprint it on that starlight and we get new absorption features, and that's the opacity of the molecules present in the planet's atmosphere."
Ten years ago, a single transiting exoplanet had been found and its atmosphere studied—today, it's more than 4,000, with more than 100 atmospheres studied. Charbonneau noted that most of these are large, uninhabitable planets, but data from the NASA Kepler mission has yielded staggering new predictions about the prevalence of potentially habitable, Earth-sized planets orbiting stars: roughly one planet for every four stars in the galaxy.
Charbonneau explained that the presence of life in general and photosynthetic plants in particular have transformed Earth's atmosphere into something unique. "The continents are green, not brown, and aliens studying the Earth from afar would see that there's something special about the third planet from the Sun," he said. "This is how we'll find life on other planets—by the inevitable chemical signature that life leaves when it dominates the surface of a planet." The MEarth project, consisting of two arrays of telescopes in Arizona and Chile, is on the hunt for Earth-like planets orbiting the closest red dwarf stars—the most plentiful type of star in the galaxy and the easiest to study. The first discovery of an Earth-sized planet that can be studied with current telescopes was reported in 2015.
Studying the atmosphere of such planets will require the largest telescope ever built—the Giant Magellan telescope. Slated to see first light in 2022, the GMT's seven enormous mirrors, coupled with the largest spectrograph ever built, will study the light from transiting exoplanets in detail, looking for oxygen, hydrogen, methane, and other gases that are the atmospheric biomarkers of life.
Brookhaven National Laboratory
Hunter College of The City University of New York
Man-Made Big Bangs
Dennis Perepelitsa makes Big Bangs. Through his work at the Large Hadron Collider (LHC), Perepelitsa studies the fundamental force that binds matter together—the strong nuclear force—through recreations of the earliest moments of the universe. He explained that studies of the strong nuclear force have long been hampered by the very nature of the force itself: in order to understand it, matter must be freed from it, an impossible reality in any scenario except one where atomic nuclei collide at 99.999 percent of the speed of light.
The LHC is capable of producing those exact conditions, accelerating beams of large nuclei and smashing them together at just shy of 186,000 miles per second. At the moment of collision, they produce a fiery new phase of matter that exists for a fraction of a second. In this phase, subnuclear quarks and gluons "melt," as they are liberated from the strong nuclear force. This quark-gluon plasma is a primordial substance, a novel regime with properties unlike any other state of matter. "This is what occurred at the very earliest microseconds of the universe," Perepelitsa explained. "The entire universe was quark-gluon plasma." He noted that while the Big Bang is "not a repeatable experiment," creating "little bangs" grants researchers the opportunity to study the conditions of the early universe, and may lead to insights about the evolutionary process of the universe from Big Bang to present day.
Landau Level Wave Function in Artificial Graphene at the Extreme Quantum Limit
Yang Liu described a novel artificial graphene lattice built to image Landau level wave functions. The lattice was built on a copper surface, which behaves like a two-dimensional electron system. Liu and his collaborators evaporated carbon monoxide molecules on the surface, which generate a local repulsive potential that repels electrons. Liu illustrated how the arrangement of these CO molecules into triangular arrays forms a lattice, with electrons situated in a pocket formed by three molecules, yet free to hop the horizontal channel between two molecules. Straining the lattice tunes the electron tunneling between lattice sites, change the hopping parameter of the electrons. This artificial graphene lattice is stable and easily manipulated, allowing researchers to adjust strain and introduce ultra-high synthetic magnetic fields. Using this platform, Liu has successfully extrapolated and imaged Landau level wave functions at different energies.
A Recipe for Mass Produced Nanoparticles
Demand for soft nanoparticles for research and industrial purposes is growing, but supply lags behind due to the labor-intensive nature of creating such particles. Arash Nikoubashman discussed a new technique for mass production of uniformly sized colloidal particles, a method "that doesn't involve getting 1,000 students with pipettes to work around the clock."
He described the process of flash nanoprecipitation, achieved with a basic mixing device with two inputs, one for a polymer solution and solvent, and the other for a nonsolvent—in this case, water. Rapid mixing results in the formation of uniform, spherical nanoparticles that require no external stabilizing agents to maintain separation. Computer simulations and experimentation showed that particle size is tunable through adjustments in the mixing rate and the ratio of polymer solution to nonsolvent. Nikoubashman reported that the technique works with a variety of electroneutral polymers, and can be used to produce nanoparticles with specific properties.
The Neuronal Plasticity of Stress Resilience
Allyson Friedman discussed her research seeking to understand why life stressors trigger brain changes that lead to depression in some people, but not others. She highlighted that while depression is increasingly prevalent, affecting at least 350 million people worldwide, most of the 7 billion people on earth are resilient to depression. Friedman's work probes the biological mechanisms of that resilience, harnessing it to create new therapeutics that "aren't anti-depressants, but rather pro-resiliency medications," she said.
Friedman reported that chronic social defeat induces depression in some mice, and experiments show that these animals evidence many of the same depressive characteristics as humans, including social isolation, anhedonia, loss of appetite and fatigue. Analysis of brain activity reveals that stress-susceptible mice show increased firing in the ventral tegmental area— the seat of dopamine production—in comparison to stress-resilient mice. "This part of the brain is highly dysregulated in depression, while a more resilient brain is able to maintain homeostatic regulation in the area," Friedman said. Such resilience is an active balancing process, as genetic studies show that there are 58 genes upregulated in resilient mice during social stress. "This tells us that the brain is responding—these mice aren't unaffected by the situation, but the brain is responding to compensate," Friedman said.
Stalling Nightmare Superbugs
"It is almost certain that the golden age of antibiotics has come to an end, and the future doesn't look good," said Jinzhong Lin in a discussion of antibiotic resistance and the looming threat of fully-resistant superbugs. Lin described the mechanism most antibiotics use to defeat bacteria, targeting the ribosome and disabling its function. Improvements in imaging techniques including x-ray crystallography and cryo-electron microscopy have allowed scientists to view the ribosome as never before, permitting studies of ribosomal function that may lead to a smarter generation of antibiotics.
Lin's efforts to unravel the workings of the ribosome led to the discovery of one of the key steps in protein synthesis in bacterial cells—the process of tRNA translocation inside the ribosome, which is driven by a single protein factor, elongation factor G. Further study showed that some older antibiotics, including dirithromycin, actually target this factor, preventing it from enabling protein synthesis. These findings are a key step in tweaking existing drugs to boost affinity for their targets and increase their efficacy. "We don't know if we can stop the nightmare of superbugs," Lin said, "But we're trying to push it back as much as possible."
Toward a Holistic Understanding of Cancer
The major difference between a regular cell and a cancer cell isn't genetic—both cell types, like every other cell in the body, have the same genome. The distinction is in how those genes are expressed and regulated, a process that goes catastrophically awry in cancer. "How do cancer cells hijack regulatory programs to achieve unstoppable growth?" asked Hani Goodarzi, introducing his efforts to create a universal framework to understand the regulation of gene expression in cancer. Taking a multidisciplinary approach blending computational and experimental techniques, Goodarzi outlined how advances in both areas are allowing researchers to better understand the pathway from healthy cell to cancer cell, and from primary tumor to highly metastatic cell. "We have used our framework quite successfully to uncover some novel biology about what makes cancer cells tick," he said.
In one instance, by using high-throughput screening to compare the RNA stability between poorly and highly metastatic cancer cells, researchers discovered a new post-transcriptional regulatory framework clearly linked to metastasis. An RNA-binding protein, TARBP2, binds and degrades hundreds of transcripts in the cell, some of which are suppressors of metastasis. TARBP2 is expressed at significantly higher levels in highly metastatic cancer cells versus poorly metastatic ones. In addition to shedding light on the regulatory pathways that drive cancer progression, Goodarzi emphasized that the research may lead to the development of therapies capable of correcting dysregulated pathways and disrupting tumor growth.
University of Washington
Massachusetts Institute of Technology
Seeing the Future of Solar Energy at the Nanoscale
David Ginger believes the smallest details may hold the solution to one of the biggest global challenges: energy production. Ginger notes that the shale oil flares in North Dakota are now visible from space, commenting, "Our energy problem is big, and if you want to impact energy consumption and production, you also have to do something that's visible from space." Ginger envisions a massive solar cell roughly equal in size to the amount of paved roadway and rooftop in the country—an epic, efficient clean energy machine capable of replacing the 3 terawatts of power the United States uses daily with solar energy. The tiny building blocks to make Ginger's vision of what he dubs "big renewables" a reality are literally coming into focus in his lab.
Perovskite crystals have emerged as a lead material for next generation solar cells. Efficiencies of up to 22 percent have been achieved in the lab—rapidly approaching the 25 perfect efficiency of traditional solar cells. Perovskites are also solution-processable, making them amenable to a range of applications. Perovskites were generally believed to be uniform in composition, but imaging techniques pioneered in Ginger's lab revealed that the crystals full of imperfections and grain boundaries that limit efficiency. He and his collaborators devised methods to visualize the crystals well below the diffraction limit using scanning probe microscopy. "We can see areas where the current's not making it through and areas where it's flowing, and adopt chemical changes to how we process these films to unblock them," he said.
Alexei Borodin began his presentation by challenging Symposium attendees to find commonality among a group of seemingly random categories—the latency period of diseases, the age of marriage, the length of spoken words in a telephone conversation. After revealing the answer—that all of their logarithms, when plotted on a histogram, will similarly approximate a bell-shaped curve— Borodin claimed that perhaps the greatest gift mathematics can impart to other branches of science is abstraction. "Abstraction should be thought of as throwing out information that's not relevant," Borodin said.
He illustrated how another set of apparently random phenomena, such as coffee stains and the classic video game "Tetris," also have interfaces that are statistically the same and follow a predictable, specialized corner growth model. Acknowledging the complexity of the math underlying this model, Borodin commented that "somehow, coffee stains know about abstract algebra—once you take the model and strip out all the inessential features, what remains is an abstract object that you can place into math... Abstraction connects things that seem totally disconnected by physics or biology, but on the level of the essential statistical features, they are the same."
Cracking the Tubulin Code
Just as cities need efficient transportation systems to thrive, so too do cells, which Antonina Roll-Mecak likens to major urban centers, with elaborate "roads" and architecture to ensure safe transport of information and cargo. Trading blacktop for a dynamic polymer called tubulin, cell pathways—or microtubules—can assume many shapes, growing and shrinking to meet transport needs. For example, a support system of microtubules is what allows neurons to assume their characteristic branched configuration.
Humans make multiple isoforms of tubulin, and it is one of the most chemically and genetically diverse proteins in cells. Microtubules are heavily post-translationally modified with chemical "tags" that customize their function. As Roll-Mecak explained, "these modifications are stereotyped in tissues and cells, so if we look at the distribution of chemical tags in a neuron or a dividing cell or an epithelial cell, the distribution will be different." This chemical diversity and stereotyped distribution has given rise to the notion of a "tubulin code"—the idea that the tags projecting from the microtubule surface are a chemical code that is deciphered by cellular effectors. Changes in the code are correlated with cancer and neurodegeneration.
Roll-Mecak described her efforts to crack the tubulin code by creating a naïve substrate—a blank microtubule free from modifications—and adding chemical tags to create different flavors of microtubules and observe their interpretation by cellular effectors. "Ultimately, we want to integrate all this information to understand how the cell actually recruits effectors, and how their activities are modulated by the tubulin code. We dream of a dynamic map of the tubulin code that would allow us to see how the modifications vary in real time, and how they change in health or disease."
Sequence-based Design of Precision Lead Medicines Targeting RNA
Matthew Disney reviewed a brief history of drug development, noting that while the process has unquestionably improved from the days when World War I-era chemical weapons were modified to treat cancer, Gleevec—a landmark lead compound for treating leukemia—took 40 years from concept to FDA approval. Today, in a post-genomic era when we are "swimming in an abundance of genome sequence" and obtaining such information is less expensive than ever before, researchers can hasten the timeline for creating new therapeutics.
Genome sequencing has revealed that non-coding RNAs are implicated in diseases ranging from cancer and ALS to Huntington's, making these key targets for small-molecule therapeutics. Disney described the unique approach his lab has developed to directly drug RNA to intervene on the disease process.
Disease-causing RNAs fold to form predictable structures of matching base-pair sequences, each with a unique pattern of loops and bulges. Disney and his colleagues have compiled a library of these RNA motifs with the goal of determining which small molecules bind these RNA structures. "We basically ask the small molecule: if you're given thousands of RNA combinations to bind to, can you please tell us which one you like to bind to best?" he said. These exposures have resulted in a catalog of thousands of small molecules and their precise RNA motif binding preferences.
In a particularly promising discovery, the researchers found a small molecule binding partner for microRNA 96, which discourages apoptosis and is associated with triple negative breast cancer. Trials in animal models show that the compound kills only cells that express the cancer-causing gene, leaving healthy cells intact.
The Complex Evolutionary History of Animal Diversity
"It's just as absurd to imply that you can add a spine to a jellyfish and get a primate as it is to imply that you can add stinging cells to a primate and get a jellyfish." So began the final talk of the Blavatnik Science Symposium, a presentation by Casey Dunn on his efforts to revise traditional perspectives of animal diversity using genomic and developmental data from a group of largely unstudied organisms.
Dunn began by exposing the fallacy of stepwise evolution from "lower" order animals, like sponges and jellyfish, to "higher" order animals, including primates. Debunking the notion that so-called lower order animals are simply a base model upon which higher order animals are built, Dunn described a drastically different view of animal diversity, one built on an understanding that all living things have singular, yet no less complex, biology suited to their living conditions. He asserted that in many cases, researchers "mistake a lack of knowledge about some organisms for a lack of complexity," and that relegation of species like sponges and jellyfish to "lower" orders ignores the context in which these animals have lived and thrived for 500 million years.
Genomic data gleaned from hundreds of species collected by Dunn and his collaborators during open-ocean dives, including many never-before sequenced species, reveal not a vertical progression of animal diversity from lower to higher complexity, but a highly variable progression during which certain traits, including nerve cords, are gained and lost by species over time.