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eBriefing

The 2018 Blavatnik Science Symposium

The 2018 Blavatnik Science Symposium
Reported by
Hallie Kapner

Posted October 02, 2018

Hallie Kapner is a freelance writer in New York.

Presented By

The Blavatnik Family Foundation

The New York Academy of Sciences

Overview

The Blavatnik Science Symposium—an annual gathering of winners and finalists of the Blavatnik Awards for Young Scientists—convened on July 16–17, 2018 at the New York Academy of Sciences. In addition to dozens of present and past honorees from the Regional and National Blavatnik Awards programs in the US, members of the inaugural cohort of Blavatnik honorees from the UK and Israel joined the Symposium for two days of research presentations and networking opportunities. Nine themed sessions tackled a wide range of issues, celebrating ingenuity and innovation in the life sciences, chemistry, physical sciences, and engineering.

Speakers

Janelle Ayres, PhD, Salk Institute for Biological Studies
Janelle Ayres, PhD, Salk Institute for Biological Studies
M. Madan Babu
M. Madan Babu, PhD, MRC Laboratory of Molecular Biology
Emily Balkus
Emily Balskus, PhD, Harvard University
Alexandra Boltasseva
Alexandra Boltasseva, PhD, Purdue University
Edward Boyden
Edward Boyden, PhD, Massachusetts Institute of Technology
Claudia de Rahm
Claudia de Rham, PhD, Imperial College London
Neal Devaraj
Neal Devaraj, PhD, University of California, San Diego
Charles Diesendruck
Charles Diesendruck, PhD, Technion – Israel Institute of Technology
Neil Garg
Neil Garg, PhD, University of California, Los Angeles
Andrew Goodwin
Andrew Goodwin, PhD, University of Oxford
Patrick Holland
Patrick Holland, PhD, Yale University
Chia Wei (Wade) Hsu
Chia Wei (Wade) Hsu, PhD, Yale University
Sergei Kalinin
Sergei V. Kalinin, PhD, Oak Ridge National Laboratory
Laura Landweber
Laura Landweber, PhD, Columbia University
Andrew Levan
Andrew Levan, PhD, University of Warwick
Michal Lipson
Michal Lipson, PhD, Columbia University
Chao Lu
Chao Lu, PhD, Columbia University
Brian Metzger
Brian Metzger, PhD, Columbia University
Wilhelm Palm
Wilhelm Palm, PhD, German Cancer Research Center, Heidelberg
Ataman Sendoel
Ataman Sendoel, MD, PhD, The Rockefeller University
Emily Weiss
Emily Weiss, PhD, Northwestern University
Visualizing Biological Processes

Speakers

Using Synthetic Lipids to Image and Understand Health and Disease

The Blavatnik Science Symposium opened with a series of presentations detailing how novel imaging and visualization techniques are allowing researchers to examine—and even influence—biological processes at unprecedented levels of detail.

2018 National Laureate Neal Devaraj began with a look inside the world of lipids. Comprising 20% of the body and more than 50% of the brain, these ancient biological molecules play vital roles in cell biology. Devaraj’s work on lipids began as a fascination with the origins of life—he notes that some of the most primitive cells on Earth are thought to have been lipid vesicles. This interest quickly progressed to efforts to recapitulate some of the earliest biological processes by creating synthetic lipid membranes capable of growing and reproducing in the presence of novel catalysts.

As Devaraj explained, however, this basic research into lipid growth and assembly has significant applications in human health and disease. “Lipid dysregulation is important for some of the most prevalent diseases in the modern world, including atherosclerosis and diabetes, rare genetic diseases, and even some cancers,” he said.  Devaraj’s group has pioneered techniques for using synthetic lipid components to image and understand the function of lipids in living cells. Among the group’s innovations are methods of introducing synthetic lipid precursors into live cells to study their role in apoptosis, as well as chemical probes that react with specific lipids and allow for imaging of molecules that are otherwise notoriously difficult to visualize. This technology may be useful as a diagnostic for disorders such as Niemann-Pick C, which is associated with lipid accumulation. It may also be useful in visualizing the efficacy of small molecules intended to disrupt the function of lipids that drive disease processes, such as the lipidation of mutated RAS proteins, which drive up to one-third of all cancers.

Chemical probes bind to specific lipids and fluoresce, facilitating the imaging of small, hydrophobic molecules that are otherwise difficult to visualize.

Chemical probes bind to specific lipids and fluoresce, facilitating the imaging of small, hydrophobic molecules that are otherwise difficult to visualize.

An Expanded View of the Brain

Jokes abound about the ability of intellectually challenging activities to “expand the mind,” but a new technology developed and described by Edward Boyden accomplishes that feat quite literally. Called expansion microscopy, the technique allows researchers to examine complex neural circuitry and other cells in unprecedented detail with conventional optics, without destroying connections or altering spatial orientation. Expansion microscopy relies on a web of water-responsive monomers that wend their way through brain or other tissues, self-assembling into long polymer chains and binding to chemical “anchors” placed throughout the sample. In the presence of water, the polymer swells, and “the molecules come along for the ride,” as Boyden described it, increasing the volume of a sample by a factor of up to 100. “Like stars in a constellation in the sky, the molecules will hover in 3D space so you can pinpoint them, but their relative organization is the same, so the biological information is preserved,” he explained.

Boyden noted that expansion microscopy can be used to better understand any type of tissue, and may be a useful diagnostic tool for the earliest-stage cancers, the cellular traces of which often evade traditional imaging. “Expanding a biopsy can make early detection easier by making the invisible traces of early disease visible,” he said.

This expanded sample of breast tissue reveals early indicators of malignancy likely to be missed by traditional imaging techniques.

This expanded sample of breast tissue reveals early indicators of malignancy likely to be missed by traditional imaging techniques.

Expansion microscopy is just one among a suite of tools Boyden’s lab is working on to enable precise mapping, controlling, and observation of the brain in action. Optogenetics tools, which deliver microbial opsins to specific brain cells to stimulate or cease their function, along with new molecular tools Boyden’s group is developing to image dynamic brain activity, are bringing the incredible complexity of the brain into focus.

Speaker Presentations

Peering Into the Lipid World


Neal Devaraj (University of California, San Diego)

Tools for Mapping and Repairing the Brain


Edward Boyden (Massachusetts Institute of Technology)

Further Readings

Devaraj

Devaraj NK.

J Org Chem. 2017 Jun 16;82(12):5997-6005.

Hardy MD, Yang J, Selimkhanov J, et al.

Proc Natl Acad Sci U S A. 2015 Jul 7;112(27):8187-92.

Rudd AK, Devaraj NK.

Proc Natl Acad Sci U S A. 2018 Jul 17;115(29):7485-7490.

Boyden

Zhao Y, Bucur O, Irshad H, et al.

Nat Biotechnol. 2017 Aug;35(8):757-764.

Chang JB, Chen F, Yoon YG, et al.

Nat Methods. 2017 Jun;14(6):593-599.

Chen F, Wassie AT, Cote AJ, et al.

Nat Methods. 2016 Aug;13(8):679-84.

Tillberg PW, Chen F, Piatkevich KD, et al.

Nat Biotechnol. 2016 Sep;34(9):987-92.

Chen F, Tillberg PW, Boyden ES.

Science. 2015 Jan 30;347(6221):543-8.

Manipulating Light

Speakers

Chia Wei (Wade) Hsu

Yale University

Next-Generation Silicon Photonics

Blavatnik Alumni Michal Lipson began a session on technologies for harnessing the properties of light to achieve seemingly impossible tasks, with an update from one of the fastest-growing fields of physics— silicon photonics. Once considered strictly a semiconductor material, silicon has evolved to become the ultimate substrate for creating optics. Over the past 15 years, silicon photonics has revolutionized optics, driven in part by enormous demand from the computing industry for solutions to one of the biggest issues of a data-driven world: power dissipation.

“Fiber is always cold, while cable is always hot,” Lipson said, in a distinct summary of one of the major advantages of using light to transmit data through lithographically defined waveguides on chips. “Moving data from your processor to memory, or from processor to processor, is what consumes power—but we can link microelectronics components using light, and that uses no power at all,” she explained.

Lipson’s lab has developed revolutionary techniques for optimizing transmission of light from fibers to silicon waveguides—advances with a wide range of applicability in fields such as medical devices, sensing, remote sensing, and integration with fluidics. One particularly exciting emerging application for silicon photonics is in autonomous driving, where LIDAR, or laser radar, has been considered to aid navigation despite logistical and cost challenges. Lipson described how next-generation LIDAR powered by silicon photonic waveguides would be “the holy grail” for autonomous vehicle navigation. By etching hundreds of waveguides onto a chip and tuning the index of refraction in some waveguides relative to others, it’s possible to achieve a moving beam that consumes very little power. Tunable waveguides that delay the propagation of light are difficult to create, although Lipson’s lab is experimenting with layering atomically-thin semiconductor materials on top of waveguides to successfully tweak the index of refraction.

Large arrays of waveguides on a chip offer an alternative to traditional LIDAR for autonomous cars. Tweaking the index of refraction for some waveguides relative to neighboring waveguides results in a moving beam.

Large arrays of waveguides on a chip offer an alternative to traditional LIDAR for autonomous cars. Tweaking the index of refraction for some waveguides relative to neighboring waveguides results in a moving beam.

Making Light Work at the Nanoscale

Alexandra Boltasseva shared a glimpse of an emerging field that complements advances in silicon photonics. Nanophotonics, driven by the development of materials that can attract and direct light at the nanoscale, stands to further broaden the number of technologies that could be transformed by next-generation optical devices. Boltasseva’s research focuses on manmade metallic nanoplasmonic materials which, thanks to their size, behave quite differently from traditional metals. Nanoscale metallic particles are essentially clouds of free electrons, Boltasseva explained, which resonate and form optical “hotspots” capable of trapping electromagnetic radiation in spaces far smaller than the wavelength of light—an impossible feat with traditional optical lenses. Such control over light at the nanoscale will enable exquisitely sensitive medical diagnostics, single-molecule sensors, and new classes of materials with effective optical properties.

Boltasseva described the potential for nanophotonic technologies with optical properties dictated by the specific geometries of their underlying nanoplasmonic materials. She explained how materials traditionally used for display panels could be tailored to exhibit plasmonic resonance, thus enabling ultra-thin, flexible conformal technologies such as lightweight optical wearables, medical diagnostics, augmented reality displays, and smart windows.

Transmitting Light Through Opaque Materials

For Chia Wei (Wade) Hsu, there’s nothing unusual about sending light through a completely opaque material. The 2017 Regional Awards finalist delivered the final presentation in this session with a review of techniques for reducing the light-scattering effects of highly disordered materials and allowing light to shine through objects that otherwise appear opaque.

Opacity is a function of light scattering many times as it encounters materials with highly disordered compositions. A single, weak scattering event results in the clear blue sky we see on a sunny day, while multiple, strong scattering events render a nearby cloud, dense with water droplets, opaque. Hsu described how an emerging technology, wavefront shaping, can control the behavior of light as it encounters a disordered medium and dramatically increase the amount of light that passes through an opaque material. When light waves are in phase with each other, they constructively interfere and the wave’s amplitude increases. Conversely, when light waves are out of phase, they destructively interfere and cancel each other out. A device called a spatial light modulator (SLM) employs both constructive and destructive interference to allow a user to simultaneously program the phase of light emitted from each pixel on the SLM screen.

Controlling the phase shift of light can help reduce the opacity of materials. Destructive interference decreases reflectivity, while constructive interference minimizes scattering.

Controlling the phase shift of light can help reduce the opacity of materials. Destructive interference decreases reflectivity, while constructive interference minimizes scattering.

Such programming controls reflectivity and minimizes scattering, and Hsu’s experiments show that waveform shaping can drastically increase transmission through some of the most opaque materials, including white paint. As the technique evolves, it may have applications in biomedical imaging, optogenetics, and photo thermal therapy.

Speaker Presentations

Silicon Photonics


Michal Lipson (Columbia University)

How Plasmonic Materials Make Light Work at Nanoscale


Alexandra Boltasseva (Purdue University)

Further Readings

Lipson

Zadka M, Chang YC, Mohanty A, et al.

Opt Express. 2018 Feb 5;26(3):2528-2534.

Boltasseva

Brongersma ML, Shalaev VM.

Science. 2010 Apr 23;328(5977):440-1.

Li M, Cushing SK, Wu N.

Analyst. 2015 Jan 21;140(2):386-406.

Li W, Guler U, Kinsey N, et al.

Adv Mater. 2014 Dec 17;26(47):7959-65.

Hsu

Hsu CW, Liew SF, Goetschy A, et al.

Nat Phys. 2017 Feb 13; 497–502.

A Cell’s View of Cancer

Speakers

Chao Lu

Columbia University

Wilhelm Palm

German Cancer Research Center, Heidelberg

Ataman Sendoel

The Rockefeller University

The Reprogrammed Tumor Genome

Mapping the epigenetic differences between cancer cells and healthy cells is an area of research Chao Lu describes as “just like a treasure hunt, except you’re often given no clues—or the wrong clues.” In the first of three presentations on the secrets of cancer cells, Lu explained that for more than 100 years, scientists have observed that cancer cells have a visibly different chromatin structure than healthy cells, but whether these alterations were a driver of cancer or simply a byproduct of abnormal proliferation remained a mystery until fairly recently.  The identification of the enzymes and effector proteins that modify histones—key structural components of chromatin involved in gene regulation—along with studies showing that these histone modifiers are genetically mutated in a large subset of cancer tumor cells, suggest that such mutations drive tumorigenesis. “Perhaps the abnormal chromatin landscape of cancer cells is actually due to genetic alteration of enzymes that help establish that landscape,” Lu said.

Recent studies published by Lu and teams of collaborators reinforce this hypothesis, demonstrating that a specific mutation in a protein that functions as a histone modifier can lock cells into a proliferative state, effectively driving some forms of cancer, including an aggressive pediatric bone cancer. In an unexpected finding, Lu and his team also discovered that a similar mutation that impairs the function of histones and thus impacts gene regulation is found in 15% of adult head and neck squamous cell carcinoma patients. “By discovering how these genetic variations relate to cancers, we can stratify and identify patients who may better respond to certain therapies,” Lu said.

How Cancer Cells Exploit the Body’s Resources

Many common oncogenes reside in growth factor signaling pathways—no surprise, as cancer is a disease of cell proliferation, explained Wilhelm Palm in his presentation on the unique ways cancer cells sense and utilize nutrients in their environment to fuel growth. In multicellular organisms, growth is regulated by both nutrient sensors and growth factor signaling, which promote growth only in the presence of adequate nutrients while preventing nutrient depletion through excess consumption. Cancer cells, however, operate outside these tight controls. Palm described the unusual means through which some cancer cells obtain enough nutrients to drive rapid proliferation, as well as the difficulties of designing therapies to target this process.

Therapies targeting the growth-promoting mTOR pathway have long been pursued as cancer therapeutics, and indeed, mTOR inhibitors have been demonstrated as effective therapies for some cancers. However, mTOR inhibitors can actually advance the progress of other cancers, and Palm and his collaborators discovered that the paradoxical impact of mTOR inhibition on cancer cells is largely due to the unconventional way some malignant cells obtain nutrients. Unlike typical cells, certain cancer cells— K-Ras mutant cells among them—often use macropinocytosis to ingest proteins, which are abundant in plasma, to fuel their growth. In nutrient-rich environments, mTOR inhibition slows cancer cell growth by discouraging macripinocytosis, while in nutrient-deplete environments, mTOR inhibition actually triggers cancer cells to utilize extracellular proteins as an energy source, driving proliferation. Palm explained that many tumors driven by K-ras mutations, such as pancreatic cancers, contain regions that are both highly vascularized (nutrient rich) and less vascularized (nutrient deplete), thus treating pancreatic cancer with mTOR inhibitors can simultaneously decrease cell growth in one area of a tumor while accelerating it in another. “These insights will be important for developing therapies that target growth factor signaling pathways or nutrient sensors,” he said.

In well-vascularized areas of a pancreatic cancer tumor, mTOR inhibition slows cell proliferation, while simultaneously promoting cell growth in the nutrient-deplete tumor core.

In well-vascularized areas of a pancreatic cancer tumor, mTOR inhibition slows cell proliferation, while simultaneously promoting cell growth in the nutrient-deplete tumor core.

Alternative Protein Translation in Cancer Stem Cells

Ataman Sendoel concluded the session by sharing the results of experiments revealing the role of unconventional protein translation processes in tumorigenesis. Translation is among the most energy-intensive process in the cell, and is tightly regulated. Deregulation of translation networks is a known driver of pathogenesis, and Sendoel reports that many oncogenes interfere with the machinery of translation. “By generating alternative networks of translation regulators, oncogenes might actually impose their own protein synthesis programs that advance tumorigenesis,” he said.

Experiments investigating the translational landscape as a cell transitions from homeostasis to malignancy confirm Sendoel’s hypothesis. Results reveal that cancer cells exhibit comparatively low protein synthesis rates, yet amid that repression, cohorts of genes associated with cancer are preferentially translated. Sendoel and his team also discovered two significant variations in the translation process during tumor initiation. First, translation is significantly shifted to the uORF of the 5’UTR; and second, rather than relying on the conventional translation initiation factor, eIF2, oncogenic cells utilize an alternative initiation factor, eIF2A, which promotes preferential translation of oncogenic RNA.

Oncogenic cells employ an alternative translation initiation factor, eIF2A, which shifts translation to the uORF and promotes tumor formation.

Oncogenic cells employ an alternative translation initiation factor, eIF2A, which shifts translation to the uORF and promotes tumor formation.

In experiments modeling squamous cell carcinoma in mice, inhibition of eIF2A prevented tumor formation. In humans, elevated levels of eIF2A are associated with shorter survival in head and neck squamous cell carcinoma patients. Both findings suggest that targeting eIF2A could be a valid treatment strategy.

Further Readings

Lu

Chow KH, Factor RE, Ullman KS.

Nat Rev Cancer. 2012 Feb 16;12(3):196-209.

Schwartzentruber J, Korshunov A, Liu XY, et al.

Nature. 2012 Jan 29;482(7384):226-31.

Behjati S, Tarpey PS, Presneau N, et al.

Nat Genet. 2013 Dec;45(12):1479-82.

Lewis PW, Müller MM, Koletsky MS, et al.

Science. 2013 May 17;340(6134):857-61.

Fang D, Gan H, Lee JH, et al.

Science. 2016 Jun 10;352(6291):1344-8.

Bui N, Huang JK, Bojorquez-Gomez A, et al.

Mol Cancer Ther. 2018 Jul;17(7):1585-1594.

Palm

Palm W, Park Y, Wright K, et al.

Cell. 2015 Jul 16;162(2):259-270.

Palm W, Thompson CB.

Nature. 2017 Jun 7;546(7657):234-242.

Palm W, Araki J, King B, et al.

Proc Natl Acad Sci U S A. 2017 Oct 10;114(41):E8628-E8636.

Ye J, Palm W, Peng M, et al.

Genes Dev. 2015 Nov 15;29(22):2331-6.

Sendoel

Sendoel A, Dunn J, Gonzales E, et al.

Nature. 2017 Jan 26;541(7638):494-499.

Creative Catalysis

Speakers

Neil Garg

University of California, Los Angeles

Bio-Inspired Catalysis Using Quantum Dots

Emily Weiss discussed her lab’s efforts to replicate the complex chemical reactions that take place in biological systems through the work of catalytic enzymes using a decidedly different type of catalyst: colloidal quantum dots. Made of a single crystal of semiconductor material, colloidal quantum dots have unique properties due to both their size and composition. Nanoscale objects are more sensitive to their environment, and in the case of colloidal quantum dots, can have half of their atoms on the surface. “This makes them extremely sensitive but also chemically tunable,” Weiss said.

Just as plants harness the energy of the sun to drive the basic chemical reactions of life, colloidal quantum dots can be used to capture light to drive similar reactions. By tuning the properties of the dot’s core as well as the chemical properties of its surface, Weiss has shown that quantum dots can behave much like biological enzymes, converting energy from one form to another to accomplish a useful reaction. This bio-inspired photocatalysis has applications in organic synthesis, solar energy conversion, and biological and chemical sensing.

Catalyzing Innovation in Cross Coupling Technology

Neil Garg shared an update from the frontiers of organic chemistry, where he and his collaborators are writing a new chapter in the story of a functional group whose structure and properties have been understood for well over a century—amides. Long considered to be fairly unreactive, amides were regarded only as stable intermediates. “If there’s one thing I teach my students about amides, it’s that they’re stable,” Garg said. “We teach students how to make them, but not how to break them.”

That paradigm has shifted considerably over the past several years, as Garg and others have begun using amides in transition metal catalyzed cross-coupling reactions. In addition to the unconventional choice of amides as cross-coupling partners, Garg opted to use nickel as a metal catalyst rather than the palladium typically used in such reactions. This less expensive approach to catalysis has shown that metal catalysts can, in fact, break amides and convert them to many other types of chemical structures, with potential applications in natural product synthesis, ligand synthesis, materials science, and drug development.

Amides can be broken in transition metal catalyzed cross-coupling reactions, resulting in the formation of many types of chemical structures.

Amides can be broken in transition metal catalyzed cross-coupling reactions, resulting in the formation of many types of chemical structures.

Making Molecules Out of Thin Air

Continuing the theme of devising methods to drive surprising reactions, Patrick Holland referenced the most prevalent gas in our atmosphere—nitrogen, which is often overlooked due to its lack of reactivity. Used as the primary source of nitrogen atoms to create ammonia—an essential component of fertilizer—nitrogen gas requires an extremely energy-intensive catalytic process to break the compound’s N-N bond and allow it to bond with hydrogen. This century-old technique, called the Haber-Bosch process, produces more waste carbon dioxide than ammonia—the equivalent of 30 coal-fired power plants every year.

Chemists have long sought an alternative, sustainable method for producing ammonia, ideally one that requires no high temperatures or pressures, utilizes renewable energy, and employs inexpensive catalysts. Holland and his students tapped their expertise in iron chemistry—the least expensive metal—to create a process whereby iron could react with nitrogen.

They designed a reaction driven by multiple iron and potassium atoms arranged in a highly specific geometry in order to break the molecule’s strong N-N bond. With the addition of water as a source of hydrogen, the researchers successfully demonstrated that iron-driven catalysis is capable of creating ammonia. Holland noted that using iron to cleave nitrogen bonds is something that natural systems may have already discovered. “The natural enzyme for reducing nitrogen, nitrogenase, uses iron atoms as a cofactor, so maybe this is just teaching us more about how nature works,” he said.

Multiple iron and potassium atoms surrounding a nitrogen molecule are capable of breaking the molecule’s strong N-N bond.

Multiple iron and potassium atoms surrounding a nitrogen molecule are capable of breaking the molecule’s strong N-N bond.

Speaker Presentation

Quantum Dots as Visible-light Photocatalysts


Emily Weiss (Northwestern University)

Making Molecules Out of Thin Air


Patrick Holland (Yale University)

Further Readings

Weiss

Umena Y, Kawakami K, Shen JR, Kamiya N.

Nature. 2011 May 5;473(7345):55-60.

Cardona T, Sedoud A, Cox N, Rutherford AW.

Biochim Biophys Acta. 2012 Jan;1817(1):26-43.

Lian S, Kodaimati MS, Dolzhnikov DS, et al.

J Am Chem Soc. 2017 Jul 5;139(26):8931-8938.

Garg

Hie L, Fine Nathel NF, Shah TK, et al.

Nature. 2015 Aug 6;524(7563):79-83.

Tasker SZ, Standley EA, Jamison TF.

Nature. 2014 May 15;509(7500):299-309.

Baker EL, Yamano MM, Zhou Y, et al.

Nat Commun. 2016 May 20;7:11554.

Simmons BJ, Weires NA, Dander JE, Garg NK.

ACS Catal., 2016, 6 (5), pp 3176–3179.

Holland

Chen JG, Crooks RM, Seefeldt LC, et al.

Science. 2018 May 25;360(6391).

Bellows SN, Arnet NA, Gurubasavaraj PM, et al.

J. Am. Chem. Soc. 2016, 138 (37), pp 12112–12123.

Skubi KL, Holland PL.

Biochemistry. 2018, 57 (26), pp 3540–3541.

Creating Unusual Materials

Speakers

Creating Unique Properties with Disordered Materials

2018 Blavatnik UK Laureate Andrew Goodwin began the first presentation of the session with a provocative question. “How can we, as chemists, encode disorder in a material the same way we might encode order?” Regarding an image of two sets of tiles, one created from a highly symmetrical pattern and the other from a pattern with lower symmetry, Goodwin explained that just as a visual pattern can be strictly ordered and repetitive, or less ordered and non-repetitive, so too can the structure of materials, which often have external properties reflective of their atomic structure.

Copies of a single tile can be put together to generate a tightly ordered pattern, or one that is less symmetrical but not random. Similarly, materials can be designed with tightly ordered structures or with degrees of disorder.

Copies of a single tile can be put together to generate a tightly ordered pattern, or one that is less symmetrical but not random. Similarly, materials can be designed with tightly ordered structures or with degrees of disorder.

Goodwin’s work focuses on understanding how different types of disorder on the atomic scale impact the behavior and properties of materials on the macroscale. To illustrate these linkages, he described research into one highly disordered material that displays a series of anomalous properties—zirconium tungstate. Among the properties that make zirconium tungstate “famous in solid state chemistry for weird properties,” according to Goodwin, are negative thermal expansion—meaning it contracts, rather than expands, when hot—and negative hydration expansion, which results in the material shrinking as it absorbs water. Goodwin and collaborators completed the first detailed measurements and calculations of zirconium tungstate, revealing how water and heat can alter the material’s crystalline atomic structure, facilitating the creation of new bonds and causing atypical contraction and vibration.

Water displaces the crystalline structure of zirconium tungstate, facilitating the formation of new bonds that cause the material to contract.

Water displaces the crystalline structure of zirconium tungstate, facilitating the formation of new bonds that cause the material to contract.

Such insights may facilitate the use of materials with unusual properties to solve common challenges—for example, zirconium tungstate added to architectural building materials may counteract weather-related expansion and contraction.

Making Materials Atom by Atom

Scanning transmission electron microscopy (STEM) brought the atomic world into focus, revealing both the structure and behavior of atoms within materials. As the technique has evolved, researchers including Blavatnik National Laureate Sergei Kalinin continue to push its boundaries. “Can we use an electron microscope to make things rather than just observe things?” Kalinin asked, explaining his lab’s efforts to understand which phenomena can be controllably induced by an electron beam, and how to visualize and reliably analyze experimental results.

Kalinin shared the outcomes of his attempts to hack the electron microscope, training the scanning beam to operate in novel configurations that resulted in the ability to shape materials under the beam and direct changes such as crystallization. Atomic-level control is also possible using the electron beam—Kalinin shared a video clip of a single carbon atom being displaced from a graphene lattice, replaced by a silicon atom, and then directed to move throughout the lattice. This technique can also be used to bring several silicon atoms together to form a structure that can be manipulated at will, bringing physicists closer to the goal of being able to build matter one atom at a time.

From Kalinin’s perspective, combining the observational capabilities of electron microscopy with deep learning algorithms that can be trained to understand material structure and dynamics is a thrilling proposition. “We are living in a really wonderful time,” he said. “Combining atomic imaging and artificial intelligence can truly move us from observation to understanding.”

Mechanochemistry of Novel Polymeric Materials

As Charles Diesendruck regards an image of a smartphone with a shattered screen, he quips, “Even as a chemist, when I look at this image I don’t think of it as science—I just see an opportunity to get a new iPhone.” But the study of how materials break in response to mechanical stress is a critical step in understanding how to build better materials. Diesendruck studies the weak points of polymers, investigating how their architecture can be tuned to increase resilience and even instill regenerative, or self-healing, properties.

Understanding how mechanical energy propagates through polymers is critical for designing more resilient materials.

Understanding how mechanical energy propagates through polymers is critical for designing more resilient materials.

Diesendruck turns to nature for inspiration, describing how the activity of the human protein titin reinforces muscle fibers in response to strain. Just as additional bonds within the titin protein absorb mechanical energy, Diesendruck employs strategically placed mechanophores to improve a polymer’s resilience. He reports that folding polymer molecules in various configurations results in different properties, and that these can be studied at both the single- molecule level as well as on the macroscale. Applications for polymers with greater ability to withstand strain or even utilize it for good include plastics that could self-reinforce or mend damage before the material breaks, or, more immediately, linear polymers that could extend the life of automotive motor oil by a factor of five.

Speaker Presentations

Creating Unique Properties with Disordered Materials


Andrew Goodwin (University of Oxford)

Making Matter Atom by Atom


Sergei V. Kalinin (Oak Ridge National Laboratory)

Mechanochemistry of Novel Polymeric Materials


Charles Diesendruck (Technion – Israel Institute of Technology)

Further Readings

Goodwin

Mary TA, Evans JSO, Vogt T, Sleight AW.

Science. 1996 Apr 05; 272 (5258):90-92.

Duan N, Kameswari U, Sleight AW.

J. Am. Chem. Soc., 1999, 121 (44): 10432–10433.

Baise M, Maffettone PM, Trousselet F, et al.

Phys Rev Lett. 2018 Jun 29;120(26):265501.

Kalinin

Dyck O, Kim S, Kalinin SV, Jesse S.

Appl. Phys. Lett. 111, 113104 (2017).

Kalinin SV, Borisevich A, Jesse S.

Nature. 2016 Nov 24. (539) 487.

Kalinin SV, Sumpter BG, Archibald RK.

Nat Mater. 2015 Oct;14(10):973-80.

Diesendruck

Diesendruck CE, Sottos NR, Moore JS, White SR.

Angew Chem Int Ed Engl. 2015 Sep 1;54(36):10428-47.

Levy A, Wang F, Lang A, et al.

Angew. Chem. Int. Ed. 2017, 56, 6431–6434.

The (Not So) Secret World of Microbes

Speakers

Laura Landweber

Columbia University

Deciphering the Human Microbiota with Chemistry

Emily Balskus gave the first of three presentations probing the remarkable interactions between humans and the microbes that live within us. Balskus briefly reviewed the state of knowledge about gut microbiota, noting that despite our increasing awareness of the deep links between gut microbiota and human health and disease, little is known about the molecular mechanisms that underlie microbiota/host interactions. Studying gut bacteria in the lab is simple, but studying their functions and interactions in their complex native environment is far more challenging. Balskus described how chemistry can help shed light on how gut microbes metabolize drugs and nutrients, and the impact of these processes on host health.

Balskus shared the results of efforts to identify how gut microbes may impact the efficacy of a commonly used Parkinson’s drug, Levodopa (L-dopa). L-dopa is metabolized in the brain, where it is decarboxylated to replenish lost dopamine. However, the enzyme that facilitates this reaction is also found in peripheral tissues. Even with drugs to block peripheral metabolism, it is estimated that up to 60% of L-dopa is metabolized outside the brain, where it is effectively useless. Gut microbes also metabolize L-dopa, however, the precise organism(s) responsible for this additional metabolism were unknown. Balskus predicted that gut microbiota likely used a decarboxylase similar to the one that drives the reaction in humans, and identified a common gut bacteria with a highly conserved L-dopa decarboxylase enzyme. Further studies showed that two distinct microbes work in tandem to facilitate the metabolism of L-dopa in the human gut, and that this metabolism can be targeted for inhibition, potentially raising the efficacy of the drug for Parkinson’s patients.

Surviving Infection with the Help of Microbes

When a person contracts an infectious disease, what dictates whether they remain healthy or get sick and die? This is the question that 2018 National Laureate Janelle Ayres is attempting to answer by investigating the factors that underlie host susceptibility and promote host fitness in the face of infection. Ayres explained her lab’s unique approach, one that “takes variations in host genetics, environmental factors, and microbiota out of the equation.” The team subjects genetically identical mice that also share housing and food, and have the same microbiome composition, to 50 times the lethal dose of a common intestinal bacterial pathogen. In every cohort, some animals succumb to the infection, while others remain healthy. Analysis of both cohorts’ vital organs at the time of peak morbidity reveals that while pathogen burden is the same in both animals, the healthy cohort showed gene expression changes that are distinct not only in comparison to the sick and dying cohort, but to uninfected controls. By categorizing these genes, Ayres and her collaborators identified specific mechanisms that drive host resilience to this particular pathogen, and learned that these pathways can be induced in other infected populations through dietary means. These healthy-but-infected mice become asymptomatic persistent carriers, and this co-existence decreases the virulence of the microbe over time.

RNA sequencing in mice that show no signs of illness 8 days after infection with 50x the lethal dose of an infectious bacteria indicates distinct patterns of gene expression that promote host health.

RNA sequencing in mice that show no signs of illness 8 days after infection with 50x the lethal dose of an infectious bacteria indicates distinct patterns of gene expression that promote host health.

Ayers’ approach upends the traditionally antagonistic approach to treating infections, which relies on eliminating microbes. Rather, it suggests that by promoting what she refers to as the host’s “cooperative defense system”—a combination of anti-virulence mechanisms and disease tolerance measures—the microbial genes that promote host health can thrive. “By driving commensalism, we can reduce the risk of infectious disease and develop better treatments,” Ayers said.

RNA-Mediated Natural Genome Editing in the Ciliate Oxytricha

Laura Landweber recapped the unusually complex genomic system of the unicellular pond-dwelling ciliate Oxytricha trifallax. Unlike most eukaryotes, where genetic information is contained within a single nucleus, Oxytricha has two nuclei, distinct in both size and function. The smaller of the two, called the micronucleus, is an archival germline nucleus. A duplicate of this archive forms the foundation of the larger macronucleus, which contains the somatic genome. The process by which the organism accomplishes the task of creating this somatic nucleus, which regulates all gene expression, is a dizzying feat of unscrambling, rearranging, and repairing. Landweber described how Oxytricha eliminates 90%-95% of its DNA, leaving behind only the coding regions and short regulatory sequences, then repackages the fragments—some 225,000 of them, many of which are flipped and out of order— into 16,000 nanochromosomes in the somatic nucleus.

Solving this “giant genomic jigsaw puzzle” is a process largely guided by small RNAs that sequentially mark fragments of the germline DNA to determine their fate. Recent work by Landweber and a team of collaborators shows that these small RNAs, called piRNAs due to their association with the PIWI family of RNA-binding proteins, first direct the retention of DNA fragments, which are transported to the developing somatic nucleus. A second, paralogous group of piRNAs then marks segments for deletion. The presence of a methyl group on one class of piRNAs allows the cell to distinguish between the directive to “retain” or “delete” in a system that underlies one of nature’s most complex genomic architectures.

Small RNAs called piRNAs mark sections of the Oxytricha genome for retention during the formation of the organism’s second (somatic) nucleus. Areas marked for deletion are denoted by the absence of piRNA binding.

Small RNAs called piRNAs mark sections of the Oxytricha genome for retention during the formation of the organism’s second (somatic) nucleus. Areas marked for deletion are denoted by the absence of piRNA binding.

Speaker Presentations

Deciphering the Human Microbiota with Chemistry


Emily Balskus (Harvard University)

Host-Microbe Interactions: Harnessing Co-evolution to Treat Disease


Janelle Ayres (Salk Institute for Biological Studies)

Further Readings

Balskus

Chittim CL, Irwin SM, Balskus EP.

Biochemistry. 2018 May 8;57(18):2567-2577.

Koppel N, Balskus EP.

Cell Chem Biol. 2016 Jan 21;23(1):18-30.

Ayers

Ayres JS, Freitag N, Schneider DS.

Genetics. 2008 Mar; 178(3): 1807–1815.

Schieber AM, Lee YM, Chang MW, et al.

Science. 2015 Oct 30;350(6260):558-63.

Landweber

Fang W, Wang X, Bracht JR, et al.

Cell. 2012 Dec 7;151(6):1243-55.

Khurana JS, Clay DM, Moreira S, et al.

RNA. 2018 Jan;24(1):18-29.

Chen X, Bracht JR, Goldman AD, et al.

Cell. 2014 Aug 28;158(5):1187-1198.

Multi-Messages from the Universe

Speakers

Gravitational Rainbows

Claudia de Rham opened a session focused on how gravitational waves and other cosmological phenomena are providing new insights into the fabric and history of the universe. The first confirmed detection of gravitational waves by the Laser Interferometer Gravitational-Wave Observatory (LIGO) in 2015 marked the beginning of a new era of research into the fundamental nature of gravity.

de Rham explained that just as light waves change frequency as they propagate through different media, so too could the medium through which gravitational waves pass impact their frequency. A physicist observing a known source of light—a star, for example–could extrapolate some information about the medium propagating light from that star simply by observing the frequency of the light. Similarly, those wishing to study the fabric of the universe may be able to glean information by studying the frequency of gravitational waves. “Understanding the spectrum of gravitational waves could allow us, in principle, to understand what the universe is made of between emission and what we observe,” de Rham said. “This could have huge consequences for understanding the universe and what it’s made of.”

de Rham referred to one of the pervasive mysteries of cosmology and physics–how to characterize and understand dark energy, which counteracts the attractive forces of gravity and is thought to account for 70% of the energy budget of the universe. Dark energy should, in theory, affect the frequency of gravitational waves, and studying those changes may shed light on the material of the universe.

Exploring the Universe with Gamma-Ray Bursts

The brightest explosions in nature are gamma-ray bursts. First discovered in the 1960s, these intense, high-energy cosmic events have since proven to be powerful tools for studying the distant universe and the oldest galaxies. Andrew Levan discussed the evolution of the study of gamma ray bursts, chronicling how these explosions, which were once notoriously difficult to study and locate due to their extreme energy and astonishing distance, have become rich sources of information about  known phenomena including the collapse of massive stars and the merging of neutron stars, and a portal through which to discover new types of cosmic events.

Levan places gamma ray bursts alongside other extrasolar “messengers” such as neutrinos and gravitational waves, which can intersect and provide a more complete picture of events in the universe. He described how gravitational waves produced by a neutron star collision 130 million years ago and detected by LIGO in August 2017 was also accompanied by a gamma ray burst that allowed scientists, for the first time in history, to understand the nature of an astronomical event through the forces of both gravity and light.

The Origin of Gold, Revealed

Brian Metzger continued the discussion about the merger of neutron star binaries, sharing a more detailed version of the events that followed the first detection of such an event by LIGO in August 2017. Metzger described the fast and furious work of astronomers around the world as they used information from LIGO and NASA’s Fermi gamma-ray telescope to locate the host galaxy and observe the after-effects of the merger. Over the course of seven days, the flare of light coming from the explosion faded and shifted from blue to red, which was “unlike any stellar explosion astronomers had seen before,” Metzger said. More exciting still was the fact that this unusual observation answered one of the longstanding questions in nuclear astrophysics—the origin of the heavy elements including precious metals, transuranics, and rare earth elements.

The dense cloud of neutron-rich material ejected from the coalescence of neutron stars gradually settles around a rapidly rotating center that collapses into a black hole. As Metzger said, “black holes are fussy eaters,” thus only a fraction of this material becomes part of the horizon, while the rest forms a cloud of radioactive nuclei of varying mass. This cloud starts out as a “blue plume,” as the lighter radioactive elements are formed. As the cloud cools and becomes less opaque, it shifts red as more light from the heavier radioactive elements, such as gold and uranium, became visible.

Over the course of a week, the neutron-rich cloud of material ejected from the merger of two neutron stars shifts from blue to red, as hot, lighter radioactive elements are formed first, followed by heavier elements like uranium and gold.

Over the course of a week, the neutron-rich cloud of material ejected from the merger of two neutron stars shifts from blue to red, as hot, lighter radioactive elements are formed first, followed by heavier elements like uranium and gold.

“This is the first time we’ve directly seen in nature these elements being formed,” Metzger said, noting that based on estimates of the quantity of heavy elements produced by just a single neutron star binary merger, these cosmic events are likely the source of most of these elements in the universe.

Speaker Presentations

Gravitational Rainbows


Claudia de Rham (Imperial College London)

Exploring the Universe with Gamma Ray Bursts


Andrew Levan (University of Warwick)

The Origin of Gold Revealed from the Radioactive Glow of Coalescing Neutron Stars


Brian Metzger (Columbia University)

Further Readings

de Rham

de Rham C, Melville S.

arXiv:1806.09417, 2018.

Levan

Tanvir NR, Fox DB, Levan AJ, et al.

Nature. 2009 Oct 29;461(7268):1254-7.

Levan AJ, Tanvir NR, Cenko SB, et al.

Science. 2011 Jul 8;333(6039):199-202.

Levan AJ, Tanvir NR, Starling RLC, et al.

Astrophys. Journ. 2014. 781 (2014) 13.

Levan AJ, Lyman JD, Tanvir NR, et al.

Astrophys Journ. Letters. 2017. 848, 2.

Metzger

Metzger BD.

Living Rev Relativ. 2017;20(1):3.

Kilpatrick CD, Foley RJ, Kasen D et al.

Science. 2017 Dec 22;358(6370):1583-1587.

Kasen D, Metzger B, Barnes J, et al.

Nature. 2017 Nov 2;551(7678):80-84.

Computational Biology

Speakers

Oded Rechavi

Tel Aviv University

Mechanisms of Non DNA-Based Inheritance

Oded Rechavi opened the final session of the Symposium by reflecting on the rivalry of the two major evolutionary theorists of the 18th and 19th centuries, Jean-Baptiste Lamarck and Charles Darwin. While Darwin rightfully prevailed, recent discoveries in the area of epigenetic inheritance have brought Lamarck out of the shadows and rocked the foundation of 150 year-old dogma.

Rechavi’s work with Caenorhabditis elegans has built upon the well-observed phenomenon that nematodes often jump the barrier between germline and soma, passing along seemingly acquired traits, such as viral immunity. The mechanisms of this inheritance have only come to light in recent years, as Rechavi and others have uncovered the process by which small RNAs mediate heritable changes in gene expression. He described how viral infections and certain environmental stressors, such as starvation, can induce heritable changes in C. elegans gene expression that confer an advantage against similar hardships for offspring.

Rechavi’s lab further elucidated the “rules” of RNA-based inheritance, discovering the mechanisms that determine the duration of inherited epigenetic responses. While most were believed to persist in C. elegans for 3–5 generations, Rechavi’s lab showed that this process is regulated, and that epigenetic responses can be both “remembered” as well as intentionally “forgotten” by the activity of a specific set of genes, dubbed MOTEK, or Modified Transgenerational Epigenetic Kinetics, which turn epigenetic inheritance on and off. “It’s a tunable mechanism,” Rechavi said. “It’s adaptive to forget things—you don’t want to remember everything your parents did, just the things that are relevant to your success,” he joked.

GPCR Pharmacogenomics: From Big Data to Personalized Medicine

Madan Babu closed the Symposium with a review of research that has significant implications for public health systems and patients. His work focuses on integrating diverse data sets to illuminate the functionality of proteins. He shared the results of an investigation into one large class of proteins, G protein-coupled receptors, or GPCRs, which have particular significance as a target of more than one-third of all FDA-approved pharmaceuticals. GPCRs are cell membrane surface proteins that undergo conformational changes when small molecules bind to them, triggering a physiologic response. “Any mutation or variation in these receptors can impact a patient’s response to a drug,” Babu said, noting that information on how patient response may be affected by genetic variation is not included in drug labeling information, nor has it been thoroughly investigated.

Babu’s lab set out to estimate the amount of genetic variability that exists in GPCR receptors among the healthy human population, and to determine how these polymorphisms impact drug response. The team discovered a high degree of genetic variation in GPCRs—approximately 68 missense mutations per person, about 8 of which have known clinical implications. Further, they noted that many of the most commonly mutated GPCRs are drug targets.

Polymorphisms in functional GPCR sites that can impact response to pharmaceutical drugs are common in the healthy human population, and many highly variable GPCRs are popular drug targets.

Polymorphisms in functional GPCR sites that can impact response to pharmaceutical drugs are common in the healthy human population, and many highly variable GPCRs are popular drug targets.

These findings have significant clinical, societal, and economic impact, as illustrated by variations in one class of GPCR, the µ-opioid receptor.  Polymorphisms in this target for opioid analgesics can alter the effects of opioid antagonists used to treat overdose, as well as decreasing the effectiveness of partial agonists used to treat dependence. Overall, Babu estimated the economic burden of drug target variability on public health systems at £500M per year in the UK alone. This research highlights benefits of a precision medicine approach over the traditional, “one treatment fits all” paradigm. “If we have information about the genotype, one can use this information to guide medication choices to tackle this genetic diversity in the human population,” he said.

Speaker Presentation

GPCR Pharmacogenomics: From Big Data to Personalized Medicine


M. Madan Babu (MRC Laboratory of Molecular Biology)

Further Readings

Rechavi

Buckley BA, Burkhart KB, Gu SG, et al.

Nature. 2012 Sep 20;489(7416):447-51.

Shirayama M, Seth M, Lee HC, et al.

Cell. 2012 Jul 6;150(1):65-77.

Ashe A, Sapetschnig A, Weick EM, et al.

Cell. 2012 Jul 6;150(1):88-99.

Luteijn MJ, van Bergeijk P, Kaaij LJ, et al.

EMBO J. 2012 Aug 15;31(16):3422-30.

Rechavi O, Houri-Ze'evi L, Anava S, et al.

Cell. 2014 Jul 17;158(2):277-287.

Houri-Ze'evi L, Korem Y, Sheftel H, et al.

Cell. 2016 Mar 24;165(1):88-99.

Babu

Venkatakrishnan AJ, Deupi X, Lebon G, et al.

Nature. 2013 Feb 14;494(7436):185-94.

Flock T, Ravarani CNJ, Sun D, et al.

Nature. 2015 Aug 13;524(7564):173-179.

Venkatakrishnan AJ, Deupi X, Lebon G, et al.

Nature. 2016 Aug 25;536(7617):484-7.

Flock T, Hauser AS, Lund N, et al.

Nature. 2017 May 18;545(7654):317-322.

Hauser AS, Chavali S, Masuho I, et al.

Cell. 2018 Jan 11;172(1-2):41-54.e19.