Fall Edition 2020 by Scripps Research Magazine

SCRIPPS RESEARCH | FALL EDITION 2020

Scripps Research Magazine | Fall Edition 2020 | Science Changing Life

Pandemic Response

Science takes on COVID-19

Adaptations

Socially distant discoveries

F A L L EDI T IO N | 2 0 2 0

Scripps Research Rapid Response

Coronavirus 101

Scripps Research scientists are uniquely prepared to meet the challenges of COVID-19.

We peel back the layers to explain how the SARS-CoV-2 virus infects and how to reduce your risk.

CA L L I N G A L L C I T I Z E N S C I E N T I ST S :

Adaptations

Order from Chaos

Whether working from the home office or social distancing in the lab, science continues at full force.

A dynamic website tackles the COVID-19 information overload to help propel research efforts worldwide.

President’s Letter 02 Discoveries 34 Translations 44 Awards and Honors 50

On the cover: Catie Anderson, a research assistant in the lab of Kristian Andersen, PhD, wears full personal protective gear—including a medical-grade N95 respirator mask to filter out airborne particles—as she processes swabs from people screened for COVID-19. “We treat all samples as though they’re infectious,” she says. Anderson’s efforts, which also include genetic sequencing, help track how the virus spreads through communities.

Science Changing Pandemics

From the President

As this edition of Scripps Research Magazine goes to print, the world remains in the grip of the COVID-19 pandemic, a historic public health crisis unlike anything weâ&#x20AC;&#x2122;ve seen in our lifetimes. The virus has upended the lives of people around the globe, causing widespread economic hardship, sickness and loss of life. The pandemic has tested our public health, civil and medical establishments in a way that is unprecedented in recent history. It is humbling to see the modern world struggle against a pathogenic threat not so different from those faced by our ancient ancestors. There is good reason, however, to be hopeful. While science can never move too fast when lives are in jeopardy, the scientific community acted with remarkable speed to respond to SARS-CoV-2. In a short amount of time, we have learned a tremendous amount about the virus and made rapid progress in developing medical therapies against it. Scripps Research has been at the vanguard of these scientific efforts, and I am proud of the contributions everyone in our community has made toward tackling this urgent threat to human health. Many of our labs dropped everything to focus their considerable capabilities on studying the novel coronavirus, and throughout the pandemic dedicated staff members have taken on new roles and responsibilities as we shift priorities with the evolving health and safety landscape. Much of this issue of Scripps Research Magazine is dedicated to our groundbreaking COVID-19 research and the herculean effort that ensured our critical work could continue during the pandemic. Please know we are working night and day to put COVID-19 where it belongsâ&#x20AC;&#x201D;as part of history and not part of our lives. Finally, it is important to recognize that the progress being made at Scripps Research and by the worldwide scientific community is the work of many smart, creative and dedicated people of diverse races, ethnicities and experiences. With the great many challenges facing our communities today, we are united around our shared purpose of building a brighter and healthier future for all. These are tough times, but I hope that reading these pages leaves you optimistic, as I am, for what lies ahead.

Peter Schultz, PhD President and CEO, Scripps Research

SCRIPPS RESEARCH MAGAZINE | FALL 2020

Hannah Turner, a research assistant in the laboratory of Andrew Ward, PhD, enjoys some fresh air in the Hazen Courtyard while processing electron microscope images of the coronavirus spike protein. (Photo by Jonathan Torres, Ward Lab)

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rapid response Scripps Research rises to meet the challenge of the historic COVID-19 pandemic. In early January, news outlets in the United States began reporting that a mysterious pneumonia-like illness was spreading through central China. The stories at first elicited only minor alarm but were a harbinger of a global health crisis like no one had seen in generations. Soon, researchers in China identified the pathogen behind the illness as a coronavirus, from the same family of viruses as the one that caused SARS, or severe acute respiratory syndrome, a disease that first emerged in 2003. SARS’ newly discovered relative was dubbed COVID-19, a name that would soon be known and feared across the planet. Within nine months of those early news stories, there would be more than 30 million confirmed cases of COVID-19 and nearly 1 million deaths attributed to the disease worldwide.

As the outbreak began to spread in early 2020, Scripps Research scientists dropped everything to focus on the nascent viral pandemic. Among the institute’s scientists are leading experts on how viruses evolve, how they infect and sicken people, and how they spread through the human population. While some laboratories had t o be temporarily shuttered to prevent an outbreak at the institute, many quickly pivoted to pursue essential COVID-19 research. The institute’s immunologists and structural biologists focused on mapping the structure of viruses and studying how the immune system responds to it at the cellular and molecular level. Other labs analyzed the dynamics of how the virus emerged and h ow new technologies can

For the latest updates, visit scripps.edu/covid-19

SCRIPPS RESEARCH MAGAZINE | FALL 2020

be used to prevent, track and mitigate epidemics. At the beginning of the pandemic, Calibr, the drug discovery division of Scripps Research, had already built the most comprehensive drug repurposing library in the world. Known as ReFRAME, the collection contains more than 14,000 drugs, and soon would become a critical resource for scientists at Scripps Research and around the world looking for therapies against the mysterious and deadly new coronavirus. In the following pages, you will find stories from the first nine months of Scripps Research’s efforts to help decipher and mitigate COVID-19. Our research continues.

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Rapid Response

GENOMICS

> Tracing the virus, from its origin to its global spread Could nature really invent a virus that spreads so easily around the world, enacting such a massive toll on human life—not to mention the economy? Yes, it can. And it did. As misinformation and conspiracy theories about the origin of the novel coronavirus abounded, Kristian Andersen, PhD, emerged as a beacon of science and reason. Soon after the COVID-19 outbreak started in China, Andersen and his team o f genomic epidemiologists began working with collaborators around the globe to figure out how the SARS-CoV-2 virus emerged. Kristian Andersen on the dangers of misinformation:

“Most theories considering a link to the lab are conspiracy theories. They are exceptionally disruptive to the efforts of getting COVID-19 under control and result in unnecessary human suffering.”

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In a widely cited study in Nature Medicine—which has gained more online attention than any study ever published, according to the research tracking service Altmetric—Andersen concluded that the virus undoubtedly evolved in nature and was not deliberately engineered. By analyzing the virus’s genomic data and molecular structure, he and his colleagues found stark similarities to coronaviruses in bats and pangolins, while revealing subtle flaws indicative of natural selection. Questions remain about exactly how the virus jumped from animals to humans, but Andersen has made clear that conspiracy theories of lab-made bioweapons must be put to rest: “Those hypotheses are not consistent with the data we see, and they don’t explain how SARS-CoV-2 emerged,” says Andersen, professor of Immunology and Microbiology. Next, the team drew from its experiences combating recent epidemics of Ebola, Lassa and Zika viruses to understand how the coronavirus is spreading. One major project is decidedly local: Working with several other institutes and health organizations in San Diego, Andersen launched a large-scale COVID-19 screening study called SEARCH, with an initial focus on healthcare workers, firefighters and other first responders. They hope to gather more complete information about how the virus is moving through the community—knowledge that will help public health officials gain the upper hand on the pandemic. “When does this end? Until we have a vaccine, it doesn’t,” Andersen says. “What we need are long-term plans for how to live with the virus. We need better early detection, better contact tracing and consistent isolation for those who a re infected. That is the only way.”

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> Repurposing existing drugs for a new threat

Malina Bakowski, a principal investigator at Calibr

“The results from the cellular assays are very promising and the need for medical remedies to address COVID-19 is incredibly urgent. It is critical we proceed with the utmost rigor to determine what is safe and effective, as diligence is the most expedient path to finding new therapies that will make a difference for patients.” Peter Schultz, PhD President and CEO, Scripps Research

Tu-Trinh Nguyen, a robotics engineer, in Calibr’s high-throughput screening facility.

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A collaboration with Dennis Burton, PhD, chair of the Department of Immunology and Microbiology at Scripps Research, and Thomas Rogers, MD, PhD, an adjunct assistant professor at Scripps Research and assistant professor of Medicine at UC San Diego, has proven particularly fruitful. Working in a specialized biosafety level 3 laboratory, the scientists treated human cells infected with SARS-CoV-2 with each of 12,000 drugs from ReFRAME. After 24 hours, they measured the level of viral infection in the cells to determine if the drugs prevented the virus from replicating. In some cases, they applied two drugs at a time to see if the compounds would work together against the virus.

When the COVID-19 pandemic began to make headlines out of China, Malina Bakowski, PhD, was focused on another part of Asia. She was working with researchers in Thailand, Cambodia and at University of Georgia to find drugs that could be repurposed against malaria. They were screening for anti-malaria drug candidates using ReFRAME, a drug repurposing library compiled by researchers at Scripps Research’s drug discovery division, Calibr. “When it became evident that we were dealing with a major pandemic, we shifted gears to focus on COVID-19,” says Bakowski, a principal investigator at Calibr. Led by Peter Schultz, PhD, the president and CEO of Scripps Research, Calibr established the ReFRAME collection in 2018 with support from the Bill & Melinda Gates Foundation to tackle areas of urgent unmet medical need, especially neglected tropical diseases. The collection has since grown to comprise over 14,000 compounds, including drugs that are already being repurposed for a number of diseases. As the pandemic spread early in the year, Arnab Chatterjee, PhD, vice president of Medicinal Chemistry at Calibr, led efforts to team up with labs at Scripps Research and other institutions in the United States, Europe and Asia to search ReFRAME for individual drugs or combinations that may be effective in treating people exposed to SARS-CoV-2, the coronavirus that causes COVID-19. “Early in the COVID-19 pandemic, we saw that ReFRAME could be leveraged to screen for hits against SARS-CoV-2,” says Chatterjee. “Since then, we have launched more than 20 scientific collaborations to have a near-term impact on COVID-19.”

The study identified more than two dozen existing drugs or drug candidates with antiviral activity against the novel coronavirus. Several of the drugs—halofantrine, amiodarone, nelfinavir, simeprevir, manidipine, ozanimod and osimertinib— are already FDA approved for use in humans, and 19 others are in various stages of the drug development process. A disease as confounding as COVID-19 is unlikely to be treated with a single drug. Early on, the team led by Schultz and Chatterjee focused on the evaluation of drug combinations, inclined to find ways to enhance the activity of drugs—such as Gilead’s remdesivir—already being tested in humans. The researchers found 24 drugs that had an additive effect when administered with remdesivir, the antiviral produced by the pharmaceutical company Gilead, that is currently being tested in human clinical trials against COVID-19. An additive effect means that the drugs were both active against the virus when applied together. Based on the results of cell culture screens, the researchers are now working to test the best-performing drug candidates in animal models to determine which are most likely to work in human patients. Those studies will pave the way to human clinical trials. “The results from the cellular assays are very promising and the need for medical remedies to address COVID-19 is incredibly urgent,” says Schultz. “It is critical we proceed with the utmost rigor to determine what is safe and effective, as diligence is the most expedient path to finding new therapies that will make a difference for patients.” SCRIPPS.EDU

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IMMUNOLOGY

> Mining for the most powerful COVID-19 antibodies Circulating in the blood of recovered COVID-19 patients are some of the best weapons against the virus: antibodies, which the immune system produces upon an encounter with an invader. However, not all antibodies are particularly effective at taking down SARS-CoV-2, the virus that causes COVID-19. It’s the job of immunologist Dennis Burton, PhD, to find the ones that are. The strongest antibodies could be fashioned into drugs and preventative medicines, Burton says. Or, they can be used to guide the development of a vaccine that will help put an end to the pandemic. In early February, Burton’s lab was still focused almost entirely on HIV—a virus known to be extremely challenging due, in part, to its fast mutation rate. For years, his team has been working to find so-called “broadly neutralizing” antibodies that protect against most or all strains of HIV. But as soon as the imminent threat of COVID-19 became clear, Burton made a shift that proved to be fruitful. Working in collaboration with the vaccine nonprofit IAVI and the University of California San Diego School of Medicine, Burton’s team put out a call for blood samples from recovered COVID-19 patients. The response was overwhelming.

Using samples from patients with the most potent immune responses, the team isolated more than 1,000 antibodies and evaluated how each one responded to COVID-19 in a test tube and in animals. A handful prevailed in both settings. The study—co-led by Thomas Rogers, MD, PhD, an adjunct assistant professor in the Department of Immunology and Microbiology at Scripps Research, and assistant professor of medicine at UC San Diego—appeared in the journal Science. Though Burton’s lab has resumed much of its HIV work, he is looking to team up with a pharmaceutical partner to produce the antibodies in greater quantities so they can be explored in the clinic. He also would like to identify broadly neutralizing antibodies that protect against all coronaviruses, including those that haven’t yet emerged. Burton notes that COVID-19 is the third dangerous coronavirus-driven disease to emerge in the past 20 years—following MERS, discovered in 2012, and SARS, in 2003. “A new coronavirus will almost certainly come again in the future,” says Burton, co-chair of the Department of Immunology and Microbiology. “When it does, we want to be better prepared. That’s why it’s imperative to continue working toward a vaccine or treatment that can take down all coronaviruses.”

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STRUCTURAL

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BIOLOGY

> Finding the enemy’s weakness Ian Wilson, DPhil, had long feared a new influenza virus would become the next global pandemic. “I’ve worried that in the worst case, it might be like 1918,” he says. For this reason, his structural biology lab has keenly focused on the flu for nearly 40 years. By early 2020, it became clear that Wilson’s concern about a new pandemic was not unfounded. “However, it turned out to be a coronavirus, not influenza,” says Wilson, chairman of Scripps Research’s Department of Integrative Structural and Computational Biology. Fortunately, his lab’s groundbreaking work on influenza—in addition to other viruses, such as HIV and hepatitis C—gave him a stockpile of expertise and the right technologies to begin immediately examining the SARS-CoV-2 virus for weak spots that could be exploited by a vaccine or treatment. Crystal structure of SARS-CoV-2 receptor binding domain in complex with neutralizing antibody CC12.1

Using sophisticated imaging equipment, Wilson’s team quickly pinpointed a potential Achilles’ heel. Wilson and others in his lab—including Meng Yuan, PhD, and Nicholas Wu, PhD—found that an antibody produced by the body in response to a previous coronavirus infection, SARS, attached to a nearly identical spot on the new coronavirus. This suggested a functionally important and vulnerable site for this family of coronaviruses. “The knowledge of sites like this on the virus can help structure-based design of vaccines and therapeutics against SARS-CoV-2, and these could also possibly protect against other coronaviruses— including those that may emerge in the future,” Wilson says. The discoveries kept coming, helped by the fact that more antibodies to COVID-19 became available to researchers after the first local patients recovered. In July, after reviewing nearly 300 of these antibodies, Wilson worked with Dennis Burton’s lab to identify a common feature among the most effective antibodies: they all stemmed from the same genetic source. The findings appeared in the journal Science. It was good news, as this type of antibody is usually present at low levels in the blood of healthy people. It suggested that boosting these antibodies, as a vaccine could do, should be able to prevent or treat the disease. Although several potential vaccines are already in clinical trials, scientists don’t yet have a full understanding of the molecular features that define a successful antibody response. In the new study, the scientists took a big step toward filling that knowledge gap. “Amidst all of this, it’s been gratifying to observe the overwhelming response from the community and from those who have recovered from COVID-19,” Wilson says. “Their efforts, from providing blood samples to supporting ongoing basic research, is making a real difference as we all work to create vaccines and therapeutics.”

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> Mapping the course for coronavirus vaccines Andrew Ward on global efforts to create the first-ever approved R NA vaccines:

“This is the greatest science experiment in vaccinology that’s ever been done. It’s literally testing all the different technologies, and it’s going to be cool to see how this all shakes out.” J U LY

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Andrew Ward, PhD, was studying coronaviruses long before they became a household name. More than three years ago, using some of the most advanced electron microscopy equipment in the world, his lab revealed the very first structure of a human coronavirus spike protein. The protein came from the HKU1 coronavirus, which causes seasonal colds. His lab then went on to do the same for more deadly coronaviruses: SARS (severe acute respiratory syndrome) and MERS (Middle East respiratory syndrome). “The reason we initially decided to work on coronaviruses was the expectation that they could cause a pandemic,” says Ward, professor of Integrative Structural and Computational Biology. “Though I can’t say I expected anything like this to happen, or to happen so quickly.” Coronaviruses use their spike proteins to invade human cells. Understanding the protein’s shape and seeing how spikes interact with protective antibodies is a critical step in designing a vaccine, Ward explains. The structures he creates using advanced microscopy techniques are, in essence, atomiclevel blueprints from which vaccines can be designed. Several years ago, these blueprints enabled Ward and his colleagues to engineer a way to stabilize the spike proteins so that they could be produced at large scale and keep their integrity in a vaccine. This innovation is used in several coronavirus vaccines now in development, including the potential COVID-19 vaccines being advanced by the pharmaceutical companies Moderna and Novavax. By exposing the immune system to this engineered spike via a vaccination, the body recognizes it as foreign and makes neutralizing antibodies that can quickly fight back upon real-life exposure to the coronavirus. 14

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Ward’s lab published structural details of the spike protein used in a COVID-19 vaccine being developed by Novavax.

The very first “blueprint” of a coronavirus spike protein was made possible with high-powered electron microscopes.

“It’s an illustration of how basic research and structural biology directly contribute to creating vaccines,” Ward says. In spring of 2020, as the first genetic sequence of SARSCoV-2 emerged, Ward and his team instantly turned their focus to the newest member of the coronavirus family. “It was literally plug-and-play,” he says. “We already had the expertise and processes in place. That’s why everything moved so fast.” The group is now working with public and private vaccine makers on new efforts to defeat COVID-19. As vaccines move forward in human trials, Ward says his team is transitioning from examining immune system interactions with SARS-CoV-2 in animals to those in actual patients.

> A vaccine prototype in under two months Scripps Research scientist Jiang Zhu, PhD, applied his nanoparticle vaccine technology—which has already been used to develop experimental vaccines for HIV, hepatitis C, Ebola and respiratory syncytial virus—to create a potential vaccine for the virus that causes COVID-19. Zhu is cofounder of the 2018 Scripps Research spinoff company Ufovax, which is built around his development of a vaccine platform that can be rapidly applied to a wide range of diseases. The vaccines rely on miniscule viral particles that induce potent immune responses, and they’re designed to be easily manufactured on a large scale. By mid-March, Zhu and his team had produced a prototype of a coronavirus vaccine, featuring SARS-CoV-2 protein spikes protruding from a nanoparticle “scaffold.” Zhu called it a “crucial first step” in efforts to develop an effective vaccine against COVID-19. He’s now running advanced tests of the prototype to gauge immune response in animals, and eventually in people.

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VIROLOGY

> Finding the mutation that enables coronavirus to infect with ease They say the little things make a marriage work. If so, Hyeryun Choe, PhD, and Michael Farzan, PhD, together more than 20 years, seem ideally matched, discussing nanoscale virus mutations late into the evening, like most people discuss food, friends or weather. The virus that causes COVID-19 is only about 130 nanometers in size. For scale, if the coronavirus were a car, taking a journey across the width of a human hair would be akin to driving from San Diego to Reno. Although this makes the virus invisible in light microscopes, Farzan and Choe speak of each tiny mutation as i f it were a person they know on sight. Michael Farzan on his and Hyeryun Choe’s discovery of a mutation that appears to make t he coronavirus more infectious:

“Viruses with more functional spikes on the surface would be more infectious. And there are very clear differences between the two viruses in the experiment. Those differences just popped out.”

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“There are very clear differences between George and David,” Farzan says, using the names as shorthand with a pair of New York Times reporters interviewing them on Zoom. David stands for aspartic acid at position D614 in the virus spike. George is glycine at the same position, D614G. “George is really more infectious,” Choe agrees, leaning into her computer camera at the couple’s condo office. “George has about four times more spike proteins.” Both Choe and Farzan are virologists. Their work has braided across their distinct interests: Farzan homes in on chemical structures and antibodies; Choe thinks deeply about viral entry into cells. They’ve gone different directions with their science through the years, but now they’re pooling their talents to address the pandemic SARS-CoV-2 coronavirus, cause of COVID-19.

They’ve studied coronaviruses since the first SARS outbreak nearly 20 years ago—working together, they co-discovered the receptor that SARS uses to infect cells. The new coronavirus uses the same receptor, called ACE2. With their deep knowledge, they’ve never been so in-demand, or found their scientific efforts so intertwined. “Mike is the creative element. He’s got 100 ideas a day,” Choe says. “Once in a while, a good one.” “Hyeryun is the analytical one. If something passes her test, we know we are on to something,” Farzan says, smiling. “Most things don’t.” The two met at Harvard in the late 1990s, when Farzan was pursuing his doctorate and Choe was a postdoctoral researcher helping t rain him. “We fought constantly,” Farzan laughs. Over what? “Everything,” Choe answers. “Bench space, hypotheses, authorship, how to do experiments.” “Especially bench space. I was consigned to a desk until my skills improved,” Farzan adds. The decision to move to Scripps Research in Florida was an easy one for the couple in 2012. Farzan had grown up in Boca Raton, where his dad worked on the IBM campus. He loved the idea of returning to the

Sunshine State. Plus, they wanted to actually help make new vaccines and medicines, to see their discoveries reach the clinic a nd have an impact. Scripps Research is a place where that can easily happen. In addition to co-chairing the Department of Immunology and Microbiology, Farzan now nurtures two start-up companies focused on advancing his and Choe’s inventions. Emmune, i n Juno Beach, uses gene therapy techniques to make antibody therapies for viral diseases including HIV and COVID-19. Bliss, in Boston, is advancing a COVID-19 vaccine prototype. On arriving in Florida, Choe set up her lab in a different building. Before the pandemic, her research program focused on Dengue and Zika viruses. Now it’s mostly coronavirus again. For all the stress and pressure of staring down a virus that has killed hundreds of thousands of people and hobbled the economy, the couple’s optimism is as obvious as the spikes on George. Farzan is quite confident that scientists will iterate a broadly effective vaccine in record time. Choe feels certain that the vaccine the two of them developed and tested is the best possible candidate. And, good news, it appears to work on both George and David. “It’s still an amazing journey,” Choe says. “I think we feel lucky that our work might be useful.” SCRIPPS.EDU

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> Detecting infection earlier with fitness wearables The wrist-worn fitness trackers that motivate so many Americans to stay active are serving another key role during the pandemic: detecting viral illnesses, including COVID-19.

Jennifer Radin on how smartwatches can pick up on illness even before symptoms emerge:

“When people get an infection, their resting heart rate tends to increase and their daily activities will change, as will sleep patterns.”

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Jennifer Radin, PhD, an epidemiologist at Scripps Research Translational Institute, is leading a nationwide study to determine whether fitness trackers can predict outbreaks faster than what’s currently possible. “Early detection is critical for effective public health response to infectious disease outbreaks,” Radin says. “We believe we can do this by leveraging the rich health data that’s already being collected by the millions of Americans who regularly use wearable devices.” The study, called DETECT, kicked off in March, just as offices and schools were shutting down. By early summer, well over 35,000 people had enrolled across the United States, consenting to share their de-identified data via an app called MyDataHelps that communicates with their tracking device. The data is then analyzed for individual changes in sleep patterns, heart rates and activity levels—all of which are known to stray from their norm during an infection. Participants also log any symptoms they’re experiencing or test results they receive. By mid-June, 54 participants had tested positive for the virus, 279 reported testing negative and thousands noted having one or more symptoms. Preliminary results of the study showed that even with the small initial sample size, researchers significantly improved the distinction between symptomatic individuals with and without a diagnosis of COVID-19, compared with an evaluation of symptoms alone. “Common screening practices for COVID-19 typically include temperature measurements and surveys focused on symptoms and travel,” Radin says. “However, these methods are likely to miss pre-symptomatic or asymptomatic cases, and that can foster further disease spread.” The DETECT study is still open for enrollment; Radin hopes to sign up more than 100,000 participants. Learn more at detectstudy.org.

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â&#x20AC;&#x153;In the setting of infectious disease, you can test negative one day and positive the next. A wearable health tracker, on the other hand, provides a continuous, unobtrusive, real-time assessment so you can see a problem emerging even before symptoms.â&#x20AC;? Eric Topol, MD Director and Founder, Scripps Research Translational Institute

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Coronavirus 101 One of the great endeavors of research is to take what we know about the tiniest molecular machines and translate that into medicines that go on to change the world. As we continue to experience the personal and societal effects of the COVID-19 pandemic, scientists are unearthing the tricks of the SARS-CoV-2 virus and developing thoughtful ways to counteract it. Whether itâ&#x20AC;&#x2122;s a precise, nanoparticle vaccine or simply scrubbing our hands, any protective measures depend on the fascinating science of this new pathogen.

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I. What are the parts of a coronavirus? Coronaviruses are a large family of viruses, some of which infect humans.

The coronavirus at the root of COVID-19 is the newest known member of this family. And like other coronaviruses that infect people, the new coronavirus causes respiratory disease, among other symptoms.

At their core, coronaviruses contain a genetic blueprint called RNA (beige), similar to DNA. The single-stranded RNA acts as a molecular message that enables production of proteins needed for other elements of the virus.

Bound to this string of RNA are nucleoproteins (dark blue discs) â&#x20AC;&#x201D; proteins that help give the virus its structure and enable it to replicate.

Encapsulating the RNA genome is the viral envelope (teal), which protects the virus when it is outside of a host cell. This outer envelope is made from a layer of lipids, a waxy barrier containing fat molecules. As well as protecting the precious genetic cargo, this layer anchors the different structural proteins needed by the virus to infect cells.

Envelope proteins (dark blue dots) embedded in this layer aid the assembly of new virus particles once it has infected a cell.

Coronavirus illustrations by Hailee Perrett, Ward Lab

The bulbous projections seen on the outside of the coronavirus are spike proteins (red-orange). This fringe of proteins gives the virus its crown or halo-like appearance under the microscope, from which the Latin name corona is derived. The spike proteins act as grappling hooks that allow the virus to latch onto host cells and crack them open for infection. Like all viruses, coronaviruses are unable to thrive and reproduce outside of a living host.

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II. How does the novel coronavirus infect a cell?

Coronavirus 101

Due to its unique features, the novel coronavirus is particularly good at infecting new cells, both in the upper respiratory tract, as well as deeper down in the lungs. Hereâ&#x20AC;&#x2122;s a look at how the process takes place.

The microscopic virus enters through the nose or mouth, where it begins its infection of our airways.

The outer spike protein of the coronavirus latches onto specific receptors on the surface of cells in our respiratory tract. In the case of COVID-19, the virus latches on to the ACE2 receptor.

This binding triggers the process by which the virus fuses into human cells. The viral envelope merges with the oily membrane of our own cells, allowing the virus to release its genetic material into the inside of the healthy cell.

The genetic blueprint of the virus is RNA (instead of DNA), which acts as a molecular message, instructing our host cell machinery to read the template and translate it into proteins that make up new virus particles.

The hijacking persists, as the human host cell continues to generate more copies of the virus, assemble these copies into viable particles and traffic them to the outer edges of the cell for release.

Each infected cell may produce and release millions of copies of the virus, which can then go on to infect other neighboring cells, as well as neighboring people when they are expelled from the airways in droplets via coughing and sneezing.

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III. How do antibodies stop the coronavirus? Antibodies to the novel coronavirus recognize the virus’s outer spike protein enabling them to bind to the surface of the virus, preventing the virus particles from attaching to the host cell. Even if the virus successfully attaches, antibodies can prevent it from penetrating our cell membranes. If the virus does manage to enter the cell, antibodies can still prevent the virus from releasing its genome into the host cell for replication.

Antibodies are Y-shaped proteins produced by our immune system after we are exposed to a disease-causing invader, such as bacteria or a virus. These proteins help the body remember the threat and be better prepared for the next encounter.

Once antibodies neutralize the virus, they can target the virus for destruction by signaling to other components of our immune system. Scientists are trying to use antibodies both as a way to treat COVID-19 and prevent the disease from taking hold.

Some researchers are studying antibodies taken from recovered COVID-19 patients. These antibodies could act as a medicine for the newly infected. Other scientists are focused on how the antibody interacts with coronavirus spike proteins, which may enable them to design a successful vaccine that instructs our bodies to generate effective antibodies against the virus. The long-term hope is that we might also be able to identify “broadly neutralizing antibodies,” a type of antibody that could defuse not just this specific viral strain, but also offshoots that occur because of natural mutations in the virus over time.

IV. How would potential antiviral drugs work against the coronavirus? In contrast to a preventative vaccine, most antiviral medicines would target the virus in people who have already been infected. These drugs can work in several different ways, targeting various aspects of the virus particle or even the human host cell that the virus invades. Some antiviral drugs in development disarm the surface spike proteins of the virus, preventing the virus from latching onto the host cell. Others are designed to stop the virus from replicating after it enters the host cell. A number of these molecules block key viral components called proteases; this prevents key viral proteins from maturing and copying the virus’s genetic material. Drugs (such as remdesivir) may also interfere with this copying process by tricking the virus into merging the drug molecules into its RNA backbone, which disrupts the genetic blueprint and prevents replication. Alternatively, the viral production line could be halted by

modifying elements of host cells. Certain treatments may interact with receptors on the inside of o ur cells that act like switches, and which are often manipulated by the virus to aid infection and replication. Just as completely novel drugs are being developed for the coronavirus, scientists are also screening treatments that are already approved for other diseases—as many of these drug molecules exhibit antiviral properties. Because existing drugs are already known to be safe in humans, they could be developed into a viable COVID-19 treatment faster than new drugs that have never been tested in people. Researchers are also testing existing drugs that could be used in combination with each other; this approach reduces the dose needed for each drug and helps to minimize side effects for patients.

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Coronavirus 101

V. How would a vaccine work against COV ID-19?

The human immune system is designed to stop diseases before they make us sick. This occurs via highly controlled inflammatory and immune reactions. But, in some severe infections, the immune system can dangerously overreact— inflicting damage on the healthy surrounding tissues. After we have been exposed to an infection, our immune system remembers the threat by producing antibodies—proteins that can prepare the body’s defenses for the next encounter. Vaccines mimic this process, encouraging the immune system to make antibodies that could quickly recognize and disable the invader upon contact, thereby preventing or minimizing illness.

recent survivors of COVID-19 or those produced by individuals in response to the closely related SARS virus from the outbreak that began in 2002.

Scientific studies have shown that human antibodies to the novel coronavirus are able to recognize the outer spike protein of the virus. These discoveries are driving several different approaches to design vaccines that could protect against COVID-19.

Once a potential vaccine is discovered, a number of checkpoints exist before it can be administered to people. First are preclinical tests, which involve experiments in a laboratory and with animals. Scientists must ensure the vaccine candidate is not only effective, but also safe. For example, an antibody response to an imperfect vaccine could, under very rare circumstances, end up increasing the danger of becoming infected.

A traditional approach to vaccine development involves testing weakened or inactivated forms of the SARS-CoV-2 virus to determine whether they can still prompt an antibody response. Alternatively, some researchers are studying whether it’s possible to use small pieces of the virus, such as isolated spike proteins, to achieve the desired immune response. This approach is known as a subunit vaccine. Antibodies themselves are also being investigated as clues for how to design a vaccine, particularly antibodies from

VI. How could anti-inflammatory d rugs work against the coronavirus?

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Recently, labs are also exploring gene-based vaccines, an approach that incorporates parts of the virus’s genetic blueprint into isolated host cells. These cells are then instructed to make the features of the virus that circulating antibodies might recognize.

When the potential vaccine achieves the necessary preclinical results, clinical trials can begin in a small group of people. As the vaccine candidate advances, it is tested on increasing numbers of people, with scientists and doctors closely monitoring safety, efficacy and dosing. Upon successful completion of clinical trials, the vaccine candidate must be reviewed and approved by regulatory agencies such as the FDA before large-scale manufacturing and distribution gets underway and the licensed vaccine is administered widely.

In patients with COVID-19, a severe immune reaction in the lungs can cause inflammation that leads to acute respiratory distress. Several ongoing clinical trials are testing drugs that may be able to prevent this dangerous inflammation in the lungs or other organs. Many of these therapies are already used to treat other diseases, where they help to temper the harmful effects of the immune system by blocking specific inflammatory signals.

VII. How do soap and hand sanitizer work against COV ID-19?

The coronavirus that causes COVID-19 can be easily destroyed by soap. But why? Soap molecules consist of long molecules called surfactants that contain a head and a tail. While the head prefers to bond with water, the tail prefers oils and fats instead. Trying to escape water, the tails bury themselves into the fatty outer layer of the virus. The soap is able to break apart the chemical bonds of this vulnerable viral envelope, forcing it to break open and spill its contents, rendering it useless. However, to do its job effectively, the soap needs to reach all the creases of our hands and requires some time to interact with the virus. This is why we should spend at least 20 seconds washing our hands. Alcohol-based hand sanitizers work in a similar way, as alcohol can destroy the essential envelope proteins that surround the virus. Hand sanitizer needs to be at least 60% alcohol to achieve this, and the approach is still less effective than diligently washing hands with soap and hot water.

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ADAPTATIONS Discovery in an era of social distancing

“Hey, you’re on mute!” To many of us, those words have become all but expected as we engage in our third online meeting of the day from our home office—which very well may be the kitchen table. It’s also the case for hundreds of Scripps Research scientists who had to begin working from home after shelter-in-place controls were implemented in March due to the unfolding COVID-19 pandemic. As labs got back up and running over the summer, researchers were still urged to work from home when possible or rethink lab schedules to prevent crowding. Even when working on-site, health requirements have reshaped everyday interactions—just as they’ve changed the way we go about grocery shopping or socializing with friends. Yet, as you might expect from those who spend much of their career trying things that have never been done before, scientists have found creative ways to not only adapt to this new world, but to continue producing life-changing research and making meaningful connections with one another.

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Adaptations 28

Shelter-in-place research breaks allowed students to catch up on reading.

Professor Keary Engle tests his infant son Oliver on organometallic chemistry.

Hannah Turner, research assistant in the Ward Laboratory, analyzes data from a safe spot outdoors.

Campus modifications help researchers maintain social distancing.

Professor Matt Disney stays safe in the lab with his Scripps Research-branded cloth face mask.

Colby Sandate broadcasts his PhD dissertation defense to the masses from his living room.

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For postdoctoral fellow Kara Marshall, working from home provided welcome distractions from her curious canine, Harry.

Nathan Beutler, a graduate student in the Burton Laboratory, suits up to search for neutralizing antibodies in the blood of recovered COVID-19 patients.

SHELTERED PROGRESS For most laboratories at Scripps Research that were not focused on COVID-19, bench-side operations ceased during the first few months of the pandemic. This presented obstacles to predominantly experimental groups but also drove investigators to rethink the process and timeline of scientific discovery.

help build my home setup,” he says. “With strategic lighting, multiple screens and a desk placed in the living room, the overall effect made me look somewhat like a news anchor.” While many defending students missed seeing their proud advisors or committee members face-to-face, the virtual broadcast allowed for greater human connection in other ways.

“Typically, we collect experimental data, draft an outline of the findings and refine it for publication,” says Keary Engle, PhD, assistant professor in the Department of Chemistry. “I’ve really pushed my students to think about the direction of their projects and draft their story so they can be very efficient when they’re in the lab.”

“I had far more people watching the event online than we would have had space for in the lecture hall,” Colby says. “Some of these groups, like my family, were also able to hold small viewing parties. The fact that I no longer had to worry about getting friends and family to and from the talk probably made me a lot less nervous.”

Just as working from h ome provided a fresh environment to inspire alternative experimental approaches, many researchers dedicated much-needed time to important aspects of everyday science.

Meanwhile, the Graduate School’s educators have hosted openaccess virtual events for college undergraduates to join from around the world. The interactive webinars have taken on topics such as “Robotics in D rug Discovery” and “Exploring the Faculty Track,” highlighting career options. They also launched a virtual summer science competition for elementary, middle and high school students, geared toward minority groups that are underrepresented in STEM.

“I’ve been able to analyze results, develop new hypotheses and prepare presentations to share my findings,” says Rebecca Berlow, PhD, a staff scientist in the Department of Integrative Structural and Computational Biology. “I know my colleagues have also been able to focus on the timeconsuming process of applying for funding to keep these projects going.” Needing little more than a high-speed internet connection and a selection of software tools, computational scientists were perhaps best positioned to work remotely. Some researchers organized informal computational biology or chemistry workshops, enabling the organic transfer of skills between trainees, as would normally happen in person.

HOME SCHOOLING The Skaggs Graduate School of Chemical and Biological Sciences took an imaginative approach to fostering education remotely—both with existing graduate students and potential future scientists in the wider community. For early-stage graduate students, all classes went virtual, with a further expansion of dynamic online tools for learners and instructors. For trainees a little further down the doctoral track, respite from long hours in the lab provided an opportunity for important thesis updates. Some students even completed their biggest PhD milestone from home: the dissertation defense. Structural biologist Colby Sandate turned it to his advantage: “I have a roommate who’s a YouTube streamer, so she was extremely supportive in letting me borrow her equipment and

FINDING A ROUTINE Who could have predicted that eliminating a long commute would take getting used to? “I miss my morning and evening drives,” says postdoctoral researcher Matthias Pauthner, PhD, in the Department of Immunology and Microbiology. “Those drives were my transition phase into and out of the working mindset, so now I try to replace them with a podcast over coffee in the morning and a walk in the evening.” For those with young infants or school-age children, establishing a new routine is not as seamless. “For my wife and I, our days are typically a series of online meetings and playing ping-pong with who is watching the baby,” says Engle via a Zoom call, as he entertains his infant son, Oliver. “It’s challenging to find those blocks of time to write papers or grants. It’s when he’s down for the night that we often find ourselves at full speed for three to four hours.” As Scripps Research faculty, staff and students face similar but distinct challenges, this has been a time of mutual understanding and increased empathy, with individual and collective wellbeing as the number one priority. “We’re honestly just trying to survive and not be too hard on ourselves,” Engle says.

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Adaptations

DISTANCING BUT NOT DISTANT A major part of the psychological resilience required as a researcher is the feeling of unity among colleagues. As social animals, substituting the most basic human interactions with a webcam has been a major adjustment. Several principal investigators are mindful of striking a balance between not enough and too much videoconferencing. To keep the camaraderie going, some labs planned virtual happy hours—complete with signature cocktails and a show-and-tell of quarantine hobbies. “Game night is every Thursday,” says Scripps Research Fellow Danielle Grotjahn, PhD. “We’ve been playing interactive games like trivia and Pictionary, and the turnout has been great.” Grotjahn’s team extended the invitation to other labs, which spurred a greater interest in new online social activities. “Some lab members have started a Friday night tradition of playing online Dungeons and Dragons,” she says.

SAFELY REOPENING RESEARCH Even though shutting down non-essential experiments caused disruption, ramping up brought its own challenges. Laboratories now have designated COVID-19 coordinators who review everyone’s experimental plans each week to ensure they conform with new health-focused policies laid out by the institute’s leadership. “It’s absolutely a work in progress,” says Mildred Kissai, a graduate student in the Department of Chemistry. “To reduce density in the lab, half of us agreed to the morning shift, with the remaining members on the afternoon shift.” Many smaller workspaces have been rearranged for greater social distancing and common-space furniture is, for the time being, gone. As on-campus activities expand, new procedures help prevent the spread of COVID-19. Employees who work on-site submit a daily certification of health prior to arriving to campus and are screened for COVID-19 weekly. Temperatures are checked prior to entering buildings. Such activities are quickly becoming second nature to scientists. Reacclimating to an environment that warns against having lunch or close conversation with colleagues may instead be the greater ordeal. Nevertheless, members of the Scripps Research community are taking each new change in stride, enthusiastic to return to the life-changing science they love. “In the grand scheme of things, a lot of us are in a privileged position,” notes Engle. “We know there are so many people who are facing significant insecurities in both health and finances, so we must keep that in perspective.” This position of gratitude echoes throughout the institute, encouraging researchers to reframe new scientific challenges as opportunities for growth. 30

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After an accelerated development and successful pilot program, Scripps Research established regular on-site COVID-19 screening for all staff and students working on the California campus, with plans to establish testing on our Florida campus as well. Emmea Mattox, who oversees our blood donor core laboratory, is seen here collecting anonymized samples at one of five COVID-19 screening sites set up on campus.

The Crisis Management Team The Crisis Management Team at Scripps Research mobilized early in the pandemic to guide the institute’s response to an ever-evolving COVID-19 landscape. The team has implemented science-based policies to protect the Scripps Research community while supporting critical ongoing research into COVID-19 and other diseases. Led by Chief Operating Officer Matt Tremblay, PhD, the team is comprised of leadership from several departments: Jamie Williamson, PhD, Exec. Vice President, Research and Academic Affairs Karen Haggenmiller, Vice President, Human Resources Megan Young, Director, Operations Alanna Rutan, Compliance Counsel, Operations Anna-Marie Rooney, Vice President, Office of Communications Chinh Dang, Chief Information Officer, IT Services Demetri Andrikos, Vice President, Legal and General Counsel Douglas Bingham, Executive Vice President, Florida Operations Scripps Research Professor Kristian Andersen, PhD, a genomic epidemiologist, has provided weekly scientific briefings on the pandemic to the team. He continues to provide guidance on the implementation of best practices, in addition to serving as a leading advisor for government and public health officials. The Crisis Management Team receives assistance and guidance from other faculty and staff from both the Florida and California campuses.

business not as usual

They mask up and show up. When Scripps Research closed its La Jolla and Jupiter campuses in March to all but the most critical scientific and administrative operations, a small cadre of employees continued to do their jobs on-site—many of them taking on added responsibilities as the COVID-19 pandemic unfolded.

LAURENCE CAGNON, PhD

DAWN KIMBALL

Biosafety Manager, Environmental Health & Safety 12 years at Scripps Research, California

Site Coordinator, Shipping & Receiving (contracted through Avantor Science) 8 years at Scripps Research, California

“As a Level 3 safety manager, I basically have my finger in each lab working with biological agents, recombinant DNA, things like that. We regularly audit labs to make sure they are in compliance with the National Institutes of Health’s safety guidelines. My job really is to facilitate research and make sure it’s done safely. ”

“Wednesdays are our busiest days; we process, on average, about 60 to 80 packages. When the institute shut down, we had one Wednesday where we had over 600 packages. About 100 of those were chemicals.”

RACHEL MARTIN

MARK VAN HOY

HR Analyst, Human Resources 3 years at Scripps Research, Florida

Supervisor of Facilities and Engineering 12 years at Scripps Research, Florida

“So much is different since COVID-19. We just have to go with the flow. Instead of face-to-face, I am texting people. I am calling them. I used to be able to walk into my colleague’s office, now I have to track her down between Zoom meetings. It’s an eye-opening experience. The thing is, we make it work. One way or the other, we get everything done.”

Projects that would normally have to be scheduled around have been wide open. Prior to the shutdown, we had committed to the installation of a new cryo-EM microscope. This project continued through the shutdown. Our group played a role in assisting the contractors in many ways. I love what I do. I love feeling that I play a small part in all of the successes we are making here.”

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Citizen Science

CA L L I N G A L L C I T I Z E N S C I E N T I ST S : “Tapping unused processing power on thousands of idle computing devices provides us with an incredible amount of computing power to virtually screen millions of chemical compounds.” — Stefano Forli, PhD, assistant professor in the Department of Integrative Structural and Computational Biology and director of the OpenPandemics project

Everyone can play an important role in stopping the spread of COVID-19, and not just by wearing a mask The value of citizen science— which harnesses the power of the public to gather important research data—is often associated with ecological projects such as the annual Christmas bird count. But the approach is also advancing key health discoveries, especially as scientists seek to understand a completely new and fastspreading virus. At Scripps Research, here’s how you can get involved.

USE YOUR COMPUTER TO DISCOVER A DRUG

DETECT OUTBREAKS WITH YOUR FITNESS TRACKER

Have a computer and an internet connection? That’s all you need to help scientists find compounds that might be effective medicines against COVID-19. The project, called OpenPandemics, is designed and led by Scripps Research and hosted on IBM's World Community Grid, a computing resource provided at no charge for scientists. Operating unobtrusively in the background of your computer, an app distributes computational assignments via the IBM cloud. Be a part of it: Volunteers need not have any special technical expertise to participate; the process is automatic and secure. Sign up at ibm.org/OpenPandemics.

If you use a wrist-worn fitness device such as Fitbit, Apple Watch, Amazfit or Garmin Watch, you can join a study focused on detecting outbreaks of viral illnesses, including COVID-19. By harnessing key data points such as heart rate and activity levels, scientists can improve real-time surveillance. Early detection is critical for effective public health response to infectious disease outbreaks. Be a part of it: Join the study and consent to share your data by downloading the MyDataHelps mobile app. The app “speaks” to your wearable devices to capture relevant data points. Visit detectstudy.org for more information.

SCRIPPS RESEARCH MAGAZINE | FALL 2020

Order from chaos As scientists and the public struggle with COVID-19 information overload, a Scripps Research team creates an online haven where data is organized, findable and usable.

The volume and speed of COVID-19 discovery around the world is nothing short of astounding. Genetic sequences of coronavirus samples are posted daily to research websites, while thousands of new studies unravel mysteries about the new disease every week.

Cumulative COVID-19 Cases Worldwide 20 million

East Asia & Paciﬁc: China East Asia & Paciﬁc North America Sub-Saharan Africa Europe & Central Asia Middle East & North Africa Latin America & Caribbean South Asia

April

July

The fact that so much scientific knowledge is being openly shared is a wonderful thing, says Scripps Research data scientist Laura Hughes, PhD. But this “explosion of information” also presents problems—for scientists and the public, she says. Data is hard to track down from different websites and appears in widely varying formats, making apples-to-apples comparisons an arduous task. For example, a drug might be listed as its marketed name on one website and its generic name on another. Hughes, who works in the lab of Andrew Su, PhD, collaborated with colleagues on a remedy: a centralized, organized research repository of all things COVID-19. You can find it online at Outbreak.info, which she hopes will become a prized resource for both scientists and the public. Visually appealing charts and graphs pull information from more than a dozen

sources “so it can be understood and accessed faster than before,” Hughes says. “We’re spending a lot of time to make data consistent, which is a very big task. It may sound boring, but it’s necessary to help scientists unite towards a common goal.” Karthik Gangavarapu, a graduate student in the labs of Su and Kristian Andersen, PhD, and a key member of the Outbreak.info team, says the website will become richer as new information becomes available. The group is creating and integrating computer programs that crawl the web for new data relevant to COVID-19. With help from bots, researchers and citizen scientists can then more easily curate data for the site, he says. “The website is just one piece of a bigger vision,” Gangavarapu says. “First and foremost, our goal is to help move research forward by making data more accessible. But in the process, we hope that we will help energize and inform the public.” The value of citizen science—which harnesses the power of the public to gather important

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Science never stops at Scripps Research, even during a pandemic. While many of our 200+ labs refocused or expanded their scope to address COVID-19, the pace of discovery remained in high gear across other critical areas of health and medicine. For more science news, visit scripps.edu/discoveries

DISCOVERIES Scripps Research

THAT CHANGE LIVES

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HEART HEALTH

Nature Chemical Biology, June 2020

Reducing ‘bad’ bacteria in the gut may improve heart health Promoting a healthy gut microbiome may be a powerful strategy for lowering cholesterol and other risks for heart attack. SCIENTISTS AT SCRIPPS RESEARCH have developed molecules that can remodel the bacterial population of intestines to a healthier state. Through experiments in mice, they have shown that this lowers cholesterol levels and strongly reduces the thickened-artery condition known as atherosclerosis.

strokes, leading causes of death among humans.

The scientists created a set of molecules that slow the growth of less-desirable species of gut bacteria. In mice that develop high cholesterol and atherosclerosis from a high-fat diet, the molecules beneficially shifted the balance of species in the gut microbiome.

The gut microbiome, which includes hundreds of bacterial species, have become a focus of intense study around the world, as scientists have discovered that the microbes not only help digest food, but play a role in metabolism, immunity and other important functions. When people overuse antibiotics or consume a diet rich in carbs, fats and sugar, the gut microbiome can be altered in ways that promote disease.

The term “microbiome” refers to the trillions of bacteria and other microorganisms that live in and on our bodies. This shift reduced cholesterol and dramatically slowed the buildup of fatty deposits in arteries—hallmarks of atherosclerosis. Atherosclerosis is the condition that leads to heart attacks and

“It was surprising to us that simply remodeling the gut microbiome can have such an extensive effect,” says Reza Ghadiri, PhD, a professor in the Department of Chemistry at Scripps Research.

That recognition has led researchers to look for ways to remodel the microbiome, with the goal of rolling back adverse changes to restore good health. Ghadiri and his team have been working on a method that involves delivering small molecules to

kill or slow the growth of bad gut bacteria without affecting good gut bacteria. “Our approach is inspired by nature,” says author Luke Leman, PhD, an assistant professor in the Department of Chemistry at Scripps Research, and also a senior author. “Our cells naturally use a diverse collection of molecules including antimicrobial peptides to regulate our gut microbe populations.” The scientists identified two molecules that significantly slowed the growth of undesirable gut bacteria. Using these molecules to treat atherosclerosis-prone mice, they found striking reductions in the animals’ cholesterol levels compared with untreated mice—about 36 percent after two weeks. After 10 weeks, plaques in the arteries of treated mice were about 40 percent reduced. The researchers are now testing the molecules in mice that model diabetes, another common condition that has been linked to an unhealthy microbiome.

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CELL SCIENCE

DISCOVERIES

Nature Communications, April 2020

WHAT ARE MICROGLIAL CELLS? Microglia both sculpt and maintain the brain, pruning damaged neurons and responding to infections to keep the nervous system

Autism disproportionately affects boys, and this may explain why MANY CASES OF AUTISM spectrum disorders (ASDs) may result from problems in immune cells that normally work to trim back unneeded brain connections in early life, suggests a new study led by scientists at Scripps Research.

healthy.

Scientists examined the effects of certain gene mutations that account for a small percentage of autism disorders. These mutations are known to cause an overproduction of many proteins in brain cells, but how that overproduction leads to autism behaviors has been a mystery. The scientists found that the most relevant effect of protein overproduction is in brainbased immune cells called microglial cells. These cells normally prune unneeded

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brain connections, or synapses, as the brain develops in childhood. Working in mice, the scientists determined that the protein overproduction impairs microglial cells and hampers their ability to prune synapses. This led to autism-like social behavior deficits, but it only occurred in males. “Our study suggests that impairments in microglia play a key role in the development of autism behaviors, at least in some cases, and may help explain the higher prevalence of autism disorders in males,” says Baoji Xu, PhD, professor in the Department of Neuroscience. “That suggests that microglia might be a good target for future drugs that prevent or treat autism spectrum disorders.”

Science, August 2020

Unleashing the immune system’s ‘STING’ against cancer SCIENTISTS AT SCRIPPS RESEARCH AND CALIBR, the institute’s drug discovery arm, have found and optimized a molecule that can activate a natural immune-boosting protein called STING to help patients fight cancer. Their work—which exemplifies the interplay between Calibr and the basic science that makes Scripps Research a renowned center of innovation—marks a key advance in the field of oncology, as the STING protein is known for its strong antitumor properties. The STING protein marshals the immune system against viral and cancerous invaders. However, its natural activators in the body are unstable molecules that don’t last long in the bloodstream. That has prompted a search for a hardier molecule—one that can circulate in the blood and work systematically against tumors, wherever they may be. The scientists characterized a set of small molecules discovered and developed at Calibr, and extensively studied in the Scripps Research labs of Luke Lairson, PhD, and John Teijaro, PhD. The Calibr team, led by Mike Petrassi, PhD, vice president of Medicinal Chemistry, then created a drug candidate that, when given to mice, greatly reduced growth of an aggressive melanoma. “A systemic STING-activating molecule could have considerable utility—not only as a therapeutic for cancer and infectious diseases, but also as a means to study STING-dependent antitumor immunity and a host of related biological processes,” says Lairson, associate professor in the Department of Chemistry.

STING, short for stimulator of interferon genes, plays a key role in activating the body’s innate immune system — our first line of defense against threats such as cancer, viruses and bacteria. A drug that can activate STING may be able to treat cancer on its own or in combination with other therapies.

eLife, February 2020

Implications for diabetes, longevity: Insulin signaling suppressed by decoys INSULIN IS A HORMONE of ancient and fundamental importance. It acts as a signal to key cells, directing them to pull in glucose from the blood so they can maintain energy and keep blood sugar within a safe range. Yet the precise causes of the insulin resistance that underlies diabetes—and is seen to some extent with normal aging—have never been fully illuminated. That’s what makes a new discovery from scientists at Scripps Research so remarkable. Their study, involving the roundworm C. elegans, reveals that a “decoy” receptor known as DAF2B is at work binding to insulin molecules and keeping them from sending signals for increased insulin production. The decoy receptor contains the usual binding site for insulin. But once it

binds, it didn’t act as a standard receptor would. “Producing these decoys appears to be a way to modulate insulin signaling,” says Matthew Gill, PhD, associate professor in the Department of Molecular Medicine and lead author of the study. Notably, overproduction of the decoy receptor increased the lifespan of roundworms. The scientists are now assessing whether a similar decoy exists in humans. If it does, the discovery suggests a new way of thinking about diabetes and aging. “You can imagine that in the prime of life, expression of DAF-2B is tightly regulated, but due to disease or aging it becomes dysregulated and leads to insulin resistance,” Gill says.

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BETTER MEDICINE

DISCOVERIES

Proceedings of the National Academies of Sciences, May 2020

Solving the 175-year-old medical mystery of anesthesia Ether’s ability to induce loss of consciousness was first demonstrated on a tumor patient at Massachusetts General Hospital in Boston in 1846, within a surgical theater that later became known as “the Ether Dome.” So consequential was the procedure that it was captured in a famous painting, “First Operation Under Ether,” by Robert C. Hinckley.

WITHOUT GENERAL ANESTHESIA, many life-saving

surgeries would be inconceivable. So, it may come as a surprise that despite its 175-year history of medical use, doctors and scientists have been unable to explain how anesthesia temporarily renders a person unconscious. A new study from Scripps Research solves the puzzle. Using sophisticated microscopy, along with clever experiments in living cells and fruit flies, scientists showed how lipid clusters in cell membranes become disorganized when exposed to anesthesia, releasing signals that result in loss of consciousness. “This is the granddaddy of medical mysteries,” says chemist Richard Lerner, MD, who made the discovery with molecular biologist Scott Hansen, PhD. “When I was in medical school at Stanford, this was the one problem I wanted to solve.” The experiments show that when lipid clusters become disordered after exposure to anesthesia,

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they release an enzyme known as PLD2 that causes further disruption as it disperses. This touches off events that freeze neurons’ ability to fire. Many other scientists, through a century of experimentation, had sought the same answers but lacked key elements. First, they didn’t have microscopes that could visualize biology smaller than the diffraction limits of light. Second, they weren’t privy to recent insights about the nature of cell membranes and the complex organization and function of the rich variety of lipid complexes that comprise them. Lerner and Hansen used a Nobel Prize-winning microscopic technology called dSTORM to view cells bathed in chloroform. The cells’ lipid clusters rapidly shifted from “a tightly packed ball to a disrupted mess,” Hansen says. The discoveries raise a host of tantalizing new possibilities that may explain other mysteries of the brain, including the molecular events that lead us to fall asleep.

Science Advances, May 2020

The main culprit for dyskinesia in Parkinson’s patients DOPAMINE REPLACEMENT THERAPY makes Parkinson’s symptoms much better at first, but eventually gives way to uncontrollable, jerky body movements called dyskinesia. The reason for this unwanted side effect has been unknown until now. An international collaboration led by Scripps Research found a key cause—and with it, a potential new route to providing relief. The new research shows that dopamine replacement therapy boosts production of a protein known by the unwieldy name “Ras-guanine nucleotide-releasing factor 1,” or RasGRP1. This uptick leads to other effects that cause the involuntary movements, says Srinivasa Subramaniam, PhD, associate professor of neuroscience at Scripps Research, Florida. Dyskinesia is different than tremor. While tremor is rhythmic and tends to focus around one joint, dyskinesia can look like fidgeting, writhing, wriggling, head bobbing or body swaying, and it can’t be suppressed by movement. After a decade, about 95 percent of Parkinson’s patients will experience some degree of dyskinesia. The collaboration found that using a drug to block the production of RasGRP1 in the brain diminished the involuntary movements without negating the useful effects of the dopamine therapy. Experiments were conducted in mice and more studies are needed, but the results are promising. “Parkinson’s patients describe treatment-induced dyskinesia as one of the most debilitating features of their illness,” Subramaniam says. “This represents an important step toward better options.”

substantia nigra Dopamine is a neurotransmitter and hormone that plays a key role in movement, learning, memory, motivation and emotion. Parkinson’s develops when dopamine-producing neurons in a part of the brain called the substantia nigra stop working or die. This brain region is associated with both movement and reward, so its impairment causes a wide variety of symptoms, including stiffness, balance problems, walking difficulty, tremor, depression and memory issues. Doctors treat Parkinson’s with dopamine replacement therapy, often a medicine called levodopa. The brain converts levodopa into dopamine, and at proper doses, this leads to resolution of symptoms. But as dose and duration grow, a side effect called dyskinesia can develop.

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BETTER MEDICINE

DISCOVERIES Molecular Psychiatry, May 2020

In human mini-brain experiments, drug preserves and rebuilds nerve connections that are lost to Alzheimer’s The drug is also being evaluated for COVID-19, as it is known to inhibit viral activity and possibly protect the brain from virus-related damage. AN EXPERIMENTAL DRUG for Alzheimer’s developed at Scripps Research protects brain synapses that are typically destroyed in patients with the neurodegenerative disease. The study was conducted in mice and with human “mini-brains,” which are created using skin cells from people with Alzheimer’s. And in an interesting twist, the drug is separately being explored for its potential to help fight key symptoms of COVID-19—a project for which the drug’s inventor, Scripps Research Professor Stuart Lipton, MD, PhD, has won funding from the California Institute for Regenerative Medicine and the National Institutes of Health. The drug, patented under the name NitroSynapsin, combines two FDA-approved medicines that, working together, may halt seizure-like electrical activity that occurs in the brain of those who have Alzheimer’s. This activity contributes to the loss of brain synapses—the connections between nerve cells that are critical for memory and other brain functions. Lipton and his team showed the drug not only prevents the loss of human brain synapses but promotes the regrowth of lost synapses. “The human context is significant, as experimental drugs for Alzheimer’s and other progressive brain diseases have an unfortunate track record of working well in mice but failing in people,” says Lipton, who is also a practicing clinical neurologist. “Interestingly, our findings suggest that it may be possible not only to intercede earlier, but also later, when synapses are already damaged.”

Nature Chemistry, February 2020

Opening a new realm: Chemistry technique acts as ‘warp drive’ for creating better synthetic molecules for medicine IN A STUDY WITH implications for the future of drug discovery, Scripps Research scientists showed they were able to turn simple chemicals into unique 3-D structures resembling those found in nature, which are desirable for drug development. “We were able to start with flat molecules and use a single chemical operation to create much more complex shapes, such as those you would expect from medicinal plants or marine organisms,” says Ryan Shenvi, PhD, Scripps Research chemistry professor and senior author of the study. In the field of drug discovery, compounds made by nature are thought to have some advantages over synthetic molecules.

SCRIPPS RESEARCH MAGAZINE | FALL 2020

Much of it has to do with their shape: so-called “natural products” tend to have complex, spherical 3-D structures that bind more precisely with molecules in the body, providing favorable drug attributes such as fewer side effects. Synthetic molecules, on the other hand, are typically flat, simple structures that are more likely to interact with other molecules in the body. Initial experiments showed that the new technique has the same effect on many different types of flat synthetic molecules, transforming them into desirable 3-D shapes that look like they could have been produced by a living cell.

Shenvi likens the reaction to “warp drive” in the TV series “Star Trek,” which enabled interstellar travelers to reach new frontiers of space faster than ever before. However, this chemical warp drive allows the researchers to explore distant regions of chemical space. Already, the approach has turned up one potential new drug lead: a compound that inhibits the expression of a protein known to play a role in autoimmune diseases. “We are now taking a step back to carefully analyze the chemistry and see if we can expand this kind of result to other areas,” Shenvi says.

Nature Chemical Biology, June 2020

New drug discovery method leads to potential treatment for obesity, diabetes MANY EXISTING DRUGS, from aspirin to common cancer therapies, work by hampering the activity of certain enzymes in the body. But scientists at Scripps Research have now found a way to identify drugs that work in the opposite way: by activating enzymes. Enzymes are vital molecules in the body that bring about chemical reactions in cells; they play an important role in digestion and metabolism. The scientists demonstrated their new technique by identifying an enzyme activator that reverses diabetes-like signs in obese mice. “We can now apply this technique to a variety of enzyme classes to find compounds with therapeutic effects,” says Enrique Saez, PhD, an associate professor in the Department of Molecular Medicine at Scripps Research. The new technique builds on a versatile method called “activitybased protein profiling” developed in the Scripps Research lab of Benjamin Cravatt, PhD. The team chose to test the new method by investigating a mysterious enzyme implicated in metabolism.

This enzyme, called LYPLAL1, has a largely unknown role in biology. However, studies have suggested it may drive metabolic disorders such as type 2 diabetes, high cholesterol and fatty liver disease. Still, scientists have not known whether such risks are due to a gene that boosts the enzyme’s activity or constrains it. Using their new method, scientists screened a collection of 16,000 chemical compounds to see if any could activate the enzyme—and to their surprise, found many. From these, they developed a potent activator that markedly improved insulin sensitivity and other symptoms in a mouse model of obesity-driven diabetes. The team continues to evaluate the compound as a potential drug while also applying their technique to other types of enzymes, with the potential to impact dozens of other diseases.

Proceedings of the National Academy of Sciences, June 2020

Promising drug target emerges for Huntington’s disease FAMILIES AFFLICTED BY HUNTINGTON’S disease face anguishing challenges. With symptoms that usually appear after age 30, parents often pass the Huntington’s gene to their children—even grandchildren—before they discover they are carriers. At least 30,000 people in the United States live with the diagnosis. “So far there has been no effective therapy for the disease because we haven’t yet understood the molecular mechanism, even though we know the faulty gene,” says neuroscientist Srinivasa Subramaniam, PhD. A recent study from Subramaniam and his team provides new insights into the events that lead to destruction of brain cells in Huntington’s. They reveal a central role for a damage-sensing enzyme called cGAS that seems to ignite a cascade of inflammation and excessive cellular housekeeping, a process called autophagy. Both inflammation and autophagy have been suspected of contributing to the neuronal destruction that underlies the disease. The findings raise the possibility that reducing cGAS activity in the brain may be worth testing as a possible therapeutic approach. “We hope this new study brings us closer to an understanding of the mechanism and eventual development of such a treatment,” says Subramaniam, who has been doing Huntington’s research for 15 years.

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BETTER MEDICINE

DISCOVERIES

Cancer Research, May 2020

Tumor cells grow when crowded, revealing a nuanced role for known cancer gene Like commuters on a crowded train, cells generally prefer not to be packed in too tightly. In fact, they have set up a mechanism to avoid this — a phenomenon called “contact inhibition.”

Arteriosclerosis, Thrombosis, and Vascular Biology, April 2020

Muscle protein abundant in the heart plays key role in blood clotting during heart attack

LIKE COMMUTERS ON a crowded train, cells generally prefer not to be packed in too tightly. They even have a way to avoid this— a mechanism called “contact inhibition.” But cancer cells lack contact inhibition, and instead they become pushy, allowing them to spread. A new study from the lab of Joseph Kissil, PhD, professor of Molecular Medicine, provides important new insights into this bad cell behavior. He and his colleagues explain how the “stop-growth” signal normally unfurls during cell-to-cell contact, and why disruption of that signal can promote cancer.

A key player is a protein called YAP, which alerts cells when they should start or stop growing, such as when they become too crowded. When this signal is blocked, the cells don’t get the message. Previously, cancer researchers understood that the YAP protein was responsible for promoting cell growth. But they didn’t realize it was also working to stop growth. The discovery of YAP’s dual role will drive efforts to make new and better cancer drugs. “When we target YAP in cancer, we are targeting its function as an activator of cancer, but we now know we also need to consider its suppressive functions, as well,” Kissil says.

A PREVALENT HEART PROTEIN known as cardiac myosin, which is released into the body during a heart attack, causes blood to thicken or clot—worsening damage to heart tissue, a new study shows. “No one had suspected it was acting in this way,” says John Griffin, PhD, a professor in the Department of Molecular Medicine who led the research. “Our findings show there’s another potentially very important factor influencing the health outcomes of people with cardiac disease.” Though blood clotting is the root cause of heart attack and stroke, scientists didn’t know until now that cardiac myosin had a role in that process. The protein’s primary job is to provide the muscle-motor action that pumps blood. Coagulants must strike the right balance between stopping bleeding and preventing excessive clotting, which happens in conditions such as deep vein thrombosis or stroke. The team is now working to create a drug that would target the procoagulant activity of cardiac myosin to reduce tissue damage from a heart attack. Anticoagulant drugs already exist, but they can cause excessive bleeding or other side effects because they act on the entire body’s coagulation system, not just the heart. Griffin envisions a medicine that targets only cardiac myosin-driven coagulation. Such a drug could theoretically be administered to patients in the hospital immediately after an acute cardiac event.

SCRIPPS RESEARCH MAGAZINE | FALL 2020

Several genes are known for contributing to multidrug resistance in cancer, but the most prominent of these is called MDR1, short for “multidrug resistance-1.” Its discovery more than three decades ago set off a race to develop drugs that would thwart the gene’s effects. Yet those drugs have consistently disappointed in clinical trials, for reasons that have been poorly understood.

Journal of Experimental Medicine, April 2020

Treating cancer drug resistance may come at a dire cost to the immune system SOONER OR LATER, most cancer patients develop resistance to the drugs designed to kill their cancer, forcing oncologists to seek alternatives. Even more problematic, once a patient’s tumor is resistant to one type of chemotherapy, it is much more likely to be resistant to others—a conundrum long known as multidrug resistance. Once patients reach this point, the prognosis is often grim. That’s why,

for the past 35 years, scientists have attempted to overcome this problem using experimental medicines. However, a new study from scientists at Scripps Research raises red flags about this strategy. They say that blocking the key gene involved in cancer drug resistance has unintended side effects on important immune system cells and could increase a patient’s vulnerability to infection.

In the new study, scientists suggest that repeated failures may be due to the gene’s previously unrecognized role in immune cells that fight infections and cancer. Drugs that block the gene may set off a chain reaction that ultimately disables these immune cells. Blocking the gene could also cripple natural immune responses to cancers, says Mark Sundrud, PhD, associate professor of Immunology and Microbiology. These insights are all the more pertinent today, given the questions and concerns related to immunity against the coronavirus that causes COVID-19, he notes. The team is now exploring ways to redesign existing MDR1-blocking drugs so they only take effect in tumors: “This way, you might be able to prevent multidrug resistance in cancer cells, without affecting the immune cells that are trying to fight off the tumor,” Sundrud says.

SCRIPPS.EDU

Translations A victory for MS patients Ozanimod, a drug invented at Scripps Research, wins market approval in U .S. and Europe for multiple sclerosis. The oral medicine also produced strong clinical trial data for ulcerative colitis, a form of inflammatory bowel disease. It’s been an exciting nine months for the

In releasing the results of its pivotal phase

Scripps Research scientists who, nearly

3 trial—which involved more than 900

20 years ago, began making a series of

patients with ulcerative colitis—Bristol Myers

key discoveries that led to a new type of

Squibb said the study produced “highly

immune-regulating drug.

statistically significant” outcomes.

That drug, known as ozanimod, won FDA

“Results like this are gratifying to see,” Rosen

approval in March to treat adults with

says. “Based on the outcome of this pivotal

relapsing multiple sclerosis—the most

trial, I am confident this approach will make a

common form of the disease. Less than

real difference for patients.”

two months later, the European Union’s drug agency followed suit.

Ozanimod is also in late-stage clinical trials for Crohn’s disease, another type of inflammatory

Hugh Rosen, MD, PhD, who invented

bowel disease. While ulcerative colitis affects

ozanimod along with fellow Scripps Research

the colon and rectum, Crohn’s disease may

professor Edward Roberts, PhD, and their

act on any part of the gastrointestinal tract

laboratory colleagues, called the back-to-

and also affect the entire thickness of the

back approvals “a celebratory milestone for

bowel wall.

the multiple sclerosis community, which is in need of new, intelligent drug interventions

Though multiple sclerosis is a vastly different

to help patients control the progression of

condition than ulcerative colitis or Crohn’s,

their disease.”

all three are a result of an overreactive immune system. Ozanimod works by acting

Multiple sclerosis affects nearly 1 million

on certain types of immune cells called

people in the United States and roughly

lymphocytes that are centrally involved in

700,000 in Europe. With the approvals,

autoimmune attacks.

Bristol Myers Squibb could officially begin

“There are hardly any other academic institutions in the world that have the multidisciplinary expertise to discover a new disease-modifying compound and generate clinical data in support of its development.” —Hugh Rosen, MD, PhD

SCRIPPS RESEARCH MAGAZINE | FALL 2020

marketing the drug, which is sold under the

In multiple sclerosis, the immune system

trade name Zeposia.

mistakenly attacks the myelin sheath, the protective layer that surrounds nerves in the

But the favorable news didn’t end there.

brain. This disrupts the flow of information

In early June, the drug hit yet another major

within the brain and between the brain and

milestone, demonstrating a clear benefit

body, bringing about symptoms that can

for patients with moderate-to-severe

range from numbness and bladder issues

ulcerative colitis. Ulcerative colitis, a chronic

to vision problems and muscle paralysis.

disease of the large intestine, is part of a group of conditions known as inflammatory

In Crohn’s disease, the autoimmune attack

bowel diseases.

occurs in the intestine, leading to symptoms

FDA-approved drugs that arose from Scripps Research labs:

Visit the Scripps Research YouTube channel to watch Hugh Rosen tell the story of ozanimod, which recently gained FDA approval.

that can include abdominal pain, bowel urgency, diarrhea and blood in the stool. The fundamental discoveries that led to ozanimod were reported by Rosen, Roberts and their colleagues in a series of papers from 2002 to 2008. In 2009, Scripps Research licensed ozanimod to biotechnology startup Receptos, which Celgene purchased

Zeposia®

is a once-daily oral medicine for patients with r elapsing forms of multiple sclerosis

Vyndaqel®

treats a debilitating, often fatal heart disease caused by protein build-up

Surfaxin®

prevents respiratory distress syndrome in premature infants and injured adults

Humira®

is prescribed worldwide to treat arthritis and other autoimmune conditions

Benlysta®

debuted in 2011 as the first new lupus therapy in 50 years

Leustatin®

cures or offers a lifetime of remission for patients with hairy cell leukemia

Cyramza®

treats advanced gastric cancer and metastatic, non-small cell lung cancer

Monoclate®

based on the discovery of Purified Factor VIII, allows patients with hemophilia to lead practically normal lives

ABthrax™

is a first-in-class treatment for inhalation anthrax

Unituxin®

is used in combination with chemotherapy to treat pediatric patients with neuroblastoma, a rare brain cancer

in 2015 for $7.3 billion. Celgene was acquired by Bristol Myers Squibb in 2019. The ozanimod approval for multiple sclerosis is the latest in a string of FDA-approved drugs to originate from Scripps Research’s laboratories, following on the most recent approval of tafamidis for the rare but often fatal heart disease known as ATTR-CM. Scripps Research also invented drugs that have been brought to market to treat more than a dozen other conditions with major unmet medical needs, including arthritis, lupus, respiratory distress syndrome, gastric cancer, metastatic non-small cell lung cancer, hemophilia, anthrax inhalation and neuroblastoma. Additional drugs are in development for more than 10 other conditions, ranging from osteoarthritis to Parkinson’s disease, with several in clinical trials.

SCRIPPS.EDU

IN MEMORIAM

Star immunologist and mentor Wendy Havran Wendy Havran, PhD, a longtime Scripps Research professor whose groundbreaking immunology research revealed important mechanisms involved in wound healing, died on January 20 due to complications following a heart attack. She was 64. “Wendy not only made significant contributions to the field of immunology and wound healing, but she inspired countless Scripps Research graduate students and postdocs through her enthusiastic mentorship spanning nearly three decades,” says Jamie Williamson, PhD, executive vice president of Research and Academic Affairs at Scripps Research. Havran, who also served as associate dean of the Skaggs Graduate School of Chemical and Biological Sciences, joined Scripps Research in 1991 after winning a prestigious Lucille P. Markey Scholar in Biomedical Science grant. She was a pioneer in the field of gamma-delta T cells—immune cells that play a key role in wound healing—resulting in several major discoveries that she and her colleagues were working to translate into medical treatments for the skin and intestines. For all of her acclaim as an immunologist, Havran also was highly noted for her ability to train the next generation of scientists and teach them how to become effective mentors in their own right. In 2002, she founded Scripps Research’s Summer Immunology Internship Program for undergraduates and directed the program from 2004 to 2006. She was named the 2018 Outstanding Mentor by the Society of Fellows, a postdoctoral organization at Scripps Research, with two dozen letters of support from current and former trainees. “Mentoring is one of the best parts of the job,” Havran said when receiving the award. Havran held a doctorate in immunology from the University of Chicago, where she published the first of many papers that would appear in the prestigious journal Nature. Throughout her remarkable career, Havran often disrupted prevailing theories for how the immune system worked to heal the body. For example, prior to a key study she published in Nature in 1990, dermatologists were convinced that there were no T cells in the skin. She proved otherwise. Havran also served as adjunct professor of dermatology for UC San Diego and was a member of the American Association of Immunologists, which named her a 2019 Distinguished Fellow.

SCRIPPS RESEARCH MAGAZINE | FALL 2020

NOTEWORTHY

Life science visionaries join Board of Overseers Scripps Research has appointed six new members to its Board of Overseers, bringing additional strength to an influential body of leaders in biotechnology, pharmaceuticals, academia, law, science policy and investment.

The Board of Overseers, established in 2018 by Scripps Research’s President and CEO Peter Schultz, PhD, amplifies the institute’s advisory network and provides support for philanthropic efforts that ensure critical research is pursued to its fullest extent. The newest members of the Board of Overseers are: Stacy Kellner Rosenberg, retired attorney, noted philanthropist and former nonprofit leader who is an ardent supporter of science. John Hood, PhD, a former research fellow at Scripps Research who has founded or cofounded multiple innovative life science companies including Endeavor Biomedicines, Impact Biomedicines and Samumed. Nate Dalton, founder of Daybreak Partners, an investment firm focused on the intersection of healthcare and technology; he is also cofounder and former CEO of global asset management company Affiliated Managers Group, where he now serves as senior advisor. Brian Dovey, a partner at life science venture capital firm Domain Associates, where he has served on the board of more than 35 companies and has been chairman of six. Sandford (Sandy) Smith, former executive vice president of Genzyme, CEO of two biopharma companies and a board member of multiple publicly traded biotech companies, where he focuses on commercial strategy. Isy Goldwasser, who transitions from the Board of Directors into a new role as Scripps Research’s inaugural Entrepreneur-in-Residence. Goldwasser is an investor, as well as a cofounder and CEO at biotech companies including Thync and Symyx Technologies. “More than ever, the world needs innovative science—and a framework that enables great science to be translated efficiently into life-saving medicines,” Schultz says.

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NOTEWORTHY

Skaggs Graduate School gains 10-year accreditation The Skaggs Graduate School of Chemical and Biological Sciences at Scripps Research has been accredited for a period of 10 years—the longest period that can be extended to a degree-granting institution—by the Western Association of Schools and Colleges’ Senior College and University Commission. Following site visits and a detailed, bicoastal institutional review, the commission commended Scripps Research for its clear vision, its widespread faculty involvement in all aspects of the graduate program, and its commitment to increasing diversity across the organization. Also lauded was the graduate school’s data-driven approach to understanding and adapting to student needs. “Our successful doctoral program reaccreditation reflects brightly on the entire Scripps Research community,” says Philip Dawson, PhD, dean of Graduate and Postdoctoral Studies and professor of Chemistry. “While these accolades are well deserved, our efforts to evolve and refine our graduate program are an ongoing commitment. I look forward to continued innovations that will ensure the Skaggs Graduate School of Chemical and Biological Sciences remains a leader in graduate education.”

Scripps Research receives highest-possible charity rating

SCRIPPS RESEARCH MAGAZINE | FALL 2020

Following a qualitative review of dozens of

in its cause. This rating was awarded by

performance metrics valued by charitable

Charity Navigator, the nation’s largest and

givers, Scripps Research has once again

most-utilized evaluator of charities and

been awarded an “exceptional” rating of

nonprofits. Only a quarter of charities rated

four stars, indicating it exceeds industry

by Charity Navigator receive the distinction

standards and outperforms most charities

of a four-star rating.

Scripps Research initiative to accelerate diversity and inclusion efforts

The life-changing science of Scripps Research benefits tremendously from the creativity, passion and perspective of people from many different backgrounds. In June, the institute announced the launch of the STEM Diversity

engaging science lessons and demonstrations to public elementary

and Inclusion Initiative to accelerate the institute’s efforts to

school students. Through this connection with K-6 students in the

increase representation within the institute and expand its

local community, the institute hopes to inspire more children from

community outreach programs.

all backgrounds to pursue science as a career.

“We will start by listening and taking a hard look at what has worked

In past years, Scripps Research has launched several ongoing

in the past and what hasn’t,” says Karen Hagenmiller, vice president

diversity and inclusion efforts including internships and educational

of Human Resources at Scripps Research. “We must do our utmost

programs for students, as well as efforts to increase the diversity of

to foster an environment that is supportive and welcoming to

the institute’s faculty, graduate students and postdoctoral researchers.

everyone who has a passion for science.”

The newly launched STEM Diversity and Inclusion Initiative will build on these existing efforts by creating a comprehensive

One initiative already taking shape is the STEM Inspiration program,

strategy and identifying further actions that the institute can take

which will organize and train Scripps Research scientists to provide

to tackle this important challenge.

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Awards&Honors SKAGGS GRADUATE SCHOOL OF CHEMICAL AND BIOLOGICAL SCIENCES

Scripps Research awards doctoral degrees to class of 2020, celebrates graduates’ diverse scientific accomplishments Scripps Research in June awarded doctoral degrees to 44 graduate students who completed the rigorous academic and research requirements of the institute’s Skaggs Graduate School of Chemical and Biological Sciences. The degree recipients comprise the 28th graduating class of Scripps Research’s graduate program. In lieu of the traditional annual commencement ceremony on the La Jolla campus, a virtual celebration for the class of 2020 was held on July 31, in consideration of public health restrictions imposed in response to the ongoing COVID-19 pandemic. “We congratulate all of our 2020 graduates on their spectacular journey at Scripps Research, where each of them contributed their boundless energy and passion to expand scientific knowledge and ultimately, improve human health,” said Phil Dawson, PhD, dean of Graduate and Postdoctoral Studies at Scripps Research, and a professor in the Department of Chemistry. “Even though we are unable to celebrate our graduates in person this year, it’s gratifying to know that so many of these outstanding young scientists are already hard at work investigating potential causes of and treatments for COVID-19 and other diseases.” Ranked among the top 10 doctoral programs of its kind in the nation by U.S. News & World Report, the Skaggs Graduate School of Chemical and Biological Sciences at Scripps Research offers training in chemistry, chemical biology, neuroscience, immunology, cell biology and other biomedical research areas. The program immerses students in intensive laboratory research while offering a customizable course curriculum that allows students to match individual research interests while exploring multidisciplinary topics at the interface of chemistry and biology.

SCRIPPS RESEARCH MAGAZINE | FALL 2020

Skaggs Graduate School of Chemical and Biological Sciences 2020 Graduating Class

Scripps Research President and CEO Peter Schultz, PhD, dons regalia to congratulate graduates during the virtual commencement ceremony.

Gabriel Brighty Jacob Bruggemann Mei Lan Chen Yanqiao Chen Wesley Cochrane Matthew Costales Christopher Cottrell Robert Demoret Yisong Deng Joseph Derosa Vivian Dien Chad Dufaud Emil Fischer Samantha Green David Hill Taka-Aki Ichu Margarete Johnson Yuzuru Kanda Murat Kilinc Liam King Tong Shu Li Gencheng Li Zhen Liu Michael Mayers Joseph McGraw Bartek Nogal Hojoon Park Ryan Paxman Colby Sandate Sergey Shnitkind Vyom Shukla Sierra Simpson Keita Tanaka Ryan Thompson Megan Vaughan Pritha Verma Mengyu Wu Yao Xiao Janice Xu Ke Yang Anzhi Yao Ai Zhang Yorke Zhang Qinheng Zheng

SCRIPPS.EDU

Multiple honors for chemist Keary Engle Assistant Professor Keary Engle, PhD, in the Department of Chemistry, has received many awards related to his development of efficient and sustainable methods of creating new compounds for medicines, research and agriculture. Among these honors are the Novartis 2019 Early Career Award, the Amgen 2020 Young Investigator Award and the Eli Lilly and Co. 2020 Organic Chemistry Award. Engle also was named a 2020 Cottrell Scholar by the Research Corporation for Science Advancement, becoming the first person from an institution without an undergraduate component to win the award for teacher-scholars. Additionally, Engle won the Office of Naval Research 2020 Young Investigator Award; he and his team will use their catalytic chemistry skillset to help the Office of Naval Research create energetic materials.

Ardem Patapoutian wins 2020 Kavli Prize and is elected to American Academy of Arts and Sciences Neurobiologist Ardem Patapoutian, PhD, is the first Scripps Research scientist to be awarded the Kavli Prize, a prestigious distinction presented by The Norwegian Academy of Science and Letters, The Norwegian Ministry of Education and Research and The Kavli Foundation. Patapoutian shares the neuroscience award with cowinner David Julius, PhD, of University of California, San Francisco. Patapoutian has catapulted scientific understanding of sensory transductionâ&#x20AC;&#x201D;the methods by which the body responds to sensory input from the eyes, tongue, nose and skin. He also has been elected to the American Academy of Arts and Sciences. Members of the academy represent the most innovative thinkers in nearly every field and profession, including more than 250 Nobel and Pulitzer Prize winners.

SCRIPPS RESEARCH MAGAZINE | FALL 2020

Awards&Honors EXCELLENCE IN ALCOHOLISM RESEARCH

Cindy Ehlers, PhD, professor in the Department of Neuroscience, received the Henri Begleiter Excellence in Research Award from the Research Society on Alcoholism. Ehlers focuses on understanding genetic risk and protective factors for alcoholism in Native, African and Hispanic Americans.

PRIZE FOR CREATIVITY IN ORGANIC SYNTHESIS

The pharmaceutical company Janssen has awarded its 2020 Prize for Creativity in Organic Synthesis to Phil Baran, PhD, professor in the Department of Chemistry. The prestigious prize is awarded every other year to a chemist under the age of 50. Jury members acknowledged Baran for “the innovative solutions he develops, the speed at which he successfully accomplishes these transformations and the industry-wide applicability of his approach.”

GERMAN NATIONAL ACADEMY OF SCIENCES LEOPOLDINA

Donna Blackmond, PhD, professor and chair of the Department of Chemistry on the California campus, has been elected to the prestigious German National Academy of Sciences Leopoldina. The Leopoldina was founded in 1652, making it the oldest continuously existing academy of natural sciences and medicine in the world. Members have included Marie Curie, Charles Darwin, Albert Einstein and Max Planck, among many other notable scientists.

GENETIC ENGINEERING TECHNOLOGIES FOR HIV CURE RESEARCH AWARD

Virologist Michael Farzan, PhD, professor and co-chair of the Department of Immunology and Microbiology, has been awarded a significant U19 research grant by the National Institute of Allergy and Infectious Diseases, in tandem with the National Institute of Mental Health. The grant will support multiple research projects that will enable a unifying strategy for using genetic engineering technologies to achieve long-term HIV remission.

OUTSTANDING ACHIEVEMENT IN CHEMISTRY IN CANCER RESEARCH

Chemical biologist Benjamin Cravatt, PhD, has been recognized by the American Association for Cancer Research for his pioneering work to enable the analysis of protein activities—work that has revealed key signaling pathways in cancer.

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Awards&Honors

BREAKTHROUGH SCIENCE INITIATIVE AWARD

Michael Erb, PhD, assistant professor in the Department of Chemistry, has been granted the highly competitive Breakthrough Science Initiative Award from the Ono Pharma Foundation. The three-year grant will support Erbâ&#x20AC;&#x2122;s creative approaches to pinpointing vulnerabilities in cancers such as acute myeloid leukemia.

NINDS AWARD

Chemistry Professor Matthew Disney, PhD, has been awarded a prestigious Research Program Award by the National Institute of Neurological Disorders and Stroke (NINDS) to aid Disney's development of potential breakthrough treatments for neurological diseases such as Alzheimer's, Parkinson's and ALS. The NINDS award lasts for five years and is extendable for up to eight.

SCRIPPS RESEARCH MAGAZINE | FALL 2020

CAREER AWARD

The National Science Foundation awarded Hans Renata, PhD, assistant professor in the Department of Chemistry, the renowned CAREER award. The award supports early-career faculty who have the potential to serve as academic role models and lead major advances at their organization. Renataâ&#x20AC;&#x2122;s lab works to develop new reaction routes for important chemical building blocks that are traditionally difficult to create.

FLORIDA CENTER FOR BRAIN TUMOR RESEARCH

Michalina Janiszewska, PhD, an assistant professor in the Department of Molecular Medicine, has received an award from the Florida Center for Brain Tumor Research (FCBTR), which supports proposals that could to lead to the discovery and development of improved brain tumor treatment modalities. Janiszewskaâ&#x20AC;&#x2122;s project centers on understanding the biological factors that cause such diversity in the pathology and progression of glioblastoma.

PREDOCTORAL FELLOWSHIP

Graduate student John Martin Gabriel Sabandal has been awarded an F31 Predoctoral Fellowship from the National Institute of Mental Health. Based in the laboratory of Ron Davis, PhD, professor in the Department of Neuroscience, Sabandal is investigating the neurobiological mechanisms that underlie transient forgetting.

Y O U N G INVESTIGATOR AWARD

Chemist Michael Bollong, PhD, and computational chemist Stefano Forli, PhD, have been named as recipients of the 2020 Young Investigator Award from the Donald E. and Delia B. Baxter Foundation. The program prepares and supports new investigators as they launch into their careers.

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Finding solutions. Empowering science. A once-in-a-lifetime challenge. The novel coronavirus driving the COVID-19 pandemic is presenting scientists with diverse and complex challenges. At Scripps Research, we’re confronting those challenges with expertise in diverse disciplines— epidemiology, microbiology, bioinformatics and drug development, to name a few. And we’re joining forces to more quickly detect the virus within our communities, create innovative treatments for patients with COVID-19 and work toward vaccines that can safeguard families and friends. Your life-saving opportunity. When you contribute to the COVID-19 Community Campaign at Scripps Research—be it a one-time donation or a monthly, recurring gift—you support scientific discovery focused on saving lives. Philanthropic contributions are immediately directed toward developing effective treatments and potential cures for patients with COVID-19. Your financial support also enables scientists to assemble the knowledge critical to preventing the next pandemic. We’re all in this together. Let’s confront it together. Go to give.scripps.edu or call (800) 788-4931 to learn how you can help.

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130 Scripps Way, #4B2 Jupiter, FL 33458

(858) 784-2915 philanthropy@scripps.edu

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