Spring/Summer Edition 2019 by Scripps Research Magazine

SCRIPPS RESEARCH | SPRING/SUMMER EDITION 2019

Science Changing Life | Spring/Summer Edition 2019

Neutralizing some of natureâ&#x20AC;&#x2122;s most evasive threats

S P R I N G/S U M M E R EDI T IO N | 2 019

Scripps Research Outsmarting Outbreaks Future of Innovation Scripps Research scientists develop super-powered vaccines and therapeutics against HIV, the flu and other deadly viruses

An in-depth look at how Scripps Research is speeding the translation of discoveries into drugs

An innovative approach to chemistry and drug discovery that clicks

Investigatiing the neural mechanisms underlying the brainâ&#x20AC;&#x2122;s recognition and interpretation of odors with Scripps Research neuroscientist Lisa Stowers

Click Chemistry

Scientist Profile: On the Nose

Presidentâ&#x20AC;&#x2122;s Letter 02 Discoveries 04 Awards/Honors/Grants 40 Events 48

Antibodies are Y-shaped proteins our immune system uses to neutralize disease-causing microorganisms, including viruses. Scientists at Scripps Research are developing special antibodies to disarm the most challenging, rapidly evolving viral pathogens such as the flu and HIV (pictured in background). Read about it on page 16.

On the cover

Science Changing Medicine

Letter from the President

Science is rich with stories of curiosity, struggle, perseverance and discovery. But where these stories begin and where they end depends upon your perspective. In this issue of Scripps Research Magazine, you’ll read about fresh discoveries and innovations recently reported in scientific journals. From deciphering the underlying causes of autism, heart disease and Alzheimer’s to innovations in synthesizing important compounds used in drug manufacturing, these stories capture the excitement of the science taking place right now in our labs. But these advances are only possible because of the work that came before. Taking the long view, one understands that science is epic in scale, an accrual of knowledge, craft and technology built over decades and generations. In a feature article in this issue, for instance, you’ll read about the discovery of a rare antibody made in 2002 by Dennis Burton, PhD, and an international team of collaborators. That discovery helped pave the way to a new class of experimental vaccines and therapies, being developed at Scripps Research, that could revolutionize how we prevent and treat HIV, influenza and other deadly pathogens. You’ll also read about the many remarkable contributions of K. Barry Sharpless, PhD, Scripps Research professor, Nobel laureate and, most recently, recipient of the Priestley Medal, the highest honor bestowed by the American Chemical Society. His inestimable innovations—spanning his career before and after he received the Nobel Prize in 2001— are now crucial tools used by scientists around the world. Rarely would it be appropriate to describe a person’s career as “epic”—it is entirely apt in Barry’s case. The most compelling stories are those where science touches people’s lives. Many have emerged from Scripps Research. No less than nine approved drugs have originated here, from tafamidis, a drug that protects the nerves of people with a rare genetic disorder, to surfaxin, a therapy that helps premature infants breathe. In the news section, you’ll read that tafamidis is nearing approval for treatment of a life-threatening heart condition, along with two more drugs originated by our scientists for other rare disorders. Many other potentially life-changing therapies are in the works at Calibr, our drug discovery division, including potential new medicines for cancer, osteoarthritis and neurodegenerative, cardiopulmonary and infectious diseases. Our unique model for accelerating the process of bringing these and other much-needed therapies to the clinic is also outlined in this issue.

Peter Schultz, PhD President and CEO, Scripps Research

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Science Changing Life

discoveries

From ice bucket challenge to possible ALS drug A NEW COMPOUND developed in the lab of chemist Matthew Disney, PhD, thanks in part to funds from the ice bucket challenge, blocks the most common genetic cause of both familial ALS and frontotemporal dementia. Disney’s group is assessing its potential to become a drug to treat both of these diseases. “Hopefully, this will be an accelerant not only for us, but for all people in the field working toward a treatment for ALS,” Disney says. The compound works differently than most drugs on the market. Rather than binding with the toxic protein behind the disease, it binds with a specific form of RNA, one folded over like a hairpin. Since RNA molecules manage the expression of genes, intervening at the RNA level goes right to the apparent cause of the disease, Disney says. “There are zero therapies that address the root cause of this disease,” Disney says. “Zero. Our goal is not to target the symptoms, it is to target the root cause, which is that RNA.” ALS, short for amyotrophic lateral sclerosis, is also known as Lou Gehrig’s disease in honor of the late baseball legend. An estimated 20,000 people in the United States currently live with the disorder.

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Our goal is not to target the symptoms, it is to target the root cause.

1 IN 5 people with breast cancer carry the HER2-positive genotype

Matthew Disney, PhD

Breast cancer cells turned HER2-positive IT CAN BE especially difficult for breast cancer patients to hear that their cancer is HER2-negative, as it means an effective group of targeted treatments, including Herceptin, isn’t available to them. Only one in five people with breast cancer carry the HER2-positive genotype. Writing in the Journal of the American Chemical Society, chemistry Professor Matthew Disney, PhD, and colleagues describe shifting three different cancer cell lines from HER2-negative to HER2-positive status with the addition of a newly designed compound, a selective microRNA-binding molecule referred to as TGP-515. “It’s possible that precision medicines like Herceptin can be made available to a wider group of people by altering gene expression with therapeutics that bind not to the proteins, but to noncoding RNA,” Disney says.

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DISCOVERIES

The new method sidesteps the dangers and high costs associated with powerful chemical reactions. electrolyte interphase (SEI), which allows the battery to be recharged. Baran’s team noted that the electrochemical reaction that forms the SEI in batteries is akin to the Birch reaction.

Electric car batteries inspire safer, cheaper way to make compounds for medicine RECENT ADVANCES in battery technology have given way to the rapid rise of Teslas, Leafs, Volts and other electric cars. Now, scientists at Scripps Research—inspired by the refined electrochemistry of these batteries—have developed a system that offers a much safer and more efficient way to manufacture medicines.

The new method, reported in Science, sidesteps the dangers and high costs associated with powerful chemical reactions known as “dissolving-metal reductions.” The Birch reduction is among the most well-known of these; it requires metals such as lithium to be dissolved in massive quantities of liquid ammonia at extremely cold temperatures.

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While incredibly useful for making compounds for medicines and a host of other high-value chemical products, “medicinal chemists traditionally avoid such chemistry due to safety concerns,” says Phil Baran, PhD, the Darlene Shiley Chair in Chemistry at Scripps Research and senior author of the Science paper. Co-author Michael Collins, a medicinal chemist at Pfizer, brought the problem to Baran’s attention. In search of a solution, Baran’s lab looked to advances in battery manufacturing. They knew that lithium-ion (Li-ion) batteries used in modern electronics such as mobile phones and electric cars rely on an internal component called the solid

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“In many ways you’re looking at similar situations—powerful reactions that, when effectively harnessed, can provide tremendous utility,” says Solomon Reisberg, a graduate student in the Baran lab and a co-author of the Science paper. The team tested a range of additives used to prevent overcharging in Li-ion batteries and found that a combination of two—dimethylurea and TPPA— made the Birch reaction possible at room temperature. After trying various other materials used in batteries, Baran’s team came up with a set of conditions that allowed them to conduct reductive electrosynthesis safely and increase the versatility of the reaction to create a wider variety of products. In contrast to the incredibly expensive equipment previously required to conduct reductive chemistry in large quantities, the team collaborated with a chemical manufacturer in China to create a small modular device capable of generating large quantities of products for less than $250.

less than $250 The cost of a modular device developed by Scripps Research scientists, capable of generating important compounds used in medicines.

Ancient evolutionary mysteries come to life in the lab USING TOOLS of synthetic biology, scientists at Scripps Research have created microorganisms with key features of organisms thought to have lived billions of years ago. The feat enables them to explore questions about how life evolved from inanimate molecules to single-celled organisms to the complex, multicellular life forms we see today.

Scientists hope to shed light on the early evolution of life

By studying one of these engineered organisms—a bacterium whose genome consists of both ribonucleic acid (RNA) and deoxyribonucleic acid (DNA)—the scientists hope to shed light on the early evolution of genetic material, including the theorized transition from a world where most life relied solely on the genetic molecule RNA to one where DNA serves as the primary storehouse of genetic information.

called mitochondria. The research was published in Proceedings of the National Academy of Sciences and the Journal of the American Chemical Society. “Access to readily manipulated laboratory models enables us to seek answers to questions about early evolution that were previously intractable,” says Peter Schultz, PhD, president of Scripps Research and senior author of the studies.

And through a second engineered organism, a genetically modified yeast containing an endosymbiotic bacterium, they hope to better understand the origins of cellular power plants

Expanded genetic code gives proteins a survival edge

A team of Scripps Research scientists pioneered a method to reprogram a cell’s biosynthetic machinery to add new amino acids to proteins, beyond nature’s limited set. In research published in the Journal of the American Chemical Society, the researchers explain how the expanded code resulted in new chemical properties that lent an evolutionary advantage.

VIRTUALLY EVERY ORGANISM on earth uses the same 20 amino acids as the building blocks to make proteins—the large molecules that carry out the majority of cellular functions.

The team started by tweaking the genome of E. coli so it could produce the important metabolic enzyme known as metA with a 21-amino acid code instead of the usual 20-amino acid code. MetA dictates the maximum temperature at which E. coli can thrive.

But what if we had access to additional amino acids, beyond what nature provides? What kinds of proteins might we be able create?

Reprogramming E.coli bacteria

Next, they let natural selection work its magic. They heated the bacteria to 44 degrees Celsius—a temperature at which normal metA protein can’t function. The mutant metA enzyme was able to withstand temperatures 21 degrees higher than normal— nearly twice the regular thermal stability. “It’s striking how making such a small mutation with a new amino acid not present in nature leads to such a significant improvement in the physical properties of the protein,” says Peter Schultz, PhD, the senior author of the study and president and CEO of Scripps Research. “This raises the question of whether a 20-amino acid code is the optimal genetic code—if we discover life forms with expanded codes will they have an evolutionary advantage?”

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DISCOVERIES

BILLIONS OF PEOPLE carry a mysterious grouping of genes that strongly increases their risk for life-threatening cardiovascular diseases such as heart attacks, aneurysms or strokes—even if they’re leading the healthiest of lifestyles. In a major recent breakthrough, Scripps Research scientists were able to identify and precisely cut the DNA culprit from the genome, thus preventing blood vessel cell abnormalities associated with these diseases. And in the process of their research they made yet another key discovery: this prevalent, yet poorly understood region of DNA may orchestrate a nefarious network of more than a third of all genes known to increase risk for coronary artery disease. This work opens the door to a new set of precision treatments aimed at cells of the blood vessel wall. In a paper published in Cell, the team reported that a large block of DNA known as the 9p21.3 cardiovascular risk haplotype causes abnormalities in vascular smooth muscular cells—the cells that enable blood vessel walls to expand and contract. When dysfunctional, these cells can contribute to plaques that clog blood vessels and lead to heart attacks and stroke.

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The 9p21.3 haplotype is the most impactful known genetic cause of cardiovascular disease worldwide. Discovered more than a decade ago, it was the first common genome region associated with increased risk of coronary artery disease and related conditions. However, until now, scientists were in the dark about how the haplotype translated into biological mechanisms that caused disease; precisely what was happening inside people’s bodies was a matter of speculation. “We may have opened a new route to interventions that could impact many millions of people worldwide,” says Kristin Baldwin, PhD, a professor at Scripps Research and senior author of the paper. Baldwin and her team tackled significant challenges that have vexed the research community for years. For one, the 9p21.3 haplotype is found only in humans, with poor similarity in mice or other laboratory animals. The region also doesn’t harbor traditional protein-coding genes, making it hard to predict what it might do. “We call such regions gene deserts,” says Ali Torkamani, PhD, associate professor at Scripps Research and director of genome informatics at the Scripps Research Translational Institute, and a co-author of the paper.

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9p21.3

Scientists cut main heart disease culprit out of DNA by genome editing

A large block of DNA known as the 9p21.3 cardiovascular risk haplotype causes abnormalities in vascular smooth muscular cells.

We may have opened a new route to interventions that could impact many millions of people worldwide. — Kristin Baldwin, PhD, professor, Scripps Research

“In the past, these regions were neglected in research because people thought it was junk DNA. With rapid advances in genome sequencing and analysis, we are finding they frequently play critical roles in the emergence of disease.” To find answers, the team collected blood from people with high-risk and low-risk versions of the haplotype and then, using molecular “scissors” known as TALE nucleases, reprogrammed those cells to become vascular smooth muscle cells. High-resolution gene profiling and bioengineering methods revealed that the high-risk cells had an unusually broad

set of abnormalities that affected more than 3,000 genes—nearly 10 percent of the total human gene catalog. Unexpectedly, the high-risk cells also showed changes in more than a third of the 100-or-so other genes linked with coronary artery disease, suggesting that the 9p21.3 haplotype interacts with or even controls this network of genes. Delving even more deeply, the group identified a potential key master regulator known as ANRIL, a member of an enigmatic class of genes that do not make proteins— instead generating genetic molecules

called long non-coding RNAs. The risk cells had higher levels of several short forms of ANRIL. When the team added these short ANRIL RNAs to healthy cells, the cells developed key signatures of disease, indicating that these ANRIL RNAs may be master conductors of the switch between health and disease in vascular smooth muscle cells. “This study demonstrates the power of genome editing of pluripotent stem cells for studying human genetic risk for disease, especially when risks are in uniquely human regions or gene deserts,” says Valentina Lo Sardo PhD, a staff scientist at Scripps Research and first author on the paper.

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DISCOVERIES

Why do antipsychotic medications drive weight gain? Scientists find answers—and a potential remedy

ROUGHLY 3 MILLION AMERICANS take antipsychotic medications for conditions such as bipolar disorder, PTSD and schizophrenia. These drugs are vital for mental health, yet many patients stop taking them because of weight gain and metabolic diseases that emerge as a common side effect. “On the surface, weight gain from these medications seems like a minor thing, but it’s not,” says Michael Petrascheck, PhD, associate professor at Scripps Research. He notes that patients on these drugs have a three to four times greater risk of developing diabetes. In some cases, people gain up to 60 pounds in a year. Petrascheck’s team pinpointed distinct mechanisms in the brain that regulate normal eating and lead to antipsychotic-induced overeating. And importantly, they found a way to counteract it, using an FDA-approved medication called minocycline that’s most commonly used as an antibiotic. Findings were published in Nature Communications.

Petrascheck’s team pinpointed distinct mechanisms in the brain that regulate normal eating and lead to antipsychotic-induced overeating.

The researchers screened 192 approved drugs, looking for one that could suppress antipsychotic-induced overeating in a worm species called Caenorhabditis elegans (C. elegans). The screen led them to minocycline, which blocked the activation of key molecules in a part of the brain known as the hypothalamus, which controls hunger. Blocking this action seemed to have no effect on the drug’s effectiveness, which had been a concern. Although it’s too early to know if minocycline could help human patients, Petrascheck says several small clinical trials are now underway. Petrascheck is now investigating other medications that could have similar effects, as long-term use of antibiotics isn’t ideal. Energized by the findings, Petrascheck wants to use the same C. elegans model to study the metabolic side effects of all FDA-approved medications. “Side effects are unwanted and we don’t know how they arise most of the time,” he says. “The worm is a great discovery system.”

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Autism-associated gene linked to altered pain and touch Children born with only one working copy of the SYNGAP1 gene can exhibit a wide range of symptoms, including seizures, intellectual disability and autistic traits. By creating a patient registry with the help of a concerned mom, Associate Professor Gavin Rumbaugh, PhD, discovered that a broken copy of the SYNGAP1

Kate Carroll, PhD

gene can also disrupt how pain and touch are experienced.

Master regulator of oxidative stress in cells revealed

“We knew SYNGAP1 was critically important for synapse plasticity,” or experience-driven changes in neural circuitry,” says Rumbaugh, whose study appeared in Nature Neuroscience. “What we found is

Whether a cell grows, specializes, works or dies depends upon chemical signals it receives. Among the important signaling molecules are a group known as “reactive oxygen species.” An imbalance can cause oxidative stress, and interfere with important cellular work, sometimes causing the cell’s death.

in addition to that, it also seems to regulate how many connections

Scripps Research chemist Kate Carroll, PhD, has revealed a basic aspect of redox signaling in cells, potentially opening up new, more precise ways to attack cancer and diseases of aging. The redox switch involves a hyperoxidized form of the amino acid cysteine, which is known as sulfinic acid or S-sulfinylation. Carroll and colleagues detailed the redox switch in a recent issue of Nature Chemical Biology. They found the S-sulfinylation switch has many functions within the cell. It regulates the structure of proteins and their activity and interactions, and it affects the movement of proteins in cells, all important factors at play in health and disease, Carroll says. Its activity is fundamental. It is also, in many cases, reversable. Fifty of the S-sulfinylation sites could be reversed back to their original cysteine form through the action of an enzyme known as sulfiredoxin, Carroll says.

now. He’s hopeful early treatment may make it possible to prevent

“Sulfiredoxin is an exciting new target for the diseases of aging, including neurodegeneration and cancer,” Carroll says.

are made in the brain’s primary somatosensory cortex, in how we process touch-related sensory information.” The next step will be developing therapies to restore the missing gene product, he adds. That work is underway at Scripps Research some of the disabilities.

The next step will be developing therapies to restore the missing gene product.

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DISCOVERIES

Biologists show inner workings of cellular ‘undertaker’

ONE OF A CELL’S most important responsibilities is to get rid of the bad stuff. Using a cellular nanomachine called the proteasome, cells break down and recycle proteins that are no longer needed or endanger the cell. Scientists from Scripps Research recently deciphered how the proteasome converts energy into a mechanical motion that untangles and unfolds proteins for destruction. The findings, published in Science, could help us understand how to keep diseases such as Parkinson’s and Alzheimer’s at bay.

The proteasome’s structure is very complex, with a motor and many moving parts.

“The proteasome is like the cellular undertaker,” says Gabriel Lander, PhD, associate professor at Scripps Research. “As we age, our proteasomes become less efficient, which can lead to a variety of diseases.” But the proteasome does not readily reveal its secrets. Lander’s lab worked for years to visualize the inner workings of the tiny protein complex. “Imagine looking up at the moon and trying to read a street sign placed on its surface— that’s the scale we’re dealing with,” says Lander.

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To further complicate matters, the proteasome’s structure is very complex, with a motor and many moving parts. For a clear view of what’s going on, the researchers used cryo-electron microscopy (cryo-EM), which freezes biological complexes in mid-motion. “Other structural methods would have required us to shut down the motor or throw a wrench into it to stall it,” says Andres Hernandez de la Peña, PhD, a postdoctoral fellow in Lander’s lab. “We were able to catch the proteasome red-handed, with pistons pumping.” The insights can fuel efforts to treat neurodegenerative conditions, many of which are marked by tightly folded proteins that accumulate in the brain. “We’ll have a much better shot at figuring out what’s happening to our proteasomes as we age and how to keep them running like well-oiled machines,” he says. The research also holds value for other disease areas. For example, some existing cancer drugs are designed to act on the proteasome, but “they target the shredder blades rather than the motor,” Hernandez says. “Now we can develop a more regulated response.”

Imagine looking up at the moon and trying to read a street sign placed on its surface— that’s the scale we’re dealing with. —Gabriel Lander, PhD, associate professor, Scripps Research

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DISCOVERIES

OZ A N I M O D Multiple Sclerosis Invented by Scripps Research professors Hugh Rosen, MD, PhD, and Edward THREE NOVEL DRUGS making their way

Roberts, PhD

to the marketplace were created at Scripps Research, reinforcing the institute’s legacy of translating discovery biology into much-needed medical treatments. In March, pharmaceutical company Celgene

Trio of new medicines originate from Scripps Research discoveries

filed an application with the U.S. Food and Drug

TA FA M I D I S

Administration for approval to treat multiple

Cardiomyopathy

sclerosis with ozanimod, a drug invented by Scripps Research professors Hugh Rosen, MD, PhD, and Edward Roberts, PhD. In January, the FDA also accepted a drug application from Pfizer for the treatment of

Invented by Scripps Research professors Jeffery Kelly, PhD, and Evan Powers, PhD

cardiomyopathy with tafamidis, a medicine invented by Scripps Research professors Jeffery Kelly, PhD, and Evan Powers, PhD. And in May of last year, individuals with a rare genetic disorder called phenylketonuria

“These three new drugs continue a long history of translating groundbreaking discoveries made at Scripps Research into new drugs used in the clinic,” says Matt Tremblay, PhD, chief operating officer of Scripps Research and its drug discovery division, Calibr. “They underscore the ability of our researchers to play a major role in creating new medicines.”

(PKU) received new hope with the FDA’s approval of BioMarin’s drug Palynziq, which was developed in collaboration with the Scripps Research laboratory of Raymond Stevens, PhD. Scripps Research has originated a total of nine approved drugs, including Surfaxin, which helps premature babies take their first breaths, and Humira, an antibody to treat rheumatoid arthritis and other conditions.

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PA LY N Z I Q Phenylketonuria Developed in collaboration with the Scripps Research laboratory of Raymond Stevens, PhD

Meanwhile, through its Calibr drug discovery

with the Bill & Melinda Gates Foundation

division, Scripps Research is advancing eight

and being evaluated in patients, with more such

additional drug candidates, notably osteoarthritis

programs entering the clinic soon.

candidate KA34, which is being evaluated in a phase 1 study. Calibr also plans to bring two

“The story of ozanimod and these other new

potential cancer therapies to clinical trials in

therapies highlights the uniqueness of Scripps

the near term, and an additional five new drugs

Research,” Rosen says. “There are hardly any

over the next few years. See our feature article,

other academic institutions in the world that

“Forging the Future of Biomedical Innovation”

have the multidisciplinary expertise to

on page 24.

discover a new disease-modifying compound and generate clinical data in support of its

Two other Scripps Research drug programs, focused on infectious diseases, are partnered

development.”

Scripps Research has originated nine approved drugs, including Surfaxin, which helps premature babies take their first breaths, and Humira, an antibody to treat rheumatoid arthritis.

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Science Changing Immunity 16

OUTSMARTING

OUTBREAKS Scripps Research scientists develop super-powered vaccines and therapeutics against HIV, flu and other deadly viruses

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Ever wondered why flu vaccines donâ&#x20AC;&#x2122;t always protect you from the flu? Or why more than three decades after the cause of AIDS was first identified, there is still no approved vaccine for HIV? The simple answer: some viruses are especially tricky. Their genomes evolve incessantly, making them slippery targets. Like criminals donning disguises to escape the police, certain viruses can rapidly change their appearance, evading detection and eradication. Now, however, science is closing in on them.

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Science Changing Immunity

The hub of a global network of

by the National Institute for Allergy and

collaborators, scientists at Scripps

Infectious Disease of the National Institutes

Research are designing and testing a

of Health. “If these strategies prove

new class of vaccines and drugs to

effective in humans, they will represent a

defeat these evasive pathogens. Their

leap forward in our ability to manage and

strategy is based on a class of immune

prevent the spread of infectious disease.”

system proteins called broadly neutralizing antibodies (bnAbs) that possess a kind of superpower: the ability to inactivate a remarkably wide range of virus strains. The

This computer-generated illustration shows an HIV virion with envelope spikes (light green)

ability stems from the property of bnAbs

Vaccines typically work by exposing the

to recognize the more stable regions of

immune system to weakened or inactivated

the outer envelope, the exposed portion

viruses, or to just a portion of a virus. When

of viruses that is typically targeted by

the vaccine is administered to a person,

antibodies.

it lacks the ability to cause illness but retains enough of the virus’s original shape

protruding from its surface (semi-transparent). The envelope

This past year has marked several

and content— collectively referred to as

spikes allow the virion to attach

milestones in the pursuit of these

“antigens”—that the body recognizes it as

itself to target cells and to

“universal” therapies. Last fall, for instance,

foreign. To fight the virus, white blood cells

Scripps Research scientists reported

produce antibodies capable of binding to it

the capsid (blue), into them.

engineering a prototype of a broadly-

at certain locations, known as epitopes. If

Illustration courtesy of Lars

neutralizing flu therapy that protected mice

a person is later exposed to the live virus,

Hangartner.

from multiple strains of influenza known to

the immune system then “remembers” the

affect humans. And in the past six months,

vaccine encounter a nd quickly ramps up its

the International AIDS Vaccine Initiative

defenses to vanquish the invader.

insert its genetic material, contained in a chamber called

“In the past, much of the interaction between vaccines, the immune system and pathogens was invisible to us. Now we can observe these interactions in detail—at the subatomic level, in some cases.” Andrew Ward, PhD, Scripps Research

Devious viruses meet powerful antibodies

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(IAVI) launched two clinical trials to test vaccines developed by Scripps Research

Unfortunately, not all viruses are readily

scientists and their collaborators.

managed. Flu, HIV and other rapidly mutating viruses present a daunting

“We’ve reached a watershed moment in

challenge, as their genomes continually

the field of immunology, where decades

evolve. Thus, the epitopes that antibodies

of research are now coming to fruition in

target to keep us free from infection are

experimental vaccines and drugs,” says

also ever changing.

Dennis Burton, PhD, co-chair of the Department of Immunology and

“Scientists were able to develop effective

Microbiology at Scripps Research and

vaccines against polio, smallpox and

head of the Center for HIV/AIDS Vaccine

measles in large part because the

Immunology and Immunogen Discovery,

neutralizing epitopes on those viruses are

a national research consortium supported

relatively stable,” says Ian Wilson, DPhil,

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chair of the Department of Integrative Structural and Computational Biology at Scripps Research. “But HIV and influenza mutate rapidly, so classic approaches result in vaccines that are quickly outpaced by viral evolution.”

Antibody Anatomy 101 Antigen Region of virus or other pathogen recognized by antibody. Antigen binding site

In the case of flu, the virus has months to evolve between the time annual vaccine

Variable region

production begins and flu season hits. Adding to the challenge, new strains and subtypes of flu not targeted by the vaccine can enter the human population from animals, mainly pigs and birds. In comparison to flu, many more different strains of HIV circulate among infected people at any given time, and even a single

Light chain

person can carry hundreds of thousands of variants of the virus. A drug or vaccine targeting one strain might work for a time

Heavy chain

Constant region

only to have a mutated form emerge that isn’t recognized by the therapies. The excitement over bnAbs stems from their potential to bring this molecular arms race to an end. The first bnAbs to HIV were discovered in the early nineties by Burton and Carlos Barbas at Scripps Research and by scientists in Vienna, Austria. In 2002, Burton led an effort by the newly formed Neutralizing Antibody Center of IAVI at Scripps Research to find and elicit more bnAbs, preferably with greater potency.

When the immune system encounters a virus or other pathogen, it produces antibodies that neutralize the pathogen by targeting molecular structures referred to as antigens.

In 2006, after analyzing 1,800 blood samples from HIV-infected people in parts of Africa, India, Southeast Asia, Australia, the United Kingdom and the United States in an effort dubbed IAVI Protocol G, the SCRIPPS.EDU

Science Changing Immunity Images of antibodies bound to surface glycoproteins of HIV (blue/purple), influenza (red/orange), and Ebola (yellow/green) viruses, generated by electron microscopy and X-ray crystallography. Scripps Research scientists are using state-of-the-art structural biology to study interactions between viruses and antibodies to develop more effective vaccines and therapies. Image courtesy of Charles Murin, Ward lab.

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team found two potent bnAbs in the white

steps that take place in a person’s body

a professor in the Department of Integrative

blood cells of one woman. In 2009, Burton

between an early progenitor antibody and

Structural and Computational Biology.

and his team reported in Science that the

a fully fledged bnAb. With a roadmap of

“Now we can observe these interactions

woman’s antibodies in laboratory tests

that progression in hand, they then set out

in detail—at the atomic level, in some

proved capable of neutralizing 70 percent

to devise ways to reproduce the process

cases. It takes much of the guesswork

of 162 different HIV strains.

through vaccination.

out of determining what’s working and what is not.”

In the time since Burton and his colleagues

The state-of-the-art cryo-electron

discovered bnAbs against HIV, many others

microscopy (cryo-EM) suite at Scripps

have been identified. Researchers also

Research has proven vital to studying

have deciphered quite a bit about what

the molecular intricacies of how the

Last fall, IAVI announced the start of

makes t his type of antibody so effective

immune system and viruses interact.

a phase 1 clinical trial to test a vaccine

against viruses. Over years of battling

Using cryo-EM—which involves deep

developed in the laboratory of William

HIV in an infected person’s body, the

freezing antibodies and surface antigens

Schief, PhD, a professor in the Department

antibodies collect genetic mutations that

from pathogens in liquid ethane and then

of Immunology and Microbiology at

morph the molecular makeup at the tips

scanning the samples with an electron

Scripps Research. The vaccine is the first

of their Y-shaped arms. These adaptions

beam—the team has captured atomic

in a sequence of engineered vaccine

target regions of HIV’s envelope that retain

resolution images of bnAbs binding to HIV

candidates designed to stimulate the

a consistent shape even as other parts

and influenza viruses. These efforts, led

immune system to initiate a key first step

of the virus morph, so the antibodies can

by Scripps Research Professor Andrew

in the generation of bnAbs against HIV.

recognize a broad range of HIV strains.

Ward, PhD, have opened new avenues

BnAbs are exquisitely adapted to home in

for structural biology research on these

“This is just the first step in what would

on and aggressively bind to HIV. Burton and

difficult targets.

be a multistage vaccination strategy. No

Wilson discovered, for example, that the

There’s a lot that seems to be working.

one has ever created or even conceived

antibodies have extra-long loops that act

Ward, and his colleague, Scripps Research

of a vaccine quite like this,” says Schief,

like super Velcro to better cling to HIV virus,

Professor Lars Hangartner, PhD, recently

who is director of vaccine design for

which are notoriously devoid of desirable

developed a technique for using cryo-

IAVI’s Neutralizing Antibody Center. “If

molecular surface features.

EM to rapidly analyze the outcome of

we can make this work for HIV, it could

experimental vaccines against HIV and

be a model for universal vaccines against

other pathogens. Their new methodology

other pathogens.”

From discovery to design Merging research on the immune system, viral pathogens, structural biology and vaccine design, the Scripps Research team has recently made significant progress in engineering a series of vaccines that could be administered in stages to coax the immune system to make bnAbs against HIV. Their strategy hinges on a forensic genomic analysis, tracing evolutionary

lets scientists quickly assess the full spectrum of antibodies a person produces

The other IAVI-led phase 1 HIV-vaccine

in response to an infection or vaccine and

clinical trial, which was announced

determine if these antibodies are likely to

this March, will test a different vaccine

be effective against the pathogen.

candidate that Ward and Wilson helped design with John Moore and Rogier

“In the past, much of the interaction

Sanders at Weill Cornell Medical College.

between vaccines, the immune system and

The vaccine is the first to use a version of

pathogens was invisible to us,” says Ward,

the highly fragile outer shell of HIV—a SCRIPPS.EDU

Science Changing Immunity

protein called Env that is shaped like a

the Scripps Research scientists and an

three-pronged spike—that maintains its

international team of collaborators,

natural shape. It has shown promising

primarily at Janssen, engineered a

results in preclinical tests.

prototype antibody drug capable of protecting against numerous strains of

Flu Snapshot During the 2016/2017 flu season*, vaccines prevented:

“Llamaceuticals” to the rescue

influenza virus.

The Scripps Research team is also applying

The advance, reported in the journal

their expertise in bnAb vaccines to develop

Science last November, received wide

new therapies for flu and malaria, studies

attention from media outlets, including

supported by the Bill & Melinda Gates

The New York Times, Smithsonian

Foundation.

Magazine, Axios, BBC and PBS. I t even garnered an enthusiastic blog post from

influenza illnesses

As much as 20 percent of the U.S.

Francis Collins, MD, PhD, director of the

population gets the flu each year, and

National Institutes of Health.

of those people, around 200,000 are hospitalized. The flu season of 2017-2018

To create the drug, the scientists pursued

was the worst since 2010, with nearly

a different approach than for HIV. Instead of

a million people hospitalized and an

prompting the immune system to produce

estimated 79,000 deaths.

a single broadly neutralizing antibody, they immunized llamas and then engineered a

medical visits

Annual vaccinations help stop the spread

multidomain antibody by tethering together

of the virus, but the shots inoculate

four different llama antibodies, two against

against only a handful of flu strains.

influenza A virus and two against influenza

Because influenza mutates so quickly,

B virus. Wilson and Ward led the X-ray and

epidemiologists must race each year to

electron microscopy structural studies

predict the identity of the next flu season’s

to show exactly where this four-in-one

The Scripps Research team

major strains and then crank out a new

antibody was binding to influenza proteins.

is developing “universal”

vaccine accordingly. Even then, the

approaches to flu therapy

best matched vaccines are only about

“In this case, the llama antibodies could

40 to 60 percent effective. For certain

be easily linked together to create multi-

could help prevent many

types and strains of influenza A viruses,

specific antibodies binding to different

more cases.

vaccine efficacy can drop to as low as

sites on different targets,” Wilson says.

10 to 20 percent. The Scripps Research

“The multi-specificity was key to having

team made news recently for advances in

broad coverage of highly variable

helping develop an experimental influenza

pathogens like influenza.”

hospitalizations

that, if they prove effective in humans,

*Estimates by Centers for Disease Control and Prevention

therapy—with the h elp of llamas. Their research showed that when

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Using a rare type of antibody produced by

administered a s an injection, the antibody

the South American cousins of the camel,

could target vulnerable sites on influenza

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A and B and protect mice against lethal infections. When they tested the multidomain antibody, it prevented 59 strains of human and avian influenza A and B viruses from multiplying in the mice—an important first step in determining whether the influenza inhibitor could possibly work in people. Working with scientists at the University of Pennsylvania, the team developed a different delivery mechanism, a “gene mist” containing viral vectors (harmless viruses used to deliver molecular payloads into the genome). When the mist was sprayed into the noses of mice, the vectors carried a genetic blueprint for the engineered antibody into cells of the animals’ respiratory systems. Those cells, now containing the flu-fighting gene in their DNA, produced the antibody, confirming immunity to dangerous strains of flu. If a similar strategy works in humans, an annual inoculation might still be required, but it would theoretically protect people against far more strains than the seasonal flu vaccine. “And there are other intriguing possible advantages,” Collins wrote of the new strategy. “For example, the rapid protection this approach might afford, along with its potential to neutralize many forms of avian influenza, suggest it might be called into action to help quell an emerging flu pandemic far more swiftly

The llama antibodies could be easily linked together to create multi-specific antibodies binding to different sites on different targets. In this case, the multi-specificity was key t o having broad coverage of highly variable pathogens like influenza.

than is possible with traditional vaccines.” Ian Wilson, DPhil

Until then, the team at Scripps Research is on the case.

Chair of the Department of Integrative Structural and Computational Biology at Scripps Research

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Science Changing Medicine

Calibr

Primer

Scripps Research

Scripps Research Translational Institute

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Creating a new medicine takes time. But time is a luxury many patients can’t afford.

Forging the future of biomedical innovation For people diagnosed with diseases that undermine their quality of life and threaten their survival—cancers, neurological diseases, deadly infections—effective new therapies can’t come soon enough.

Translational Institute founded by Eric Topol, MD, to individualize healthcare by leveraging the remarkable progress being made in human genomics and combining it with the power of wireless digital technologies and artificial intelligence.

With this urgency in mind, Scripps Research has pioneered a new nonprofit research model to dramatically accelerate the translation of groundbreaking scientific discoveries into life-changing therapies. Over the past several years, Scripps Research—which has originated nine approved drugs—has greatly expanded its translational research capacity. Under the leadership of Peter Schultz, PhD, the institute is simultaneously fueling fundamental scientific discoveries that give new insights into human diseases and speeding their translation into new medicines.

The addition of Calibr, which specializes in the identification, optimization and early-stage clinical testing of drug candidates, provides a seamless path for advancing promising Scripps Research discoveries into human trials. Recently, the institute launched Primer, a novel funding vehicle that will be used to advance a portfolio of candidate medicines to treat cancer, osteoarthritis and neurodegenerative, cardiopulmonary and infectious diseases. Initial funding has been committed through a lead grant from the Bill & Melinda Gates Foundation, and most recently, the Hearst Foundations. The investments in Primer are made as recoverable grants that are returned to contributors upon licensing of programs in the Primer portfolio for further development.

At the heart of this evolution is the merger of Scripps Research with two other entities: Calibr, a nonprofit drug discovery center founded by Schultz in 2012; and the Scripps Research

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Science Changing Medicine

chondrocytes, specialized cells that produce healthy cartilage in the knee joint. When given to animals, the compound was effective at regenerating cartilage. KA34 was created as the result of medicinal chemistry optimization of physical properties and toxicology studies in animals. “The story of KA34 is proof positive that integrating academic science and drug discovery capabilities offers incredible potential for speeding translation of basic discoveries into medicines in the nonprofit sector,” says Schultz. KA34 is being tested as a treatment for osteoarthritis of the knee in a phase 1 clinical trial run by Calibr scientists and funded by the California Institute for Regenerative Medicine (CIRM). Another regenerative program for multiple sclerosis has been partnered to advance into a phase II clinical trial.

“ Primer enables us to develop innovative medicines that impact public health and creates an evergreen model for funding basic and translational research in the nonprofit sector.” Peter Schultz, PhD President and CEO of Scripps Research and Calibr

Scripps Research has created this novel approach not only to change the way new medicines are developed, but also to ensure the long-term sustainability and growth of nonprofit research by capturing more of the value in its science and reinvesting it back into research. “Primer enables us to develop innovative medicines that impact public health and creates an evergreen model for funding basic and translational research in the nonprofit sector,” says Schultz, president and CEO of Scripps Research and Calibr. The initial Primer portfolio includes 10 select drug candidates in varying stages of development. Among the assets in the initial Primer-funded portfolio is KA34, a small molecule that stimulates cartilage production and repair in osteoarthritis, t he prevalent form of arthritis that affects tens of millions of people worldwide. The only nonsurgical therapies for the disease are drugs that treat the pain and inflammation but have no impact on the loss of cartilage, the underlying cause of the disease. The idea for KA34 stemmed from a discovery of a compound at Scripps Research that generates 26

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Primer will also support the clinical evaluation of DUPA-CD3, a novel bispecific antibody for metastatic prostate cancer that harnesses the patient’s own immune system to eliminate tumor cells. Calibr expects to begin treating patients with DUPA-CD3 i n the second half of 2019. Primer’s other lead cancer program is a “switchable” Chimeric Antigen Receptor T-cell (CAR-T) cancer therapy, which will be advanced by the Calibr team into a phase 1 clinical trial in cancer patients this year in partnership with AbbVie. Calibr’s innovative CAR-T therapy program is designed to enhance safety, versatility and efficacy through a CAR-T cell that uses antibody-based molecules to control the activation and antigen specificity of CAR-T cells. AbbVie entered into a significant partnership with Calibr with the belief that this technology will allow CAR-T therapy to safely treat solid tumors, such as breast and prostate cancer, which have eluded conventional CAR-T therapies to date. Primer includes two additional immune-based therapies for cancer as well as candidate medicines for degenerative disease and chronic diseases of aging. These latter programs include a novel immunomodulatory therapy for Parkinson’s disease, an engineered peptide that stimulates regeneration of the intestinal barrier for gastrointestinal disease, a drug for lung fibrosis, and a long-acting oral preventative for Lyme disease. The early stages of drug development—identifying and optimizing lead drug candidates, preclinical studies and early human trials for safety and efficacy—are notorious for presenting significant barriers to progress. These stages are commonly referred to as the “valley of death” by researchers, a reference to the challenges of finding public and private funding and partners with translational research expertise for

Primer supports translational research on ten drug candidates

Primer New medicines on the horizon Leveraging the unique scientific framework of Scripps Research, Calibr has created a portfolio of drug candidates based on Scripps technologies, and is shaping a new paradigm for advancing nonprofit biomedical research to impact patients while re-investing in further innovative research. Primer supports taking advanced assets through IND-enabling studies and early clinical development. Aiming to accelerate an impact on patients and create significant value to support scientific research, Primer advances a portfolio of new medicines to treat cancer, degenerative diseases, and chronic diseases that affect either children or the aging population.

an as-yet untested experimental medicine. Many promising ideas for new therapies stall due to these barriers. Scripps Research Professor Hugh Rosen, MD, PhD, says in his experience it required tremendous effort to bring a laboratory discovery to the point of testing a drug in clinical trials. Discoveries by Rosen and another Scripps Research professor, Edward Roberts, PhD, in the early 2000s led to the drug ozanimod, which is expected to be approved by the U.S. Food & Drug Administration for the treatment of multiple sclerosis later this year. “The translational scientific infrastructure and expertise at Scripps Research are now established and funding mechanisms already in place, which will help overcome many of the hurdles we faced in the past,” Rosen says. “It serves everyone well— the scientists, the institute and, most importantly, patients.” SCRIPPS.EDU

Calibr Capabilities and Infrastructure From bench to bedside

Science Changing Medicine

discovery

Protein Engineering • Fusions of antibodies with bioactive peptides and proteins • Semi-synthetic peptide technology • Switchable CAR-T cell therapy

Small Molecule Discovery • Library of >850,000 drug-like compounds • Best-in-class drug repurposing collection • State-of-the-art robotics • Expertise in cell-based screening and mechanistic deconvolution

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optimization

translation Pharmacology & Safety

IND-Enabling Studies

• Dedicated core group supports rapid model development and proof-of-concept rodent studies

• Dedicated internal team and network of trusted contractors and consultants

• In-house/CRO support for PK/ PD, in vitro safety assessment and toxicology

• GLP toxicology and safety studies • Multi-species PK and allometric scaling • Regulatory expertise

Medicinal Chemistry

Clinical Safety & Proof-of-Concept

• Optimize small molecules to enhance drug-like properties

• Phase 1 safety and Phase 1b/2a proof-of-concept (PoC) studies

• Transform biological tools into bona fide experimental medicines

• Capacity to take a number of programs through early clinical studies

• Leverage chemical biology expertise to design “smart” drugs

• Leverage nonprofit clinical partners to gain unique access and speed

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CLICK CHEMISTRY

An innovative approach to chemistry and drug discovery that clicks.

SCRIPPS.EDU

Science Changing Discovery

Think about the sound that Legos make when they snap together. They click. In 2001, K. Barry Sharpless, PhD, won the Nobel Prize in Chemistry for his work on chiral catalysts. That same year, he published another body of work, just as impactful. Dubbed “click chemistry,” it described a collection of reactions that enable larger molecules to snap together easily, like Legos. What’s more, they link only with each other, without reacting with other nearby biological molecules. It was as though the chemistry world had received a gift of the best Lego set ever made.

K. Barry Sharpless, PhD; Click chemistry methods make it possible to attach DNA “barcodes” to molecules so that experiments can be miniaturized, lowering costs.

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Since then, Sharpless’ “click chemistry” has transformed how scientists approach drug discovery, bioimaging and much more. Sharpless’ paper, “Click Chemistry: Diverse Chemical Function from a Few Good Reactions,” published in the German scientific journal Angewandte Chemie with co-authors Hartmuth Kolb, PhD, and M.G. Finn, PhD, has been cited by other scientists 8,500 times, according to the Web of Science—an extraordinary number.

f them that we discovered in 2002 and o 2013 nearly are.”

Also impressive is click chemistry’s impact on both science and society. New drug discovery methods, new medicines, new scientific tools, new bioimaging methods and contrast media—click chemistry has produced them all, catalyzing the field of biochemistry and transforming the global search for medicines.

“Click chemistry is a reaction that gives us these unique properties: You can do it in water, and the two halves of the ‘click’ don’t click with anything else,” Williamson adds. “This enables anyone to join two molecules by clicking them together, which is useful for all kinds of experiments where you want to put a specific label in a certain position.”

Today, scientists at Scripps Research are working on faster, less costly, more efficient ways of creating the individualized therapies that genomic medicine demands. Click chemistry serves as a critical enabling technology for those new methods.

Click chemistry explained Sharpless’ team described click chemistry as, “a fast, modular approach to find and manufacture new molecules and materials with superior properties, and at much lower cost.” “The force at the heart of this discovery engine is almost entirely down to the rarity of the reactions we allow to be involved in the intermolecular module linking steps,” Sharpless adds. “These reactions need to be perfect. In other words, they need to produce 99.999-plus percent yield. Two

James Williamson, PhD, the institute’s executive vice president of Research and Academic Affairs and a professor in the Department of Chemistry and the Department of Integrative Structural and Computational Biology, says click chemistry has enabled all sorts of discoveries that couldn’t be made any other way.

Williamson studies how ribosomes, the cell’s protein-building factories, assemble and then build complex molecules that drive growth and life. His laboratory has used click chemistry to “tag” the newly synthesized proteins in bacteria for analysis of their synthesis and degradation rates.

Medicines inspired by nature In his Nobel lecture, Sharpless recounted how he had loved fishing as a child. After joining Scripps Research in 1990, he frequently contemplated his science during long walks or runs along the Torrey Pines Mesa, the Pacific Ocean horizon by his side. In his mind, Sharpless said, he would turn over the three-dimensional shapes of various molecules, pondering how the molecules of life assembled and behaved. In the same way, he had once gazed at interesting sea creatures during childhood fishing outings.

In the seminal click chemistry paper, Sharpless observes that carbon dioxide serves as nature’s starting material. He notes that nature’s reactions happen mainly in water. He further observes that DNA molecules, proteins and polysaccharides are polymers—subunits linked together with carbon-based bonds. Click chemistry, then, was nature’s chemistry, using the same raw materials, in water, to make chains. Its elegant simplicity was seized upon by chemists across the globe, who began using it for many purposes, including assembling compound libraries for drug discovery. Among the first beneficiaries were people with HIV. Viruses including HIV-1 use enzymes called proteases in the final phase of their maturation. Drugs designed to inhibit proteases have helped people infected with the HIV virus to lower their viral loads, so that today the life expectancy for a treated person with HIV compares with that of an uninfected person. Click chemistry methods made it possible to assemble large “libraries” of potential drug molecules, to select for the optimal molecule. And so, with the HIV epidemic raging, protease-inhibiting libraries were made, enabling discovery of new and more effective drugs. Click chemistry has also been used to create “libraries” of potential drugs for diabetes, Alzheimer’s, Parkinson’s, cancer and many other diseases. Today, to test these compound libraries at a large scale, scientists use plates of microwells—tiny test tubes—and robotic arms able to test hundreds of thousands of compounds in a matter of days. This industrial system does in short order what

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Science Changing Discovery

Asking good questions is vital. Strong inference, a multitude of working hypotheses, and the periodic table will never let you down. — K. Barry Sharpless, PhD | 2019 Priestley Medal Address

From the bench to the robot, click chemistry enables vast “libraries” of potentially important molecules to be built, combined with other molecules and studied for potential benefit to humanity.

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an individual scientist would once have needed years to accomplish with the standard tools, pipettes and test tubes. If high-throughput robotic systems enabled by click chemistry are now the state-of-the-art in drug discovery, some scientists predict the future will be smaller. Much smaller–yet still made possible through Sharpless’ click chemistry.

Clicking toward the future

what enables us to sequence genomes at a fraction of the cost of what we used to pay,” Paegel says. “This is what will unlock the human genome to drug discovery.” Click chemistry enables the design of compound libraries for his miniaturized system. The compounds he’s working with now have antibiotic-like traits. He uses click chemistry to affix unique DNA barcodes to each new substance, so the results can be read using his microchips.

In the Jupiter, Florida, laboratory of Scripps Research Chemistry Professor Brian Paegel, PhD, lasers spark in a curtained- off back room. Researchers assemble spaghetti-like pieces of tubing onto microchips etched with channels. They’re preparing to test a collection of drug-like compounds for their ability to become novel antibiotics.

“Click chemistry is something that we use as a tool. It’s a given, it’s ubiquitous, like Legos,” Paegel says.

Paegel believes these microfluidic devices will one day supplant those futuristic-looking high-throughput screening robots. The robots are at work in pharmaceutical companies globally, and also at the Scripps Research-Florida campus and the Calibr translational drug discovery division at Scripps Research in La Jolla. These systems have revolutionized drug discovery. But they are expensive to build and operate, and ripe for disruption, he argues. To address the world’s vast and growing unmet medical needs and take advantage of genomic data, Paegel believes the future will require miniaturization.

In April, the American Chemical Society presented Sharpless, Scripps Research’s W. M. Keck professor of chemistry, with the 2019 Priestley Medal, the highest honor the organization bestows. The society said it is recognizing Sharpless for multiple advances: “the invention of catalytic, asymmetric oxidation methods, the concept of click chemistry and development of the coppercatalyzed version of the azide- acetylene cycloaddition reaction.”

“Miniaturization is what enables us to live our lives on computers and phones. It is

Williamson says what have made click chemistry such a gift to researchers are its simplicity, reliability, and ready availability of so many reagents for a wide variety of applications.

“Dr. Sharpless has made numerous contributions to chemistry that have each significantly moved the field forward,” said Thomas Connelly, Jr., PhD, executive director and CEO of the society, announcing the award. “His service to advancing chemistry is beyond measure.”

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Science Profile

On the Nose

Investigating the neural mechanisms underlying the brain’s recognition and interpretation

of odors with Scripps Research neuroscientist Lisa Stowers, PhD

Ever wrinkled your nose at a garbage can or leaned into a fragrant blossom? Odors, even imperceptible ones, regularly influence our behavior. Neuroscientist Lisa Stowers investigates the neural mechanisms underlying our brain’s recognition and interpretation of odors, with some surprising discoveries, including the fact that female mice cannot smell male p heromones when it is not time to mate, becoming virtually “blind” to the males’ presence. Recently, she and her lab received an NIH grant to describe a complete neural circuit in a mammalian brain—a first for science.

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What drew you to neuroscience as an academic field? I took a nontraditional path, initially pursuing cancer research as a graduate student, where I identified signaling cascades in cells. But so much was already known in these areas; I needed the “big black box,” something with lots of questions. So, as a postdoc, I turned to neuroscience. Maybe I’ve been primed for this field since childhood. I had a very influential grandmother, a postal worker and early feminist, who always challenged me to think big. She encouraged me to be a lawyer or a doctor, even suggesting I should become a neurosurgeon because that was one of the most difficult medical specialties to pursue.

After earning your doctorate in molecular and cellular biology from Harvard, did you come straight to Scripps Research? Actually, no. Upon completing my postdoc, I found myself rather burned out and considered doing something completely different from science. I applied to become a florist because of the creative aspect but couldn’t get hired because I had no experience! My postdoc advisor in Boston continued to encourage me and I ended up interviewing for a biochemistry position at GNF (The Genomics Institute of the Novartis Research Foundation), where they said I sounded like a research scientist and recommended Scripps Research. This was the luckiest series of events because I love working here. There’s little bureaucracy and I have plenty of opportunity to explore big questions.

Favorite outside-the-lab pursuits? I enjoy running, road biking and swimming, and I swim in La Jolla Cove with department members. My husband, daughter and I go on family hikes, most recently to Mt. Rainier in Washington. We ski in winter. But I have trouble turning off my mind. I’m constantly thinking about science and all its questions.

Since you study smells, are you more aware of odors or your reaction to them in daily life? Yes, I do notice odors and think about how they affect our behavior. I’m aware that some stores have a signature scent designed to motivate shoppers, although there’s not a lot of science behind that. Because my husband has odor-triggered migraines, we keep a low odor profile at home. So, when I’m out, I put my nose in everything.

Decoding behavior: How a smell sparks action Neurons don’t act alone. Rather, they’re organized into interconnected circuits that carry out specific functions when activated. In certain parts of our brain— especially in the complex limbic system, which controls our emotions and drives—these circuits ultimately shape our behavior. With support from the National Institutes of Health’s BRAIN Initiative, Stowers is documenting the intricate logic of a social behavior circuit. As with many of the brain’s more complicated functions, research models of circuits for social behavior have never been created. Using experiments involving mice and pheromones, she’s creating the first. Stowers likens the project to understanding computer software: Studying individual lines of coding can only reveal the range of possible capabilities; true understanding occurs when the entire code, in a specific order, is investigated and manipulated. For Stowers, this means she’ll be looking at the neural coding in its entirety, across brain regions, from beginning to end. The resulting knowledge will hold unquestionable value for the neuroscience community and fuel additional discovery that will benefit human health, much like the first genome sequence did.

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Science Profile

Lisa Stowers, PhD, studies how certain smells affect how we act.

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Awards Honors Grants PIONEERING NMR STUDIES OF DISORDERED PROTEINS

Scripps Research scientists Peter Wright, PhD, and Jane Dyson, PhD, both professors in the Department of Integrative Structural and Computational Biology, have been awarded the prestigious 2019 ISMAR Prize from the International Society of Magnetic Resonance for their “pioneering NMR studies of disordered proteins.”

International Society of Magnetic Resonance: 2019 ISMAR Prize

Many scientists who contributed to the early development of magnetic resonance went on to win Nobel Prizes, underscoring the importance of this research area. Dyson is the first woman to win the ISMAR Prize, and she and Wright will receive their award at the Joint Meeting of ISMAR and EUROMAR in Berlin later this year.

AMERICAN ACADEMY OF ARTS AND SCIENCES

Chemist Jin-Quan Yu elected to American Academy of Arts and Sciences Yu, the Frank and Bertha Hupp Professor of Chemistry, is known globally for his work in organic synthetic chemistry, having developed new approaches for making molecules used for medicine and other applications. He pioneered many of the first practical and robust carbon-hydrogen (C–H) bondAcademy members are world leaders in the arts and sciences, business, philanthropy activation reactions now used in nearly every sector of chemical science. and public affairs. The society, which also functions as an independent research Yu joins 20 other Scripps Research faculty center, emphasizes interdisciplinary study who have been named as members of the to address significant challenges. Academy. The new class will be inducted at a ceremony in October 2019 in Cambridge, “Jin’s election to the Academy as a scientist reflects a special distinction of achievement Massachusetts, joining the company of that is recognized well beyond our immediate members elected before them, including Benjamin Franklin, Ralph Waldo Emerson, scientific circles,” says James Williamson, Albert Einstein, Robert Frost, Margaret PhD, executive vice president of Research Mead and Martin Luther King, Jr. and Academic Affairs at Scripps Research. The American Academy of Arts and Sciences, one of the world’s most prestigious honor societies, elected Scripps Research chemist Jin-Quan Yu, PhD, as a member of its 2019 class.

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CHEMICAL BIOLOGY

2019 Sackler Prize The 2019 Raymond and Beverly Sackler Prize in the Physical Sciences in the field of Chemistry/Chemical Biology was awarded to Matthew Disney, PhD, a professor in the Department of Chemistry at Scripps Research. He shared the prize with Christopher Chang, PhD, a professor at the University of California, Berkeley, and Jason Chin, PhD, a professor at the University of Cambridge and Programme Leader at the Medical Research Council Laboratory of Molecular Biology in Cambridge. The Sackler Prizes are administered by Tel Aviv University and awarded to scientists under the age of 45 who have made outstanding contributions to their field. The $100,000 prize alternates each year between the fields of chemistry and physics. This yearâ&#x20AC;&#x2122;s award was given in chemical biology as a special field of chemistry.

CANCER RESEARCH

American Association for Cancer Research: 2019 NextGen Star

CHEMICAL SYNTHESIS

2019 Sloan Research Fellow Keary Engle, PhD, an assistant professor in the Department of Chemistry, has been named a Sloan Research Fellow for 2019. The two-year fellowship is designed to stimulate fundamental research by earlycareer scientists of outstanding promise. In his lab, Engle and his team harness the power of catalysis to make chemical synthesis more efficient, effective and sustainable. Engle earned his PhD in chemistry and DPhil in biochemistry as a Skaggs Oxford Scholar within the graduate school program at Scripps Research. He joined the institute in 2015.

The NextGen Stars program of the American Association for Cancer Research (AACR) recognized 16 outstanding earlycareer scientists at its annual meeting in Atlanta. Among the honorees was Michalina Janiszewska, PhD, an assistant professor in the Department of Molecular Medicine. In her lab, Janiszewska is working on intratumor heterogeneity in breast and brain cancer, developing in vitro and in vivo methods to investigate relations between genetically distinct cancer cell populations. She joined Scripps Research last year after completing postdoctoral research and serving as an instructor at the Dana-Farber Cancer Institute.

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Awards Honors Grants Eric Topol pens book on artificial intelligence in medicine The greatest opportunity offered by AI is not reducing errors or workloads, or even curing cancer: it is the opportunity to restore the precious and time-honored connection and trust —the human touch—between patients and doctors. Eric Topol, MD Executive Vice President, Scripps Research

Preparing medicine for the digital future The National Health Service (NHS) of the United Kingdom has announced the launch of the Topol Program for Digital Fellows, an initiative to train clinical staff in specialist digital skills, including the use of digital technologies, while giving clinicians enough time outside of the clinic to receive dedicated training for a digital future. The fellowship program follows recommendations laid out in the recently released Topol Review, an independent review headed by Eric Topol, MD, executive vice president of Scripps Research, to prepare the NHS workforce to deliver the digital future of healthcare. Read more at scripps.edu/TopolFellows

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The relationship between doctors and patients has eroded over recent decades, with minimal time and keyboards as the main culprits. Physicians—and all clinicians—are experiencing burnout at increasing rates, and superficial contact with patients is resulting in diagnostic errors and unnecessary tests and procedures. In his latest book, Deep Medicine: How Artificial Intelligence Can Make Healthcare Human Again, Eric Topol, MD, tackles the complex and fascinating topic of artificial intelligence (AI) in medicine. Released in March, and featured by CNBC, NPR and The New York Times, Deep Medicine explores how AI is transforming medical care and its great potential in areas such as mental health, nursing and personalized nutrition. A pioneer of individualized medicine and founder of the Scripps Research Translational Institute, Topol is a physician-scientist who melds genomics, digital medicine and, increasingly, AI. Described by many in the medical field as a futurist, Topol gives readers a deep dive into how AI will not only transform the practice of medicine, but also radically reshape health systems and impact biomedical science. By sharing examples from his own life as a cardiologist, researcher and patient, combined with expert interviews and in-depth reviews of current AI literature, Topol engagingly narrates a provocative vision of the future of medicine.

Sydney Brenner, Nobel laureate and genetics pioneer, dies at 92 Sydney Brenner, PhD, a pioneer in genetics, molecular biology and neuroscience who collaborated closely with Scripps Research scientists, died April 5 at the age of 92. Brenner devoted his career to conducting groundbreaking basic research, making seminal discoveries about how the genetic code is expressed to produce proteins and establishing the roundworm C. elegans as a critical model organism in science, which laid the groundwork for decoding the human genome. “Simply put, he was one of the greatest minds of the 20th Century,” says Kim Janda, PhD, the Ely R. Callaway, Jr. Professor of Chemistry at Scripps Research, who worked closely with Brenner. Born in South Africa, Brenner studied at Oxford University and was one of the first people to see the DNA model created by James Watson, PhD, and Francis Crick, PhD. “The double helix was a revelatory experience; for me everything fell into place, and my future scientific life was decided there and then,” Brenner wrote.

He then turned his attention to studying a tiny roundworm, Caenorhabditis elegans, better known as C. elegans, and established it as a primary model organism for studying the genome, nervous system and developmental biology. With colleagues, he made numerous advances in studying C. elegans, leading to the discovery of programmed cell death. For their achievements in this area, Brenner, H. Robert Horovitz, PhD, and John Sullivan, PhD, shared the Nobel Prize in Physiology or Medicine in 2002.

He later worked closely with Crick, sharing an office with him for 20 years at the Medical Research Council Laboratory of Molecular Biology at Cambridge, UK. Crick and Brenner showed that DNA is a triplet code, where groups of three DNA letters specify each link in the amino acid chains that serve as the backbones of proteins. Brenner also co-discovered messenger RNA (mRNA), a critical intermediary in the expression of genes into proteins.

In the early 1990s, Brenner began a fellowship at Scripps Research, where he collaborated closely with Richard Lerner, PhD, then director of the institute. In 1992, they published a paper introducing the concept of DNA-encoded libraries, a technology for using DNA barcodes to organize large libraries of chemical compounds. Working with Janda, Brenner and Lerner implemented one of these DNA-indexed chemical libraries in 1993. The technique has since become a powerful and widespread research method in academia and the pharmaceutical industry.

Elected Fellows

AMERICAN ASSOCIATION FOR THE ADVANCEMENT OF SCIENCE & AMERICAN ACADEMY OF MICROBIOLOGY

Friedbert Weiss, PhD, a professor in the Department of Neuroscience, has been named a fellow of the American Association for the Advancement of Science (AAAS), the world’s largest multidisciplinary scientific society. Michael Farzan, PhD, co-chair of the Department of Immunology and Microbiology, has been named a fellow of the American Academy of Microbiology (AAM), the honorific leadership group within the American Society for Microbiology (ASM), the world’s oldest and largest life science membership organization.

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Awards Honors Grants

2019 IUPAC DISTINGUISHED WOMEN IN CHEMISTRY OR CHEMICAL ENGINEERING

To celebrate International Day of Women and Girls in Science on February 11, the International Union of Pure and Applied Chemistry (IUPAC) named Donna Blackmond, PhD, co-chair of the Department of Chemistry, to its 2019 list of Distinguished Women in Chemistry or Chemical Engineering. She joined 11 other honorees from around the world, each selected for their excellence in basic or applied research, distinguished accomplishments in education or demonstrated leadership in the chemical sciences. Blackmond will receive her award in July at the IUPACâ&#x20AC;&#x2122;s World Chemistry Congress in Paris.

WHITEHALL FOUNDATION HONORS TWO SCRIPPS RESEARCH NEUROSCIENTISTS

Giordano Lippi, PhD, and Li Ye, PhD, both assistant professors in the Department of Neurology, have received grants from the Whitehall Foundation to support their studies into brain function. Each researcher will receive $225,000 over three years. In the Lippi lab, the new funding will support research into microRNAs, the regulatory molecules that control brain development, particularly miR-218, which has been linked to epilepsy and cognitive impairment. The separate award to the Ye lab will support research to identify the brain circuits that drive organisms to eat more food when they are in a cold environment. The Whitehall Foundation, founded in 1937, focuses exclusively on funding neurobiology research in the U.S.

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ROYAL SOCIETY OF CHEMISTRY: 2019 RSC MEDIMMUNE PROTEIN AND PEPTIDE SCIENCE AWARD

The Protein and Peptide Science Group of the Royal Society of Chemistry honored Philip Dawson, PhD, with its biennial RSC Medimmune Protein and Peptide Science Award for his “creative and impactful work in peptide and protein science.” Dawson, a professor in the Department of Chemistry, is also dean of graduate and postdoctoral studies at the institute and oversees its Skaggs Graduate School of Chemical and Biological Sciences.

NATIONAL FOUNDATION FOR CANCER RESEARCH: SALISBURY AWARD

The inaugural Salisbury Award for Entrepreneurial Translational Research was given to Eduardo Laborda, PhD, associate director of immuno-oncology at Calibr, while Luke Lairson, PhD, (shown here) assistant professor of chemistry at Scripps Research, was recognized as runner-up. Laborda won for his work on a switchable next-generation CAR-T cell therapy and Lairson was honored for his unique chemical genetics-based approach for the identification of new cancer-relevant mechanisms and lead candidates for drug development programs.

AMERICAN CHEMICAL SOCIETY: 2019 E.B. HERSHBERG AWARD

The 2019 E.B. Hershberg Award for Important Discoveries in Medicinally Active Substances was given to Jeff Kelly, PhD, by the American Chemical Society (ACS) at its national meeting in Orlando, Florida. Kelly received recognition “for his understanding of transthyretin aggregation and discovering tafamidis, the first regulatory agencyapproved drug to slow the progression of a neurodegenerative disease by inhibiting protein aggregation.” Kelly is a professor in the Department of Chemistry and also the faculty appointee to the Scripps Research Board of Directors.

NASA: PCE3 CONSORTIUM LEADERSHIP

Scripps Research Associate Professor Ramanarayanan Krishnamurthy, PhD, has been named co-leader of a new NASA initiative to investigate how life emerged from Earth’s early environments. The initiative, called the Prebiotic Chemistry and Early Earth Environments (PCE3) Consortium, will explore the chemical processes that occurred on early Earth and the advent of the first biological molecules and pathways, leading to the emergence of systems harboring the potential for life.

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Our stars shine bright Scripps Research receives highest possible charity rating Following a qualitative review of dozens of performance metrics valued by charitable givers, Scripps Research has been awarded an “exceptional” rating of four stars, indicating it exceeds industry standards and outperforms most charities in its cause. The four-star designation from Charity Navigator, an independent evaluator, is the highest rating possible. “This recognition from Charity Navigator is so important to us because it acknowledges our dedication to financial stewardship,” says Jennifer Crosby, vice president of Philanthropy and Community Engagement for Scripps Research. “We’re grateful for all of the support we receive from our donors and our community, and they can expect the best from us in return.” Financial gifts to Scripps Research enable scientific discovery that advances the field of medicine, ultimatel y to improve or save lives. Among the many FDA-approved drugs to result from ingenuity at Scripps Research are treatments for several cancers, leukemia, arthritis and respiratory distress syndrome. Dozens of additional drug candidates—targeting pain, multiple sclerosis, dementia and other disease areas—are currently undergoing analysis and refinement. In addition to its reliance on philanthropic gifts and funding from the National Institutes of Health, Scripps Research has established a first-of-its-kind translational research model for funding nonprofit research institutes. Through industry partnerships and licensing agreements, the organization is advancing new drug candidates and bringing yet another layer of financial sustainability to fuel its mission.

Science changing life

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SCRIPPS RESEARCH

2019 – 2020 Your front row seat to history, as some of the world’s leading scientists share their view of science and medicine. June 13, 2019 Arnab Chatterjee, PhD

VP of Medicinal Chemistry, Calibr

Kristen Johnson, PhD

Principal Investigator, Biology, Calibr

Travis Young, PhD

Scientists at Calibr, the drug discovery division of Scripps Research, are advancing new medicines to treat cancer, degenerative diseases a nd chronic illnesses that affect children and the aging population. Three lead Calibr scientists will talk about some of the most promising drug candidates in the pipeline for treating unmet medical needs.

VP of Biologics, Calibr

August 15, 2019 Kristian Andersen, PhD

Associate Professor, Department of Immunology and Microbiology, Scripps Research; Director of Infectious Disease Genomics, Scripps Research Translational Institute

Infectious disease genomics is solving mysteries about how dangerous viruses such as Zika and Ebola evolve and spread around the world. Andersen spearheads large international collaborations that seek to improve outbreak response and prevent the future transmission of viral pathogens by outlining their evolutionary history and factors contributing to their spread.

October 17, 2019 Matthew D. Disney, PhD Professor Department of Chemistry Scripps Research

Disney invents new ways to address supposedly “undruggable” diseases by designing precision, RNA-binding medicines rather than targeting proteins, the usual approach. His group’s active targets include adult onset muscular dystrophy, dementia, ALS, Parkinson’s, heart failure, cancer and infectious diseases.

January 23, 2020 Lisa Stowers, PhD Professor Department of Neuroscience Scripps Research

How we are feeling shapes our behavior in surprising ways. Stowers’ research is shedding new light on how the brain creates and responds t o our emotions, with a special focus on how stress and pleasure alter o ur social interactions.

March 26, 2020 Donna Blackmond, PhD Professor Department of Chemistry Scripps Research

What do your hands, the smell of caraway seeds and spearmint leaves, and Lewis Carroll’s “Through the Looking-Glass” have to do with the search for new drugs to cure diseases like Alzheimer’s, autoimmune disorders and addiction? Blackmond will explore fascinating connections to groundbreaking science at Scripps Research.

Join us for our 2019-2020 season! To reserve your seat and learn more, visit us at frontrow.scripps.edu SCRIPPS.EDU

Events

From Discoveries to Medicine

Left to right: Claudia Skaggs Luttrell, Dallas Luttrell and Bill Self

Courtney Miller, PhD, shares research on new avenues to treat addiction relapse and PTSD.

Scripps Research-California welcomed more than 200 foundation representatives, philanthropists, biopharma leaders, healthcare investors and scientists to its inaugural Spectrum symposium on Feb. 20 in La Jolla. Designed to foster relationships to help accelerate the delivery of novel medicines to patients, the daylong event featured panel discussions, scientific presentations and keynote speakers.

Shining a Light on Prader-Willi Nearly 100 floating lotus lights dappled the lake on the Scripps Research-Florida campus during the inaugural Light Up the Lake event in January to raise funds for Prader-Willi syndrome research. Children with the disease have a specific type of genetic damage to chromosome 15 which leads them to experience insatiable hunger. The luminescent floating flowers were purchased for a donation by children and families affected by the condition, as well as their supporters, to bring awareness to the disorder and inspire scientists to keep working for a cure.

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The Future of Medicine The Future of Individualized Medicine conference drew scientists from across the globe in March to the Scripps Seaside Forum for two days of discussions and presentations about the roles that genomics, digital medicine, artificial intelligence and behavioral science play in transforming medicine.

Dr. Eric Topol (left) interviewed Sonia Vallabh and Eric Minikel about their efforts to find a treatment for human prion disease, a fatal neurodegenerative disease for which Vallabh has inherited a genetic mutation.

Why Storytelling Matters in Science

Science journalist Ed Yong delivered a talk on the art of storytelling and the craft and ethics of good science writing before a full auditorium of Scripps Research scientists on Feb. 21. Kristian Andersen, PhD, hosted the presentation by Yong, who reports for The Atlantic, among other publications.

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Fund knowledge. Fuel health.

“An investment in knowledge always pays the best interest.”

Endow a graduate student fellowship at Scripps Research and drive the transformation of health.

—Benjamin Franklin

When you join Scripps Research faculty and supporters in a campaign to endow fellowships for students in our nationally ranked graduate program, you drive the California Philanthropy office Meredith Johnston Senior Director merejohn@scripps.edu (858) 784-2874

future of healthcare. Nature Index names Scripps Research #1 in the world for its impact on innovation, citing the thousands of health-related inventions arising from discoveries made here. Many of the young scientists emerging from the Skaggs Graduate School of Chemical and Biological Sciences contributed to those discoveries. They carry their exceptional education and training into the

India Mittag Senior Director india@scripps.edu (858) 784-2037

world, where they continue to lead advances in science and healthcare.

Florida Philanthropy office

Research will be supplemented by an equal amount, enabling you to establish

Tara Holcomb Senior Director tholcomb@scripps.edu (561) 228-2013

a $1 million graduate student endowed fellowship. Your investment in knowledge

Sue Rode Director scrode@scripps.edu (561) 228-2056

Innovative minds produce the most life-changing science. To learn how you can

Now, your support can have double the impact. Thanks to a commitment by a generous donor, each $500,000 gift to the graduate program at Scripps

supports—in perpetuity—generations of dedicated young scientists working to transform our future.

fund knowledge that fuels health, please contact our Philanthropy department. Or visit us at give.scripps.edu.

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 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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