Winter/Spring Edition 2020 by Scripps Research Magazine

Scripps Research Magazine | Winter/Spring Edition 2020 | Science Changing Life

| The Age of Digital Medicine

Information Is Power

| Overcoming Barriers

Women Changing Science

S C R I P P S R E S E A R C H M A G A Z I N E | W IN T ER/S P RIN G 2 0 2 0

Scripps Research Seeing life up close

Information is power

Like cartographers, structural New wearable devices provide an biologists map lifeâ&#x20AC;&#x2122;s molecules with unprecedented opportunity to study the help of specialized microscopes. human health at high resolution.

Women in science

Noteworthy

To support the careers of women in science, Scripps Research is pursuing a number of innovative initiatives.

Iconic actor Alan Alda is teaming up with Scripps Research to train scientists to become better communicators.

Presidentâ&#x20AC;&#x2122;s Letter 02 Discoveries 04 Awards/Honors/Grants 39 Events 44

Mia Huang, PhD, assistant professor in the Department of Molecular Medicine, works alongside postdoctoral associate Tesia Stephenson, PhD, on the Jupiter, Florida, campus.

Women Changing Science

From the President

Many of the tools of science—microscopes, telescopes, spectroscopes and so on—end with a suffix derived from the Greek word skopein, meaning “to look.” The word “science” itself stems from the Latin word scire, meaning “to know.” Together, these are the driving forces of science: to see so that we can know. In this issue of Scripps Research Magazine, you will encounter stories from our quest to better observe and understand our world and to use that knowledge to improve the lives of people around the globe. A significant problem in biology is visualizing the tiniest building blocks of life. Rising to the challenge, Scripps Research scientists are capturing some of the first images of molecules that keep the human body healthy. In one example of this, you’ll read how researchers on our Florida campus used cryogenic electron microscopy to capture the first images of the protein metavinculin, which plays a critical role in heart function. Another challenge is observing phenomena that are in constant flux, such as human heart rhythms. At this moment, you may be wearing a Fitbit, Apple Watch or other wearable device that records your heartbeat, sleep schedule, physical activity or even your blood pressure. You’ll learn how Scripps Research Translational Institute is leveraging these emerging technologies to help usher in a new era of digital medicine. This issue also explores the concept of perspective—the different points of view from which one can see things. Oftentimes, approaching a problem from a new direction, one overlooked by others, can pave the way to an innovative solution. At Scripps Research, we are committed to attracting and empowering a diverse array of students, staff and faculty, and here we highlight some of our efforts to support the careers and educations of women in science. Lastly, one thing scientists see far too often—I speak from personal experience—is bewildered looks on other people’s faces. With that in mind, Scripps Research has partnered with Alan Alda, the iconic actor, science advocate and author of the book “If I Understood You, Would I Have This Look On My Face?” to offer science communications workshops on our La Jolla campus. It is critical that we scientists communicate the excitement and impact of our work to the rest of the world. Our partnership with Alan Communications Training, outlined in these pages, will help us do a better job at this vital aspect of science.

Peter Schultz, PhD President and CEO, Scripps Research

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DISCOVERIES Scripps Research

THAT CHANGE LIVES

SCRIPPS RESEARCH MAGAZINE | WINTER/SPRING 2020

OBESITY/METABOLISM

Impactful scientific findings emerge on nearly a daily basis from our 200+ laboratories in La Jolla, California, and Jupiter, Florida— appearing on the pages of prestigious peer-reviewed journals and making headlines across the country. Because it's hard to keep up with it all, we've compiled a selection of recent discoveries that showcase the breadth and depth of our life science research. Every new piece of knowledge enlightens yet another path of inquiry, opening the door to new possibilities for human health.

For more science news, visit scripps.edu/discoveries

Current Biology, November 2019

Brain receptor that regulates body heat may speed weight loss MAINTAINING A CONSTANT BODY TEMPERATURE is a lot of work. Up to half of the calories we consume each day is turned into energy for that very purpose, says Scripps Research Professor Bruno Conti, PhD. So when food is scarce, mammals adapt by lowering their temperature—limiting energy expenditure so they don’t lose too much body weight. Some animals even go into hibernation. “It’s a basic survival mechanism,” Conti says. “The body is saying: Let’s save energy today and maybe we’ll find food tomorrow.” For humans who are dieting to lose weight, this can be a problem. Conti’s team wondered if by blocking the brain’s kappa receptor, which regulates body heat, animals would continue to burn calories for heat even when food was restricted. In experiments involving mice, they found the approach indeed led to significant weight loss—but only among mice on a calorie-restricted diet. Blocking the receptor did not have the same effect on mice who ate freely. The findings will be further explored as a potential treatment approach for obesity, which the World Health Organization has called a global epidemic. It’s possible that existing medicines already known to block the kappa receptor could be repurposed to safely treat obesity, Conti says. “The tools to interact with this mechanism may already be available—and if they are, they may be able to translate quickly into a medicine,” Conti says. “Unfortunately for many people who are obese, losing weight isn’t as simple as eating less.”

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OBESITY/METABOLISM

DISCOVERIES

Development, October 2019

Young brain cells can bounce back to health after food deprivation In research that’s relevant for prenatal health and brain injury, scientists identify cellular workings that stop and restart early brain development HOW IS EARLY BRAIN GROWTH shaped by nutrition? The cellular mechanisms aren’t well understood, in part due to the difficulty of studying animals before they’re born, says Scripps Research cell biologist Caroline McKeown, PhD. But in a study involving tadpoles, she and Scripps Research Professor Hollis Cline, PhD, unearthed new findings about how young brain cells respond to—and recover from—lack of food. Typically, brain stem cells known as “neural progenitors” flourish during early stages of development. These cells eventually mature into neurons, which control thought and action. The scientists found that when tadpoles are deprived of food, their neural progenitor cells stop dividing and their body growth decreases. But as long as tadpoles access food within about nine days, the cells start dividing again and tadpoles catch up on growth.

Scientists found that when tadpoles are deprived of food, their neural progenitor cells stop dividing and their body growth decreases. But as long as tadpoles

McKeown wanted to understand what was happening on a cellular level to tell neural progenitors to stop dividing or to start up again. She and Cline traced it to a well-known signaling pathway known as mTOR, which regulates cell metabolism, growth, proliferation and survival.

access food within about nine days, the cells start dividing again and tadpoles

Interestingly, even without providing hungry tadpoles with food, their brains could be relaunched into growth mode by activating the insulin receptor that sits on the surface of neural progenitor cells, Cline says. Being able to bypass the need for food on a cellular level could advance medical therapies for poor nutrition. “We envision this knowledge becoming useful in understanding what can go wrong in the absence of maternal nutrition, and how important it is to respond quickly to such an event,” says Cline, chair of the Department of Neuroscience at Scripps Research's La Jolla, California, campus.

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catch up on growth.

Nature Communications, November 2019

Repurposed cancer drug holds potential for innovative diabetes treatment SCIENTISTS AT CALIBR, the drug discovery and development arm of Scripps Research, have found what may be the beginnings of a new approach to treat diabetes. And they found it in an unexpected place: a drug currently used to treat a form of breast cancer. The discovery has jumpstarted efforts to refine the drug for non-cancer diseases and highlights the value of assessing approved medicines for unexpected therapeutic benefits.

Nature, November 2019

Little-known protein may play key role in obesity, diabetes A RECENTLY DISCOVERED protein, PGRMC2, had been detected in the uterus, liver and several other areas of the body. But the lab of Scripps Research’s Enrique Saez, PhD, saw that the protein was also abundant in fat tissue, and they wanted to know why. Their findings, published in Nature, may lead to new treatments for diabetes and other metabolic diseases. The mystery protein, they learned, plays the indispensable role of “chaperone” to an equally vital molecule known as heme. Heme, which contains iron, travels within cells to enable crucial life processes such as cell proliferation, cell death and circadian rhythms. But heme can’t travel alone because it’s toxic to the cellular materials around it; without being encapsulated by a chaperone, heme would destroy everything in its path.

With this discovery, Saez and his team established PGRMC2 as the first intracellular heme chaperone to ever be described in mammals. “There were many hypotheses, but the proteins that traffic heme had not been identified,” Saez says. Next, the team designed experiments to discern why this protein is prevalent in fat. They found that without PGRMC2 in fat tissues, mice that were fed a high-fat diet became intolerant to glucose and insensitive to insulin—key symptoms of diabetes. By contrast, obese-diabetic mice treated with a drug to activate PGRMC2 showed major improvements in diabetes symptoms. Saez believes it’s possible that activating the heme chaperone in other organs—including the liver, where a large amount of heme is made—could mitigate the effects of other metabolic disorders such as nonalcoholic steatohepatitis (NASH), a major cause of liver transplantation today.

The drug, neratinib, was shown to protect insulin-producing beta cells in the pancreas. The loss of these cells is a hallmark of both forms of diabetes: type 1, an autoimmune disease that typically emerges early in life; and type 2, which is influenced by both genetics and lifestyle. Neratinib is already widely used as a targeted drug for early stage breast cancer, with efficacy for patients whose tumors test positive for the HER2 gene. “The speed of the translation was perhaps the most exciting part of the project,” says Matthew Tremblay, PhD, chief operating officer of Calibr and Scripps Research, and a senior author of the study. “We were able to find a compound very quickly that we could deploy as a tool in mouse models of diabetes. And because the drug already has FDA approval, we were able to understand its selectivity and pharmacology very readily.” NERATINIB

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BETTER MEDICINE

Human white blood cells are central to the immune response, making them an ideal cell type to map out new druggable targets.

Nature Chemistry, October 2019

Creative twist on chemistry method reveals treasure trove of new targets for small-molecule drugs THE WORLD OF POSSIBILITY for new and better medicines has widened significantly thanks to chemists at Scripps Research. A team led by Christopher Parker, PhD, and Ben Cravatt, PhD, found a way to quickly identify—in living cells—proteins that interact with potential drug candidates. “Even with all of the advances in drug development and medical care, only a small fraction of our 20,000-or-so human proteins are targeted by drugs today,” says Parker, assistant professor of chemistry on Scripps Research’s Florida campus. “We found a way to survey the landscape of

proteins that exist in human cells and identify ‘druggable’ areas that are still flying under the radar of modern medicine.” The majority of all medicines today are what’s known as “small molecule” drugs, encompassing everything from aspirin to antidepressants. Usually taken by mouth, these drugs act on proteins in the body. Some may stimulate a cellular process that creates a desired effect; others may block a process that’s causing trouble. Aspirin, for example, inactivates a type of protein that causes inflammation.

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In the new study, scientists built a library of specialized “probes”— essentially, tiny drug fragments— that could reveal new interactions in human cells that may be useful for future therapies. They did this by creating pairs of drug fragments that were mirror images of one another; they weren’t superimposable, but otherwise identical. “By minimizing the structural differences between probes, we were able to home in on uniquely druggable protein targets,” Parker says. “It’s an expedited way to map targets and gain confidence that you’re hitting druggable sites.”

DISCOVERIES ADDICTION/DISEASE

Cell Reports, October 2019

Key mechanism of opioid addiction is identified SCIENTISTS AT SCRIPPS RESEARCH discovered a molecular process in brain cells that may be a major driver of drug addiction, and thus may become a target for future addiction treatments. The team used an advanced imaging technique to visualize brain cell activity during exposure to an opioid, focusing in on a part of the brain known to be centrally important for addiction. They found that key brain cell changes that occur with addiction and help sustain addiction behavior are accompanied by—and plausibly driven by—particular changes in a signaling system involving a messenger molecule called cyclic AMP, or cAMP. “Our findings suggest the possibility, which we now want to test, that an intervention to reverse these cAMP changes could reduce symptoms of addiction, such as drug cravings and withdrawal dysphoria,” says the study’s senior author Kirill Martemyanov, PhD, professor and chair of the Department of Neuroscience at Scripps Research in Jupiter, Florida.

70,000 people die every year in the United States from drug overdoses— most of which involve opioids. And on the whole, drug addiction or dependency is estimated to affect tens of millions of Americans.

Immunity, November 2019

Experimental HIV vaccine successfully elicits broadly neutralizing antibodies to the virus AN EXPERIMENTAL HIV VACCINE developed jointly by scientists at Scripps Research and the nonprofit vaccine research organization IAVI has reached an important milestone by eliciting special antibodies that can neutralize a wide variety of HIV strains. “It’s an initial proof of principle but an important one, and we’re now working to optimize this vaccine design,” says the study’s senior author Richard Wyatt, PhD, a professor in the Department of Immunology and Microbiology at Scripps Research. The tests, in rabbits, showed that these “broadly neutralizing” antibodies (bnAbs), targeted at least two critical sites on the virus. Researchers widely assume that a vaccine must elicit these antibodies to multiple sites on HIV if it is to provide robust protection against the ever-changing virus. The promising results suggest that researchers are one step closer to developing an effective HIV vaccine—a major goal of medical science ever since the virus was identified in 1983.

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NEW TREATMENTS

DISCOVERIES

Science, October 2019

Powerful new genomics technique reveals the causes of rare diseases Nature, October 2019

Ginkgo tree compound could serve as ‘green’ insecticide

The ginkgo tree is considered a living fossil. Closely related species lived 270 million years ago, before dinosaurs, and managed to survive global cataclysms that extinguished most other kinds of plants and animals.

THERE’S NOW AN EASY and affordable way to make a synthetic version of the plant compound bilobalide, which is naturally produced by ginkgo trees to ward off pests. The method, an invention of Scripps Research chemists, is a significant feat because bilobalide holds potential commercial value for medicines and environmentally friendly insecticides. The compound is known to be nontoxic to humans. Ginkgo trees are unusually hardy and longlived; some are believed to be thousands of years old. Insect-killing compounds in the trees’ leaves and nuts likely contribute to their longevity. In addition to bilobalide’s potential as an insecticide, previous studies found that the compound reverses cognitive deficits in an animal model of Down syndrome and protects dopamine neurons in a model of Parkinson’s disease. “We were first interested in bilobalide because of its potential relevance for neuroscience,” says Ryan Shenvi, PhD, professor in the Department of Chemistry. “However, since word has spread about the new synthesis, we’ve had the strongest expression of interest from the agrochemical industry.”

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ONE OF THE BIGGEST HURDLES for the rare disease community is that of timely diagnoses—especially when life-threatening diseases emerge early in life. Standard methods of gene sequencing can sometimes reveal the cause, but only if the disease-driving mutations are obvious and result in missing or severely truncated proteins. For at least half of rare genetic diseases, however, the cause is more subtle and can’t be detected using those methods. A team led by a scientist at Scripps Research has created a new technique for solving these genetic mysteries. The approach makes use of the fact that people inherit two copies or “alleles” of virtually every gene—one from each parent. By comparing activity levels of maternal and paternal alleles across the genome, it detects when the activity of an allele lies far enough outside the normal range to be a plausible cause of disease. “Compared with other methods, it dramatically cuts down on the number of genes you have to analyze,” says Pejman Mohammadi, PhD, assistant professor in the Department of Integrative Structural and Computational Biology at Scripps Research. He and his colleagues demonstrated their new method, known as ANEVA-DOT, by applying it to patients with rare muscular dystrophies. They successfully detected the disease-linked genes in cases where there was already a diagnosis and an expected major imbalance in allele activity. In many undiagnosed cases, the technique uncovered a short list of plausible diseaselinked, muscle-related genes. The scientists now are using the method to help a San Diego children’s hospital diagnose genetic disease in newborns.

The new finding centers on caraphenol A, a small molecule closely related to resveratrol, naturally produced by grapes and found in red wine. Resveratrol is widely known as an antioxidant and antiinflammatory agent. Similar to resveratrol, caraphenol A is anti-inflammatory, but in this study, it served a different role.

Leukemia cells (pictured) can be destroyed using gene therapy, but today's treatment process is arduous.

Blood, October 2019

When added to gene therapy, plant-based compound may enable faster, more effective treatments GENE THERAPY has broadened the treatment possibilities for immune system deficiencies and blood-based conditions, such as sickle cell anemia and leukemia. These diseases, which once would require a bone marrow transplant, can now be treated by modifying patients’ own blood stem cells to correct the genetic problem. But administering gene therapy is expensive and time-consuming—a result of the many steps required to deliver the healthy genes into the patients’ blood stem cells.

In new research published in the journal Blood, scientists at Scripps Research believe they found a way to sidestep some of the current difficulties, resulting in a more efficient method that would save money and improve treatment outcomes. “If you can repair blood stem cells with a single gene delivery treatment, rather than multiple treatments over many days, you can reduce the clinical time and expense,” says Bruce Torbett, PhD, associate professor in the Department of Immunology and Microbiology, who led the research.

Torbett and his team became interested in the unique chemical properties of the molecules and believed it might be able to enable viral vectors, used in gene therapy to deliver genes, to enter blood stem cells more easily. This would be momentous because stem cells—and in particular, self-renewing blood stem cells—have many barriers of protection against viruses, making them challenging for gene therapy to infiltrate. “We saw a way to potentially make the treatment process significantly more efficient,” Torbett says. By adding caraphenol A to human blood stem cells, along with the therapeutic vector mix, the team found that cells let down their natural defenses and allowed vectors to enter more easily. Another key benefit of the approach is time: If gene delivery can be accomplished faster, the cells can be re-administered to the patient sooner. This makes treatment more convenient and helps to ensure the stem cells don’t lose their self-renewing properties. Because many of the diseases treatable with gene therapy affect children, Torbett says he feels a special urgency to advance this discovery from the lab into the clinic.

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CELL SCIENCE

DISCOVERIES

Cell Reports, December 2019

New screening method identifies potential anticancer compounds that reawaken T cells CANCEROUS TUMORS often thrive

more than 12,000 drug compounds—

by wearing out the immune system’s

uncovering 19 that can reawaken

T cells, rendering them “exhausted.”

exhausted T cells.

by scientists at Scripps Research speedily

Michael Oldstone, MD, who led the

identifies medicinal compounds that can

research, notes that the new screening

restore the function of immune cells,

approach is flexible enough to adapt

making cancers vulnerable once again.

for finding compounds that have other effects on T cells, such as reducing

The method should accelerate

their activity to treat autoimmune

development of new cancer and

conditions. Not only does the method

infectious-disease immunotherapies,

identify compounds with the right

including those that can be combined

properties, but also quickly analyzes

with existing immunotherapy drugs for a

T cells to determine how the

more pronounced effect. The scientists

compounds work on them,

showcased the utility of their approach by

Oldstone says.

SCRIPPS RESEARCH MAGAZINE | WINTER/SPRING 2020

Scientists rapidly screened

A new drug-screening method developed

using it to rapidly screen a collection of

12,000 a collection of more than 12,000 drug compounds— uncovering 19 that can reawaken exhausted T cells.

Nature Chemistry, September 2019

Solving the chirality puzzle: Energy difference may not be the answer, after all

WHAT IS CHIRALITY? The word chirality is derived from the Greek word for hand, which is perhaps the most

ARE YOU LEFT-HANDED OR RIGHT-HANDED? Much like people, very few biological building blocks are ambidextrous. Rather, they exist in shapes that— like human hands—are nearly identical but cannot be superimposed onto one another. While this geometric property known as “chirality” is widely evident across nature in RNA, DNA, proteins and countless other molecules essential to life, scientists are still not sure how or why it emerged on Earth. Why is it that molecules can exist in two mirror-image forms, but only one of those forms will be found in living things? The quandary harkens back to the chemical reactions that shaped the earliest stages of life. Up until now, a leading theory is that chirality emerged due to tiny differences in the chemical energies of molecules’ mirror images. The idea was that the energy “advantage” would push a molecule in one direction or the other. However, novel discoveries made by chemists at Scripps Research have now thrown that theory into question. Led by Scripps Research Professor and Chemistry Department Co-Chair Donna Blackmond, PhD, the

study evaluated key chemical reactions to determine what level of energy is required for a biomolecule to favor its left- or righthand version. From a series of kinetic experiments and meticulous calculations, Blackmond and her team established that the energetic difference between left- and right-hand molecules would likely have been far too low to account for the preferences established for life on early Earth. Some leaders in the field believe Blackmond’s findings effectively rule out previous theories.

familiar chiral object of all. An object or a system is chiral if it is distinguishable from its mirror image; that is, it cannot be superposed onto it. The concept is important in medicine because one mirror image of a drug molecule may work for a particular disease, while its counterpart could be toxic.

Aside from the breathtaking subject of origins of life, these chemical breakthroughs have far-reaching implications for the way scientists everywhere design future therapeutic compounds, as the chirality of a molecule affects how it interacts with other components of the cell. Much like the way a right hand requires a right-handed glove, the response of our body’s molecular machinery to pharmaceuticals often depends on finding a perfect fit.

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CELL SCIENCE

DISCOVERIES

Nature Communications, November 2019

How to kickstart self-cleaning mode in brain cells? Scientists may have solved the puzzle BRAIN CELLS LIKE TO KEEP things tidy. They use a process called autophagy as their waste disposal and housekeeping system, recycling damaged and potentially harmful proteins as well as other cellular components. Because most nerve cells are not replaced in adulthood, it’s especially important that the process works seamlessly. When it doesn’t, brain disorders can emerge. Neuroscientists at Scripps Research have identified a molecule in brain cells that regulates this critical process. Their finding illuminates an important feature of nervous system biology and opens the door to new approaches for treating a range of neurodegenerative diseases.

Neuroscientists at Scripps Research have identified a molecule in brain cells that regulates autophagy, a critical process in a cell's waste-disposal system. Their finding illuminates an important feature of nervous system biology and opens the door to new approaches for treating a range of neurodegenerative diseases.

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“How autophagy is regulated in the brain has remained cryptic, but here—for the first time—we’ve found a molecule that potentially does just that,” says Brock Grill, PhD, associate professor of neuroscience at Scripps Research, who led the research. “There’s potential for clinical applications down the road, given the growing evidence that neurodegenerative diseases such as Alzheimer’s feature prominent abnormalities in autophagy in nerve cells.” The scientists show that a protein responsible for switching on autophagy in cells is regulated by an enzyme called RPM-1. Although the scientists did their principal experiments in the simple roundworm C. elegans, tests in human cells suggest that this important relationship could exist in most or all animals.

Cell, November 2019

In a first for cell biology, scientists observe ribosome assembly in real time Ribosomes are the complex and evolutionarily ancient “molecular machines” that make proteins in cells; they are essential for all life forms

SCIENTISTS AT SCRIPPS RESEARCH, working with a team from Stanford

with greater specificity—and fewer side effects. More generally, the findings provide

University, have recorded a key step in the assembly of ribosomes, capturing the process in unprecedented detail. The imaging feat, reported in Cell, overturns the dominant theory that ribosomes are assembled in a tightly controlled, step-wise process.

biologists with a powerful new approach to study RNA molecules, hundreds of thousands of which are active at any given time in a typical cell.

“We revealed a far more chaotic process,” says Jamie Williamson, PhD, professor in the Department of Integrative Structural and Computational Biology. “It’s not a sleek Detroit assembly line—it’s more like a trading pit on Wall Street.” Williamson is also executive vice president of Research and Academic Affairs at Scripps Research. His team’s discovery is expected to enable important advances in medicine. For example, some antibiotics work by inhibiting bacterial ribosomes; the research opens up the possibility of designing future antibiotics that target these ribosomes

“This has been a very difficult thing to study because it involves several distinct biological processes that are dependent on each other and have to be detected simultaneously,” says Scripps Research postdoctoral fellow Olivier Duss, PhD, who was the first author of the study.

“It’s not a sleek Detroit assembly line—it’s more like a trading pit on Wall Street.” — Jamie Williamson, PhD

The findings also hint at the existence of unknown RNA assembly factors, most likely proteins, that boost the efficiency of RNA folding. The team will extend this research to study not only the rest of ribosome assembly, which involves multiple RNA strands and dozens of proteins, but also many other types of RNA folding and RNA-protein interactions in cells. Scientists believe that many diseases involve improper folding and processing of RNAs in cells.

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Science Changing Exploration

In 2018, a team of NASA astronomers shared a photo of Icarus, an individual star 9 billion light-years from Earth. It was the most distant star ever seen, and it was the Hubble telescope that enabled its discovery. To a structural biologist, the body is its own universe. Within each cell, each uncharacterized protein, peptide, enzyme or lipid represents an undiscovered new world no less awesome than the stars and planets. Like astronauts or explorers of old, structural biologists seek out unexplored terrain. If the great Greek cartographer Ptolemy had lived today, he might have chosen structural biology for his life’s quest. Microscopes, rather than telescopes or ships, open these new worlds to modern-day explorers of inner space.

A new world

Viewing a protein’s structure for the first time—seeing its arrangement of atoms, how it folds into origami-like shapes and how those shapes dictate the protein’s role in the living organism—that’s the thrill of discovery that motivates Florida-based biologist Tina Izard, PhD. “The first time I saw a three-dimensional structure, it just took my breath away,” Izard says. Using a specialized technique called cryo-electron microscopy, Izard recently enjoyed yet another first, seeing the structure of a protein critical to a healthy heart and implicated in heart aging and stiffness. Known as metavinculin, the protein tethers the cardiac cell’s membrane to the matrix within.

THE HEART OF AN EXPLORER 16

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Heart Wall SMALL: The wall of the right 3 MILLIMETERS

ventricle is about 3 mm thick.

Heart Cells SMALLER: A cardiomyocyte has a 10-25 MICROMETERS

cylindrical shape and measures about 100 micrometers long by about 10 to 25 micrometers in diameter. A micrometer is 1/1000th of a millimeter.

The green dots at the tips of the heart cells represent the location of metavinculin proteins.

Heart Proteins

Metavinculin

SMALLEST: The metavinculin 100 ANGSTROMS

protein structure is seen in a cryo-electron microscope image for the first time, folded as it appears in the actual heart cell. It is about 100 angstroms long. An angstrom is 1/10,000th of a micrometer.

This protein connects to a group of other proteins, which includes actin, talin and integrin. They all work together to give the heart cell its structure.

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Science Changing Exploration

Structural biologist Tina Izard, PhD, holds a crystal cube etched with a "ribbon" model depicting vinculin. Vinculin is a protein that enables cells to adhere to one another. To see a protein like vinculin, one must go small—much smaller than a traditional light microscope can see. A human hair is about 29,000 nanometers wide. A red blood cell is about one-fifth that width, around 6,000 nanometers. Light microscopes, at their limits, enable us to see things the size of a bacterium, as small as about 200 nanometers. The protein that Izard studies is about 16 times smaller than that. A light microscope won’t do the job. Standard transmission electron microscopes can visualize static things that small, but they destroy biological molecules in the process. Cryo-electron microscopy has made visualization of these tiny biomolecules possible.

She saw a bundle of four helices, a shape that allows for tightening and loosening, like a cluster of woven finger-trap toys. “I can’t even describe it. It’s just like, ‘Oh my gosh, it worked! Oh my gosh, we got the structure!” Izard says. “It’s a motif that you see in a lot of proteins, the four-helix bundle.” The tool Izard used to see metavinculin was a very special microscope, one that involves freezing samples instantly down to hundreds of d egrees below zero. It takes thousands of images, like a CT scanner, and then stitches them together to reveal a three-dimensional

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Below: A three-dimensional, 6-angstrom photograph of metavinculin, a form of vinculin that exists in heart cells.

structure. The cryo-electron microscope model Izard used is being installed at Scripps Research in Florida later t his year. On a mission to Japan to learn how to use the new equipment, Izard brought along her metavinculin protein samples in the hopes of seeing its structure. “Time on a cryo-electron microscope is very precious, so I said, ‘Let’s do a real protein,’” Izard recalls. “They collected data in two days, and suddenly it pops out, and I can’t even describe it. It doesn’t happen that often that you put the first one in and there it is. It was quite a historic moment.”

Life in motion Izard is fascinated by the vinculin proteins because of their many roles in living cells. In the beating heart cell, metavinculin connects to the actin cytoskeleton. Actin is a protein filament that expands and contracts with the moving heart cell. Studies suggest that excess accumulation of metavinculin may occur with age and may be to b lame

Examining critical biomolecules like vinculin through cryo-electron microscopy involves several steps. First, a sample of the biomolecule must be made. For this, a screenlike grid so tiny that it requires forceps to hold is coated in a film of the sample. Next, it is transferred to a device called a plunge freezer. Below, Izard and her research associate, Marino Candido Primi, PhD, demonstrate sample preparation.

Because the vinculin protein also anchors cells together, if it is removed, the cells disperse. That’s why it’s important in the spread of cancer.

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Science Changing Exploration

Various cryogen solutions are used to freeze the sample, including liquid nitrogen and liquid ethane. They cool the sample to hundreds of degrees below zero. In a state of suspended animation, the molecule can be photographed thousands of times with the digital cryo-electron microscope. The digital images are then stitched together with software to reveal a three-dimensional picture. Because form dictates function, important insights about health and disease often result from these images. For molecules at the root of disease processes, this visual information can play a central role in helping scientists develop potential therapies or vaccines. Once prepared, the grid is moved to the plunge freezer. In these images, Izard’s research associate, Rangarajan Erumbi, PhD, prepares the plunge freezer with liquid nitrogen.

for symptoms such as cardiac stiffening and diastolic dysfunction, which affects how the heart fills with blood. Beyond the thrill of seeing something new, understanding the precise structure of a biomolecule associated with a disease presents chemists with an opportunity to design therapies to intervene, Izard explains. Vinculin isn’t only important in heart disease, she adds. A slightly different form of vinculin plays a critical role in binding cells to one another, like adhesive tape. In this context, vinculin can change shape to help generate cellular movement. This becomes a key issue in enabling cancer cells to spread. Because the vinculin protein also anchors cells together, if it is removed, “the cells just g o everywhere,” Izard says.

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DISCOVERY

Rapid response to infectious disease threats depends on understanding structure

In the H7N9 flu strain, N stands for "neuraminidase," an enzyme that releases viral copies. These are actual cryo-EM images of that enzyme molecule bound with several types of antibodies. Images courtesy of the Ward Lab, Scripps Research.

At Scripps Research in La Jolla, California, structural biologist Andrew Ward, PhD, uses cryo-electron microscope imagery to study how our immune system defends against pathogens by attacking them with unique antibodies. Of key interest is how those antibodies bind to proteins on the surface of the virus. Recently the team studied antibodies from survivors of H7N9 flu and compared them to antibodies from two volunteers who were vaccinated against it. Flu strains are named for how they enter and exit cells. The H in H7N9 stands for hemagglutinin, a protein that recognizes and latches onto cell-surface molecules to infect a cell. The N stands for neuraminidase, a scissors-like enzyme that releases the viral copies so they can seek out fresh, new cells to infect. The antibodies from both infected and vaccinated individuals worked in similar ways, the team wrote in the journal, Cell Host & Microbe. Both bound to neuraminidase and successfully prevented the exiting of new viral particles from infected cells.

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Science Changing Digital Medicine 22

Information is: power.

accessible, thought-provoking, life-saving, preventative, empowering, digital, intelligent, fluid, cohesive, adaptable, eye-opening, immediate, global, personal, universal, customized, individualized, life-affirming

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A digital world reveals new possibilities for medicine Just over a decade ago, Fitbit made fitness-tracking fashionable—and the concept of digital health exploded on the consumer scene. Today, while the digital health industry continues to engage consumers a t extraordinary levels, it’s also spawning sophisticated devices that provide scientists and doctors with rich, personalized health information that’s never before been available. With the help of body sensors, activity trackers and digital imaging tools, patients are partnering with the research world to shape a new era of data-driven discovery. “Science, technology and medicine are now intersecting in ways that allow us to understand and take ownership of our own health information, and make new connections about factors that underlie health and disease,” says Eric Topol, MD, founder and director of Scripps Research Translational Institute and executive vice president of Scripps Research. Digital health technologies are also enhancing early disease detection and “democratizing” medicine for those with limited access to nearby care. Topol, who is also a practicing cardiologist, and his team are combining the latest wearable devices with genomic technologies and advances in artificial intelligence to transform the future of medicine and human wellness. “Information is power, and we’re only at the beginning of what’s possible,” Topol says. “There’s never been more promise or opportunity to reboot the way healthcare is managed.” >>

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Science Changing Digital Medicine

Outsmarting Outbreaks Vital sign biosensor

Checking the Filter Kidney function test kit An at-home urine test kit that pairs with a mobile phone can rapidly provide a picture of kidney health. This tool, which uses a color-changing strip that’s photographed with a phone and uploaded to an app, can be provided to patients with hypertension or diabetes who are at high risk for kidney disease, a serious condition in which kidneys lose their ability to remove waste from the body and balance fluids. By detecting elevated levels of proteins in urine, the tool can help identify kidney abnormalities early, when there’s time to intervene before kidney failure occurs.

With the ability to remotely monitor an individual’s vital signs—such as respiratory function, heart activity and body temperature—scientists and clinicians can gather key patient data and change treatment plans even from thousands of miles away. Field-work scientists from Scripps Research are assessing wearable patch technology in Sierra Leone to precisely track disease symptoms in patients with Lassa fever, an acute hemorrhagic fever caused by the Lassa virus. By accessing data from the patch, caregivers can examine patients continuously and intervene if a patient is in distress. With the help of machine-learning tools that analyze the vast pool of data from these devices, researchers can also identify patterns of infectious disease progression, which can then be used to improve care on a local or global scale.

High risk of infection and tough environmental conditions in outbreak zones present barriers to sustained patient care.

Approximately 30 million Americans have chronic kidney disease.

Nearly 90 percent of people with chronic kidney disease don’t know they have the condition, as symptoms often emerge after kidneys are significantly impaired.

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Roughly 15-20 percent of patients hospitalized for Lassa fever will die from the illness, typically within two weeks after symptoms begin.

Science in a digital world The growing ability to collect data from patients in real time is powerfully shaping the next phase of personalized medical treatments

A Medical Selfie Smartphone ultrasound A handheld, portable ultrasound device is used with a smartphone to generate high-resolution, clinical-grade images of almost every tissue in the body. This device holds potential to overhaul the way we monitor pregnancy, examine the thyroid gland or even diagnose gallbladder disease. By enabling fast, on-site biological imaging, this technology provides a mobile solution for a wide range of clinical research projects and can bring medical assessments to more remote communities.

“With every patient I see as a cardiologist I use a smartphone ultrasound for their heart exam... I haven’t used a stethoscope in 10 years.” Eric Topol, MD Scripps Research Translational Institute

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Science Changing Digital Medicine

Keeping the Rhythm Electrocardiogram (ECG) patch sensor A small, non-invasive chest patch can be used for patients with atrial fibrillation, an irregular heartbeat that often results in poor blood flow. The sensor essentially acts as a mobile electrocardiogram, or ECG, measuring the electrical activity of the heartbeat. The Scripps Research Translational Institute uses this technology in clinical trials to monitor heart rhythms continuously across multiple days, allowing them to detect and measure atrial fibrillation episodes that would previously only be captured at a doctorâ&#x20AC;&#x2122;s office. Earlier detection of the disorder and better identification of subtypes leads to personalized interventions that can dramatically reduce the risk of stroke.

Personal (and drug-free) Painkillers

Lifetime risk for atrial fibrillation for those with an optimal health profile

Pain relief cuff A lightweight cuff uses neurostimulation technology to train the body to produce its own natural analgesic chemicals. Scientists and clinicians at Scripps Research Translational Institute are assessing whether these tools can help young children with sickle cell anemia, cystic fibrosis or cancer m anage chronic pain, which can be debilitating at times. By personalizing pain management approaches with digital technologies, the side effects of traditional opioids can be avoided, and suffering can be prevented for children and their families.

Enduring pain is one of the most feared and challenging symptoms of various chronic diseases. Novel technologies can revolutionize the treatment of pain and help stop the opioid epidemic.

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Approximately

of all strokes are attributed to atrial fibrillation.

Lifetime risk for people with at least one risk factor.

Sugar Surveillance Continuous glucose monitor (CGM) Among those with diabetes, blood sugar levels are too high and must be tightly controlled. A biosensor placed under the skin can track blood glucose levels in real time, 24 hours a day. Clinical scientists can use this tool to examine the daily glucose profiles not only of diabetic patients, but also of obese individuals and healthy people, to expand their understanding of how different people respond to foods, exercise and life stressors. The sensors provide immediate feedback and result in data-rich records that support recommendations for lifestyle changes or other interventions to prevent metabolic disease. Existing treatment strategies can be refined for those with sub-optimal glycemic control.

More than

Without continuous monitoring, dangerous glucose spikes and drops can go undetected.

U.S. adults have pre-diabetes, increasing their risk of type 2 diabetes, heart disease and stroke.

Wearing Hearts on Sleeves Smartwatch A digital wristwatch assesses daily physical activity and sleep patterns, and continuously monitors heart rate and blood pressure. Participants who have enrolled in the All of Us Research Program are able to share their own activity data with researchers in the name of science. The Scripps Research Translational Institute is leading key aspects of this unprecedented, nationwide study that explores the relationship between key biological indicators and other critical health outcomes. Instead of limited biological snapshots in a clinical setting, comprehensive real-world data provides important insights into how individual differences in genes, environment and lifestyle can influence health and disease. Detecting early signs of hypertension, or abnormally high blood pressure, can reduce the global burden of cardiovascular disease, which caused more than 17 million deaths worldwide in 2017. adult Americans have high blood pressure, which can lead to heart disease.

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Women Changing Science

Empowering women in science: Infinite possibilities There’s power in numbers. Even if the number is just two. This is what Courtney Miller, PhD, learned early in her career when she met another female researcher, Ghazaleh Sadri-Vakili, PhD. “We were both postdocs and both exploring epigenetics in neuroscience, something very new at the time,” says Miller, now an associate professor of neuroscience at Scripps Research. “I raised my hand and asked about a technique she’d described. It was something I wanted to learn but had been told it was too difficult to teach. Ghazaleh said, ‘Come up to MassGeneral and I’ll teach you.’” Miller and Sadri-Vakili, now director of neuroepigenetics at the MassGeneral Institute for Neurodegenerative Disease, became friends and came to realize they had both experienced numerous challenges as female scientists and that neither had scientific mentors who were women. “We decided that had to change,” says Miller. “Even though we were young, we decided to take action.”

Overcoming the hurdles to diversity Study after study has demonstrated that diverse groups—those comprising a mix of gender, race and ethnicity—are more innovative in their thinking, thereby producing more impactful scientific discovery. Yet women continue to be underrepresented in the STEM (science, technology, engineering and mathematics) fields, especially at the upper levels. Multiple factors stack the deck against women and underrepresented minorities in the life sciences. The momentum of numbers, for one. Faculty and leadership positions at universities and other research institutes have been overwhelmingly held by white males, at least until recent years. This means that decisions on hiring and promotions were made by men who, whether consciously or not, may have favored other men. Across the industry, males continue to be paid more than their female peers and are promoted sooner. >>

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Women Changing Science

EMPOWERING WOMEN IN SCIENCE

There are many levers one can pull to better support girls and women as they move through their educations and careers, and we want to make sure weâ&#x20AC;&#x2122;re pulling all the ones we can. Donna Blackmond, PhD | Co-chair, Chemistry Department, Scripps Research

February 11, 2020 International Day of Women and Girls in Science Acknowledging that science and gender equality are both vital for the achievement of the worldâ&#x20AC;&#x2122;s development goals, the United Nations established the International Day of Women and Girls in Science in 2015.

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While more women than men currently earn degrees in STEM fields (encompassing science, technology, engineering and mathematics), according to a 2017 report by the U.S. Department of Commerce, only 25 percent of these gifted graduates end up actually working in STEM occupations. Scripps Research is working to change that.

four junior faculty hired in 2018.] Another recommendation: Make every effort to increase faculty diversity while maintaining academic excellence. “The challenge of women in science extends from early education all the way to retirement,” says Blackmond. “There are many levers one can pull to do a better job of supporting girls and women as they move through their educations and careers, and we want to make sure we’re pulling all the ones we can.”

This bias extends to other important aspects of science. Studies have shown that reviewers given identical resumes still tend to rate a man as being more highly qualified for a scientific position than a woman. And, of course, biology presents a high hurdle. Women who decide to start a family must step out of the lab and then, according to a number of studies, usually shoulder the majority of the responsibilities at home. While they were long denied positions of leadership, however, women are now heading the change to make science more diverse.

Taking the lead If you want to solve a complex problem, put a scientist on it. That’s what Scripps Research did when assessing its own record and practices around gender equity in hiring and promoting women faculty. Three years ago, Donna Blackmond, PhD, co-chair of the chemistry department at Scripps Research, was named to head a committee to examine the issue and identify ways to create the best possible environment for anyone pursuing scientific research at the institute. At Scripps Research, the Gender Parity Committee worked with institute leadership to ensure equal pay for equally qualified faculty members. The committee discovered that salaries and time to promotion were equal for male and female faculty members at Scripps Research. To bolster the overall number of women faculty members, the committee recommended that the institute accelerate efforts to recruit women early in their scientific careers. [See sidebar about the

Advocacy in numbers One important lever is the support from peers, an invaluable resource for women scientists at any stage of their careers. On the California campus of Scripps Research, the Network for Women in Science (NWiS) helps fill that role. “We define challenges that disproportionately affect women here, then create conversations about how to implement change,” says the group’s advocacy co-chair Sophie Shevick, a student at Skaggs Graduate School of Chemical and Biological Sciences at Scripps Research. “Our current goals include ensuring that every building has a gender-neutral bathroom as well as a lactation room.” The group hosts panels on pertinent topics, such as parental leave and sexual harassment, as well as coffee hours for informal discussion. In addition to advocating for career scientists, NWiS members inspire young science enthusiasts. Millie Kissai, another student in the Skaggs Graduate School, coordinates the group’s many outreach activities, including partnering with DETOUR, an organization that “introduces girls of color to fields they are not typically exposed to.” Last spring, she and her fellow researchers taught a group how to extract DNA from strawberries, a hands-on experience met with infectious enthusiasm, Kissai says. On its Florida campus, Scripps Research is hosting a series of fundraising events designed to establish a fellowship for a woman student enrolled in its Skaggs Graduate School. The Women in Science Education (WISE) initiative launched last year and, in February, a symposium aligned with the International Day of Women and Girls in Science celebrated the many achievements of the institute’s scientists while pointing to a bright future.

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Women Changing Science

EMPOWERING WOMEN IN SCIENCE

We define challenges that disproportionately affect women here, then create conversations about how to implement change. Sophie Shevick | Advocacy Co-chair / Student, Skaggs Graduate School of Chemical and Biological Sciences

Members of the Network for Women in Science (NWiS) strive to increase visibility, leadership and community for female scientists.

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Scripps Research continues to diversify its faculty. Of five junior faculty members hired in July 2018, four are highly accomplished women from varied disciplines. Jamie Williamson, PhD, executive vice president of Research and Academic Affairs, says, “These scientists are demonstrating incomparable talent across some of the most pioneering areas of current research. They represent the future of Scripps Research.”

Mia Huang, PhD, explores chemical glycobiology for its applications to regenerative medicine.

Michalina Janiszewska, PhD, studies intratumor heterogeneity to uncover more effective cancer treatments.

Silke Paust, PhD, is harnessing natural killer cells to develop new immunotherapies.

Lisa Racki, PhD, is investigating how bacterial starvation is linked with chronic infections.

Peer power

Working for change

The push to bring more women into science isn’t just about achieving balanced numbers and employment equity. As more women direct their own labs and programs, research heads into unexplored areas, often ones that impact women’s health.

As for Courtney Miller, her conversations with Ghazaleh Sadri-Vakili led her to reflect early in her career on her own experiences as a female scientist—and spurred her to action.

Jennifer Radin, PhD, a researcher at the Scripps Research Translational Institute, for example, is working to fill the knowledge gap about the physiological changes that occur during pregnancy and how those changes vary by race, age and pre-existing conditions. Pregnant women remain one of the least studied populations in medical research, even while maternal morbidity and mortality rates in the United States are on the rise. Radin directs the POWERMOM study, which uses digital technologies to gather health data from a diverse group of pregnant women. Participants in the study can compare their data with peers and receive individualized feedback. “We’re hoping this will be a multi-decade research project that will empower pregnant women in their own health and help researchers understand how to improve the health of expecting mothers and babies,” says Radin. Another example of how women are pioneering research of particular relevance to women is the work of Hyeryun Choe, PhD, a Scripps Research professor in the Department of Immunology and Microbiology. When the Zika virus emerged in Brazil in 2015 and began spreading, doctors and scientists didn’t know how the virus caused microcephaly and other severe birth defects. Choe was the first to uncover the details behind the Zika virus’s unique ability to cross the placental barrier and expose a fetus to multiple health dangers.

Now she and Sadri-Vakili make it a priority to educate and encourage women scientists through a bimonthly blog and in-person gatherings. At the annual Society for Neuroscience conference, they host a “Breaking Barriers for Young Women in Science” event and recruit top researchers to lead a panel discussion then interact with the early-career attendees. Invariably, hundreds flood the room. The questions vary by experience, says Miller, but range from how to overcome assumptions that women are less talented to how to balance career and family life. Seasoned scientists often want to discuss implicit biases against women in the sciences. Miller tells women that she has never accepted the status quo in her field that favors male scientists, and they shouldn’t either. “Everyone develops their own style for dealing with it,” Miller says. “Some endure it. Some work to change it. I’m doing what I can to change it.”

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Noteworthy Iconic actor Alan Alda, Scripps Research join forces to bring science communication training to West Coast

ALAN ALDA, who continues to be widely known for his Emmy-award- winning role of Hawkeye Pierce on the classic television series M*A*S*H, holds international recognition as an actor, writer and director. But his role as a science communicator is equally distinguished. Before launching Alda Communication Training and the Alan Alda Center for Communicating Science, he hosted the award-winning series “Scientific American Frontiers” on PBS for 11 years, interviewing leading scientists from around he world. He also hosted the PBS mini-series “The Human Spark” and “Brains on Trial.” Alda is author of the science communication book “If I Understood You, Would I Have This Look on My Face?,” and is host of the popular “Clear+Vivid” podcast about connecting and communicating.

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The partnership between the Alda Communication Training Company® and Scripps Research will empower scientists and medical professionals to convey complex topics to the public

Alan Alda, the Emmy-award winning actor, director and writer who has become a leading advocate for effective science communication, has partnered with Scripps Research to bring immersive communication training to scientists and medical professionals on the West Coast. With sessions to be held on Scripps Research’s picturesque campus in

participants learn to empathize with the audience and present their

La Jolla, California, Alda Communication Training will deliver its unique

story in a way that connects with different stakeholders. The skills

storytelling approach to leaders in biotechnology, research and medicine.

and strategies can help participants relate to prospective investors, government officials, media, peers across scientific disciplines and

“Alda Communication Training is thrilled to work with Scripps Research to

the general public.

empower scientists with clear and vivid communication,” says Alda, who announced the partnership in January with Peter Schultz, PhD, president

“The overarching goal of our program is to teach scientists how to

and CEO of Scripps Research. “Researchers and industry leaders up and

engage in productive, memorable conversations about the work that

down the West Coast are doing such important work to advance science

drives them,” says Laura Lindenfeld, PhD, executive director of the Alan

and medicine, but often they struggle to reach audiences who don’t

Alda Center for Communicating Science and interim dean of the Stony

share their knowledge and experience. This partnership will help these

Brook University School of Journalism. “But as we all know, that’s easier

brilliant minds make important new connections and spread the wonder

said than done; for many scientists, their immeasurable knowledge

of science with the rest of us.”

actually stands in the way of the relatable human stories that call people to action. We help them overcome this barrier.”

Alda Communication Training works in tandem with the Alan Alda Center for Communicating Science at Stony Brook University, a

The first two-day training session at Scripps Research will be held

nonprofit organization Alda helped found in 2009 to teach scientists

June 4-5, open to biotechnology industry executives, research

the “Alda Method®,” a form of communication training that combines

scientists and others who play a role in the vibrant life sciences markets

improvisational theater techniques and message-design strategies Alda

of the West Coast, including San Diego, Los Angeles, San Francisco

cultivated over his decades-long acting career. Operating out of its New

and Seattle. Additional sessions will be held in October and December.

York headquarters, the program has trained 15,000 scientific leaders. In

More information is available at scripps.edu/alda.

large part because of this work, Alda in 2016 won the National Academy of Sciences’ highest honor, the Public Welfare Medal.

In announcing the partnership, Alda took the stage at the Scripps Research Auditorium in La Jolla—along with Schultz and Lindenfeld—

“By giving scientists the tools to better relate with the public and tell

to share stories about how powerful communication has changed the

compelling stories, Alan Alda is amplifying the impact of the work

course of scientific careers and shifted public perceptions. At its core,

we do as scientists,” says Schultz, a pioneer in the field of chemical

good communication is about relating, he says.

biology and drug discovery research. “We share Alan’s passion for communicating science and we’re pleased to be partnering with him

“When you allow yourself to fully relate with another person, you’re

as he brings his program to the West Coast.

listening and engaged, riding the waves of uncertainty inherent in any conversation,” Alda says. “When you embrace that uncertainty, rather

More than 30 of Scripps Research’s scientists recently participated in

than try to control it, that’s when you hit gold. That’s when you have the

the Alda Center’s training program—an immersive experience that helps

opportunity to make a meaningful connection.”

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NOTEWORTHY

Scripps Research and AbbVie collaborate to develop a broad range of new medicines Under a new agreement announced in December, the global biopharmaceutical company AbbVie will collaborate with Scripps Research to develop new therapies for a range of diseases—including indications spanning oncology, immunology, neurology and fibrosis AbbVie and Scripps Research began

Under the terms of the deal, Scripps

working together in 2018 to create innovative

Research will continue to conduct pre-clinical

cell therapies for cancer, leveraging the

research and development activities for

power of Calibr’s “switchable” CAR-T therapy

certain drug programs—and, in some cases,

platform. CAR-T (short for chimeric antigen

move those programs into early clinical trials.

receptor T-cell) therapies harness the power

AbbVie will have an exclusive option to further

of a patient’s own immune system to attack

develop and commercialize the potential

and destroy cancer cells.

new drugs.

“Based on our strong switchable CAR-T

“The best way to develop transformational

alliance, we feel the expanded relationship

medicines is through collaborations that

with AbbVie represents a robust path forward

bring together the brightest minds,” says

for some of our programs, complementing

Mohit Trikha, PhD, vice president and head

a diverse ecosystem of innovation we’ve

of oncology early development, AbbVie.

created over the past several years,” says

“We are eager to partner with Scripps

Peter Schultz, PhD, president and CEO

Research on these assets as they enter the

of Scripps Research and Calibr, its drug

clinic over the next few years, as Scripps

discovery and development division.

has one of the strongest track records of any academic institution when it comes to

In addition to programs initially named in the collaboration, Scripps Research will present AbbVie with additional preclinical programs of mutual interest. Scripps and AbbVie will also work together to advance cancer drugs known as “CD3 bi-specifics” which can bind to two different targets in the body.

Top: "Switchable" CAR-T cells are a potential new treatment for many types of cancers, including solid tumors. Bottom: Calibr headquarters in La Jolla, California.

SCRIPPS RESEARCH MAGAZINE | WINTER/SPRING 2020

advancing novel medicines for patients.”

Scripps Research’s Florida campus added at least $3 billion to local economy since 2004 Through spinoff companies, eye-opening internships and its draw of other scientific organizations, Scripps Research has infused a new kind of energy into Florida's Palm Beach County

In 2003, Florida government leaders

in the company’s supply chain and induced

concluded that the state needed to diversify

spending by workers on items such as real

Florida’s narrow economy beyond tourism,

estate, meals, taxes, insurance and other

agriculture and real estate.

items.

With new federal economic stimulus dollars

Scripps Research also recently looked back

available, their search took them to Scripps

at the intellectual property created from its

Research in La Jolla, California. Over about

discoveries in Florida, revealing 162 clusters

50 years, the institute has become the

of patent applications, each cluster containing

nucleus of a thriving bioscience, research

up to six patent applications. Patents are a

and university sector in San Diego.

key marker of innovation and potential economic growth.

Just 15 years after the successful recruitment of Scripps Research to Jupiter, Florida, a

Douglas Bingham, executive vice president

cluster is building there, too. The Max Planck

of Florida Operations, noted that Palm

Society of Germany opened its only U.S.

Beach County students also have benefitted

institute next to Scripps Research. Florida

from the institute’s presence, marking an

Atlantic University, meanwhile, is adding a

economic and societal value likewise not

new neuroscience research building and data

reflected in the economic impact analysis.

Seth Tomchik, PhD, associate professor in the Department of Neuroscience in Jupiter, Florida, with Kenan Fellows high school intern Eliza Grenci, now a student at Emory University.

science program. Multiple other life science companies are moving into the Donald Ross

“Our undergraduate internship program has

Road innovation corridor nearby.

enabled more than 300 Florida Atlantic University Honors College STEM majors to

In fact, a study that uses industry-standard

conduct their theses work and gain valuable

evaluation methods for economic impact has

lab experience,” Bingham says.

calculated that the Florida campus of Scripps Research has contributed at least $3 billion

Likewise, the Kenan Fellows internship

to the economy since its founding.

program has enabled 177 Palm Beach County high school students and 24 science

Using a model known as IMPLAN, the

educators to gain lab experience alongside

study considered direct spending on

Scripps Research scientists. “The impact

wages, services and supplies, and then

of that experience on the lives of those

calculated indirect spending by businesses

participants really cannot be measured,” Bingham says.

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NOTEWORTHY

Calibr and Cystic Fibrosis Foundation work together to find medicines for hard-to-treat lung infections Under a two-year contract and funding agreement, Calibr will screen its vast library of drug molecules for compounds that work against a rare but vexing family of bacteria

Calibr, the drug discovery and development

“We’re privileged to work alongside the

arm of Scripps Research, has entered into a

Cystic Fibrosis Foundation on a program

two-year agreement with the Cystic Fibrosis

with such critical importance for the patient

Foundation to identify existing medicinal

community,” says Arnab Chatterjee, PhD,

compounds that work against one of the

vice president of medicinal chemistry for

hardest-to-treat infections for patients with

Calibr. “By growing bacteria in a way that

cystic fibrosis.

imitates the infection environment, and then employing our library of more than

Efforts will focus on screening for novel

13,000 compounds that are already known

antibiotics that may be able to combat any of

to be safe in humans, we hope to identify

the 22 bacterial species that comprise the

promising antibiotics and accelerate the

Burkholderia cepacia complex, which pose

timeline for developing a drug.”

a serious health risk to patients with cystic fibrosis.

Chatterjee notes that the same approach could be applied to other bacteria

To do this, Calibr will leverage the power of

relevant to cystic fibrosis patients, such

its ReFRAME drug repurposing collection,

as Achromobacter and Pseudomonas

an extensive library of nearly all existing,

aeruginosa. Many types of bacteria that are

safe small-molecule drugs shown to be

problematic for cystic fibrosis patients are

appropriate for direct use in humans. The

resistant to today’s antibiotics and in dire

collection offers great potential for finding

need of more precise treatment options.

therapies quickly and cost-effectively for high-need conditions, including infectious

Solving this challenge is a priority of the

diseases.

Cystic Fibrosis Foundation, which has committed at least $100 million from 2019

Top: Arnab Chatterjee, PhD. Bottom: Chronic and intractable lung infections are a hallmark of cystic fibrosis—a progressive, genetic disease that affects about 30,000 people in the United States. Despite recent FDA approvals of innovative drugs that address some of the underlying causes of cystic fibrosis, many people with the disease continue to need treatments throughout their life for infections.

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WINTER/SPRING 2020

Contracting a B. cepacia infection is

through 2023 to a sweeping effort to

rare—only 2.6 percent of the cystic fibrosis

address chronic and intractable infections

population in the U.S. tested positive

through better detection, treatment and

for it in 2018—but it’s severe and few

outcomes.

effective treatments exist. Patients who’ve contracted a particular species known as B. cenocepacia are often rejected as transplant candidates due to their risk of infection after the transplant.

Awards Honors Grants SOCIETY FOR NEUROSCIENCE

Mika Saltpeter Lifetime Achievement Award During a ceremony at the Neuroscience 2019 conference, Hollis Cline, PhD, chair of the Scripps Research Department of Neuroscience in La Jolla, received the Mika Saltpeter Lifetime Achievement Award. The honor, bestowed by the Society for Neuroscience, recognizes highly accomplished neuroscientists who have significantly promoted the professional advancement of women in the field.

Diane Lipscombe, PhD (left), and Hollis Cline, PhD

Diane Lipscombe, PhD, president of the Society for Neuroscience, cited Cline as among “outstanding neuroscientists with exemplary careers who have also devoted themselves to the professional development of women through generous and thoughtful mentorship.” Cline was commended for having trained “over 40 graduate students and postdoctoral scientists in her lab, over half of which have been women, and many more undergraduates and research assistants.” At Scripps Research, Cline has made fundamental contributions to the understanding of how sensory experience affects the development of brain structure and function. She combines molecular and genetic techniques with quantitative observations to reveal how activity-dependent brain plasticity is implemented at the cellular level. Cline’s contributions to science go beyond her exceptional research. She has served as a council member for the National Eye Institute and the National Institute of Neurological Disorders and Stroke and participated on the Blue Ribbon Panel for the National Institute of Child Health and Human Development. Cline is also a past president of the Society for Neuroscience.

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Awards Honors Grants

COLUMBIA UNIVERSITY

Louisa Gross Horwitz Prize Peter Vogt, PhD, a Scripps Research professor who has uncovered new genetic underpinnings of cancer, is among three scientists to receive Columbia University’s prestigious 2019 Louisa Gross Horwitz Prize. Vogt, a professor in the Department of Molecular Medicine, shares the prize with Lewis Cantley, PhD, of Weill Cornell Medicine and David Sabatini, PhD, of Massachusetts Institute of Technology. Together, they are recognized for their seminal contributions to understanding of the role played by the phosphoinositide 3-kinase (PI3K) pathway in oncogenesis, or the process by which healthy cells become cancer cells. The three scientists received their prize and delivered individual lectures in January at an awards ceremony in New York. “The work of Cantley, Sabatini and Vogt has totally transformed cellular physiology and has profound implications for our understanding of cancer development,” says Gerard Karsenty, MD, PhD, chair of the Horwitz Prize Committee. The prize honors outstanding basic research in the fields of biology or biochemistry. Of the 100-plus Horwitz Prize winners to date, 50 percent have gone on to receive a Nobel Prize. Scripps Research Nobel laureate Kurt Wüthrich, PhD, received the Horwitz Prize in 1991.

SCRIPPS RESEARCH MAGAZINE | WINTER/SPRING 2020

BRANDEIS UNIVERSITY

Lewis S. Rosenstiel Award Ardem Patapoutian, PhD, a professor in the Department of Neuroscience, has been named a recipient of the 49th Lewis S. Rosenstiel Award for Distinguished Work in Basic Medical Research for his contributions to the understanding of the mechanisms of touch and pain. He shares the award with David Julius, PhD, a professor at the University of California, San Francisco. After making important contributions to studies of temperature sensation, Patapoutian and his laboratory team began investigating how the skin senses mechanical stimuli. They identified two proteins—PIEZO1 and PIEZO2—that enable touch sensing and proprioception, the awareness of body position and movement. They went on to show that these channels play unexpected roles in cell physiology, including the regulation of red blood cell volume and the properties of airways in the lungs. The Rosenstiel Award was established at Brandeis University as “an expression of the conviction that educational institutions have an important role to play in the encouragement and development of basic science as it applies to medicine.” More than 30 percent of the recipients of the Rosenstiel Award have gone on to win a Nobel Prize. Patapoutian and Julius will receive their award and deliver lectures at an April 2020 ceremony at Brandeis University.

CHEMICAL BIOLOGY

Tetrahedron Prize for Creativity The 2019 Tetrahedron Prize for Creativity in Organic Chemistry was awarded to Peter Schultz, PhD, president and CEO of Scripps Research, in recognition of his advances in the fields of chemical biology and drug discovery. The award was established in 1980 by Elsevier, which publishes the prestigious Tetrahedron journal series. In announcing the award, Elsevier noted that Schultz developed new methods to expand the genetic code of living organisms and forged technologies that address key problems in chemistry, biology and medicine.

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Awards Honors Grants

AMERICAN CHEMICAL SOCIETY

GENOMIC AND DIGITAL TECHNOLOGIES

Kathryn C. Hach Award for Entrepreneurial Success

Cardiovascular Research Foundation

The American Chemical Society (ACS) has named Paul Schimmel, PhD, the recipient of its 2020 Kathryn C. Hach Award for Entrepreneurial Success. Schimmel, a professor in the Department of Molecular Medicine, is a world-renowned expert in studying the enzymes and processes involved in correcting errors that can occur in the interpretation of genetic information. Research he published in the early 1980s established the concept of ESTs (expressed sequence tags) and the strategy of shotgun sequencingâ&#x20AC;&#x201C;work that Nature magazine cited as one of the four foundations of the human genome project. Schimmel has founded or co-founded multiple biotechnology companies to advance his discoveries toward patients.

Eric Topol, MD, founder and director of the Scripps Research Translational Institute, was honored by the Cardiovascular Research Foundation for his contributions in genomic and digital technologies to transform the practice of medicine. Topol, who is executive vice president of Scripps Research and a cardiologist, merges genomics and digital medicine with artificial intelligence to tailor medicine to the individual.

SCRIPPS RESEARCH MAGAZINE | WINTER/SPRING 2020

As a physician-researcher, Topol has published over 1,200 peer-reviewed articles, with more than 250,000 citations. In the last seven years he has published three books on the future of medicine, covering digitization, democratization and deep learning.

HIGHLY CITED RESEARCHERS LIST

Scripps Research scientists landed 20 spots on the 2019 Highly Cited Researchers list, which identifies scientists who have “disproportionately” influenced their fields of research. The institute has doubled its presence on the list from five years earlier. The annual ranking includes researchers from nearly 60 nations whose studies were among the top 1 percent of most-cited publications in their fields over the prior decade. NATIONAL INSTITUTES OF HEALTH: PATHWAY TO INDEPENDENCE AWARD

The National Institutes of Health has given a prestigious Pathway to Independence award to Matthew Gardner, PhD, a researcher in the Department of Immunology and Microbiology, and Yuchen Wang, PhD, a researcher in the Department of Neuroscience. The award funding, which spans five years, is intended to take early-career scientists from trainee to principal investigator.

HUMAN PROTEOME ORGANIZATION: DISCOVERY IN PROTEOMIC SCIENCES AWARD

The Human Proteome Organization (HUPO) named John Yates, PhD, a professor in the Department of Molecular Medicine, the recipient of its 2019 Discovery in Proteomic Sciences Award. HUPO cited his contribution of “numerous methods to comprehensively study proteomes to highlight the biological context in question in quantitative approaches.”

UNIVERSITY OF PITTSBURGH: SCHOOL OF PHARMACY DISTINGUISHED ALUMNI AWARD

Pamela Garzone, PhD, chief medical officer of Calibr, the drug discovery and development division of Scripps Research, received the 2019 School of Pharmacy Distinguished Alumni Award from her alma mater, the University of Pittsburgh. Garzone earned her master’s degree in pharmacy practice at the university then followed that with a doctoral degree in clinical services.

OUTSTANDING MENTOR

Kirill Martemyanov, PhD, professor and co-chair in the Department of Neuroscience, has been named “Outstanding Mentor” on the Florida campus of Scripps Research. He received his award and gave a lecture during the annual fall Research Fest.

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Events

Front Row Lecture Series: Snapshots of pioneering explorations

On October 17, Matthew Disney, PhD, a professor in the Department of Chemistry, spoke before a packed auditorium on Scripps Researchâ&#x20AC;&#x2122;s La Jolla campus about how he and his team design medicines for diseases with no cures. His novel technique for identifying drug candidates holds promise for people with myotonic dystrophy type 1, frontotemporal dementia, ALS, some cancers, and a variety of rare genetic diseases.

SCRIPPS RESEARCH MAGAZINE | WINTER/SPRING 2020

WISE initiative underway to create educational endowment Known for its climate of diversity—where women number 39 out of the 72 students attending its internationally recognized graduate program—Scripps Research in Florida launched its Women in Science Education (WISE) initiative December 3 on the Jupiter campus. Christoph Rader, PhD, associate dean of Florida’s graduate program, provided attendees with an overview of the initiative and its goal to raise a $500,000 match through a series of charity events to create a $1 million WISE educational endowment. In the coming months, the WISE committee will hold private dinners, a symposium aligned with the International Day of Women and Girls in Science, and an inaugural science stroll throughout the Florida campus. From left: Professors Laura Bohn, PhD and Christoph Rader, PhD; graduate student Rebecca Goydel, and Executive Vice President Douglas Bingham.

Food for Thought: Luncheon lecture connects community with biomedical researchers

Drug-resistant supergerms was the topic of the season’s first Food for Thought lunch December 11 at Scripps Research in Florida. Noted Scripps Research chemists Arnab Chatterjee, PhD, and Ben Shen, PhD, spoke about innovations on both coasts. Shen discussed how the battle for survival between host and pathogens begins and ends with elements found in nature, and how those elements are being used in his laboratory to search for the next generation of antibiotics and other medicines. From left: Food for Thought event sponsor Pam Dean of PNC Wealth Management, Professors Arnab Chatterjee, PhD, and Ben Shen, PhD, and event chair Nancy Hart.

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Upcoming 2020 WISE Events Scripps Researchâ&#x20AC;&#x2122;s mission is to advance scientific understanding, educate the scientists of tomorrow and impact human health across the globe.

WISE Symposium

Science Stroll

International Day of Women and Girls in Science

A family-friendly event to engage the community

February 11, 2020

March 28, 2020

Scripps Research, Jupiter campus

Featuring leading women scientists and graduate students

VIP Pavilion

Keynote speaker:

Vendors

Tina Sloan, actress and author

scripps.edu/wise

Breakfast and lunch included

Science experiments and demonstrations

Take a front row seat to history as some of the world’s leading scientists share their discoveries and views on the future of science and medicine. The frontiers of drug discovery, the brain’s emotional memory center, next-generation vaccines—Scripps Research scientists will discuss all of that and more as they take you to the edge of science and keep you on the edge of your seat.

California campus “Mirror Images: The Fascinating Science of Chirality and What It Means for Medicine” Thursday, March 26, 2020 4-6 pm Donna Blackmond, PhD Professor, Department of Chemistry

Florida campus “The Surprising Science of Memory Erasure” Wednesday, February 19, 2020 4-6 pm Courtney Miller, PhD Associate Professor, Departments of Neuroscience and Molecular Medicine

“Advancing Precision Medicines to Stop Cancer, ALS, Muscular Dystrophy and More” Wednesday, March 18, 2020 4-6 pm

Scripps Research Auditorium

10620 John Jay Hopkins Drive San Diego, CA 92121 For questions or more information, call (858) 784-2915 or email frontrow@scripps.edu. RSVP California: scripps.edu/frontrow

Rodney B. Fink Education Pavilion 120 Scripps Way, Building B Jupiter, FL 33458 For questions or more information, call (561) 228-2084 or email frontrowfl@scripps.edu. RSVP Florida: scripps.edu/frontrowfl

Matthew Disney, PhD Professor, Department of Chemistry

“Next-Generation Vaccines to Stop HIV, Influenza, Zika and Beyond” Wednesday, April 22, 2020 4-6 pm Michael Farzan, PhD Co-Chair, Department of Immunology and Microbiology

These events are free and open to the public, but seating is limited. RSVP today t o reserve your space.

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From a single spark rises an enduring flame. When you champion student scientists at Scripps Research, you forever transform the future of health. California Philanthropy office 10550 North Torrey Pines Road, TPC-2 La Jolla, California 92037 (858) 784-2915 philanthropy@scripps.edu

Florida Philanthropy office 130 Scripps Way, #4B2 Jupiter, Florida 33458 (561) 228-2016 philanthropy-florida@scripps.edu

Innovative minds produce the most life-changing science. Please join our campaign and our commitment to educating and training the next generation of scientific talent. To learn how you can transform the future of health by supporting the educational programs at Scripps Research today, please contact our Philanthropy department. Or visit us at give.scripps.edu.

Science changing education

Peter G. Schultz President & CEO, Scripps Research Eric Topol Executive Vice President, Scripps Research; Director, SRTI Anna-Marie Rooney Vice President, Communications Chris Emery Senior Director, Communications Virginia Chambers Senior Manager, Communications & Digital Strategy Stacey Singer DeLoye Director, Communications Florida Diane Wilson Senior Manager, Communications California Anna Andersen Communications Manager Kelly Quigley Senior Science Writer & Communications Officer Drew Duglan Communications & Scientific Liaison Care Dipping Executive Assistant, Communications Faith Hark Graphic Designer, Communications Michelle Aranda / Adam Rowe Creative Design Don Boomer / Scott Wiseman Photographers

This high-resolution view of the dangerous H5N1 bird flu strain is possible using a sophisticated imaging technique known as cryo-electron microscopy (cryo-EM). By understanding the architecture of viruses and cells at an atomic level, scientists gain key insights for vaccine and drug design. Image courtesy of the National Institutes of Health.

Office of Communications SGM-300 3344 N. Torrey Pines Court La Jolla, CA 92037 scripps.edu

Scripps Research is active on many fronts to engage women and girls in science, and inspire them to pursue rewarding careers in science-related fields.

Winter/Spring Edition 2020

Articles inside

Information is: power.

Empowering women in science: Infinite possibilities

THE HEART OF AN EXPLORER