This issue of The Caltech Effect features researchers who forge divergent paths to medical breakthroughs.
On the cover are microbes, an organic compound, an anatomical feature, and medical instruments that relate to the stories in this issue. Clockwise from top left: Zika virus, MRSA bacterium, biosensor electrode array, SlipChip (microfluidic device), E. coli bacterium, neural activity in the brain, human immunodeficiency virus, lactic acid, and (center) microfluidic-based sweat patch.
“Antibiotics are a pillar of civilization,” says Rustem Ismagilov, Caltech’s Ethel Wilson Bowles and Robert Bowles Professor of Chemistry and Chemical Engineering. “But humanity completely misuses them.”
Four members of Ismagilov’s laboratory explain how their research could help solve the problem.
Assistant professor of medical engineering Wei Gao is enriching the field of personalized and precision medicine with an abundant source of chemical data: sweat.
Dean Mobbs, assistant professor of cognitive neuroscience and affiliated faculty member of the Tianqiao and Chrissy Chen Institute for Neuroscience at Caltech, uses fMRI technology in the Caltech Brain Imaging Center to learn what happens in the brain when people feel threatened. New knowledge about these neural circuits could lead to new treatments for conditions such as PTSD and anxiety and panic disorders. Mobbs draws inspiration for his experiments from an unlikely source: horror movies.
Caltech’s Pamela Bjorkman uses leading-edge technologies to view biological structures at the molecular level. Her discoveries plot the course to an HIV vaccine that may protect against the pandemic.
Scholars across disciplines explain their health-related research.
Jessica Wang (Class of 2019)
Division of Biology and Biological Engineering
Jessica Wang describes T-cell therapy research under way in the laboratory of David Baltimore.
Francois Tissot, Assistant Professor of Geochemistry
Division of Geological and Planetary Sciences
Francois Tissot’s investigations into how the solar system was formed are not entirely separate from his cancer research. He explains the connection.
Jinglin Huang, Graduate Student
Division of Engineering and Applied Science
Jinglin Huang shares an example of how patients can benefit from fundamental discoveries in fluid mechanics. She works in the lab of Morteza Gharib.
Jade Livingston (Class of 2020)
Division of Biology and Biological Engineering
Jade Livingston explains research on opportunistic pathogens that is taking place in the laboratory of Dianne Newman.
Ewa Rej, Troesh Postdoctoral Scholar
Division of Physics, Mathematics and Astronomy
Ewa Rej elucidates her work with Michael Roukes on nanodevices to tackle fundamental challenges in medicine.
Each year, millions of Americans get antibiotic-resistant infections.
“The more we use antibiotics, the less efficacious they become,” says graduate student Nathan Schoepp.
Some bacteria survive each encounter with antibiotics. These bacteria proliferate and transfer their genes for resistance to different species of bacteria. Then, as treatment-resistant pathogens spread among people, medicines begin to fail.
That is why misuse and overuse of antibiotics jeopardize humanity’s defenses against infectious disease. Bacteria have more opportunities to adapt when health-care providers mistakenly prescribe antibiotics for colds, sore throats, and sinus infections that they are powerless against; when patients do not finish the full course of treatment; and when farmers use antibiotics that are vital to human medicine as feed additives for livestock.
“As soon as 5 percent of patients resist an antibiotic, then health-care providers stop prescribing it,” says graduate student Emily Savela.
The newest and strongest antibiotics are overprescribed simply because there is no fast way to check if a given patient’s bacteria are treatment-resistant. Ismagilov’s research group aims to change that.
Current tests take days. Doctors and nurses feel compelled to act quickly, especially when patients have an infection that progresses fast, such as sepsis, in which the chance of survival decreases 9 percent per hour.
“My friends and family are always surprised when I explain, ‘Right now, your doctor is making an informed guess about what your infection is and what antibiotics it will or won’t respond to,’” says research technician Matt Cooper.
“If doctors have to choose between antibiotic stewardship and the safety of a patient, the choice is obvious,” says MD/PhD student Eric Liaw. “In order to minimize the chance that the patient’s infection is resistant and does not improve, they choose the stronger antibiotic.”
Ismagilov’s research group develops antimicrobial susceptibility tests (ASTs) that can verify which medicine a specific patient needs, during that patient’s visit. Seed-funds from Caltech’s Joseph J. Jacobs Institute for Molecular Engineering for Medicine allowed the group to initiate this effort.
On a microfluidic chip invented in their laboratory, the researchers treat part of a urine or blood sample with an antibiotic, wait briefly, and then read out an ultra-fast count of DNA and RNA molecules. If the medicine slows the pathogen’s DNA replication, the treated portion will contain fewer bacterial nucleic acids.
“We’re making very sensitive measurements of how much damage the antibiotic can do in 15 minutes,” Savela explains.
In 2017, Schoepp and colleagues demonstrated the first AST to produce results from a clinical sample within 30 minutes. Schoepp’s work on this AST, for urinary tract infections (UTIs), was supported by the Weldon Brown Graduate Fellowship, endowed with a gift to the Break Through campaign.
“UTIs are a nice test case,” Schoepp says. “E. coli causes 80 percent of them, and only four antibiotics are used to treat the vast majority.”
Savela adapts the technique to gonorrhea. “With gonorrhea, we are on our last medicine, and it has failed in certain cases,” she says. “E. coli can double in about 15 minutes, but gonorrhoeae needs 60 to 90. It’s a challenge to design a 30-minute test.”
Liaw focuses on a test for resistance to beta-lactams, a class of antibiotics that includes several once-popular medicines that have been phased out because of resistance, and newer ones to which resistance is still rare. If doctors can quickly check that their patients’ infections will respond to the older beta-lactams, then they may prescribe the newest ones less often, slowing the spread of resistance.
ASTs will give physicians the information they need to prescribe the right antibiotics, slow the spread of antibiotic resistance, and reduce treatments’ impact on patients’ microbiomes. “We will maximize the lifetime of the antibiotics we have and improve patient outcomes,” Schoepp says.
“Ninety-five out of 100 patients could benefit from antibiotics that have been phased out,” Savela says. ASTs to verify that patients are among the 95 percent will bring back some of humanity’s most powerful defenses against infections.
Liaw says, “When this kind of test becomes available, the practice of infectious disease will change.”
Gao’s perspiration-analysis technology enables early detection of physiological aberrations, customized treatment plans, and greater accuracy in drug monitoring. Low energy, for example, is a symptom that could be associated with a multitude of health concerns, but a sweat-reading biosensor can detect abnormal chemical reactions in the body that are associated with specific conditions.
What follows are three examples of how Gao’s biosensors one day may help physicians interpret what might be ailing you.
Low energy is a common indicator of various metabolic disorders, but a sensor readout that displays imbalances in sugar and electrolytes would prompt a physician to screen for diabetes.
Wearable sweat analyzers could help 30 million Americans who have diabetes monitor their condition. And for the additional 84 million U.S. citizens with pre-diabetes, biosensors could help provide early detection of Type 2 diabetes, heart disease, and stroke. The sensors also could track biomarkers that point to imbalances associated with cystic fibrosis and gout.
“The sensor can work as both a diagnostic and a disease-management tool,” says Caltech graduate student Yiran Yang, who develops wearable sensors that monitor metabolic disorders. She explains: “Although many foods carry nutrition labels, this doesn’t help patients with certain metabolic disorders understand their personal limits. By monitoring the composition of their sweat throughout the day, patients can see how diet affects them.”
In 2017, Yang became the first researcher to join Gao’s lab. Since then, the group has grown to include three additional graduate students, three postdoctoral scholars, four visiting scholars, and four undergraduates. The team works with Gao on biosensor technology and other synthetic micro- and nano-bioelectronic medical devices.
Low energy also could be a symptom of depressive disorders, but diagnoses for post-traumatic stress, postpartum depression, or suicidal ideation today are based largely on questionnaires. Gao aims to replace this subjective process with objective measurements.
“Lots of people don’t know they’re depressed, and others know they are but don’t say anything about it,” Gao says. “Chemical analysis of their sweat could give early warning for these conditions and help caregivers differentiate between types of depressive disorders and identify the best treatment options.”
High levels of stress hormones such as cortisol, and markers of inflammation such as cytokines, are associated with depressive disorders. But normal values for these biomarkers are different for everyone, and fluctuate throughout the day. “With a biosensor, we could continuously monitor an individual’s molecular data over time and determine his or her personal baseline,” Gao explains. “Then we could quantitatively see if there’s a problem.”
In 2017, Gao was among the first researchers to receive support through Caltech’s Carver Mead New Adventures Fund. Former students of Mead established the fund in 2014 to support innovative, early-stage research. “This grant gave me confidence to develop the mental health monitoring,” Gao says, “and we are making nice progress in this direction.”
In other cases, low energy might signal that a patient’s prescription is off. “Some people need lower dosages, while others need higher dosages,” Gao explains. “Some over-medicate, and many simply forget to take their medicines.” Biosensors could greatly improve physicians’ ability to track patient compliance and evaluate drug efficacy.
Until now, pharmacokinetics (the study of how drugs are absorbed, distributed, and metabolized) has been informed primarily by data gathered in hospital and lab settings.
Prescription dosages and therapeutic windows are extrapolated from relatively small patient populations because the collection of data about drug concentrations requires blood withdrawals at timed intervals. Wireless, wearable biosensors would enable continuous monitoring of larger patient populations over longer periods of time.
“As we develop this low-cost, wearable technology, we think about how it could especially help people in developing countries where there are few medical resources,” Gao says. “But certainly it can also benefit millions here in the United States.”
Bjorkman, recently appointed as Caltech’s David Baltimore Professor of Biology and Bioengineering, works to develop molecules that are better than the body’s natural defenses at counteracting HIV. She and her team start with broadly neutralizing antibodies, proteins found in the immune systems of a subset of HIV-infected patients, and engineer them to increase their potency.
The image above, revealed through cryo-electron microscopy (cryo-EM), captures a close-up of the first steps in HIV’s infiltration into a host cell. The HIV trimer, a structure on the virus’s surface that enables it to enter human cells, is shown in shades of gray. The yellow shapes represent receptors from the surfaces of host immune cells.
While the trimer helps the virus lock onto cells, it also can serve as a target for protective antibodies that can prevent infection by, for example, blocking the binding of the HIV trimer to its host receptor.
Above, at left, is a view of the HIV trimer as shown from raw cryo-EM data. Based on what is known about the chemistry of amino acids (the building blocks of antibodies and other proteins), Bjorkman and her team can painstakingly decode the arrangement of amino acids present in the trimer and the bound antibodies. A snapshot of that work, showing a cryo-EM density map (gray mesh) with the interpreted structure (colored sticks), appears at right.
“The fundamental knowledge of protein structure goes back to Linus Pauling,” Bjorkman says, noting that the Caltech chemist’s early breakthroughs guide structural biologists to this day.
This image builds on information gleaned from the previous figure. A trio of antibodies (pink) latches onto the HIV trimer (gray). The teal spheres represent sugars, which are one of the features the virus uses to try to keep the HIV trimer hidden from virus-fighting antibodies.
Studies of these interactions help Bjorkman and her research group learn how the natural antibodies nullify the virus.
Ultimately, Bjorkman and her team aim to stimulate the human body to produce its own copies of the antibodies that have been engineered in the lab to ward off HIV.
Bjorkman, pictured at far right with her research team, traces her interest in HIV to the mid-2000s and a collaboration with Nobel laureate and then–Caltech president David Baltimore, now the Robert Andrews Millikan Professor of Biology.
Baltimore had proposed a novel method to combat HIV infection. The immune system’s natural response to HIV is generally inadequate, but by “engineering immunity,” he suggested that scientists could deliver effective antibodies via gene therapy.
That idea inspired Bjorkman’s efforts to design antibodies the virus had not evolved to fight because they did not exist in nature.
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