Science Changing Life
Vital Connections, Global Impact
Science Changing Global Health 2
GLOBAL HEALTH INITIATIVE AT SCRIPPS RESEARCH
Every year, hundreds of millions of people around the world are impacted by infectious diseases. Old foes, such as flu, malaria and tuberculosis, continue to evade elimination and eradication efforts, while largescale outbreaks of emerging infectious diseases pose significant threats to populations across the globe. To ensure the future of human health worldwide, new technologies, vaccines, diagnostics and drugs are needed to rapidly detect, prevent and cure infections before they become global health emergencies. A transformative vision for global health research is needed to achieve this goal, and Scripps Research is uniquely positioned to deliver that, given its long history of excellence in infectious disease research. Some of the many diseases researched, including flu, HIV, TB, arboviruses and viral hemorrhagic fevers, impact the most vulnerable populations around the globe and present serious health threats to the United States. Drawing on wide-ranging expertise in drug discovery, vaccine design and disease detection, the Global Health Initiative at Scripps Research fosters multidisciplinary research aimed at reducing the burden of disease worldwide. By establishing a unique global health research and training program, Scripps Research will leverage its scientific leadership to transform our ability to detect, prevent, and cure infectious disease.
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Detect. Prevent. Cure. As a result of expanding and increasingly mobile human populations, infectious diseases in particular have demonstrated their ability to cause unpredictable, widespread health and economic disruption. In today’s interconnected world, these new challenges require urgent action. The Global Health Initiative at Scripps Research will merge our cross-disciplinary strengths in basic and translational research to accelerate the discovery and development of medicines, vaccines and therapeutic strategies. The Initiative focuses on three key pillars that leverage the long-standing expertise in global health research at Scripps Research to ensure a world that is safer and better prepared for the threats from infectious diseases via: • The development of technologies and computational tools for ultra-rapid detection and forecasting of infectious disease. • The creation of novel vaccines to prevent and eradicate some of the most pressing human pathogens. • The discovery and early-stage development of medicines and effective drugs against wide-ranging pathogens and human diseases.
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GLOBAL HEALTH INITIATIVE AT SCRIPPS RESEARCH
More information globalhealth.scripps.edu
Contact us
globalhealth@scripps.edu
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Science Changing Immunity
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 don’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
Allergy and Infectious Disease of the
collaborators, scientists at Scripps
National Institutes of Health. “If these
Research are designing and testing
strategies prove effective in humans,
a new class of vaccines and drugs
they will represent a leap forward in
to defeat these evasive pathogens.
our ability to manage and prevent the
Their strategy is based on a class of
spread of infectious disease.”
immune system proteins called broadly neutralizing antibodies (bnAbs) that possess a kind of superpower: the
Devious viruses meet powerful antibodies
ability to inactivate a remarkably wide
“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
range of virus strains. The ability stems
Vaccines typically work by exposing
from the property of bnAbs to recognize
the immune system to weakened
the more stable regions of the outer
or inactivated viruses, or to just a
envelope, the exposed portion of
portion of a virus. When the vaccine
viruses that is typically targeted
is administered to a person, it lacks
by antibodies.
the ability to cause illness but retains enough of the virus’s original shape
This past year has marked several
and content— collectively referred to as
milestones in the pursuit of these
“antigens”—that the body recognizes
“universal” therapies. Last fall, for
it as foreign. To fight the virus, white
instance, Scripps Research scientists
blood cells produce antibodies capable
reported engineering a prototype of
of binding to it at certain locations,
a broadly-neutralizing flu therapy that
known as epitopes. If a person is later
protected mice from multiple strains of
exposed to the live virus, the immune
influenza known to affect humans. And
system then “remembers” the vaccine
in t he past six months, the International
encounter and quickly ramps up its
AIDS Vaccine Initiative (IAVI) launched
defenses to vanquish the invader.
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
of research are now coming to fruition in
antibodies target to keep us free from
experimental vaccines and drugs,” says
infection are also ever changing.
Dennis Burton, PhD, co-chair of the
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Department of Immunology and
“Scientists were able to develop
Microbiology at Scripps Research and
effective vaccines against polio,
head of the Center for HIV/AIDS Vaccine
smallpox and measles in large part
Immunology and Immunogen Discovery,
because the neutralizing epitopes on
a national research consortium
those viruses are relatively stable,”
supported by the National Institute for
says Ian Wilson, DPhil, chair of the
GLOBAL HEALTH INITIATIVE AT SCRIPPS RESEARCH
Department of Integrative Structural and Computational Biology at Scripps
Antibody Anatomy 101
Research. “But HIV and influenza mutate rapidly, so classic approaches result in
Antigen
vaccines that are quickly outpaced by
Region of virus or other pathogen recognized by antibody.
viral evolution.”
Antigen binding site
In the case of flu, the virus has months to evolve between the time annual
Variable region
vaccine 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
Light chain
given time, and even a single person can carry hundreds of thousands of variants of the virus. A drug or vaccine
Heavy chain
Constant region
targeting one strain might work for a time 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
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.
find and elicit more bnAbs, preferably with greater potency. 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
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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-theart 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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Protocol G, the team found two potent
hinges on a forensic genomic analysis,
“In the past, much of the interaction
bnAbs in the white blood cells of one
tracing evolutionary steps that take
between vaccines, the immune
woman. In 2009, Burton and his team
place in a person’s body between an
system and pathogens was invisible
reported in Science that the woman’s
early progenitor antibody and a fully
to us,” says Ward, a professor in the
antibodies in laboratory tests proved
fledged bnAb. With a roadmap of that
Department of Integrative Structural
capable of neutralizing 70 percent of
progression in hand, they then set
and Computational Biology.
162 different HIV strains.
out to devise ways to reproduce the
“Now we can observe these
process through vaccination.
interactions in detail—at the atomic level, in some cases. It takes much
In the time since Burton and his colleagues discovered bnAbs against
The state-of-the-art cryo-electron
of the guesswork out of determining
HIV, many others have been identified.
microscopy (cryo-EM) suite at Scripps
what’s working and what is not.”
Researchers also have deciphered
Research has proven vital to studying
quite a bit about what makes this
the molecular intricacies of how the
type of antibody so effective against
immune system and viruses interact.
viruses. Over years of battling HIV in an
Using cryo-EM—which involves deep
Last fall, IAVI announced the start of
infected person’s body, the antibodies
freezing antibodies and surface
a phase 1 clinical trial to test a
collect genetic mutations that morph
antigens from pathogens in liquid
vaccine developed in the laboratory
the molecular makeup at the tips of
ethane and then scanning the samples
of William Schief, PhD, a professor in
their Y-shaped arms. These adaptions
with an electron beam—the team has
the Department of Immunology and
target regions of HIV’s envelope
captured atomic
Microbiology at Scripps Research.
that retain a consistent shape even
resolution images of bnAbs binding
The vaccine is the first in a sequence
as other parts of the virus morph,
to HIV and influenza viruses. These
of engineered vaccine candidates
so the antibodies can recognize a
efforts, led by Scripps Research
designed to stimulate the immune
broad range of HIV strains. BnAbs are
Professor Andrew Ward, PhD, have
system to initiate a key first step
exquisitely adapted to home in on and
opened new avenues for structural
in the generation of bnAbs against HIV.
aggressively bind to HIV. Burton and
biology research on these
Wilson discovered, for example, that
difficult targets.
the antibodies have extra-long loops
There’s a lot that seems to be working.
“This is just the first step in what would be a multistage vaccination strategy.
that act like super Velcro to better cling
Ward, and his colleague, Scripps
No one has ever created or even
to HIV virus, which are notoriously
Research Professor Lars Hangartner,
conceived of a vaccine quite like this,”
devoid of desirable molecular
PhD, recently developed a technique
says Schief, who is director of vaccine
surface features.
for using cryo-EM to rapidly analyze
design for IAVI’s Neutralizing Antibody
the outcome of experimental vaccines
Center. “If we can make this work for
against HIV and other pathogens.
HIV, it could be a model for universal
Their new methodology lets scientists
vaccines against other pathogens.”
From discovery to design Merging research on the immune
quickly assess the full spectrum of
system, viral pathogens, structural
antibodies a person produces in
The other IAVI-led phase 1 HIV-vaccine
biology and vaccine design, the
response to an infection or vaccine
clinical trial, which was announced
Scripps Research team has recently
and determine if these antibodies are
this March, will test a different vaccine
made significant progress in
likely to be effective against
candidate that Ward and Wilson helped
engineering a series of vaccines that
the pathogen.
design with John Moore and Rogier
could be administered in stages to
Sanders at Weill Cornell Medical
coax the immune system to make
College. The vaccine is the first to use
bnAbs against HIV. Their strategy
a version of the highly fragile outer
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Science Changing Immunity
shell of HIV–a protein called Env that is
of collaborators, primarily at Janssen,
shaped like a three-pronged spike—that
engineered a prototype antibody drug
maintains its natural shape. It has shown
capable of protecting against numerous
promising results in preclinical tests.
strains of influenza virus.
Flu Snapshot
“Llamaceuticals” to the rescue
The advance, reported in the journal
During the 2016/2017
The Scripps Research team is also
attention from media outlets, including
flu season*, vaccines
applying their expertise in bnAb
The New York Times, Smithsonian
vaccines to develop new therapies for
Magazine, Axios, BBC and PBS. I t even
flu and malaria, studies supported by the
garnered an enthusiastic blog post from
Bill & Melinda Gates Foundation.
Francis Collins, MD, PhD, director of the
prevented:
Science last November, received wide
National Institutes of Health. As much as 20 percent of the U.S. influenza illnesses
population gets the flu each year, and
To create the drug, the scientists
of those people, around 200,000 are
pursued a different approach than
hospitalized. The flu season of 2017-
for HIV. Instead of prompting the
2018 was the worst since 2010, with
immune system to produce a single
nearly a million people hospitalized and
broadly neutralizing antibody, they
an estimated 79,000 deaths.
immunized llamas and then engineered a multidomain antibody by tethering
medical visits
Annual vaccinations help stop the
together four different llama antibodies,
spread of the virus, but the shots
two against influenza A virus and
inoculate against only a handful of flu
two against influenza B virus. Wilson
strains. Because influenza mutates so
and Ward led the X-ray and electron
quickly, epidemiologists must race each
microscopy structural studies to show
year to predict the identity of the next flu
exactly where this four-in-one antibody
The Scripps Research
season’s major strains and then crank
was binding to influenza proteins.
team is developing
out a new vaccine accordingly. Even
“universal” approaches
then, the best matched vaccines are
“In this case, the llama antibodies could
only about 4 0 to 60 percent effective.
be easily linked together to create multi-
For certain types and strains of influenza
specific antibodies binding to different
could help prevent
A viruses, vaccine efficacy can drop to
sites on different targets,” Wilson says.
many more cases.
as low as 10 to 20 percent. The Scripps
“The multi-specificity was key to having
Research team made news recently
broad coverage of highly variable
for advances in helping develop an
pathogens like influenza.”
hospitalizations
to flu therapy that, if they prove effective in humans,
*Estimates by Centers for Disease Control and Prevention
experimental influenza therapy—with the help of llamas.
Their research showed that when administered a s an injection, the
Using a rare type of antibody produced
antibody could target v ulnerable sites
by the South American cousins of
on influenza A and B and protect mice
the camel, the Scripps Research
against lethal infections. When they
scientists and an international team
tested the multi-domain antibody, it prevented 59 strains of human and
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GLOBAL HEALTH INITIATIVE AT SCRIPPS RESEARCH
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 flufighting 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 than is possible with traditional vaccines.” Until then, the team at Scripps Research is on the case.
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. Ian Wilson, DPhil Chair of the Department of Integrative Structural and Computational Biology at Scripps Research
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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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GLOBAL HEALTH INITIATIVE AT SCRIPPS RESEARCH
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.
Top: Scripps Research's Kristian Andersen working with local researcher, Mambu Momoh, in Sierra Leone. Bottom: Electron microscope image of Lassa virus.
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. The Scripps Research team also focuses on Zika and West Nile, mosquito-borne 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.
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
“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 molecular biology science and gotten some high-tech training to enable us, the citizens, to carry out highly specialized scientific work in our lab.”
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rugged roads; Local research staff scientist works in the lab at Kenema Government Hospital.
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,
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Science Changing Global Health
that also includes Tulane University, University of California Los Angeles, MIT and Harvard Medical School. The center analyzes blood from survivors of past outbreaks of Lassa and Ebola to learn how they fought off the virus, merging computational analysis, machine learning and new technologies to discover how to minimize sickness and death in the future. One possible explanation for why some people fight off infections better than others is that they may produce special versions of immune system proteins, called human leukocyte antigens, that are particularly effective at recognizing infected cells. This would allow the immune system to more rapidly destroy infected cells, and hence clear the infection. Identifying and mimicking these highly
human toll. Generally considered to be a mild disease, when Zika virus infects pregnant women it can cause serious birth defects in babies, including smaller heads and brain damage. First discovered in Africa in 1947, Zika was found in Brazil in September 2014. Using genomic analysis, Andersen’s team at Scripps Research determined that Zika circulated for more than a year and a half before being detected. From Brazil, a large outbreak spread throughout the Americas in 2015 and 2016, with 62 cases reported in travelers returning to the United States from affected areas in 2015, growing to more than 4,800 travel-related cases and 224 local mosquito-borne infections in the United States in 2016. The Scripps Research team also discovered that Zika entered Florida several times via travelers from the
effective variants could serve as the basis for developing new types of vaccines and antiviral drugs.
Caribbean before it was discovered. More recently, a genomics study of travel-associated Zika cases by Andersen’s team revealed an undiscovered outbreak in Cuba in 2017, underscoring the need for coordinated disease surveillance. This new field of “genomic epidemiology” will be critical to understanding and preventing future outbreaks.
Troublesome family trees In addition to deciphering what leads to different outcomes when humans become infected with a virus, the scientists also track how viruses spread. Similar to the way companies like Ancestry or 23andMe can trace a person’s ancestry by analyzing the DNA from a saliva sample, the Scripps Research team uses samples taken from various areas of Sierra Leone to create family histories of Lassa virus strains. Genomic similarity between different virus strains can be used to track how fast and far viruses spread as well as how quickly they evolve. Creating viral family trees isn’t just an academic exercise. Deciphering what factors allow viruses to spread rapidly through and between host populations – whether rodents, insects or humans – is key to predicting and controlling future outbreaks. Some viruses move far more quickly than others. The global outbreak of swine flu in 2009, for example, took just six weeks to spread as widely as the typical seasonal flu travels in six months. First reported in Mexico, the flu rapidly spread around the globe, resulting in as many as 89 million cases and 18,000 deaths, according to the U.S. Centers for Disease Control and Prevention. The rapid spread of Zika in the Americas is another case study of a virus taking a surprising turn and a severe
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Raphaëlle Klitting, PhD, another postdoctoral researcher on Andersen’s team, is attempting to explain why certain viral strains spread so aggressively. To do this, she uses skills honed as a graduate student at France’s Aix-Marseille University, where she studied yellow fever, an acute—and often fatal—viral disease transmitted by infected mosquitoes. Lassa virus is classified as a biosafety level 4 (BSL4) infectious agent, the most dangerous class, so working with the live virus in the United States requires an elaborate and expensive facility, including specially sealed rooms, pressurized protective suits and elaborate decontamination protocols. In the lab at Scripps Research, Klitting avoids the cost and hassle by working with what are called “surrogate systems,” safe noninfectious viruses modified to carry only a portion of the Lassa virus. Among other things, in recent experiments she has engineered surrogate viruses mounted with the molecular “key” Lassa uses to enter cells’ outer envelope. By swapping out different versions of the Lassa envelope, she tests their penetrating power. “We want to know which variants are better at entering human cells 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 human. With this information, we can deploy
“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
countermeasures and stop that from happening. You could also imagine at the beginning of an 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 20132016 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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Calibr accelerates drug discovery.
A drug designed to treat leprosy was repurposed as an effective treatment for childhood diarrhea—a life-threatening illness—and delivered in record time, progressing from laboratory to clinical trial in only three years.
To overcome the barriers that slow the translation of new scientific discoveries to innovative medicines for patients, Scripps Research has created internal drug discovery and development capabilities. Calibr, an operating division, possesses the expertise and infrastructure (among its chemical libraries is the unique ReFRAME repurposing library) to bridge basic discoveries to innovative early preclinical drug discovery and human proof-of-concept clinical development, providing a framework for seamless integration of research and development activities. These efforts have already produced a pipeline of innovative candidate medicines. Several drugs have entered human clinical trials, including a regenerative approach to osteoarthritis and treatments for tuberculosis and cryptosporidiosis. A significant drug discovery portfolio at Calibr
Scientists are engineering a longacting antibody that protects against neuroinflammation in patients with Parkinson's disease.
is focused on neglected tropical diseases that disproportionately affect global health in the developing world including tuberculosis, malaria, HIV, helminth infections, and diarrheal disease. The challenges created by pathogen resistance and/or the lack of efficacy with current drugs, and limited access driven by cost-of-goods or lengthy treatment protocols, have been exacerbated by the slow development of effective new drugs. To meet these challenges, Calibr has partnered with the Bill and Melinda Gates Foundation to form an integrated drug discovery platform to identify and develop innovative approaches to new medicines for neglected diseases including tuberculosis, malaria, and HIV. We work closely with the Foundation to streamline efforts and accelerate drug discovery relevant to global health. Calibr will also be expanding these efforts as an anchor partner in the Wellcome Trust’s new Hub for Innovative Technologies for Neglected Tropical Diseases Flagship.
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GLOBAL HEALTH INITIATIVE AT SCRIPPS RESEARCH
When researchers found that isoxazolines, commonly used in veterinary products to protect pets from fleas and ticks, also killed disease -carrying mosquitoes, they identified a strategy to stem global outbreaks of malaria, Zika virus and potentially Lyme disease.
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. DIVERSE PIPELINE 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. RESEARCH ALLIANCES Partnerships with organizations such as the Bill & Melinda Gates Foundation, Wellcome Trust, and the California Institute for Regenerative Medicine, and pharmaceutical companies like AbbVie 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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