Fall Edition 2019

SCRIPPS RESEARCH | FALL EDITION 2019

Science Changing Life | Fall Edition 2019

Vital connections, global impact

F A L L EDI T IO N | 2 019

Scripps Research Genomic detectives

Patients before profits

Scientists travel to outbreak zones Meet Chief Medical Officer Pam around the world to improve prevention Garzone, PhD, who is ushering multiple and detection of deadly viruses. drug candidates into clinical trials.

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28

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Nature’s medicines

Empowering moms-to-be

A historic collection of microbial organisms may hold the key to countless future therapies.

A smartphone app is at the center of a plan to build the largest maternal health community and improve health outcomes.

President’s Letter 02 Discoveries 04 Translations 46 Awards/Honors/Grants 52 Events 56

Starting on page 20, read how our scientists are working with communities in Sierra Leone to understand some of the world’s most dangerous infectious diseases.

In this Issue

Science Changing Global Health

From the President

The raison d'être of science is the quest to discover—the pursuit of moments when rigorous inquiry leads to profound insight. The engine of this pursuit is a characteristic common to scientists the world over—insatiable curiosity. When I consider the many scientists I have known and admired, however, another trait strikes me as equally important. That is the desire and ability to connect what they do with the world outside of the laboratory.

In this issue of Scripps Research Magazine, you will encounter stories of scientists doing just that, engaging with people, places and problems far beyond our campuses in California and Florida.

They do this in pursuit of knowledge, certainly, but also to better the lives of people around the world. They are driven by both curiosity of mind and generosity of spirit.

You’ll read how Kristian Andersen, PhD, and his team travel to Sierra Leone to study one of the world’s most virulent diseases, Lassa fever, using advanced genomic sequencing techniques to track how the virus evolves and spreads. Their work in genomic epidemiology combines field and laboratory research to develop powerful ways to track and predict the movements of viruses such as Lassa, Zika, Ebola and West Nile.

While Kristian and his team travel to other parts of the world, Ben Shen, PhD, has brought the world to Scripps Research. Through a partnership with the pharmaceutical company Pfizer, Ben’s team has established on our Florida campus one of the world’s most comprehensive collections of microbial organisms from all over the planet. The samples were collected by scientists over 75 years and likely contain millions of unknown compounds with untold capabilities for generating new medicines.

This issue also profiles Pam Garzone, PhD, who recently joined Scripps Research as the inaugural chief medical officer at Calibr, our drug development division. As we accelerate our efforts to turn discoveries into therapies, Pam brings deep experience in translational research and clinical development to advance Calibr’s growing pipeline of drug candidates. These therapies have the potential to address unmet medical needs the world over.

Through these stories, I hope you will come to appreciate as I do, the global, interconnected nature of Scripps Research science and how those connections hold tremendous potential for helping humankind.

Peter Schultz, PhD President and CEO, Scripps Research

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Biological samples in Scripps Research’s Natural Products Discovery Center, located in Jupiter, Florida. Read more on page 30.

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DISCOVERIES Scripps Research

THAT CHANGE LIVES

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BRAIN POWER

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

For more science news, visit Scripps.edu/discoveries.

PLOS Biology, April 2019

Love chemical may help with alcohol addiction OXYTOCIN, A BRAIN PEPTIDE known for its role in love and bonding, may hold potential for treating alcohol addiction. In a study with the National Institute on Drug Abuse, scientists at Scripps Research discovered that oxytocin blocked enhanced drinking in alcohol-dependent rats, concluding that targeting the oxytocin system may be a successful pharmaceutical approach for treating alcohol-use disorder, potentially via a nasal spray. Research was led by neuroscience professor Marisa Roberto, PhD.

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BRAIN POWER

DISCOVERIES

At Scripps Research, we decode the staggering complexity of the brain to understand how it works and how to keep it healthy, and we educate the next generation of scientists to carry on this crucial work.

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eLife, April 2019

Adults with autism can be treated, too IT’S TIME TO CHALLENGE the presumption that people born with developmental brain disorders such as severe autism won’t benefit from medical interventions unless treated in infancy or early childhood. A team led by Gavin Rumbaugh, PhD, associate professor in the Department of Neuroscience at Scripps Research, studied adult mouse models of a genetic

nanotube tunnel

cause of autism called SYNGAP1 disorder and found multiple improvements in seizure and memory after genetically restoring levels of the SynGAP protein.

Journal of Cell Biology, May 2019

“Our findings in mice suggest that neurodevelopmental disorders’ disease

Brain disease spreads through nanotubes

course can be altered in adult patients,” Rumbaugh says.

SCRIPPS RESEARCH neuroscientist Srinivasa

Subramaniam, PhD, has discovered that nanotubes may contribute to the progression of Huntington’s disease. His team captured images of the toxic protein linked to Huntington’s actually traveling from neuron to neuron through the extension of nanoscale filaments between the cells. The nanotubes’ construction is initiated by a protein called Rhes. “The Rhes protein makes its own road. That is what is surprising to us,” says Subramaniam. “But it not only transports itself. Once the road is made, many things can be transported.”

Huntington’s disease patients inherit a damaged protein that is complicit in destroying brain cells. As the neurons deteriorate, people lose motor control, they can have emotional problems, and their thinking and memory suffer. This discovery may offer a new way to intervene.

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Proceedings of The National Academy of Sciences, July 2019

Exosomes may hold the answer to treating, diagnosing developmental brain disorders Exosome bioactivity illuminated: Neurons proliferated in the developing hippocampus of a mouse following an injection of neuronal exosomes.

(Cell proliferation in red.)

Her research team examined exosomes from healthy human neurons and those from a disease model of Rett syndrome, a genetically-driven developmental brain disorder that causes autism-like symptoms.

Through cellular and functional assays, they found that the Rett-affected exosomes didn’t contain any harmful proteins, but also didn’t have essential signaling proteins found in healthy exosomes. “They lacked the good stuff,” says neuroscientist Pranav Sharma, PhD, who designed the experiments.

The team used CRISPR gene editing to correct the mutation that causes Rett syndrome, and found that fixing the mutation reversed the exosome’s deficits. For this part of the study, the team relied on human neurons derived from induced pluripotent stem cells (iPSCs) from Rett patients.

They also tested whether adding healthy exosomes to a culture-dish model of Rett syndrome would provide a therapeutic effect. It did.

“That was perhaps our most exciting finding: that exosomes from healthy cells can indeed rescue neurodevelopmental deficiencies in cells with Rett syndrome. We see this as very promising

MOLECULAR “PACKAGES” called exosomes are continuously

because of the many neurodevelopmental

deployed from all cells in the body—each one brimming with an assortment of contents another cell may unpack and use. By sending off these biological parcels, cells communicate with each other via shared proteins and genetic material.

disorders in need of a treatment—disorders

Once simply thought to be microscopic sacks of cellular garbage, exosomes are now understood to hold immense importance for our health. An outflowing of research in recent years has even shown they can transport molecules linked to the spread of cancer and neurodegenerative disorders such as Alzheimer’s. Yet, until recently, their role in brain development remained a mystery.

In new research, Hollis Cline, PhD, and her colleagues at Scripps Research have begun to close that knowledge gap by showing that exosomes are not only integral to the development of neurons and neural circuits, but they can restore health to brain cells affected by developmental disease.

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for which we already have a deep understanding of the underlying gene deficiencies but are lacking a therapy.”

— Hollis Cline, PhD

Armed with their findings, Cline and her team now intend to explore a slew of new questions related to bioactivity and clinical applications: Could exosomes be measured in a blood test to detect disease or measure treatment efficacy? Do these findings also apply to autism spectrum disorders (ASDs) and other neurodevelopmental diseases, such as Fragile X? Could exosome-based therapies one day help patients with brain disorders?

“This research has huge relevance for many diseases related to brain development,” Cline says. “It’s very interesting biology that has a lot of scientists excited about the possibilities.”

DISCOVERIES BRAIN POWER

Molecular Psychiatry, June 2019

PTSD strategy targets traumatic memories Communications Biology, April 2019

A mouse model that really reflects Parkinson’s SCIENTISTS FOUND A WAY to

create a mouse model that better mimics Parkinson’s disease in humans, making it possible to screen drug candidates more reliably and investigate the root cause of the disease. The lack of effective mouse models for Parkinson’s has stymied research efforts to date. But a team led by Steven Reed, PhD, a professor in the Department of Molecular Medicine, found that by tweaking mice DNA, the mice developed Parkinson’s gradually, much like people do.

EMOTIONAL MEMORIES of trauma are the

driver of distressing PTSD symptoms. What if those symptoms could be disarmed by targeting the memory storage mechanism?

A new discovery offers a potential target.

Scripps Research neuroscientist Courtney Miller, PhD, and her team have discovered that trauma elevates a specific microRNA in an area of the brain known as the basolateral amygdala complex, where long-term memories of fear reside. Suppressing the molecule appears to enable faster recovery from trauma. The microRNA was altered in both stress-conditioned mice and in military veterans who had been diagnosed with PTSD following deployment in Afghanistan. “There are limited options for people with PTSD,” Miller says. “I’m excited about the potential of this as a therapeutic target.”

Cell Reports, May 2019

Unexplored brain circuit controls memory strength LEARNING TO AVOID negative

experiences requires an interplay of two distinct brain circuits: one to interpret “yikes!” and drive learning, and the other, unexpectedly, to dial in the strength of that memory, a new fruit fly study shows. The findings provide insights into our own, more complex brains, insights that could help us understand issues like addiction, PTSD, depression and neurodevelopmental disorders, notes Scripps Research neuroscientist Seth Tomchik, PhD, lead author of the study.

There are limited options for people with PTSD. I’m excited about the potential of this as a therapeutic target.

— Courtney Miller, PhD

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DISCOVERIES

JAMA Network Open, May 2019

Prescription drug costs steadily soar, yet price transparency is lacking AFTER REVIEWING tens of millions of

insurance claims for the country’s 49 most popular brand-name prescription drugs, a team from Scripps Research Translational Institute found that net prices rose by a median of 76 percent from January 2012 through December 2017—with most products going up once or twice per year.

Substantial price increases were not limited to drugs that recently entered the marketplace, as one might expect, or to those lacking generic equivalents.

Furthermore, the increases often were “highly correlated” with price bumps by competitors.

The team, led by Eric Topol, MD, concluded that the current rebate system, which incentivizes high list prices for drugs and relies heavily on privately-negotiated rebates to pharmacies, plays a central role in driving up costs for consumers. The byzantine and secretive rebate system, they noted, prevents consumers from making

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informed decisions about purchasing medications.

“It’s no secret that health care prices are growing exponentially in the United States, but what has been less clear is the extent to which certain prescription drugs are contributing to that trend—especially when prices are clouded by a complicated rebate system,” says lead author Nathan Wineinger, PhD, director of biostatistics at Scripps Research Translational Institute and assistant professor in Scripps Research’s Department of Integrative Structural and Computational Biology.

The Scripps Research team obtained the prescription data from a proprietary Blue Cross and Blue Shield data set known as BCBS Axis, which includes commercial insurance claims from more than 35 million Americans covered by independent Blue Cross and Blue Shield companies in the United States.

76% Median price increase for top-selling branded prescription drugs from January 2012 through December 2017.

It’s bad enough to see the relentless increase in drug prices, but this work underscores it is occurring without transparency or accountability. — Eric Topol, MD

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HIV/AIDS

DISCOVERIES

neutralizing antibodies (bnAbs). In multiple animal studies, bnAbs have been shown to provide long-lasting protection against exposure to multiple HIV strains.

The award will fund the Scripps CHAVD comprised of 26 investigators: eight principal investigators at Scripps Research and 18 principal investigators at 13 other CHAVD-affiliated scientific organizations, including projects at four foreign sites.

1 MILLION

3 research victories in race against HIV

people die of HIV/AIDS-

Scripps Research-led consortium receives $129 million NIH award to bring new HIV vaccination approach into clinical testing THE CONSORTIUM FOR HIV/AIDS

Vaccine Development (CHAVD), an international collaboration led by Scripps Research, has received a $129 million award from the National Institutes of Health to advance next-generation vaccines designed to coax the immune system into producing antibodies capable of disarming numerous strains of HIV.

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The seven-year award from NIH’s National Institute of Allergy and Infectious Diseases will support refinement and manufacturing of novel HIV vaccine candidates so that they can move into early-stage human clinical testing. The vaccines are designed to be administered in multiple stages to induce immune system proteins called broadly

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“Previous NIH support for this international collaboration allowed us to lay the scientific foundation for developing an unprecedented and highly promising approach to HIV vaccination,” says Dennis Burton, director of the Scripps CHAVD and co-chair of the Department of Immunology and Microbiology at Scripps Research. “This new award provides critical funding to refine this approach and bring it into human clinical testing.”

Despite new forms of HIV prevention, globally 1.8 million people acquired HIV in 2017 (about one person every 15 seconds) and nearly 37 million people were living with the virus, underscoring the urgency of developing a vaccine to halt the epidemic.

related illnesses each year.

Vanquishing HIV’s ‘death star’ strain with a rebel virus AMONG HIV RESEARCHERS, one seemingly

“No other vaccine, antibody or biologic protects against the two viruses for which we have demonstrated robust protection.”

— Michael Farzan, PhD

indestructible HIV-like strain has earned the nickname “death star.” That’s due to the strain’s reputation for killing off hopes for potential vaccines and immunotherapies that could prevent the disease.

A team at Scripps Research reports successfully beating that challenge by employing a harmless virus to fight the dangerous one. It relies on muscle cells rather than immune cells to generate the protective agents.

In a paper published in the journal Science Translational Medicine, lead authors Michael Farzan, PhD, and Mathew Gardner, PhD, say their research suggests it may be possible to protect uninfected individuals from multiple forms of HIV with their nontraditional vaccine.

Their unusual approach achieved another critical goal: durability. This means it protected the research animals from infection long-term, with a single inoculation, Farzan says.

“We have solved two problems that have plagued HIV vaccine studies to date—namely, the absence of duration of response and the absence of breadth of response,” Farzan says. “No other vaccine, antibody or biologic protects against the two viruses for which we have demonstrated robust protection.”

Globally, about 180,000 new HIV infections occur in children annually, according to the Joint United Nations Programme on HIV/AIDS, and about 1 million people a year die of HIV/ AIDS-related illnesses. Developing long-term protection with a single dose is an important goal, especially in places where medical resources can be scarce and the risk of motherto-infant transmission of HIV can be high.

Front to back: HIV researchers Mathew Gardner, PhD, and Christoph H. Fellinger, PhD, work closely with mentor Michael Farzan, PhD, co-chairman of the Scripps Research Department of Immunology and Microbiology

Monkey-infecting virus may provide part of future HIV vaccine A PROTEIN FROM Simian Immunodeficiency Virus (SIV), which can infect monkeys

and apes, has shown promise as a potential component of a vaccine against HIV. Chimpanzee SIV, which can cause an AIDS-like disease in the natural host, is the virus that “jumped” to humans and evolved into HIV roughly a century ago in Africa. SIV’s outer-envelope protein, Env, shares a key structure with HIV’s Env; that and other properties make SIV Env attractive as a potential component of a future vaccine against HIV infection. In a new study, published in Cell Reports, Scripps Research scientists found that inoculating mice with SIV Env proteins elicited antibodies that neutralize infection against multiple HIV strains.

“We’ve shown here that one can use shapes from chimpanzee-infecting SIV to stimulate the production of antibodies against the human-infecting HIV,” says co-senior author Dennis Burton, PhD. “It’s a simple but inspired strategy, reminiscent of the use of cowpox virus to immunize against smallpox virus over 200 years ago, and should help us in making an HIV vaccine.”

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DISCOVERIES Journal of The American Chemical Society, June 2019

An antibody may be able to prevent death from fentanyl overdoses The discovery also holds relevance in national defense, as an uber-potent form of fentanyl is considered a chemical terrorist threat

“The rise in synthetic opioid misuse and overdose has intensified the need for new and creative ways to both treat and counter the effects of these powerful drugs,” says Kim Janda, PhD, chemistry professor at Scripps Research, who led the study.

SYNTHETIC OPIOIDS—most notably, the class of drugs known

A medication known as naloxone is most commonly used today as a “rescue” treatment for those who overdose on opioids.

While naloxone generally works well in reversing heroin and prescription opioid-related overdose, it is less effective against fentanyl and especially carfentanil.

as fentanyls—have become the leading cause of drug-related deaths in recent years. This is due not only to their extreme potency and addictive properties, but because current approaches to treating overdoses fall short.

In a potentially life-saving breakthrough, scientists at Scripps Research developed experimental antibodies that block the lethal effects of synthetic opioids, preventing death.

In a rodent study, the team found that their “broadly neutralizing antibodies” worked against an array of fentanyls, including a notorious form known as “China White” and the most powerful of all fentanyls, carfentanil.

Notably, the Scripps Research antibodies have a significantly longer half-life than naloxone, remaining active in the body for more than a week, which is critical because carfentanil persists in the body and can reactivate. Under current treatment standards, individuals who overdose on fentanyl often remain hospitalized for extended periods of time, receiving multiple rounds of naloxone via infusion.

“Our proof-of-concept study gives us confidence in an antibody-based approach to block the effects of synthetic opioids, including those produced in clandestine laboratories,” Janda says.

“Antibodies may be an effective route for treating synthetic opioid overdose, either in combination with naloxone or stand-alone.”

Janda also sees potential applications in national defense. This is especially important with carfentanil, which is 100 times stronger than fentanyl and is classified as a chemical terrorist threat, he says. Although the drug has long been commercially available as a large-animal tranquilizer, it can be readily aerosolized and can be used in more sinister ways. Such was the case in a 2002 hostage crisis at a Moscow theater, which resulted in 125 deaths.

Also, because of carfentanil’s perilous potency, drug enforcement officers and drug-sniffing canines are at risk when encountering the drug, Janda says. A broadly neutralizing antibody to counter carfentanil’s effects could save lives in either scenario.

Synthetic opioids, primarily the class known as fentanyls, have surpassed prescription opioids as the most common drugs involved in overdose deaths.

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As a next step, Janda is looking to translate his lab’s recent discoveries into a human-antibody-based vaccine. Janda’s laboratory will be advancing the research in partnership with Cessation Therapeutics Inc., a San Diego-based biotech company that has licensed the technology.

Cell, May 2019

Recycling process is fundamental to life

Cells’ recycling process is linked to many diseases.

IMAGINE YOUR HOUSE if nobody

ever took out the trash. Cells require trash removal, too. Without it, they die. A new study from Claudio Joazeiro, PhD, published online in the journal Cell, uncovers how simpler organisms—bacteria and archaea—manage the recycling of incomplete proteins, the equivalent of cellular trash.

It shows that recycling is fundamental to life, says Joazeiro, who holds a joint appointment at Scripps Research in Florida. If cells’ recycling

process falters, abnormal protein fragments accumulate, potentially causing the cell’s death.

In nerve cells, this is linked to a variety of diseases, including ALS and dementia.

Bacteria have somewhat more direct systems for addressing protein fragments than animal cells do, according to the Cell report.

“Shortly after cells invented how to make proteins, they were also faced with determining how to deal

with incompletely made proteins,” Joazeiro says.

The Joazeiro team found a system that flags things for destruction so they can be broken up and eliminated from the cell.

The findings not only offer new directions for fighting dangerous pathogens, including listeria, staph and streptococcus, they have implications for our understanding of how life evolved.

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DISCOVERIES

Cell Host & Microbe, June 2019

A mutation that may lead to better egg-grown flu vaccines

ONE REASON SEASONAL flu vaccines aren’t always

He and his team looked at other known mutations

effective has to do with how they’re made.

that crop up on the same receptor site as L194P

Vaccine manufacturers typically inject the virus

and found one that doesn’t interfere with the

into chicken eggs—an affordable way to allow the

vaccine’s effectiveness.

virus to replicate, as it can’t replicate without the help of other living cells. But this method comes

Proactively adding this less-troublesome

with drawbacks.

mutation—known as G186V—prevents the problematic mutation from occurring.

“These are human viruses, and you’re growing

The ultimate goal is to improve seasonal flu vaccines so fewer

them in an avian species,” says Ian Wilson, PhD,

“These two mutations are incompatible

Hansen Professor of Structural Biology at Scripps

with each other,” says Nicholas Wu, PhD, a

Research. Putting the virus in this challenging

research associate who led the work to analyze

environment forces it to mutate to adapt and

mutations in flu vaccines. In other words,

survive. “They’re acquiring mutations in order to

whichever mutation occurred at that site first

grow better.”

was there to stay.

As the virus mutates inside eggs, it becomes

Going forward, the team hopes to screen

less like the viral strains circulating among

influenza for more mutations that occur during

the human population and less likely to prompt

the egg-based manufacturing process and better

the immune system to recognize and attack

understand how these mutations interact. The

the real virus. A mutation known as L194P is a

ultimate goal is to improve seasonal flu vaccines

particular problem.

so fewer people get sick; influenza killed about

people get sick.

80,000 people in the U.S. during the 2017-2018

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Wilson co-led a study that uncovered a possible

flu season, according to the Centers for Disease

way to prevent this mutation occurring.

Control and Prevention.

SCRIPPS RESEARCH MAGAZINE | FALL 2019

PD-1 PD-L1 Journal of Experimental Medicine, June 2019

Harnessing the power of killer T cells to build better cancer drugs SCIENTISTS AT SCRIPPS Research

have found a way to ramp up the body’s production of an especially powerful type of disease-fighting immune cell, offering a potential new avenue to more effective cancer therapies that work across larger patient populations.

New drugs known as PD-1 and PD-L1 inhibitors have become standardof-care for treating many different forms of cancer, from melanoma to bladder cancers. These socalled “checkpoint inhibitors” work by blocking proteins that would otherwise stop the immune system from attacking cancer cells.

But these groundbreaking drugs, while effective for some patients,

Patients without a sustained response of killer T cells are often unable to overcome disease.

don’t work for everyone. Those who do respond tend to have something in common: Their bodies unleash a surge of killer T cells, also called CD8+ cells, which play an important role in targeting tumors and helping the body fight back against viral infections.

However, over the course of disease, these cells can become exhausted and die off. Patients without a sustained response of killer T cells are often unable to overcome disease.

Led by John Teijaro, PhD, assistant professor in the Department of Immunology and Microbiology at Scripps Research, the researchers turned their focus to a distinct type

of self-renewing killer T cell that has a unique ability to continue responding during a persistent infection and proliferate after treatment with PD-1 checkpoint inhibitors.

Notably, scientists found that a protein called interleukin-27, or IL-27, is able to boost the body’s production of these ultra-beneficial T cells and prevent them from dying off in the face of disease.

The findings may help improve response to checkpoint blockade in human cancer patients and may also be useful in driving out persistent viruses such as HIV or hepatitis C, for which eliminating all infected cells remains a challenge.

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DISCOVERIES Science Immunology, May 2019

Natural killer cells have a hidden talent: remembering old enemies TEXTBOOKS WILL TELL you that “natural

killer” cells are short-lived, indiscriminate attackers of disease threats.

But scientists from Scripps Research found these immune cells are capable of much more: They can recall past threats, allowing them to hone their attack when the disease returns.

The discovery may allow scientists to design vaccines that train natural killer cells to target tough infectious diseases and possibly cancer.

“We found the immune system has another way of remembering prior infection or vaccination,” says Silke Paust, PhD, associate professor at Scripps Research and senior author of the new study.

Natural killer cells are a type of white blood cell traditionally thought of as part of the body’s “innate” immune system, a set of fast-responding cells that don’t remember specific pathogens. Over the last decade, however, Paust and other researchers began to suspect that these cells were more complex. Research showed that— at least in mice—natural killer cells had “immunological memory,” meaning they could more quickly target a past attacker.

Could the same hold true in humans?

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“Because so much about these cells is unknown, and so many dogmatic ideas are being challenged, there is a lot of opportunity to explore these cells in ways never done before,” says research associate Rana Nikzad, PhD, first author of the study.

The team studied human volunteers who had gotten chickenpox when they were younger. To the researchers’ surprise, the study participants’ natural killer cells remembered the virus and could specifically target the antigens even decades after infection.

Then the researchers tested how natural killer cells respond to a trickier virus: HIV. Working with a mouse model that produces many of the same cells as the human immune system, Nikzad administered a vaccine containing pieces of HIV’s outerenvelope protein. Later, the mice’s natural killer cells targeted HIV antigens and ignored other pathogens. This type of specificity was not thought possible for cells of the innate immune system.

The team now wants to study additional human samples of natural killer cells to see how they respond to other diseases and gain a more complete understanding of how their memory works.

The natural killer cells remembered the virus and could specifically target the antigens even decades after the infection.

?

Research showed that—at least in mice— natural killer white blood cells had “immunological memory.”

Could the same hold true in humans?

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Science Changing Global Health

Matthias Pauthner, PhD, opened the internet browser on his laptop and there, snaking across the screen, was the heartbeat of a 4-year-old boy.

Pauthner sat at his small lab desk in La Jolla, California, surrounded by scientists working in white lab coats. The boy lay in a hospital bed in Sierra Leone, half a world away in West Africa, surrounded by nurses dressed head-to-toe in biosafety gear. The boy had Lassa fever, a disease that kills around 80 percent of the people who contract it. He was in the hot zone, fighting for his life.

A small white patch stuck to the boy’s chest connected the scientist in America and the young patient in Sierra Leone. Paired with a smartphone in the hospital where the boy was being cared for and where he was enrolled in a study of Lassa patients, the wireless heart monitor transmitted real time electrocardiogram readings of the boy’s heartbeat to a secure internet portal accessible to

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OUTSMARTING OUTBREAKS

Genomic detectives are hot on the trail of deadly viruses Scripps Research scientists work in outbreak zones to transform disease prevention, diagnosis and treatment

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Science Changing Global Health

the doctors and research team in Sierra Leone and to Pauthner and his colleagues in California.

“We were able to record a continuous ECG reading of his heart for five consecutive days, something that isn’t even regularly done for patients in the United States,” said Pauthner, several months after the boy was admitted to the hospital. “His temperature when he was first admitted was really high, and his heart rhythm erratic. His heart stabilized the next day when his temperature came down. He lived, but it was touch and go initially.”

Pauthner is a postdoctoral researcher and part of a team of scientists at Scripps Research who study the life-and-death dance between humans and some of the world’s most dangerous viruses. Led by Kristian Andersen, PhD, an associate professor in the Department of Immunology and Microbiology at Scripps Research, the team has developed a unique system for studying pathogenic viruses, applying infectious disease genomics to track how viruses emerge and spread to cause large-scale outbreaks. They combine this deep profiling of viruses with medical data gathered from patients to look for clues to why some pathogens are more virulent and why some people are better able to survive infections.

Working with scientific collaborators around the globe, the team studies several dangerous viruses that have emerged in recent time. They include Lassa and Ebola viruses, highly lethal pathogens that cause viral hemorrhagic fevers, so named because the infection can cause blood vessels to rupture, resulting in severe internal and external bleeding.

Top: Scripps Research's Kristian Andersen working with local researcher, Mambu Momoh, in Sierra Leone.

Bottom: Electron microscope image of Lassa virus.

The Scripps Research team also focuses on Zika and West Nile, mosquitoborne viruses that were first identified in Africa but now plague other continents as well, including North America.

“We want to understand how these viruses travel so that we can improve early detection and predict how quickly a virus will spread,” says Andersen, who is also director of infectious disease genomics at Scripps Research Translational Institute. “Beyond that, our research aims to improve prevention, diagnosis and treatment of emerging viruses— whether they are known diseases or something we have yet to discover.”

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Kenema Government Hospital Field Site Sierra Leone

Lassa risk zone 2013-2016 Ebola outbreak

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Science Changing Global Health

Science in Sierra Leone The Lassa fever research program in Sierra Leone is a case study in the promise and challenges of studying emerging viruses. Kenema district was a flashpoint of the civil war that engulfed Sierra Leone from 1991 to 2002. The region is rich in alluvial diamonds, which were used to finance the brutal rebel group, the Revolutionary United Front. The war-torn country was dramatized as the backdrop for the 2006 movie Blood Diamond, which starred Leonardo DiCaprio. As the country has recovered from the long conflict that killed around 50,000 people and devastated its infrastructure, including its health systems, it has contended with multiple outbreaks of endemic disease.

Andersen and his team are part of the Viral Hemorrhagic Fever Consortium, an international collaboration of researchers studying Lassa and Ebola with the intention of reducing the number of infections and deaths caused by the viruses. The consortium conducts research with local scientists and doctors at a hospital site in Kenema, the country’s second-largest city and capital of the Eastern Province, known for having the highest incidence of Lassa in the world. People who contract Lassa and come to Kenema for treatment are admitted to the Lassa ward at the Kenema Government Hospital. The Kenema ward was also used to treat Ebola patients during the 2013-2016 Ebola epidemic in West Africa that infected 28,000 people and killed more than 10,000.

Building relationships with Sierra Leone’s government and local research staff has been critical to studying the viruses. Mambu Momoh, a medical laboratory scientific officer of Sierra Leone’s Ministry of Health and Sanitation who works at the Kenema Government Hospital Viral Hemorrhagic Laboratory, says collaborating with Scripps Research scientists has been instrumental in expanding local expertise and capacity to respond to outbreaks. He worked on the front lines of the 2013-2016 Ebola epidemic and his team diagnosed the first case in Sierra Leone using diagnostics developed and deployed by Andersen and his colleagues.

“I have always enjoyed working alongside colleagues from the United States who are not only giving financial and logistic support to our site but also expertise and mentorship,” Momoh says. “It has been very inspirational for me, and I’ve gained much more experience in

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SCRIPPS RESEARCH MAGAZINE | FALL 2019

Photos clockwise from top left: An aging electrical generator for Kenema Government Hospital; Scripps Research scientists Raphaëlle Klitting, Kristian Andersen and Matthias Pauthner; Children in Sierra Leone learning about disease prevention; Research vehicle being prepared for Sierra Leone’s sometimes rugged roads; Local research staff scientist works in the lab at Kenema Government Hospital.

molecular biology science and gotten some high-tech training to enable us, the citizens, to carry out highly specialized scientific work in our lab.”

Members of the Scripps Research team travel to Sierra Leone to work with Momoh and the other local staff on research projects. Pauthner has been to Kenema twice for field work, most recently for a month in January 2019. Many of the roads were muddy from the heavy rains and the trip from the international airport in Freetown, the country’s capital, to the Eastern Province was a rugged five-hour drive in a 4-wheel drive truck. During the trip, he stayed at a compound in Kenema maintained by the Viral Hemorrhagic Fever Consortium as a base of operations for local research staff and visiting scientists.

One of Pauthner’s tasks was to teach the nurses at the hospital to apply the heart monitor patches to Lassa patients and sync the monitors to smartphones to transmit data via the internet. The patches are a pilot study that feeds data directly to researchers in the United States. He also worked in the hospital’s Viral Hemorrhagic Laboratory processing samples, which required donning a biosafety gown, double gloves, headcover, boots and goggles. The air conditioner for the lab is notoriously unreliable.

“Once, I was suited up and the air conditioner went out,” Pauthner says.

“It got so hot I was soaked in sweat within minutes.”

Pauthner rode along on expeditions to villages in the Eastern Province where cases of Lassa had recently been reported. Lassa is transmitted from rodents to humans, typically when rats get into homes and infect food or when people eat the rodents. To prevent infections, local staff of Kenema Government Hospital travel to the villages to educate people on ways to avoid infections and unintentionally spreading viruses. Sierra Leone’s population is young, with about 42 percent under the age of 15, so the team piques their interest with popular African rap music and movies, then educates them on how to avoid infection.

The team also collected rats from the homes of people who caught Lassa to gather samples of viruses infecting the rodents. They collected blood samples from people in the villages who may have been recently exposed to infection. The blood samples are studied by the Center for Viral Systems Biology, a NIH-funded collaboration led by Andersen, that

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Science Changing Global Health

also includes Tulane University, University of California

considered to be a mild disease, when Zika virus infects pregnant

Los Angeles, MIT and Harvard Medical School. The center

women it can cause serious birth defects in babies, including smaller

analyzes blood from survivors of past outbreaks of Lassa and

heads and brain damage. First discovered in Africa in 1947, Zika was

Ebola to learn how they fought off the virus, merging computational

found in Brazil in September 2014. Using genomic analysis, Andersen’s

analysis, machine learning and new technologies to discover

team at Scripps Research determined that Zika circulated for more than

how to minimize sickness and death in the future. One possible

a year and a half before being detected. From Brazil, a large outbreak

explanation for why some people fight off infections better than

spread throughout the Americas in 2015 and 2016, with 62 cases

others is that they may produce special versions of immune system

reported in travelers returning to the United States from affected areas

proteins, called human leukocyte antigens, that are particularly

in 2015, growing to more than 4,800 travel-related cases and 224 local

effective at recognizing infected cells. This would allow the immune

mosquito-borne infections in the United States in 2016. The Scripps

system to more rapidly destroy infected cells, and hence clear the

Research team also discovered that Zika entered Florida several times

infection. Identifying and mimicking these highly effective variants

via travelers from the Caribbean before it was discovered. More recently,

could serve as the basis for developing new types of vaccines and

a genomics study of travel-associated Zika cases by Andersen’s team

antiviral drugs.

revealed an undiscovered outbreak in Cuba in 2017, underscoring the

Troublesome family trees

need for coordinated disease surveillance. This new field of “genomic epidemiology” will be critical to understanding and preventing future outbreaks.

In addition to deciphering what leads to different outcomes when humans become infected with a virus, the scientists also track how

Raphaëlle Klitting, PhD, another postdoctoral researcher on Andersen’s

viruses spread. Similar to the way companies like Ancestry or

team, is attempting to explain why certain viral strains spread so

23andMe can trace a person’s ancestry by analyzing the DNA from

aggressively. To do this, she uses skills honed as a graduate student

a saliva sample, the Scripps Research team uses samples taken

at France’s Aix-Marseille University, where she studied yellow fever,

from various areas of Sierra Leone to create family histories of

an acute—and often fatal—viral disease transmitted by infected

Lassa virus strains. Genomic similarity between different virus

mosquitoes. Lassa virus is classified as a biosafety level 4 (BSL4)

strains can be used to track how fast and far viruses spread as well

infectious agent, the most dangerous class, so working with the live

as how quickly they evolve.

virus in the United States requires an elaborate and expensive facility, including specially sealed rooms, pressurized protective suits and

Creating viral family trees isn’t just an academic exercise.

elaborate decontamination protocols. In the lab at Scripps Research,

Deciphering what factors allow viruses to spread rapidly through

Klitting avoids the cost and hassle by working with what are called

and between host populations – whether rodents, insects or

“surrogate systems,” safe noninfectious viruses modified to carry only

humans – is key to predicting and controlling future outbreaks.

a portion of the Lassa virus. Among other things, in recent experiments

Some viruses move far more quickly than others. The global

she has engineered surrogate viruses mounted with the molecular “key”

outbreak of swine flu in 2009, for example, took just six weeks to

Lassa uses to enter cells’ outer envelope. By swapping out different

spread as widely as the typical seasonal flu travels in six months.

versions of the Lassa envelope, she tests their penetrating power.

First reported in Mexico, the flu rapidly spread around the globe, resulting in as many as 89 million cases and 18,000 deaths,

“We want to know which variants are better at entering human cells

according to the U.S. Centers for Disease Control and Prevention.

versus rodent cells,” she says. “This could help us identify which strains are likely to jump from rats to humans or to spread from human to

26

The rapid spread of Zika in the Americas is another case study of

human. With this information, we can deploy countermeasures and stop

a virus taking a surprising turn and a severe human toll. Generally

that from happening. You could also imagine at the beginning of an

SCRIPPS RESEARCH MAGAZINE | FALL 2019

“Doing field work really made me a better scientist. You have to structure your research to work with the conditions you’re given. And it’s where you see what’s happening in real life, where the virus is spreading.”

– Raphaëlle Klitting, PhD

outbreak analyzing the virus to predict how fast it could transmit and by what means it could spread, which could help public health officials respond more effectively.”

During her first visit to Kenema at the peak of the dry season in January 2019, Klitting came to appreciate that conducting research in a laboratory in Sierra Leone presents a different set of challenges than in a La Jolla laboratory.

To freeze safe, deactivated samples to ship outside Sierra Leone, the team needed liquid nitrogen, but the liquid nitrogen generator was struggling because the air conditioner couldn’t cool the room enough. Klitting and her colleagues were coaxing the machine to eke out just enough liquid nitrogen when their generator ran out of fuel and they had to wait days for a money wire to buy more.

“Doing field work really made me a better scientist,” she says. “You have to structure your research to work with the conditions you’re given. And it’s where you see what’s happening in real life, where the virus is spreading.”

She was also impressed with the bravery and skill of the hospital’s medical staff, many of who put themselves at risk caring for patients during past Lassa and Ebola outbreaks. Tragically, during the 2013-2016 Ebola epidemic, several of the hospital staff became infected and died from caring for patients.

“It’s remarkable how they stay motivated,” she says. “Some people are just heroes.”

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Science Changing Medicine

Calibr’s inaugural chief medical officer is leading the charge to bring multiple drug candidates through early clinical trials

Patients before profits “I’ve been fortunate to plot my career journey unknowingly,” says Pam Garzone, PhD, who arrived at Scripps Research in May 2019 to fill the key role of chief medical officer at Calibr.

She says this with a laugh, recognizing that her decades-long journey—with twists and turns through the academic and for-profit realms of drug development—has prepared her almost impossibly well for the job she has now taken on. She also recognizes that although her prior job titles have varied, one common thread is evident throughout: patients are her driving force.

Most recently an executive at Pfizer, where she guided early-stage cancer medicines into clinical development, Garzone is now helping Calibr bring multiple drug candidates through early-stage human trials.

Calibr’s pipeline includes the potential osteoarthritis therapy KA34—the most advanced of Calibr’s drug candidates—and two novel cancer therapies: a bispecific antibody for prostate cancer and a “switchable” CAR-T

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SCRIPPS RESEARCH MAGAZINE | FALL 2019

therapy that could potentially be a universal approach for treating many different tumor types. Within two to three years, up to five more programs rooted in discoveries made at Calibr and Scripps Research are expected to advance to clinical trials.

And Garzone is at the center of it all. Based in Calibr’s state-of-the-art headquarters complex in La Jolla, California, Garzone brings expertise in designing patient-centric clinical trials and working hand-in-hand with regulatory agencies to ensure that potential new drugs can move as swiftly as possible to the people who need them most.

Garzone shares that she was initially drawn to Calibr out of a long-standing respect for the science at Scripps Research: “Being close to that science was a big motivator for me to explore this avenue,” she says. But she was equally intrigued by Calibr’s nonprofit drug development business model. She realized that the job of chief medical officer would give her the opportunity to pursue the aspects she loved most about working in industry and academia. >>

How does Calibr translate groundbreaking discoveries into lifesaving drugs?

Calibr, the drug discovery and development division of Scripps Research, was founded on the principle that new medicines can be created faster by pairing world-class biomedical research with advanced technologies and clinical expertise. Here’s a look at what makes Calibr different.

“Calibr is this ideal environment for me in that it combines the spirit and hunger of biotech to bring drugs to patients as quickly and efficiently as possible,” Garzone says, “with the freedom of a nonprofit to go after the unmet patient need—even if the drug isn’t going to be a blockbuster.”

DIVERSE PIPELINE

She’s alluding to several medicines that Calibr is advancing in partnership with the Bill & Melinda Gates Foundation to treat neglected tropical diseases including malaria, tuberculosis

RESEARCH ALLIANCES

and diarrheal diseases. These are indications that big pharma typically shies away from.

“It’s professionally gratifying for me to be able to contribute to these programs,” says Garzone, an avid scuba diver who recently relocated to San Diego from the San Francisco Bay area with her husband and son.

In November, Garzone will travel to University of Pittsburgh—her alma mater and past employer— to receive the 2019 School of Pharmacy Distinguished Alumni award. The honor goes to one individual per year who has “shown exemplary achievements over the course of their career.”

“Pam’s background and skillset couldn’t be more ideal for what we’re seeking to accomplish here at Calibr—both in terms of our mission to create new medicines for diseases with serious unmet need and our near-term goals to move drug candidates into clinical trials,” says Peter Schultz, PhD, president and CEO of Scripps Research and head of Calibr.

In addition to her professional work, Garzone is a passionate supporter of women in STEM and plays an active volunteer role in the nonprofit organization Women in Bio. “I’m a strong believer in giving back,” she says.

Calibr has created a broad therapeutic pipeline extending from early stage discovery through clinic-ready programs, including candidate medicines for cancers, osteoarthritis, Lyme disease and multiple sclerosis.

Partnerships with organizations such as the Bill & Melinda Gates Foundation and the California Institute for Regenerative Medicine, and pharmaceutical companies AbbVie and Bristol-Myers Squibb extend Calibr’s capabilities and reach.

DEEP (LAB) BENCH The 72,000-square-foot facility houses state-of-the-art instrumentation and over 100 interdisciplinary scientists with decades of industry experience.

HIGH-THROUGHPUT ROBOTICS The institute’s robotics platform, built around technologies first developed in the auto industry, allows scientists to rapidly screen thousands of compounds to find new drug candidates.

DRUG REPURPOSING Calibr scientists built an extensive library of nearly all existing small-molecule drugs, called ReFRAME, to identify drugs that can be repurposed to treat major diseases.

CLINICAL TRIALS Calibr scientists conduct first-in-human clinical trials of promising therapeutic candidates, applying their deep expertise to advance therapies from the lab to the clinic.

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How does Calibr translate groundbreaking discoveries into lifesaving drugs?

Calibr, the drug discovery and development division of Scripps Research, was founded on the principle that new medicines can be created faster by pairing world-class biomedical research with advanced technologies and clinical expertise. Here’s a look at what makes Calibr different.

“Calibr is this ideal environment for me in that it combines the spirit and hunger of biotech to bring drugs to patients as quickly and efficiently as possible,” Garzone says, “with the freedom of a nonprofit to go after the unmet patient need—even if the drug isn’t going to be a blockbuster.”

DIVERSE PIPELINE

She’s alluding to several medicines that Calibr is advancing in partnership with the Bill & Melinda Gates Foundation to treat neglected tropical diseases including malaria, tuberculosis

RESEARCH ALLIANCES

and diarrheal diseases. These are indications that big pharma typically shies away from.

“It’s professionally gratifying for me to be able to contribute to these programs,” says Garzone, an avid scuba diver who recently relocated to San Diego from the San Francisco Bay area with her husband and son.

In November, Garzone will travel to University of Pittsburgh—her alma mater and past employer— to receive the 2019 School of Pharmacy Distinguished Alumni award. The honor goes to one individual per year who has “shown exemplary achievements over the course of their career.”

“Pam’s background and skillset couldn’t be more ideal for what we’re seeking to accomplish here at Calibr—both in terms of our mission to create new medicines for diseases with serious unmet need and our near-term goals to move drug candidates into clinical trials,” says Peter Schultz, PhD, president and CEO of Scripps Research and head of Calibr.

In addition to her professional work, Garzone is a passionate supporter of women in STEM and plays an active volunteer role in the nonprofit organization Women in Bio. “I’m a strong believer in giving back,” she says.

Calibr has created a broad therapeutic pipeline extending from early stage discovery through clinic-ready programs, including candidate medicines for cancers, osteoarthritis, Lyme disease and multiple sclerosis.

Partnerships with organizations such as the Bill & Melinda Gates Foundation and the California Institute for Regenerative Medicine, and pharmaceutical companies AbbVie and Bristol-Myers Squibb extend Calibr’s capabilities and reach.

DEEP (LAB) BENCH The 72,000-square-foot facility houses state-of-the-art instrumentation and over 100 interdisciplinary scientists with decades of industry experience.

HIGH-THROUGHPUT ROBOTICS The institute’s robotics platform, built around technologies first developed in the auto industry, allows scientists to rapidly screen thousands of compounds to find new drug candidates.

DRUG REPURPOSING Calibr scientists built an extensive library of nearly all existing small-molecule drugs, called ReFRAME, to identify drugs that can be repurposed to treat major diseases.

CLINICAL TRIALS Calibr scientists conduct first-in-human clinical trials of promising therapeutic candidates, applying their deep expertise to advance therapies from the lab to the clinic.

SCRIPPS.EDU

29

Science Changing Discoveries

Biodiversity beyond the horizon Historic natural collection may hold the key to future therapies

PAM GARZONE, PHD TITLE:

Chief medical officer, Calibr at Scripps Research INDUSTRY HIGHLIGHTS:

Vice president of Pfizer’s early clinical oncology group; senior director of clinical development at Elan Pharmaceuticals, where she designed and led more than 20 first-in-human studies of novel compounds ACADEMIA HIGHLIGHTS:

Associate director, University of Pittsburgh Center for Pharmacodynamic Research; assistant professor, University of Pittsburgh Department of Pharmacy and Therapeutics EDUCATION:

PhD in Clinical Sciences, University of Pittsburgh; MS in Pharmacy Practice, University of Pittsburgh; BS in Pharmacy, Purdue University

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SCRIPPS RESEARCH MAGAZINE | FALL 2019

Science Changing Discoveries

Biodiversity beyond the horizon Historic natural collection may hold the key to future therapies

PAM GARZONE, PHD TITLE:

Chief medical officer, Calibr at Scripps Research INDUSTRY HIGHLIGHTS:

Vice president of Pfizer’s early clinical oncology group; senior director of clinical development at Elan Pharmaceuticals, where she designed and led more than 20 first-in-human studies of novel compounds ACADEMIA HIGHLIGHTS:

Associate director, University of Pittsburgh Center for Pharmacodynamic Research; assistant professor, University of Pittsburgh Department of Pharmacy and Therapeutics EDUCATION:

PhD in Clinical Sciences, University of Pittsburgh; MS in Pharmacy Practice, University of Pittsburgh; BS in Pharmacy, Purdue University

30

SCRIPPS RESEARCH MAGAZINE | FALL 2019

A Chinese parable tells of a man who lives at the bottom of a deep well. He gazes above him and sees a fragment of clear-blue sky. “The sky is a little circle,” he thinks.

One day, he’s rescued. Upon reaching the surface, he realizes the sky stretches from horizon to horizon, seemingly without limit.

Its enormity fills him with awe and wonder.

This is precisely the feeling now shared by the scientists who study natural products, explains chemist Ben Shen, PhD. >>

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Science Changing Discoveries 32

In Jupiter, Florida, Shen’s team has amassed one of the world’s largest—and most comprehensive— collections of microbial organisms that are prolific producers of natural chemical compounds.

The one-of-a-kind collection contains microbial samples gathered by scientists worldwide over 75 years, in the hopes they might contain the next transformative medicine— comparable to penicillin’s discovery in the 1920s, but targeting today’s most urgent unmet medical needs. Several FDA-approved drugs have already been discovered among the strains, drugs that have changed history and extended the human life span.

SCRIPPS RESEARCH MAGAZINE | FALL 2019

Nature’s medicines Penicillin to battle staph, strep and a host of other once life-threatening germs, came from foodspoiling fungus

Streptomycin to defeat tuberculosis came from soil bacteria

The natural world has given humanity a bounty of history-changing drugs

PENICILLIN

STREPTOMYCIN

Lovastatin, used to lower cholesterol and prevent stroke and heart attack, came from Japanese rice fungus

LOVASTATIN

Ivermectin, to overcome parasitic infections from lice to river blindness, was isolated from Japanese soil bacteria

IVERMECTIN

Tetracycline to kill bacterial infections was isolated from cemetery soil by a researcher in Wisconsin

Sirolimus, used to coat coronary arterial stents and prevent organ rejection in transplant patients, came from fungus collected on Easter Island

TETRACYCLINE

SIROLIMUS

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Science Changing Discoveries 34

SCRIPPS RESEARCH MAGAZINE | FALL 2019

The history of medicine is full of remarkable stories of how the discovery of a natural product profoundly impacted advances in biology and inspired drug discovery and therapies.

—BEN SHEN, PhD

Yet the potential to discover new natural products and

Nature has invented a bounty of such complex molecules.

beneficial medicines from this collection is far from

Many of them act in unexpected or tangential ways, so

fully realized, Shen says. Unlocking that potential could

scientists might never have found them on their own in the lab,

revolutionize natural product discovery and the generation

Shen says. That’s why these natural products are invaluable in

of much-needed new medicines.

uncovering new biology relevant to drug discovery, he adds.

Globally, scientists know of about half a million natural products

Finding and cataloging every natural product encoded

from plants, animals and microbes. About 70,000 of them

within the microbes’ genomes requires innovation, insight

originate in microbes, which have produced or inspired about

and creativity, says Shen, director of the Natural Products

500 drugs. Like the man at the bottom of the well, at various

Discovery Center and co-chair of the bicoastal Chemistry

times, chemists have debated whether they were seeing the

Department at Scripps Research. He’s excited about the

limits of chemical biodiversity, Shen says.

challenge ahead. If successful, he says, having a database of all of those natural products encoded within the genomes of

The genome era has settled that question. The potential

the strains in the collection would be like opening the vastness

number of diverse natural compounds stretches beyond our

of the sky to science. The potential benefits to humanity could

imagining, as vast and inspiring as the sky.

be immense.

“Seventy thousand known microbial natural products is great,

Rethinking nature’s limits

it’s a lot. But within the Scripps Research collection, we could have two orders of magnitude more,” he says.

To a scientist, the term “natural product” means a substance created by a living organism to provide it with an evolutionary

To underscore the point, he begins sketching on paper. Each

advantage. These substances by definition have biological

microbe encodes, on average, 30 biosynthetic gene clusters,

activity, such as improving fitness, disarming competitors,

meaning each offers the potential of biosynthesizing 30 natural

or poisoning foes.

products, he says.

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The strains, now part of the Natural Products Discovery Center at Scripps Research, number about 210,000, including both his own collection and the historic pharma collection that

Science Changing Discoveries

Pfizer just contributed to Scripps Research.

Multiplied by about 30 potential new natural products per strain, it means there could be over 6 million new natural products waiting to be discovered in the sealed glass ampules and frozen specimens at the institute, he says.

Six million. More than 85 times the number of microbial natural products known to science today.

If he can develop the technology to efficiently characterize and catalog all 6 million, they can be systematically screened and applied to creating better tools for fighting the most devastating diseases facing humanity today, he says.

“The challenge is daunting, but if we can do it, we can change the world,” Shen says.

Nobel Prize-worthy discoveries Natural products are the result of evolutionary processes that have existed for thousands of years. All around us, microscopic organisms wage a war for survival. Among decaying leaves on the forest floor; within the cloudy waters of the brackish marsh; inside the gnarly bark of an evergreen tree; atop the rotting peel of a lemon—each new fungal or bacterial attack drives the host to invent new defenses.

If successful, the new defense generates an adaptation written into the next generation’s genome. Through countless years of these life-and-death microbial struggles, the recipes for making powerfully bioactive natural products have evolved within our soils, waters, plants and animals.

It may not be surprising then that medications made or inspired by nature, specifically ones produced from bacteria and fungi, have already changed the course of human history. Think of not just penicillin, the accidentally discovered first antibiotic, but also of streptomycin, the first anti-tuberculosis drug. Ivermectin, from a filamentous bacterium, became the first anti-parasitic drug, and lovastatin, from a fungus, the first cholesterol-lowering drug.

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SCRIPPS RESEARCH MAGAZINE | FALL 2019

BEN SHEN, PhD

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37

All of these discoveries resulted in Nobel Prizes because

“Due to the advance of genome sequencing, we know now

of their transformative impact on disease and the innovative

that a single microorganism has the potential to produce not

research underlying them.

one natural product but 30 natural products,” Shen says.

Science Changing Discoveries

“The biosynthetic potential of a microorganism to produce Because of those drugs and other natural product-inspired

natural products is massively underestimated based on the

medications, leading causes of death have shifted from

compounds we have isolated to date.”

infectious diseases of childhood to chronic diseases of aging.

Though only a fraction of the collections’ riches have been “These drugs have served humanity well for almost a

characterized so far, they have made history. The antibiotic

century. Causes of death have completely changed

tetracycline, the immune suppressant drug rapamycin

because of these drugs,” Shen says.

(sirolimus), and Mylotarg, an antibody-drug complex based on the soil-derived compound calicheamicin and used to

The natural product biodiversity within the microbial strain

treat resistant acute myeloid leukemia, all came from or were

collection at Scripps Research may hold the next generation

inspired by microbes within the collection. Recognizing that

of antibiotics, potential anti-cancer drugs, new important

deeper exploration of the collection by applying contemporary

research probes and other unknown substances that could

and emerging technologies was warranted, Pfizer last year

one day benefit human health and wellness, Shen says.

engaged organizations in the life science community through a competitive process to identify a new home for the collection.

The majority of this collection arrived from Pfizer this spring, Shen explains, brought in a succession of freezer

Shen, who has devoted his career to exploring natural

trucks, bar-coded, cataloged, handled with care, and

products, won the bid, in part because of the exceptional

arranged in their new home in Jupiter, Florida, available

and rare expertise that Scripps Research has developing

for study. Through the years, Pfizer had consolidated

new, scalable technologies for research, and translating lab

the strain collections from a multitude of commercial

discoveries into new medicines for unmet medical needs.

sources, as well as through the acquisition of collections

Traditionally, useful natural products are identified from

from pharma companies including Wyeth (which included

microbial strains through a painstaking process, by incubating

collections from Lederle Labs and American Cyanamid),

the microbes to grow larger quantities of them for study, and

Cetek/Millenium and Pharmacia. Generations of scientists

then using various chemistry techniques to purify and isolate

over the course of decades have been scooping soil, scraping

the key natural products. The active natural products can then

bits of fungus and sampling the marine environment for tiny

be studied for their effects on cells or disease targets.

organisms, then bringing them home to grow, isolate and study. Why? Because nature is the ultimate experimentalist;

To rapidly find and study such natural products, Shen intends

the innovator to outthink all innovators.

to capitalize on recent advances in genomic sequencing, computing and high-throughput molecular screening, and

A glimpse of the horizon

apply some other innovations, as well. The sky is the limit, the saying goes. But how big is the sky? Technology has

With advances in genomic sequencing and analysis,

enabled science to glimpse the horizon.

scientists now realize that vastly more healing gifts await discovery within the biodiversity of the natural world,

“The 70,000 microbial natural products known to date already

Shen explains.

afforded us around 500 life-saving drugs,” Shen says.

“If history is any indication, tens of thousands of new drugs could be awaiting discovery from the 6 million natural products encoded by the strains in our collection.”

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SCRIPPS RESEARCH MAGAZINE | FALL 2019

QUESTION:

What is a natural product?

ANSWER:

It’s a chemical substance created by a living plant, animal or microbe to provide a fitness advantage.

The approximate number of natural products encoded within the genome of each strain of fungi and bacteria.

30

70,000

The number of known microbial natural products characterized by science to date.

500

The number of drugs made or inspired by microbial natural products.

210,000

The number of microbial strains in the Natural Products Discovery Center at Scripps Research in Jupiter, Florida.

6.3 million The number of natural products predicted to be encoded by the newly expanded microbial strain collection at Scripps Research.

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Science Changing Maternal Health

How a smartphone app is transforming pregnancy research

Empowering moms-to-be

In the United States, spending on hospital-based maternity care surpasses that of any other country.

Yet, the rates of maternal morbidity and mortality are

4 MILLION

rising here, even as other areas of the world see marked improvements.

Scripps Research epidemiologist Jennifer Radin, PhD, Nearly 4 million women in the U.S. give birth every year

is trying to change this. She and her colleagues at the Scripps Research Translational Institute recently launched a digital research platform called POWERMOM, which is collecting pregnancy-related health data from women all over the country to better understand what factors contribute to healthy pregnancies.

55%

of pregnant women are using an app related to pregnancy, birth and/or child care

Radin’s goal is to build the largest maternal health research community in the world, with an emphasis on addressing the current lack of diversity in pregnancy research. Here, she explains how POWERMOM came to be—and how it’s overcoming the barriers of traditional medical studies to find answers that change lives. >>

Source: npj Digital Medicine volume 1, Article number: 45 (2018)

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SCRIPPS RESEARCH MAGAZINE | FALL 2019

60% of the global population will be mobile internet users by 2020

+7% More than 7% of all mobile health apps are focused on women’s health and pregnancy

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Science Changing Maternal Health

What drew you to maternal health research?

It started on a personal level. When I was pregnant, I had so many questions: How much weight did women like me typically gain? Were my leg cramps and lack of sleep in the last trimester normal? What was the optimal amount of exercise?

Should I stop taking certain medications?

Some questions I could ask friends or doctors. But I quickly learned that not all of my friends experienced the same things as me, and that today’s pregnancy guidelines are filled with generalizations and research gaps.

After talking with colleagues who are experts in bioinformatics and digital medicine, I realized that we could begin to answer some important questions by crowdsourcing information on a large scale directly from pregnant women; we could do it via a mobile app they install on their smartphone. Importantly, this approach would also allow us to return useful information to study participants.

Jennifer Radin, PhD

Why does an app-based study make sense for pregnant women, in particular?

Pregnant women are inherently curious about their health. They want to understand what’s normal and how they can keep themselves and their developing baby healthy. Increasingly, they’re turning to apps to find this information and using sensors to track and monitor their health. We’re tapping into this wealth of information.

We also considered that pregnant women have historically been underrepresented in biomedical research due in large part to fear of harming the fetus, but also because of the hassles of being in a trial. By leveraging wireless sensors and apps, we can collect detailed data on a frequent basis without requiring in-person clinic visits. Pregnant women only need a smartphone or internet access to participate.

The convenience factor is huge.

What questions do you hope to address with the data you collect through POWERMOM? The app collects lots of different survey and sensor data so there are many questions that we can delve into. For example, we’re looking at weight gain by race, age, height and number of previous pregnancies. We’re gathering information on the most commonly taken prescribed and over-the-counter medications and supplements. We also want to learn the average amount of sleep that pregnant women get, and how sleep during pregnancy is related to health outcomes.

With every new piece of data, we move closer to building a database of unprecedented size and depth, and fundamentally changing pregnancy research and knowledge.

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SCRIPPS RESEARCH MAGAZINE | FALL 2019

TELECONSULTS

PERIPARTUM DEPRESSION GESTATIONAL DIABETES

PREECLAMPSIA

LIFESTYLE PROTEINURIA & URINARY TRACT INFECTION

INFORMATION

Building a Healthy Pregnancy Research Community

A pilot study conducted by our researchers enrolled over 4,000 participants from all 50 states via a Research Kit iOS app, with 15% of participants being from rural zip codes, 13% being African American and 4 % being over 40 years old.

Learn more at powermom.scripps.edu

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Translations

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Scientists at Calibr have created a unique strategy for preventing Lyme disease— an approach that involves repurposing a powerful molecule currently used for pets

Time is ticking against Lyme Lyme disease is already the most widespread tick-borne infection, but it’s becoming even more problematic as tick populations boom across the United States. Notorious in the Northeast, where it’s still rampant, Lyme now spans the country.

For those bitten by a deer tick, a characteristic red “bulls-eye” rash is often the first sign of trouble. Symptoms can then evolve into fever, headache and fatigue.

Fortunately, people who realize they’ve contracted the bacterial infection can usually clear up symptoms completely with a regimen of antibiotics. But if it’s not caught right away, Lyme can lead to painful, long-term effects as it spreads to joints, the heart and the nervous system.

“There are a lot of great ways for people to protect themselves from ticks,” says Arnab Chatterjee, PhD, vice president of medicinal chemistry at Calibr, the drug development arm of Scripps Research.

“But nothing is foolproof.”

At least nothing yet. Chatterjee is leading efforts to create a new longacting oral medicine that may be able to stop the spread of Lyme. The drug, based on a discovery at Calibr, relies

on a potent class of molecules known as isoxazolines that are already used in medicines for companion animals.

The idea is that people could take the medicine once before tick season and it would remain active in the body for up to several months, killing any tick that attempts to draw blood.

Combating Lyme: An urgent need

60,000+ In 2018, state and local health departments reported a record number of cases of tickborne diseases to the Centers for Disease

Importantly, Chatterjee says, ticks would perish before they have a chance to transmit the Borrelia burgdorferi bacteria that causes Lyme.

“That’s the real power of this approach,” says Chatterjee, who refers to the medicine as a chemical vaccine. “It could prevent people from contracting Lyme disease, while also significantly reducing the tick population. So, you would realize a health benefit not only among those who take the drug, but for everyone else in the family and community.”

Chatterjee and his team at Calibr are now optimizing drug candidates to ensure they are as safe and effective as possible before human testing begins.

He expects the first clinical trial to kick off in late 2020 or early 2021. Though Lyme disease is the top priority, Calibr plans to explore the drug’s efficacy against other tick-borne and mosquitoborne illnesses.

Control and Prevention. Though more than 60,000 cases of Lyme disease were reported, thousands more likely occurred.

The number of U.S. counties with blacklegged ticks (also known as deer ticks), which are responsible for most cases of Lyme disease, more than doubled over the past 20 years.

Ticks are tiny and abundant in grassy or wooded areas where they feed on white-footed mice, which carry the disease-causing bacteria.

Lyme disease can be hard to detect, and traditional preventative measures—bug spray, long pants, tick checks—can only go so far.

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TRANSLATIONS

FDA approves Scripps Research-originated drug for cardiomyopathy The U.S. Food and Drug Administration in May approved tafamidis, a medicine invented by Scripps Research professor Jeffery Kelly, PhD, and investigator Evan Powers, PhD, for the treatment of heart disease (cardiomyopathy) caused by mutant or wild-type transthyretin aggregation in adults.

The two formulations of the drug approved by the FDA, Vyndaqel and Vyndamax capsules, are the first FDAapproved treatments for a disease known as transthyretin amyloid cardiomyopathy, or ATTR-CM. If untreated, the disease is typically fatal within five years.

Jeffery Kelly, PhD

“As the first approved therapy for this deadly disease, tafamidis represents a watershed for patients and a milestone for the development of therapies targeting amyloid diseases,” says Kelly, the Lita Annenberg Hazen Professor of Chemistry at Scripps Research.

“Clinical data suggest these drugs will significantly improve the prognosis for many ATTR-CM patients.”

Transthyretin amyloidosis is rarer than other amyloid diseases such as Alzheimer’s disease, which are caused by misfolded proteins that build up in the body's organs and tissues. ATTRCM is a result of transthyretin proteins that aggregate in the heart, resulting in shortness of breath, abnormal heart rhythms and chest pain.

Vyndaqel and Vyndamax are oral medicines that bind to transthyretin, stabilizing the protein to prevent it from aggregating. Pfizer recently completed a phase 3 clinical trial of Vyndaqel in

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individuals with familial and sporadic ATTR-CM, demonstrating a significantly reduced risk of all-cause mortality and cardiovascular-related hospitalizations, and a 30 percent reduced risk of death compared with placebo. Based on those results, the FDA granted tafamidis a fast track designation, expediting the regulatory review process so the medicine could reach patients earlier.

Norman Stockbridge, MD, PhD, director of the Division of Cardiovascular and Renal Drugs in the FDA’s Center for Drug Evaluation and Research, called the treatments “an important advancement in the treatment of the cardiomyopathy caused by transthyretin-mediated amyloidosis.”

While only about 2,000 to 5,000 patients globally are diagnosed with the progressive heart disease, Pfizer estimates about 100,000 people in the United States have the condition.

Tafamidis has also been approved in 40 countries for familial amyloid polyneuropathy, a neurodegenerative disorder that results from transthyretin aggregation in the nervous system.

Calibr gets OK to start patient trials for novel prostate cancer drug Scripps Research’s drug development arm, Calibr, made headlines in August when the FDA approved its investigational new drug (IND) application for a novel immunotherapy for patients with metastatic castration-resistant prostate cancer.

The drug, known as CCW702, has the potential to be effective in patients who have failed prior therapies and exhausted their treatment options. Metastatic castration-resistant prostate cancer occurs when cancer spreads beyond the prostate and it is able to grow even when the patient receives hormone-reducing treatments to manage the cancer.

“Our drug candidate works differently than traditional chemotherapeutics and androgen-deprivation therapies,” says Travis Young, PhD, vice president of biologics at Calibr, who led the preclinical development of the molecule.

“We are truly excited about the opportunity to evaluate the safety and anti-tumor activity of this molecule in patients.”

CCW702 is a first-of-its-kind molecule that seeks to redirect a patient’s immune system to eliminate cancer cells. The molecule’s unique design combines the specificity of a validated imaging agent for prostate cancer with the potency of immunotherapy. In preclinical work, it proved highly effective at completely eliminating prostate cancer tumors.

another major milestone for the new model being pioneered by Scripps Research, where innovative discoveries are translated into new medicines within the nonprofit enterprise.

CCW702 began as a research project in the laboratory of Peter Schultz, PhD, at Scripps Research and progressed to the IND stage by Calibr through support from the Wellcome Trust.

The molecule is manufactured using unnatural amino acid technology pioneered in Schultz’s laboratory in collaboration with Ambrx Inc. “This program exemplifies how Scripps Research and Calibr are able to bring high-risk, high-reward programs into clinical trials to impact patients while creating value that stimulates and supports further research,” says Schultz, president and CEO of Scripps Research. “This model can be transformative in the way new medicines are developed.”

The launch of the clinical program— Calibr's fourth overall and second being run independently by the institute—is

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TRANSLATIONS

Liver cancer drug launches into clinical phase

FDA evaluates ozanimod as a new treatment for multiple sclerosis The FDA in June accepted a New Drug Application for ozanimod, a potential treatment for multiple sclerosis that was created at Scripps Research.

A liver cancer therapy developed in the laboratory of Scripps Research professor Luc Teyton, MD, PhD, may now proceed to clinical trials, the FDA decided in May. The drug, known as ABX196, is licensed to French pharmaceutical company Abivax. The FDA’s approval of the investigational new drug application (IND) for ABX196 allows Abivax to test the therapy in patients with hepatocellular carcinoma, the most common form of liver cancer.

“The translation of basic research discoveries to the clinic is the greatest achievement we can hope for as clinician scientists,” says Teyton, who is also a member of Abivax’s Scientific Advisory Board. “We are looking forward to impacting the disease in patients with hepatocellular carcinoma, especially given the limitations of current therapies.”

Abivax will test ABX196 in combination with nivolumab (marketed as Opdivo by Bristol-Myers Squibb), a checkpoint inhibitor, in a phase 1/2 clinical trial to treat patients with hepatocellular carcinoma. The initial doseescalation phase of the study will be conducted at the Scripps MD Anderson Cancer Center in San Diego; other leading cancer centers in the U.S. will be involved in the subsequent expansion phase of the study.

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Pharmaceutical company Celgene, which controls rights to the drug and filed the application, said the FDA is expected to issue its final decision on whether to approve ozanimod for relapsing forms of multiple sclerosis—the most common forms of the disease—by March 25 of next year.

“This is a major step in bringing ozanimod to patients with relapsing multiple sclerosis, providing a new treatment option that has shown great promise in clinical testing,” says Hugh Rosen, MD, PhD, who invented ozanimod along with fellow Scripps Research professor Edward Roberts, PhD. The European Medicines Agency also accepted an application to market ozanimod in the European Union to adults with relapsing-remitting MS. The applications are based on results from two pivotal phase 3 trials. Treating inflammation is key to reducing disease “flare-ups” among those with relapsing-remitting MS. In the clinical trials, ozanimod significantly reduced brain lesions and brain volume loss compared with the first-line treatment.

In 2015, Celgene acquired the rights to ozanimod, which is also being studied for treating inflammatory bowel disease.

Celgene’s phase 3 studies for ulcerative colitis, a form of the disease, are on track to be completed by mid-2020.

Ozanimod acts on immune cells involved in inflammatory attacks on nerve fibers and the myelin sheaths (pictured) that protect them.

Top: healthy Bottom: diseased

Scripps Research spin-off Abide Therapeutics acquired by Danish pharma company Abide Therapeutics Inc., a clinical-stage biopharmaceutical company founded by Scripps Research professors Benjamin Cravatt, PhD, and Dale Boger, PhD, was bought out by the Danish pharmaceutical firm H. Lundbeck A/S (Lundbeck).

Under the terms of the agreement announced in May, Lundbeck will pay $250 million upfront with a commitment to pay up to $150 million upon future milestones to the current owners. Scripps Research will receive a portion of upfront proceeds as a result of its equity holdings, and is eligible to receive a royalty on the lead drug candidate, ABX-1431, and other portfolio assets.

Abide uses a unique chemo-proteomic platform to discover new classes of drugs for a range of brain diseases, focusing on therapies that target the endocannabinoid system. ABX-1431 is in a phase 2 trial for Tourette syndrome and is entering phase 2 trials for other neurological diseases.

“From its inception, Abide has displayed the courage to pursue first-in-class therapeutics" for central nervous system disorders, says Cravatt, the Gilula Chair of Chemical Biology at Scripps Research. “The acquisition by Lundbeck speaks to the promise of the innovative approach that Abide has taken.

It’s a very special day for the company and great news for the San Diego biotech sector.”

Abide’s laboratory in La Jolla will become a U.S. drug discovery hub for Lundbeck. Alan Ezekowitz, CEO of Abide, said the acquisition was the best way to achieve the company’s goal of developing novel therapeutics for patients with a range of neurological and mood disorders.

“This, together with the support for the La Jolla discovery site, means that we can continue to leverage the insights of Ben Cravatt’s laboratory at Scripps Research and maintain our outstanding discovery team,” Ezekowitz says.

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Awards Honors Grants ROYAL SOCIETY OF CHEMISTRY

Jeremy Knowles Award Benjamin Cravatt, PhD, the Gilula Chair of Chemical Biology, has received the prestigious Jeremy Knowles Award for 2019 from the Royal Society of Chemistry. Cravatt was recognized for pioneering a powerful new approach for identifying protein classes based on their activity, greatly expanding the possibilities of small-molecule drug discovery. His work uncovered countless new insights into disease biology that may lead to treatments for critical conditions that include cancers and neurological disorders. The award honors the late Jeremy R. Knowles, a professor of chemistry at Harvard University and legendary figure in the fields of enzymology and chemical biology.

AMERICAN ASSOCIATION OF IMMUNOLOGISTS

Wendy Havran and Linda Sherman elected Distinguished Fellows Wendy Havran, PhD, and Linda Sherman, PhD, have been elected Distinguished Fellows of the American Association of Immunologists (AAI), one of the highest honors bestowed by the organization.

The inaugural program honors active, long-term members who have demonstrated excellence in research accomplishment in the field of immunology, exceptional leadership to the immunology community or notable distinction as an educator.

Havran is a professor in the Department of Immunology and Microbiology as well as associate dean of Graduate Studies. Last year, she received the Distinguished Service Award from AAI and the Outstanding Mentor Award at Scripps Research. Sherman is also a professor in the Immunology and Microbiology Department and a member of the graduate program faculty.

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THE CAMILLE AND HENRY DREYFUS FOUNDATION

Keary Engle receives 2019 Teacher-Scholar Award The Camille and Henry Dreyfus Foundation, a nonprofit dedicated to advancing chemical sciences, selected Keary Engle, PhD, assistant professor in the Department of Chemistry, for its 2019 Camille Dreyfus Teacher-Scholar Award. The award supports “exceptional young academic researchers at an early and crucial stage in their careers.” Engle concentrates his research on organic chemistry methods, seeking to streamline the synthesis of new complex molecules with applications to pharmaceuticals or agriculture. He is also committed to educating the younger generation of scientists at Scripps Research and won the Outstanding Mentor Award at the institute in 2017.

AMERICAN SOCIETY FOR MASS SPECTROMETRY

John B. Fenn Distinguished Contribution Award At this year’s annual meeting of the American Society for Mass Spectrometry, John Yates III, PhD, a professor in the Department of Molecular Medicine, received the John B. Fenn Award for a Distinguished Contribution in Mass Spectrometry. Yates is the lead inventor of the SEQUEST software and algorithm that laid a critical foundation for the field of proteomics and dramatically enhanced the accuracy and effectiveness of mass spectrometry. Researchers around the world now use proteomics to study proteins in almost every organelle in order to understand differences between normal and disease states.

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Awards Honors Grants AMERICAN CHEMICAL SOCIETY

2020 Horace S. Isbell Award

INTERNATIONAL SOCIETY OF HETEROCYCLIC CHEMISTRY

E.C. Taylor Senior Award The Division of Carbohydrate Chemistry (CARB) of the American Chemical Society (ACS) has announced that Peng Wu, PhD, associate professor in the Department of Molecular Medicine, is the recipient of the 2020 Horace S. Isbell Award. Given to scientists under the age of 45, the Isbell Award “acknowledges excellence in and promise of continued quality of contribution to research in carbohydrate chemistry and biochemistry.” Wu and his laboratory team at Scripps Research discovered that an enzyme, fucosyltransferase, has the ability to transfer antibodies to surface molecules on cancer cells. They are using this insight to develop “antibodycell conjugates” that locate and destroy aggressive breast cancer cells in mouse models. Wu will receive his award at the 2020 Spring ACS national meeting in Philadelphia where he will also give an award lecture.

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During the 27th Congress of the International Society of Heterocyclic Chemistry in Kyoto, Japan, Dale Boger, PhD, received the E.C. Taylor Senior Award in Heterocyclic Chemistry. Boger is the Richard and Alice Cramer Professor of Chemistry and focuses his research on synthetic organic and bioorganic chemistry. Discoveries in his lab have led to an experimental cancer vaccine that boosts the immune system’s ability to fight cancers and a structurally modified form of vancomycin that makes the antibiotic 25,000 times more potent. Along with Scripps Research professor Ben Cravatt, PhD, Boger founded a clinical-stage biopharmaceutical company, Abide Therapeutics, that uses a unique chemoproteomic platform to identify new classes of drugs for a range of clinical disorders. Abide was acquired by Danish pharmaceutical firm H. Lundbeck A/S in May.

AMERICAN CHEMICAL SOCIETY: JEFF KELLY INDUCTED INTO MEDICINAL CHEMISTRY HALL OF FAME

Medicinal Chemistry Hall of Fame

Jeffery Kelly, PhD, professor in the Department of Chemistry, has been named to the 2019 class of inductees into the Medicinal Chemistry Hall of Fame. In May of this year, tafamidis, a drug developed in Kelly’s laboratory, was approved by the FDA for the treatment of cardiomyopathy caused by mutant or wild-type transthyretin aggregation in adults. The two formulations of the drug, Vyndaqel (tafamidis meglumine) and Vyndamax (tafamidis) are the first FDA-approved treatments for transthyretin amyloid cardiomyopathy. An induction ceremony and reception were held at the American Chemical Society’s Fall National Meeting in San Diego.

AMERICAN CHEMICAL SOCIETY: KIM JANDA HONORED WITH PORTOGHESE LECTURESHIP AWARD

Philip S. Portoghese Medicinal Chemistry Lectureship Award

The Medicinal Chemistry Division of the American Chemical Society (ACS), along with the Journal of Medicinal Chemistry, has given the 2019 Philip S. Portoghese Medicinal Chemistry Lectureship Award to Kim Janda, PhD. The lectureship honors Janda, the Ely R. Callaway, Jr. Professor of Chemistry at Scripps Research, for his many contributions to medicinal chemistry research. In recent months, Janda and his laboratory team have developed a first-ever monoclonal antibody that mitigates the effects of fentanyl and carfentanil, two powerful synthetic opioids; designed an experimental dual vaccine for treating substance use disorders against both heroin and fentanyl; and created a urine diagnostic dipstick to detect the parasitic worms that cause onchocerciasis, better known as river blindness. Janda received his award at the ACS Fall National Meeting and Expo.

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Events

Front Row Lecture Series: Inspiring the public with cutting-edge science

On August 15, Kristian Andersen, PhD, an associate professor in the Department of Immunology and Microbiology, spoke before a standing-room-only audience in La Jolla about Scripps Research’s use of infectious disease surveillance and viral genome sequencing to help manage global pandemics.

Three of Calibr’s lead scientists (left to right: Travis Young, PhD; Arnab Chatterjee, PhD; and Kristen Johnson, PhD) took to the stage in California on June 13 to discuss efforts to create medicines for some of the most critical and widespread health concerns facing the world.

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Institute awards doctorates to its largest graduating class Scripps Research’s Skaggs Graduate School of Chemical and Biological Sciences conferred doctoral degrees on more than 50 graduate students, the largest graduating class in the program’s history. The 27th annual commencement ceremony was held May 17 at the institute’s La Jolla campus.

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Events

Kenan Fellows internship program celebrates 15 years

Left to right: Rosie Albarran-Zeckler, education outreach coordinator of the Scripps Research SF Grad Program; Dorian Burton, assistant executive director and chief program officer of the William R. Kenan, Jr. Charitable Trust; and Douglas Bingham, executive vice president, Scripps Research Florida Operations

The Florida campus of Scripps Research celebrated the 15th anniversary of its highly competitive internship program on Aug. 1 with a dinner and program recognizing the generous sponsorship of its benefactor, the William R. Kenan, Jr. Charitable Trust.

More than 40 Kenan Fellows from across the United States returned to the campus to thank the trust and the Kenan family, and recall the first summer they set foot in a laboratory.

“Without this program, I don’t think I would have discovered my love for research so early on,” says Gabrielle Marvez, studying Brain and Cognitive Sciences at MIT. Since the program’s 2004 launch, 165 Palm Beach County high school students and 24 science teachers have become Kenan Fellows, working and learning alongside the institute’s scientists and graduate students.

Their fellowships were made possible thanks to over $2 million donated by the charitable trust since 2005.

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Kenan Fellow Andrew Acevedo, PhD, says the fact that he pursued a doctorate in biomedical engineering at Boston University had much to do with the inspiration he experienced as a Kenan Fellow.

“I am the first person in my family to pursue a career in science and obtain a PhD degree,” says Acevedo. “The summer I spent as a Kenan Fellow was the first step on this journey...It was eye-opening and exciting.”

‘Sneakers for Science’ helps Florida campus make strides against incurable diseases Scripps Research’s Florida campus sits a stone’s throw away from the home of the Miami Marlins’ minor league baseball team, the Jupiter Hammerheads, so the Hammerheads wanted to support the exceptional science and educational programming happening in their neighborhood.

With collectable sneakers trending and back-to-school shoe shopping in full swing, the Hammerheads organized a unique fundraiser, “Sneakers for Science,” to support research on incurable diseases at Scripps Research. Shoe vendors and fun science education tables filled the ballpark concourse, and collectable shoes signed by athletes and local celebrities were raffled between innings of the Hammerheads vs.

Fort Myers Miracle baseball game.

Before the game, five players and the team’s general manager visited the labs to learn about the research and compare shoes with scientists for a fun “Whose shoes?” video.

“The amount of unique and advanced work they’re doing is unbelievable until you really see it for yourself,” stated Jupiter Hammerheads General Manager Jamie Toole.

Scripps Research Executive Vice President Douglas Bingham said the money raised at “Sneakers for Science” will help scientists tackle unmet medical needs and enable them to offer more educational opportunities for local students.

“The community’s support for ‘Sneakers for Science’ and for our work in general means so much to us,” Bingham said.

Art (and music) in the air The Dorris Neuroscience Center at Scripps Research hosted its third-annual art show highlighting the creations of scientists and staff on July 12. The event included lunch and a performance by the Deranged Narcissistic Cephalopods, a jazz band comprised of institute scientists Ardem Patapoutian, PhD, Michael Petrascheck, PhD, Lucio Schiapparelli, PhD, and Federico Zampa, PhD.

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Events

From left: Travis Young, PhD; Eduardo Laborda, PhD; Eric Hampton, PhD; surfing legend Candice Woodward; and Vadim Klyushnichenko, PhD

Luau and Legends Scripps Research hit the waves this summer, surfing for a cure. Members of the institute’s drug discovery division Calibr took part in the Luau and Legends Surf Contest August 18 in La Jolla. The 26th annual event was dedicated to raising money for cancer research, in collaboration with the Moores Cancer Center at UC San Diego. Congratulations to our team, who won the “crowdsurfing” prize for the greatest number of unique donations. They raised over $1,400 from 35 donations.

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Experience America experiences Scripps Research More than 35 ambassadors representing countries across four continents toured Scripps Research June 17 to learn more about San Diego’s biomedical research sector as part of a three-day U.S. State Department-sponsored visit called Experience America. The diplomats, representing countries from Albania to Uzbekistan, heard from Scripps Research scientists who are developing new medicines and international partnerships to improve lives around the world, in some cases directly altering medical care and disease prevention in the countries from which the ambassadors hail. The ambassadors toured Scripps Research’s state-of-the-art scientific facilities, including the cryo-electron microscopy facility and the Skaggs Graduate School of Chemical and Biological Sciences, the institute’s top 10 ranked graduate program. During their stay, the diplomats heard how research, technology and entrepreneurship are transforming the region and powering innovation that changes and improves individuals, countries and societies.

Communications & Scientific Liaison Drew Duglan (front) guided ambassadors through the Hazen courtyard, highlighting the institute’s history, architecture and cutting-edge science.

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New biomarkers to detect Parkinson’s. Robots that discover drugs faster than ever before. Breakthroughs that can prevent the spread of Ebola and other deadly infectious diseases.

These and other fascinating topics are explored in Scripps Research’s podcast, PreSCRIPPSion Sound. Through engaging interviews with scientists, our cutting-edge biomedical research comes to life in a way that’s important to you.

Find PreSCRIPPSion Sound on iTunes, GooglePlay, SoundCloud and your smartphone podcast app. Or simply visit www.scripps.edu/podcast.

“We’re focused on targeting someone’s drug-associated memories. On top of existing support, they would receive a medication that would excise their meth-associated memories that can drive cravings.”

Courtney Miller, PhD

Department of Molecular Medicine

“One of the most powerful aspects of our drug collection is that it’s open-access and freely available.

In many ways, it’s the democratization of biology.”

Arnab Chatterjee, PhD Calibr, Scripps Research

scripps.edu/podcast

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

California campus

Florida campus “Advancing Precision Medicines to Stop Cancer, ALS, Muscular Dystrophy and More” Thursday, October 17, 2019 4-6 pm Matthew Disney, PhD

“Accelerating Translation of Discoveries into Medicine” Wednesday, January 22, 2020 4-6 pm Peter Schultz, PhD President and CEO, Scripps Research

Professor, Department of Chemistry

“Stress, Pleasure and Social Connection: How the Brain Reacts to Emotion to Shape Behavior” Thursday, January 23, 2020 4-6 pm Lisa Stowers, PhD Professor, Department of Neuroscience

“Mirror Images: The Fascinating Science of Chirality and What It Means for Medicine”

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

“Advancing Precision Medicines to Stop Cancer, ALS, Muscular Dystrophy and More”

Thursday, March 26, 2020 4-6 pm

Thursday, March 18, 2020 4-6 pm

Donna Blackmond, PhD

Matthew Disney, PhD

Professor, Department of Chemistry

Scripps Research Auditorium

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

Professor, Department of Chemistry

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

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

Rodney B. Fink Education Pavilion

RSVP Florida: scripps.edu/frontrowfl RSVP California: scripps.edu/frontrow

For questions or more information about the Florida events, call (561) 228-2084 or email frontrowfl@scripps.edu.

120 Scripps Way, Building B, Jupiter, FL 33458

scripps.edu

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From a single spark rises an enduring flame.

When you champion student scientists at Scripps Research, you forever transform the future of health.

California Philanthropy office 10550 North Torrey Pines Road, TPC-2 La Jolla, California 92037 (858) 784-2915 philanthropy@scripps.edu

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

Innovative minds produce the most life-changing science. Please join our campaign and our commitment to educating and training the next generation of scientific talent.

To learn how you can transform the future of health by supporting the educational programs at Scripps Research today, please contact our Philanthropy department.

Or visit us at give.scripps.edu.

Science changing education

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

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