Creative Minds
From Electrical Brain Maps to Learning More About Migraines
Posted on by Dr. Francis Collins
One of life’s greatest mysteries is the brain’s ability to encode something as complex as human behavior. In an effort to begin to unravel this mystery, neuroscientists often zoom in to record the activities of individual neurons. Sometimes they expand their view to look at a specific region of the brain. But if they zoom out farther, neuroscientists can observe many thousands of neurons across the entire brain firing at once to produce electrical oscillations that somehow translate into behaviors as distinct as a smile and a frown. The complexity is truly daunting.
Rainbo Hultman, University of Iowa Carver College of Medicine, Iowa City, realized years ago that by zooming out and finding a way to map all those emergent signals, she could help to change the study of brain function fundamentally. She also realized doing so offered her an opportunity to chip away at cracking the complicated code of the electrical oscillations that translate into such complex behaviors. To pursue her work in this emerging area of “electrical connectomics,” Hultman recently received a 2020 NIH Director’s New Innovator Award to study the most common human neurological disorder: migraine headaches.
A few years ago, Hultman made some impressive progress in electrical connectomics as a post-doctoral researcher in the lab of Kafui Dzirasa at Duke University, Durham, NC. Hultman and her colleagues refined a way to use electrodes to collect electrical field potentials across an unprecedented seven separate mouse brain regions at once. Using machine learning to help make sense of all the data, they uncovered a dynamic, yet reproducible, electrical brain network encoding depression [1].
What’s more, they found that the specific features of this brain-wide network could predict which mice subjected to chronic stress would develop signs of major depressive disorder. As Hultman noted, when measured and mapped in this way, the broad patterns of electrical brain activity, or “Electome factors,” could indicate which mice were vulnerable to stress and which were more resilient.
Moving on to her latest area of research, Hultman is especially intrigued by the fact that people who endure regular migraine attacks often pass through a characteristic sequence of symptoms. These symptoms can include a painful headache on one side of the head; visual disturbances; sensitivity to light, odors, or sound; mood changes; nausea; trouble speaking; and sometimes even paralysis. By studying the broad electrical patterns and networks associated with migraine in mice—simultaneously capturing electrical recordings from 14 brain regions on a millisecond timescale—she wants to understand how brain circuits are linked and work together in ways that produce the complex sequences of migraine symptoms.
More broadly, Hultman wants to understand how migraine and many other disorders affecting the brain lead to a state of heightened sensory sensitivity and how that emerges from integrated neural circuits in the brain. In her studies of migraine, the researcher suspects she might observe some of the same patterns seen earlier in depression. In fact, her team is setting up its experiments to ensure it can identify any brain network features that are shared across important disease states.
By the way, I happen to be one of many people who suffer from migraines, although fortunately not very often in my case. The visual aura of flashing jagged images that starts in the center of my visual field and then gradually moves to the periphery over about 20 minutes is pretty dramatic—a free light show! I’ve wondered what the electrical component of that must be like. But, even with treatment, the headache that follows can be pretty intense.
Hultman also has seen in her own life and family how debilitating migraines can be. Her goal isn’t just to map these neural networks, but to use them to identify where to target future therapeutics. Ultimately, she hopes her work will pave the way for more precise approaches for treating migraine and other brain disorders that are based on the emergent electrical characteristics of each individual’s brain activity. It’s a fascinating proposition, and I certainly look forward to where this research leads and what it may reveal about the fundamentals of how our brains encode complex behaviors and emotions.
Reference:
[1] Brain-wide electrical spatiotemporal dynamics encode depression vulnerability. Hultman R, Ulrich K, Sachs BD, Blount C, Carlson DE, Ndubuizu N, Bagot RC, Parise EM, Vu MT, Gallagher NM, Wang J, Silva AJ, Deisseroth K, Mague SD, Caron MG, Nestler EJ, Carin L, Dzirasa K. Cell. 2018 Mar 22;173(1):166-180.e14.
Links:
Migraine Information Page (National Institute of Neurological Disorders and Stroke/NIH)
Laboratory for Brain-Network Based Molecular Medicine (University of Iowa, Iowa City)
Hultman Project Information (NIH RePORTER)
NIH Director’s New Innovator Award (Common Fund)
NIH Support: Common Fund; National Institute of Mental Health
An Evolutionary Guide to New Immunotherapies
Posted on by Dr. Francis Collins
One of the best ways to learn how something works is to understand how it’s built. How it came to be. That’s true not only if you play a guitar or repair motorcycle engines, but also if you study the biological systems that make life possible. Evolutionary studies, comparing the development of these systems across animals and organisms, are now leading to many unexpected biological discoveries and promising possibilities for preventing and treating human disease.
While there are many evolutionary questions to ask, Brenda Bass, a distinguished biochemist at University of Utah, Salt Lake City, has set her sights on a particularly profound one: How has innate immunity evolved through the millennia in all living things, including humans? Innate immunity is the immune system’s frontline defense, the first responders that take control of an emerging infectious situation and, if needed, signal for backup.
Exploring the millennia for clues about innate immunity takes a special team, and Bass has assembled a talented one. It includes her Utah colleague Nels Elde, a geneticist; immunologist Dan Stetson, University of Washington, Seattle; and biochemist Jane Jackman, Ohio State University, Columbus.
With a 2020 NIH Director’s Transformative Research Award, this hard-working team will embark on studies looking back at 450 million years of evolution: the point in time when animals diverged to develop very distinct methods of innate immune defense [1]. The team members hope to uncover new possibilities encoded in the innate immune system, especially those that might be latent but still workable. The researchers will then explore whether their finds can be repurposed not only to boost our body’s natural response to external threats but also to internal threats like cancer.
Bass brings a unique perspective to the project. As a postdoc in the 1980s, she stumbled upon a whole new class of enzymes, called ADARs, that edit RNA [2]. Their function was mysterious at the time. It turns out that ADARs specifically edit a molecule called double-stranded RNA (dsRNA). When viruses infect cells in animals, including humans, they make dsRNA, which the innate immune system detects as a sign that a cell has been invaded.
It also turns out that animal cells make their own dsRNA. Over the years, Bass and her lab have identified thousands of dsRNAs made in animal cells—in fact, a significant number of human genes produce dsRNA [3]. Also interesting, ADARs are crucial to marking our own dsRNA as “self” to avoid triggering an immune response when we don’t need it [4].
Bass and others have found that evolution has produced dramatic differences in the biochemical pathways powering the innate immune system. In vertebrate animals, dsRNA leads to release of the immune chemical interferon, a signaling pathway that invertebrate species don’t have. Instead, in response to detecting dsRNA from an invader, and repelling it, worms and other invertebrates trigger a gene-silencing pathway known as RNA interference, or RNAi.
With the new funding, Bass and team plan to mix and match immune strategies from simple and advanced species, across evolutionary time, to craft an entirely new set of immune tools to fight disease. The team will also build new types of targeted immunotherapies based on the principles of innate immunity. Current immunotherapies, which harness a person’s own immune system to fight disease, target infections, autoimmune disorders, and cancer. But they work through our second-line adaptive immune response, which is a biological system unique to vertebrates.
Bass and her team will first hunt for more molecules like ADARs: innate immune checkpoints, as they refer to them. The name comes from a functional resemblance to the better-known adaptive immune checkpoints PD-1 and CTLA-4, which sparked a revolution in cancer immunotherapy. The team will run several screens that sort molecules successful at activating innate immune responses—both in invertebrates and in mammals—hoping to identify a range of durable new immune switches that evolution skipped over but that might be repurposed today.
Another intriguing direction for this research stems from the observation that decreasing normal levels of ADARs in tumors kickstarts innate immune responses that kill cancer cells [5]. Along these lines, the scientists plan to test newly identified immune switches to look for novel ways to fight cancer where existing approaches have not worked.
Evolution is the founding principle for all of biology—organisms learn from what works to improve their ability to survive. In this case, research to re-examine such lessons and apply them for new uses may help transform bygone evolution into a therapeutic revolution!
References:
[1] Evolution of adaptive immunity from transposable elements combined with innate immune systems. Koonin EV, Krupovic M. Nat Rev Genet. 2015 Mar;16(3):184-192.
[2] A developmentally regulated activity that unwinds RNA duplexes. Bass BL, Weintraub H. Cell. 1987 Feb 27;48(4):607-613.
[3] Mapping the dsRNA World. Reich DP, Bass BL. Cold Spring Harb Perspect Biol. 2019 Mar 1;11(3):a035352.
[4] To protect and modify double-stranded RNA – the critical roles of ADARs in development, immunity and oncogenesis. Erdmann EA, Mahapatra A, Mukherjee P, Yang B, Hundley HA. Crit Rev Biochem Mol Biol. 2021 Feb;56(1):54-87.
[5] Loss of ADAR1 in tumours overcomes resistance to immune checkpoint blockade. Ishizuka JJ, Manguso RT, Cheruiyot CK, Bi K, Panda A, et al. Nature. 2019 Jan;565(7737):43-48.
Links:
Bass Lab (University of Utah, Salt Lake City)
Elde Lab (University of Utah)
Jackman Lab (Ohio State University, Columbus)
Stetson Lab (University of Washington, Seattle)
Bass/Elde/Jackman/Stetson Project Information (NIH RePORTER)
NIH Director’s Transformative Research Award Program (Common Fund)
NIH Support: Common Fund; National Cancer Institute
Finding New Ways to Fight Coronavirus … From Studying Bats
Posted on by Dr. Francis Collins
David Veesler has spent nearly 20 years imaging in near-atomic detail the parts of various viruses, including coronaviruses, that enable them to infect Homo sapiens. In fact, his lab at the University of Washington, Seattle, was the first to elucidate the 3D architecture of the now infamous spike protein, which coronaviruses use to gain entry into human cells [1]. He uses these fundamental insights to guide the design of vaccines and therapeutics, including promising monoclonal antibodies.
Now, Veesler and his lab are turning to another mammal in their search for new leads for the next generation of antiviral treatments, including ones aimed at the coronavirus that causes COVID-19, SARS-CoV-2. With support from a 2020 NIH Director’s Pioneer Award, Veesler will study members of the order Chiroptera. Or, more colloquially, bats.
Why bats? Veesler says bats are remarkable creatures. They are the only mammals capable of sustained flight. They rarely get cancer and live unusually long lives for such small creatures. More importantly for Veesler’s research, bats host a wide range of viruses—more than any other mammal species. Despite carrying all of these viruses, bats rarely show symptoms of being sick. Yet they are the source for many of the viruses that have spilled over into humans with devastating effect, including rabies, Ebola virus, Nipah and Hendra viruses, severe acute respiratory syndrome coronavirus (SARS-CoV), and, likely, SARS-CoV-2.
Beyond what is already known about bats’ intriguing qualities, Veesler says humans still have much to discover about these flying mammals, including how their immune systems cope with such an onslaught of viral invaders. For example, it turns out that a bat’s learned, or adaptive, immune system is, for the most part, uncharted territory. As such, it offers an untapped source of potentially promising viral inhibitors just waiting to be unearthed, fully characterized, and then used to guide the development of new kinds of anti-viral therapeutics.
In his studies, Veesler will work with collaborators studying bats around the world to characterize their antibody production. He wants to learn how these antibodies contribute to bats’ impressive ability to tolerate viruses and other pathogens. What is it about the structure of bat antibodies that make them different from human antibodies? And, how can those structural differences serve as blueprints for promising new treatments to combat many potentially deadly viruses?
Interestingly, Veesler’s original grant proposal makes no mention of SARS-CoV-2 or COVID-19. That’s because he submitted it just months before the first reports of the novel coronavirus in Wuhan, China. But Veesler doesn’t consider himself a visionary by expanding his research to bats. He and others had been working on closely related coronaviruses for years, inspired by earlier outbreaks, including SARS in 2002 and Middle East respiratory syndrome (MERS) in 2012 (although MERS apparently came from camels). The researcher didn’t see SARS-CoV-2 coming, but he recognized the potential for some kind of novel coronavirus outbreak in the future.
These days, the Veesler lab has been hard at work to understand SARS-CoV-2 and the human immune response to the virus. His team showed that SARS-CoV-2 uses the human receptor ACE2 to gain entry into our cells [2]. He’s also a member of the international research team that identified a human antibody, called S309, from a person who’d been infected with SARS in 2003. This antibody is showing promise for treating COVID-19 [3], now in a phase 3 clinical trial in the United States.
In another recent study, reported as a pre-print in bioRxiv, Veesler’s team mapped dozens of distinct human antibodies capable of neutralizing SARS-CoV-2 by their ability to hit viral targets outside of the well-known spike protein [4]. Such discoveries may form the basis for new and promising combinations of antibodies to treat COVID-19 that won’t be disabled by concerning new variations in the SARS-CoV-2 spike protein. Perhaps, in the future, such therapeutic cocktails may include modified bat-inspired antibodies too.
References:
[1] Cryo-electron microscopy structure of a coronavirus spike glycoprotein trimer. Walls AC, Tortorici MA, Bosch BJ, Frenz B, Rottier PJM, DiMaio F, Rey FA, Veesler D. Nature. 2016 Mar 3;531(7592):114-117.
[2] Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Walls AC, Park YJ, Tortorici MA, Wall A, McGuire AT, Veesler D. Cell. 2020 Apr 16;181(2):281-292.e6.
[3] Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody. Pinto D, Park YJ, Beltramello M, Veesler D, Cortil D, et al. Nature.18 May 2020 [Epub ahead of print]
[4] N-terminal domain antigenic mapping reveals a site of vulnerability for SARS-CoV-2. McCallum M, Marco A, Lempp F, Tortorici MA, Pinto D, Walls AC, Whelan SPJ, Virgin HW, Corti D, Pizzuto MS, Veesler D, et al. bioRxiv. 2021 Jan 14.
Links:
COVID-19 Research (NIH)
Veesler Lab (University of Washington, Seattle)
Veesler Project Information (NIH RePORTER)
NIH Director’s Pioneer Award Program (Common Fund)
NIH Support: Common Fund; National Institute of Allergy and Infectious Diseases
Taking a Community-Based Approach to Youth Substance Abuse Prevention
Posted on by Dr. Francis Collins
As a child born and raised in a low-income, urban neighborhood of Jersey City, NJ, Ijeoma Opara counted herself lucky. She had strong support from her parents, both college-educated Nigerian immigrants. But she also saw firsthand the devastating effects that gang violence, crime, drugs, and alcohol were having on too many young people in her community. When she was in high school, her family bought their first house about 20 miles away in the middle-class, suburban neighborhood of Roselle, NJ. The dramatic differences between these two worlds drove home for her how significant a zip code can be in determining a child’s outlook and opportunities.
Today, inspired by this childhood moment of truth, Opara, an assistant professor of social work at The State University Stony Brook University, NY, is the recipient of an NIH Director’s Early Independence Award, tackling the complex relationships between neighborhoods, substance use, and mental health among urban youth. She’s focusing her efforts on Paterson, NJ, a city of about 150,000 people where the rates of substance abuse are among the highest in the country. She hopes to develop community engagement models that will work not only in Paterson, but in struggling urban communities across the United States.
Opara first explored the streets of Paterson, which is located about 20 miles west of New York City, and ultimately fell in love with the place as a PhD fellow studying substance abuse and mental health services. She got to know the youth of Paterson and heard from them directly about what their community was lacking to help them build a brighter future.
She also fell in love with community-based participatory research (CBPR). In this approach, researchers immerse themselves in a community and work as partners with community members, leaders, and organizations to understand the issues that matter, gather essential information and data, and translate them into efforts needed for a community and its youth to thrive.
When Opara decided to apply for the high-risk, high-reward Early Independence Award, she knew her proposal must be innovative and creative. Ultimately, though, Opara realized she needed to propose an idea about which she was passionate.
Opara remembered her love for Paterson and decided to go back there, focusing her attention on filling the many gaps in that community to prevent substance abuse among young people. True to her CBPR approach to research, she also spent weeks meeting with the people of Paterson to ensure that her work would address the community’s most-critical needs and strongest desires from day one.
Opara’s first aim is to look at neighborhoods across the city of Paterson and their relationship to substance abuse and mental health symptoms, including anxiety and depression among its youth. Her work will factor in access to safe housing, healthy food, parks, and playgrounds.
She’ll also recruit young people, including those who are most at risk, to get their take on their community including the prevalence of drug use. Opara won’t just be checking with kids at school. She’ll also spend lots of time with them on basketball courts, in grocery store parking lots, or wherever they like to congregate. What she learns will help her craft evidence-based and community-driven substance abuse interventions for young people at risk. She’ll then work with her partners in the community to help put the interventions to the test.
She recognizes that many consider urban youth too hard to reach. In her view, that’s simply not true. It’s her job to meet these young people where they hang out, learn to engage them, and listen to their needs.
In Paterson, she wants to build vibrant neighborhood models that will enrich the community and help more of its children get ahead. Most of all, she wants to change the way substance abuse and mental health work is done in urban communities like Paterson, and see to it that more resources for youth are put into place.
Opara hopes one day to inhabit a world where urban kids have access to the emotional and mental health resources that they need to cope with the many challenges that confront them. She also wants to inhabit a world where young girls growing up in the inner-city, as she did not so long ago, will be nurtured to move upward and onward as leaders. Her efforts and the strength of her example are certainly a push in the right direction.
Links:
Ijeoma Opara (The State University Stony Brook University, NY)
The Substance Abuse and Sexual Health Lab (Stony Brook)
Opara Project Information (NIH RePORTER)
NIH Director’s Early Independence Award
NIH Support: Common Fund
Tackling Cancer Metastasis with Engineered Blood Platelets
Posted on by Dr. Francis Collins
Credit: Dan Hixson/University of Utah College of Engineering, Salt Lake City
When cancer cells spread to new parts of the body in a process called metastasis, they often get there by traveling through the bloodstream. To avoid alerting the immune system and possibly triggering their demise, cancer cells coax circulating blood platelets to glom onto their surfaces and mask them from detection. This deceptive arrangement has raised a tantalizing possibility: What if blood platelets could be programmed to recognize and take out those metastasizing cancer cells?
Tara Deans, University of Utah, Salt Lake City, was recently awarded a 2019 NIH Director’s New Innovator Award to do exactly that. It’s an exciting opportunity for a researcher who stumbled onto this innovative strategy quite by accident.
Deans is a bioengineer and expert in designing synthetic gene circuits. These circuits consist of small collections of genetic “parts” that can be assembled and integrated to program cells to behave differently than their natural counterparts [1]. In her initial work, Deans got these specialized gene circuits to prompt blood-forming stem cells to mass-produce platelets in the lab.
But blood platelets are unusual cells. They’re packed with many proteins that help to repair small nicks in blood vessels and stop the bleeding when we’re injured. Blood platelets do so even though they lack a nucleus and DNA to encode and make any of the proteins. Their protein cargo is pre-packaged and comes strictly from the bone marrow cells, called megakaryocytes, that produce them.
Deans realized that engineering platelets might pose a rare opportunity. She could wire the needed circuitry into the blood-forming stem cells and engineer them to make any desired therapeutic proteins, which are then loaded into the blood platelets for their 8- to 10-day lifespan. She started out producing blood platelets that could safely carry functional replacement enzymes in people with certain rare metabolic disorders.
As this research progressed, Deans got some troubling personal news: A friend was diagnosed with a blood cancer. At the time, Deans didn’t know much about the diagnosis. But, in reading about her friend’s cancer, she learned how metastasizing tumor cells interact with platelets.
That’s when Deans had her “aha” moment: maybe the engineered platelets could also be put to work in preventing metastasizing tumor cells from spreading.
Now, with her New Innovator Award, Deans will pursue this novel approach by engineering platelets to carry potentially promising cancer-fighting proteins. In principle, they could be tailored to fight breast, lung, and various other cancer types. Ultimately, she hopes that platelets could be engineered to target and kill circulating cancer cells before they move into other tissues.
There’s plenty of research ahead to work out the details of targeting the circulating cancer cells and then testing them in animal models before this strategy could ever be attempted in people. But Deans is excited about the path forward, and thinks that platelets hold great promise to function as unique drug delivery devices. It has not escaped her notice that this approach could work not only for controlling the spread of cancer cells, but also in treating other medical conditions.
Reference:
[1] Genetic circuits to engineer tissues with alternative functions. Healy CP, Deans TL. J Biol Eng. 2019 May 3;13:39.
Links:
Metastatic Cancer (National Cancer Institute/NIH)
Deans Lab (University of Utah, Salt Lake City)
Deans Project Information (NIH RePORTER)
NIH Director’s New Innovator Award (Common Fund)
NIH Support: Common Fund; National Cancer Institute
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