Interview With a Scientist: Namandjé Bumpus, Drug Metabolism Maven

Medications are designed to treat diseases and make us healthier. But our bodies don’t know that. To them, medications are merely foreign molecules that need to be removed.

Before our bodies can get rid of these drug molecules, enzymes in the liver do the chemical work of preparing the molecules for removal. There are hundreds of different versions of these drug-processing enzymes. Some versions work quickly, others work slowly. In some cases, the versions you have determine how well a medication works for you, and whether you experience side effects from it.

Namandjé Bumpus Exit icon, a researcher at Johns Hopkins University School of Medicine, is interested in how human bodies respond to HIV medications. She studies the enzymes that process these drugs. Her research team discovered that a genetic variant of a liver enzyme impacts the way some people handle a particular HIV drug. This variant is found in around 80 percent of people of European descent. She describes her work in this video.

Bumpus recently presented her research to a more scientifically advanced audience at an Early Career Investigator Lecture at the National Institutes of Health. Watch her talk titled Drug Metabolism, Pharmacogenetics and the Quest to Personalize HIV Treatment and Prevention.

Dr. Bumpus’ work is supported in part by NIGMS grant R01GM103853.

Interview With a Scientist: Thomas O’Halloran, Metal Maestro

Inside our bodies is a surprising amount of metal. Not enough to set off the scanners at the airport or make us rich, but enough to fill each of our cells with billions of metal ions, including calcium, iron, copper and zinc. These ions facilitate critical biological functions.

However, too much of any metal can be toxic, while too little can cause disease. Our cells carefully monitor and control their metal content using a whole series of proteins that bind, sense and transport metal ions.

Keeping tabs on why and how metals flow into and out of our cells is a passion of Thomas O’Halloran Exit icon, professor of chemistry and molecular biosciences at Northwestern University in Illinois. For the past three decades, O’Halloran has investigated how fluctuations in the amount of metal ions inside cells influence gene expression, cell growth and other vital functions. Using a variety of approaches, he has uncovered new types of proteins that bind metal ions and investigated the role that imbalances in these ions play in a number of disease-related physiological processes.

One recent focus of his studies has been how zinc regulates oocyte (egg cell) maturation and fertilization. Ultimately, his work could help us better understand infertility, cancer and certain bacterial infections.

Interview With a Scientist: Laura Kiessling, Carbohydrate Scientist

The outside of every cell on Earth—from the cells in your body to single-celled microorganisms—is blanketed with a coat of carbohydrates, or sugar molecules, that extend from the cell surface, branching off and bending as they interface with the extra-cellular space. The specific patterns in which these carbohydrates are arranged serve as an ID code that help cells recognize each other. For example, human liver cells have one pattern, while human red blood cells another. Certain diseases can even alter the pattern of surface carbohydrates, which is one way the body can recognize damaged cells. On foreign cells, including invading bacteria such as Streptococcus pneumoniae, the carbohydrate coat is even more distinct.

Laura Kiessling Exit icon, a professor of chemistry at the University of Wisconsin, Madison, studies how carbohydrate coats are assembled and how cells use these coats to tell friend from foe. The implications of her research suggest strategies for targeting tumors, fighting diseases of inflammation and, as she discusses in this video, developing new classes of antibiotics.

Nature’s Medicine Cabinet

More than 70 percent of new drugs approved within the past 30 years originated from trees, sea creatures and other organisms that produce substances they need to survive. Since ancient times, people have been searching the Earth for natural products to use—from poison dart frog venom for hunting to herbs for healing wounds. Today, scientists are modifying them in the laboratory for our medicinal use. Here’s a peek at some of the products in nature’s medicine cabinet.

Vampire bat

A protein called draculin found in the saliva of vampire bats is in the last phases of clinical testing as a clot-buster for stroke patients. Vampire bats are able to drink blood from their victims because draculin keeps blood from clotting. The first phases of clinical trials have shown that the protein’s anti-coagulative properties could give doctors more time to treat stroke patients and lower the risk of bleeding in the brain.

Continue reading

Data-Mining Study Explores Health Outcomes from Common Heartburn Drugs

Results of a data-mining study suggest a link between a common heartburn drug and heart attacks. Credit: Stock image.

Scouring through anonymized health records of millions of Americans, data-mining scientists found an association between a common heartburn drug and an elevated risk for heart attacks. Their preliminary results suggest that there may be a link between the two factors.

For 60 million Americans, heartburn is a painful and common occurrence caused by stomach acid rising through the esophagus. It’s treated by drugs such as proton-pump inhibitors (PPIs) that lower acid production in the stomach. Taken by about one in every 14 Americans, PPIs, which include Nexium and Prilosec, are the most popular class of heartburn drugs.

PPIs have long been thought to be completely safe for most users. But a preliminary laboratory study published in 2013 suggested that this may not be the case. The study, led by a team of researchers at Stanford University, showed that PPIs could affect biochemical reactions outside of their regular acid suppression action that would have harmful effects on the heart. Continue reading

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

Field Focus: Making Chemistry Greener

Bob Lees
NIGMS’ Bob Lees answers questions about green chemistry. Credit: National Institute of General Medical Sciences.

Chemists funded by NIGMS are working to develop “greener” processes for discovering, developing and manufacturing medicines and other molecules with therapeutic potential, as well as compounds used in biomedical research. One of our scientific experts, organic chemist Bob Lees, recently spoke to me about some of these efforts.

What is green chemistry?

Green chemistry is the design of chemical processes and products that are more environmentally friendly. Among the 12 guiding principles of green chemistry Exit icon are producing less waste, including fewer toxic byproducts; using more sustainable (renewable) or biodegradable materials; and saving energy. 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

Meet Alfred Atanda Jr.

Alfred Atanda Jr.
Credit: Cynthia Brodoway, Nemours/Alfred I. duPont
Hospital for Children
Alfred Atanda Jr.
Fields: Pediatric orthopedic surgery, sports medicine
Works at: Nemours/Alfred I. duPont Hospital for Children
Blogs: as Philly.com’s Sports Doc at http://bit.ly/sportsdoc Exit icon
Family fact: Youngest of seven children
Musical skills: Piano and trumpet
Kitchen talent: Baking chocolate desserts for his pediatrician wife and their two young children

As a kid, Alfred Atanda loved science, sports and tinkering. He dreamed of being a construction worker or an engineer. Today, he works on one of the most complex construction projects of all: the human body.

As a pediatric orthopedic surgeon, Atanda focuses on sports medicine and injuries to children. He has a special passion for young baseball pitchers who have torn the ulnar collateral ligament (UCL) in the elbow of their throwing arm.

This sort of injury is most often caused by overuse. Many small tears accumulate over a long period, resulting in pain and slower, less accurate pitches. Decades ago, this sort of damage occurred almost exclusively in elite athletes. Now, Atanda sees it in children as young as 12 years old. He aims not only to study and treat these injuries, but also to find ways to prevent them.

His Findings

Atanda was first introduced to research on UCL injuries while working alongside team physicians for the Phillies, the professional baseball team in Philadelphia. The physicians wanted to determine whether ultrasound imaging could detect early warning signs—slight anatomical changes in the ligament—before the damage became severe enough to warrant an operation known as Tommy John surgery.

The research focused on Phillies pitchers who had no pain or other symptoms of injury. The multi-year project showed that the UCL in the throwing elbows of these players got progressively thicker and weaker compared to the same ligament in the players’ nonthrowing elbows. The scientists concluded that these physical changes are caused by prolonged exposure to professional-level pitching.

Alfred Atanda Jr. with Joe Piergrossi
Atanda examines the elbow of a young patient. Courtesy: Cynthia Brodoway, Nemours/Alfred I. duPont Hospital for Children

Atanda wondered whether ultrasound imaging could also detect early signs of UCL damage in young pitchers—those in Little League through high school. There has been a dramatic rise in the number of young pitchers who are experiencing the same injuries and undergoing the same surgery as the pros.

Atanda secured funding for this project from an Institutional Development Award (IDeA). The IDeA program builds research capacities in states like Delaware, where Atanda works, that historically have received low levels of funding from the National Institutes of Health.

Atanda’s project began about a year ago, and has examined 55 young athletes so far.

“We found similar results to what we found with the Phillies,” Atanda says, indicating that the UCL in the throwing elbows of young athletes was noticeably thicker than the UCL in the nonthrowing elbows. And the damage seems progressive, he says: “We saw that these ligaments got thicker as the pitchers got older and had more pitching experience.”

The immediate goal of this project, which he hopes to continue for another 3 years, is prophylaxis. “We’re trying to prevent any kind of overuse elbow injuries and the need for Tommy John surgeries later on,” Atanda says. He also hopes to establish quantitative correlations between pitching behavior and anatomical changes.

Atanda also has longer-term aspirations. “My goal is to change the culture in sports for young athletes in general,” he says. “I want to show there are downsides to pitching so much.”

In addition to championing pitch count limits recommended by the American Sports Medicine Institute, Atanda advises a focus away from excess competition and toward getting exercise, enjoying social inter­action, building self-confidence and having fun.

Atanda’s research is funded by the National Institutes of Health through grant P20GM103464

Content adapted from the NIGMS Findings magazine article Game Changer

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.