From Basic Research to Bioelectronic Medicine

Kevin Tracey
Kevin J. Tracey of the Feinstein Institute for Medical Research, the research branch of the North Shore-LIJ Health System, helped launch a new discipline called bioelectronic medicine. Credit: North Shore-LIJ Studios.

By showing that our immune and nervous systems are connected, Kevin J. Tracey Exit icon of the North Shore-LIJ Health System’s Feinstein Institute for Medical Research helped launch a new discipline called bioelectronic medicine. In this field, scientists explore how to use electricity to stimulate the body to produce its own disease-fighting molecules.

I spoke with Tracey about his research, the scientific process and where bioelectronic medicine is headed next.

How did you uncover the connection between our immune and nervous systems?

My lab was testing whether a chemical we developed called CNI-1493 could stop immune cells from producing inflammation-inducing molecules called TNFs in the brain of rats during a stroke. It does. But we were surprised to find that this chemical also affects neurons, or brain cells. The neurons sense the chemical and respond by sending an electrical signal along the vagus nerve, which runs from the brain to the internal organs. The vagus nerve then releases molecules that tell immune cells throughout the body to make less TNF. I’ve named this neural circuit the inflammatory reflex. Today, scientists in bioelectronic medicine are exploring ways to use tiny electrical devices to stimulate this reflex to treat diseases ranging from rheumatoid arthritis to cancer.

Why were you surprised by what you were finding?

Prior to this work, there was no direct evidence that the immune system could be controlled by neural reflexes. When we first noticed that delivering CNI-1493 to the brain somehow turned off TNF production, I realized that this connection must be really important. But even as a neurosurgeon who had thought about physiology and inflammation for 20 years, I couldn’t understand how it actually worked. Then, the idea that the immune and nervous systems might be connected through an inflammatory reflex struck me as such a simple concept that I began to wonder whether someone else had thought of it already.

Do scientific advances often seem obvious in hindsight?

The most important ones usually do. Many new findings seem so logical that you may ask: Why weren’t they revealed before? That’s because scientists must delineate molecular mechanisms, explain how these processes work at the cellular and atomic levels, and put the results into a meaningful context. If a researcher is fortunate, all this effort can produce insights that change how everyone thinks about a biological process from that time on.

What are you working on now?

We’re mapping the molecular mechanisms that allow signals to pass through the inflammatory reflex. The more we learn about how the reflex works, the more opportunities we’ll have to develop therapies directed at its individual components. We’re also identifying new reflexes that may one day be targets for bioelectronic medicine.

Has anyone already benefitted from bioelectronic medicine?

Yes. So far there’ve been two small clinical trials where people received vagus nerve stimulation to treat rheumatoid arthritis. I met the first patient who received this treatment. Before participating in the trial, his arthritis wasn’t responsive to any therapy that was available to him. After receiving a bioelectronic device treatment in the trial, he was dramatically better within weeks. Today, 3 years later, he’s still in remission. This patient isn’t the only one in remission as a result of participating in the trials. The challenge now is to understand how to identify other patients who will respond to this type of therapy.

Where do you foresee bioelectronic medicine going next?

Today, we understand that neural circuits can be targeted for therapy. This created an opportunity to determine how many other circuits we can target. There are probably hundreds of specific molecular mechanisms under the control of nerve fibers. By targeting these nerves, we may be able to develop therapies for many chronic conditions such as diabetes, inflammatory bowel disease and cancer.

Read more about Tracey’s journey in a Findings profile article about him.

Designing Drugs That Kill Invasive Fungi Without Harming Humans

Top to bottom: Cryptococcus, Candida, Aspergillus, Pneumocystis
Invasive fungal infections kill more than 1 million people worldwide every year. Almost all of these deaths are due to fungi in one of these four groups. Credit: Centers for Disease Control and Prevention.

Invasive fungal infections—the kind that infect the bloodstream, lung and brain—are inordinately deadly. A big part of the problem is the lack of drugs that are both effective against the fungi and nontoxic to humans.

The situation might change in the future though, thanks to the work of a multidisciplinary research team led by chemist Martin Burke at the University of Illinois. For years, the team has focused on an antifungal agent called amphotericin B (AmB for short). Although impressively lethal to fungi, AmB is also notoriously toxic to human cells.

Most recently, the research team chemically modified the drug to create compounds that kill fungi, but don’t disrupt human cells. The scientists explain it all in the latest issue of Nature Chemical Biology.

Invasive fungal infections are so intractable because most antifungal drugs aren’t completely effective. Plus, fungi have a tendency to develop resistance to them. AmB is a notable exception. Isolated 50 years ago from Venezuelan dirt, AmB has evaded resistance and remains highly effective. Unfortunately, it causes side effects so debilitating that some doctors call it “ampho-terrible.” At high doses, it is fatal.

For decades, scientists believed that AmB molecules kill fungal cells by forming membrane-piercing pores, or ion channels, through which the cells’ innards leak out. Last year, Burke’s group overturned this well-established concept using evidence from nuclear magnetic resonance, chemistry and cell-based experiments. The researchers showed that AmB molecules assemble outside cells into lattice-like structures. These structures act as powerful sponges, sucking vital lipid molecules, called ergosterol, right out of the fungal cell membrane, destroying the cell. Continue reading

Scientists Shine Light on What Triggers REM Sleep

Illustration of a brain.

While studying how the brain controls REM sleep, researchers focused on areas abbreviated LDT and PPT in the mouse brainstem. This illustration shows where these two areas are located in the human brain. Credit: Wikimedia Commons. View larger image

Has the “spring forward” time change left you feeling drowsy? While researchers can’t give you back your lost ZZZs, they are unraveling a long-standing mystery about sleep. Their work will advance the scientific understanding of the process and could improve ways to foster natural sleep patterns in people with sleep disorders.

Working at Massachusetts General Hospital and MIT, Christa Van Dort Exit icon, Matthew Wilson Exit icon and Emery Brown Exit icon focused on the stage of sleep known as REM. Our most vivid dreams occur during this period, as do rapid eye movements, for which the state is named. Many scientists also believe REM is crucial for learning and memory.

REM occurs several times throughout the night, interspersed with other sleep states collectively called non-REM sleep. Although REM is clearly necessary—it occurs in all land mammals and birds—researchers don’t really know why. They also don’t understand how the brain turns REM on and off. Continue reading

Meet Maureen L. Mulvihill

Maureen L. Mulvihill, Ph.D.
Credit: Actuated Medical, Inc.
Maureen L. Mulvihill, Ph.D.
Fields: Materials science, logistics
Works at: Actuated Medical, Inc., a small company that develops medical devices
Second job (volunteer): Bellefonte YMCA Swim Team Parent Boost Club Treasurer
Best skill: Listening to people
Last thing she does every night: Reads to her 7- and 10-year-old children until “one of us falls asleep”

If you’re a fan of the reality TV show Shark Tank, you tune in to watch aspiring entrepreneurs present their ideas and try to get one of the investors to help develop and market the products. Afterward, you might start to think about what you could invent.

Maureen L. Mulvihill has never watched the show, but she lives it every day. She is co-founder, president and CEO of Actuated Medical, Inc. (AMI), a Pennsylvania-based company that develops specialized medical devices. The devices include a system for unclogging feeding tubes, motors that assist MRI-related procedures and needles that gently draw blood.

AMI’s products rely on the same motion-control technologies that allow a quartz watch to keep time, a microphone to project sound and even a telescope to focus on a distant object in a sky. In general, the devices are portable, affordable and unobtrusive, making them appealing to doctors and patients.

Mulvihill, who’s trained in an area of engineering called materials science, says, “I’m really focused on how to translate technologies into ways that help people.” Continue reading

A Bright New Method for Rapidly Screening Cancer Drugs

Illustration of red, green and blue fluorescent proteins.
Chemists have devised a new approach to screening cancer drugs that uses gold nanoparticles with red, green and blue outputs provided by fluorescent proteins. Credit: University of Massachusetts Amherst.

Scientists may screen billions of chemical compounds before uncovering the few that effectively treat a disease. But identifying compounds that work is just the first step toward developing a new therapy. Scientists then have to determine exactly how those compounds function.

Different cancer therapies attack cancer cells in distinct ways. For example, some drugs kill cancer cells by causing their outer membranes to rapidly rupture in a process known as necrosis. Others cause more subtle changes to cell membranes, which result in a type of programmed cell death known as apoptosis.

If researchers could distinguish the membrane alterations of chemically treated cancer cells, they could quickly determine how that chemical compound brings about the cells’ death. A new sensor developed by a research team led by Vincent Rotello Exit icon of the University of Massachusetts Amherst can make these distinctions in minutes. Continue reading

New Streamlined Technique for Processing Biological Samples

Illustration of Slug flow microextraction.
Researchers have discovered a faster, easier and more affordable technique for processing biological samples. Credit: Weldon School of Biomedical Engineering, Purdue University.

It’s not unusual for the standard dose of a drug to work well for one person but be less effective for another. One reason for such differences is that individuals can break down drugs at different rates, leading to different concentrations of drugs and of their breakdown products (metabolites) in the bloodstream. A promising new process Exit icon called slug-flow microextraction could make it faster, easier and more affordable to regularly monitor drug metabolites so that medication dosages could be tailored to each patient’s needs, an approach known as personalized medicine. This technique could also allow researchers to better monitor people’s responses to new drug treatments during clinical trials. Continue reading

Outwitting Antibiotic Resistance

Marine scene with fish and corals
The ocean is a rich source of microbes that could yield infection-fighting natural molecules. Credit: National Oceanic and Atmospheric Administration Exit icon.

Antibiotics save countless lives and are among the most commonly prescribed drugs. But the bacteria and other microbes they’re designed to eradicate can evolve ways to evade the drugs. This antibiotic resistance, which is on the rise due to an array of factors, can make certain infections difficult—and sometimes impossible—to treat.

Read the Inside Life Science article to learn how scientists are working to combat antibiotic resistance, from efforts to discover potential new antibiotics to studies seeking more effective ways of using existing ones.

 

New Research Sheds Light on Drug-Induced Salivary Issues

Open human mouth
Scientists have discovered a possible mechanism behind the bad taste and dry mouth caused by some drugs. Credit: Stock image.

The effects some medicines have on our salivary glands can at times extend beyond the fleeting flavor we experience upon ingesting them. Sometimes drugs cause a prolonged bad taste or dryness in the mouth, both of which can discourage people from taking medicines they need. Now, a research team led by Joanne Wang of the University of Washington has discovered a possible mechanism behind this phenomenon. Working primarily with mice and using a commonly prescribed antidiabetic drug known to impair taste, the scientists identified a protein in salivary gland cells that takes up the drug from the bloodstream and secretes it in saliva. Wang and her colleagues were also able to pinpoint a specific gene that, when removed, hindered this process. They hope their new insights will aid efforts to develop medicines that do not cause salivary issues.

This work also was funded by NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Learn more:
University of Washington News Release Exit icon

Anesthesia and Brain Cells: A Temporary Disruption?

Hippocampal neuron in culture.
Hippocampal neuron in culture. Dendrites are green, dendritic spines are red, and DNA in cell’s nucleus is blue. Credit: Shelley Halpain, University of California, San Diego.

Anesthetic drugs are vital to modern medicine, allowing patients to undergo even the longest and most invasive surgeries without consciousness or pain. Unfortunately, studies have raised the concern that exposing patients, particularly children and the elderly, to some anesthetics may increase risk of long-term cognitive and behavioral issues.

A scientific team led by Hugh Hemmings Exit icon of Weill Cornell Medical College and Shelley Halpain Exit icon of the University of California, San Diego, examined the effects of anesthesia on neurons isolated from juvenile rats. Given at doses and durations frequently used during surgery, the commonly administered general anesthetic isoflurane did in fact reduce the number and size of important structures within neurons called dendritic spines. Dendritic spines help pass information from neuron to neuron, and disruption of these structures can be associated with dysfunction in thinking and behavior.

Promisingly, the shrinkage observed by the researchers appeared to be temporary: After the researchers washed the anesthetic out of the cell cultures, the dendritic spines grew back. But because neurons in culture do not reproduce all aspects of intact neuronal networks, the scientists explain that the findings should be verified in more complex models. Other molecular mechanisms may also potentially contribute to late effects of anesthesia exposure.

This work also was funded by NIH’s National Institute of Mental Health.

Learn more:
University of California, San Diego News Release Exit icon
Understanding Anesthesia from Inside Life Science

The “Virtuous Cycle” of Technology and Science

A scientist looking through a  microscope. Credit: Stock image.
Whether it’s a microscope, computer program or lab technique, technology is at the heart of biomedical research. Credit: Stock image.

Whether it’s a microscope, computer program or lab technique, technology is at the heart of biomedical research. Its central role is particularly clear from this month’s posts.

Some show how different tools led to basic discoveries with important health applications. For instance, a supercomputer unlocked the secrets of a drug-making enzyme, a software tool identified disease-causing variations among family members and high-powered microscopy revealed a mechanism allowing microtubules—and a cancer drug that targets them—to work.

Another theme featured in several posts is novel uses for established technologies. The scientists behind the cool image put a new spin on a long-standing imaging technology to gain surprising insights into how some brain cells dispose of old parts. Similarly, the finding related to sepsis demonstrates yet another application of a standard lab technique called polymerase chain reaction: assessing the immune state of people with this serious medical condition.

“We need tools to answer questions,” says NIGMS’ Doug Sheeley, who oversees biomedical technology research resource grants. “When we find the answers, we ask new questions that then require new or improved tools. It’s a virtuous cycle that keeps science moving forward.”