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Two NIGMS MARC Scholars Receive Prestigious Rhodes Scholarship

Fri, 2018-01-12 11:53
Oxford University. Credit: Andrew Shiva, Wikimedia Commons CC BY-SA.

MARC U-STAR Scholars Jasmine Brown and Naomi Mburu were among 32 Americans to recently receive the prestigious Rhodes Scholarship at Oxford University in England. Rhodes Scholars are chosen for their academic and research achievements, as well as their commitment to others and leadership potential.

As current MARC U-STAR Scholars, Brown and Mburu are part of an NIGMS research training program for undergraduate junior and senior honor students. MARC is designed to increase the number of people from groups underrepresented in biomedical sciences by preparing students for high-caliber, doctorate-level training.

Here’s more about these two distinguished women:

Credit: The Source, Washington University in St. Louis.

Jasmine Brown, 21

Brown, of Hillsborough, New Jersey, is a senior at Washington University in St. Louis and works as a research assistant at the Washington University School of Medicine. There, she studies genes that are protective against mental defects that result from West Nile-induced brain inflammation. After she receives her bachelor’s degree in biology, she plans to earn a doctorate degree in neuroscience as a Rhodes Scholar at Oxford University.

In addition to her current training as a MARC Scholar, Brown has spent her summers as an undergraduate research assistant, engaging in the study of these other notable subjects:

  • Lung cancer, at the Broad Institute of MIT and Harvard (2017)
  • Specific drugs’ cough-suppressing effects, at Johns Hopkins University School of Medicine (2015)
  • Long-term neurological effects of cocaine and other stimulants on the teen brain, at the University of Miami Miller School of Medicine (2014)

“What I love about science is that it gives me tools to generate answers and to improve human health. It’s a fun process for me, but also a satisfying one because I can make an impact,” Brown said in a statement.

Equally important to her studies, Brown is a champion for other underrepresented students in the sciences. After her own experience as the target of prejudice, Brown started the Minority Association of Rising Scientists (MARS) to support underrepresented students participating in research and inform faculty members about implicit bias. With the help of the National Science Foundation, Brown is working to expand MARS nationwide.

Brown has given back to the community in other ways. She was a member of The Synapse Project , which prepares high school students for a neuroscience competition called Brain Bee . She was also a 2014-2015 candidate for Mx. WashU , an organization that raises money for a children’s program called City Faces .

Naomi Mburu, 21

Credit: Marlayna Desmond for UMBC.

Naomi Mburu, of Ellicott City, Maryland, is the daughter of Kenyan immigrants and the first student in the history of the University of Maryland Baltimore County (UMBC) to receive the Rhodes Scholarship. The senior in chemical engineering plans to complete a doctorate in engineering science and to research heat transfer applications for nuclear fusion reactors.

“I believe the Rhodes Scholarship will allow me to foster a stronger community amongst my fellow scholars because we will all be attending the same institution,” Mburu said in a statement.
Mburu is currently working with Gymama Slaughter , UMBC associate professor of computer science and electrical engineering, to develop a machine that ensures human organs remain healthy as they await transplant.
During her recent summer internship with Intel, Mburu developed an interactive model to estimate the cost of coatings applied to equipment. Her work helped improve pricing negotiations and established additional cost estimates for other chemical processes.

Her other areas of research have included:

  • Assessing phosphate’s effects on the ribosomal protein L4 as a student at Mount Hebron High School
  • Measuring the impurities found in the Large Hadron Collider particle accelerator, at the European Organization for Nuclear Research, Geneva, Switzerland

Mburu’s aspirations involve not just science but education advocacy. Her passion for STEM education and increasing diversity in STEM fields led to her current involvement as a MARC trainee, where she’s learned to communicate her desire to make a global impact through her science research and her efforts to remove barriers to education equality.

In her free time, Mburu has helped K-12 students with their homework during her time at UMBC. She continues to mentor youth and helps high school girls on STEM-related research projects.

The changing needs of a cell: No Membrane? No Problem!

Wed, 2018-01-03 10:21

Russian nesting dolls. Credit: iStock.

How “membrane-less” organelles help with key cellular functions

Scientists have long known that animal and plant cells have specialized subdivisions called organelles.  These organelles are surrounded by a semi-permeable barrier, called a membrane, that both organizes the organelles and insulates them from the rest of the cell’s mix of proteins, salt, and water.  This set-up helps to make cells efficient and productive, aiding in energy production and other specialized functions. But, because of their semi-permeable membranes, organelles can’t regroup and reform in response to stress or other outside changes. Cells need a rapid response team working alongside the membrane-bound organelles to meet these fluctuating needs. Until recently, who those rapid responders were and how they worked has been a mystery.

Recent research has led biologists to learn that the inside of a cell or an organelle is not just a lot of different molecules dissolved in water. Instead, we now know that cells contain many pockets of liquid droplets (one type of liquid surrounded by a liquid of different density) with specialized composition and function that are not surrounded by membranes. Because these “membrane-less organelles” are not confined, they can rapidly come together in response to chemical signals, such as those that indicate stress, and equally rapidly fall apart when they are no longer needed, or when the cell is about to divide. This enables membrane-less organelles to be “rapid responders” They can have complex, multilayered structures that help them to perform many critical cell functions with multiple steps, just like membrane-bound organelles. Scientists even suspect that the way these organelles form as droplets may shed light on how life on Earth first took shape (see sidebar below).

The Many Membrane-less Organelles

Scientists have identified more than a dozen membrane-less organelles at work in mammalian cells. Several kinds found inside the nucleus—including nuclear speckles, paraspeckles, and Cajal bodies—help with cell growth, stress response, the metabolizing (breaking down) of RNA, and the control of gene expression—the process by which information in a gene is used in the synthesis of a protein. Out in the cytoplasm, P-bodies, germ granules, and stress granules are membrane-less organelles that are involved in metabolizing or protecting messenger RNA (mRNA), controlling which mRNAs are made into proteins, and in maintaining balance, or homeostasis, of the cell’s overall health.
The nucleolus, located inside the nucleus, is probably the largest of the membrane-less organelles. It acts as a factory to assemble ribosomes, the giant molecular machines that “translate” messenger RNAs to make all cellular proteins.

The nucleolus is a large organelle without a membrane that forms in the cell nucleus. Scientists have learned that the nucleolus (pictured here) actually contains three layers, separated not by membranes but by differences in surface tension, much like a mixture of oil, water and certain types of alcohol will naturally settle into three layers. The rRNA starts in the central layer and works its way outward, receiving modifications along the way. The completed subunits travel out of the nucleus to the cytoplasm to assemble into ribosomes. Credit: NIGMS.

The rate that ribosomes are assembled allows cells to regulate their growth and activity. Behind this growth is the nucleolus. It can increase ribosome production to allow for more growth, such as when the cell is preparing to divide in two or halt ribosome production to respond to changes in the cell’s environment, such as those brought on by stress. Recently, scientists found that, at least in some animals, the nucleolus itself grows in parallel with the growth of both the cell and the organism. Its growth levels out as the organism reaches maturity, when the cell no longer needs an increasing number of ribosomes to produce proteins. As a membrane-less organelle, the nucleolus has the flexibility to respond quickly to changes in the cell’s environment. And with its prominent role in cell growth it’s believed to be at the center of many human diseases. For example, it may be a good target for cancer treatments, because out-of-control cell growth and enlarged nucleoli are hallmarks of cancer.

Free-Flowing Proteins
Imagine a lava lamp with its slowly flowing colored globules. Those drops of color can maintain clear separation from the surrounding liquid because they contain molecules that are electrostatically attracted to each other, like the static electricity that causes two socks just taken out of a dryer to weakly cling to each other. They condense to form a separate droplet, or phase. This is known as phase separation, and membrane-less organelles follow the same principle.

Lava lamp. Credit: Wikimedia Commons, Risa1029.

Membrane-less organelles only exist temporarily and there needs to be a mechanism to both bring them together (condense them) and separate them when they’re no longer needed. Richard Kriwacki and his colleagues at St. Jude Children’s Research Hospital in Memphis, Tennessee, have discovered that a protein called nucleophosmin (NPM1) helps the chemical building blocks of the nucleolus phase separate to form a droplet. NPM1 acts as a glue, forming loose networks with many different proteins and RNAs. The researchers believe such networks are necessary for the proteins and RNAs in the nucleolus to condense and separate in response to stress. These findings provide the first insights into the role of NPM1 in the molecular organization of the nucleolus. The next challenge is to understand how this organization promotes the production of ribosomes and helps the cell to respond to stressful situations.

Kriwacki and his colleagues also found recently that NPM1 is among the targets of toxic “repeat” polypeptides that are produced in amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s disease) and other neurodegenerative diseases. The repeat polypeptides’ structure changes NPM1’s glue-like activity and interferes with the function of the nucleolus. These changes could lead to the rapid deterioration of nerve cells seen in such diseases.

Cell as cruise-director: keeping membrane-less organelles in line and under control

Although they appear to take shape spontaneously, membrane-less organelles are very much under the cell’s control. Cells can raise and lower the concentrations of key structural molecules to affect whether a droplet forms. Ashok Deniz and his colleagues at the Scripps Research Institute in La Jolla, California, recently studied the effects of different amounts of RNA on the formation of membrane-less ribonucleoprotein (RNP) granules, which are involved in regulating gene expression. The scientists found that while initial increases in RNA concentrations play a role in inducing granule formation, further increases in RNA can make the RNP granules dissolve. The phenomenon resembles using Elmer’s glue for an elementary school project: you need to add enough to get one piece of construction paper to stick to another piece, but if you add too much glue, both pieces turn into mush and the project is ruined. This RNA mechanism provides the cell with a simple way to control RNP granule activity. The study helps scientists learn more about how membrane-less organelles form in real cells as well as in artificial (man-made) cells. This could be important because there may be diseases where the treatment could be to ramp production of membrane-less organelles up or down.

Adding single-stranded RNA to synthetic peptides—or chains of amino acids—leads to the formation of RNP granules inside of cells. When RNA levels get too high, the granules are disrupted. Credit: The Scripps Research Institute.

From the Inside Out

Proteins and RNA pooling together, or “condensing,” in response to changing environmental conditions explains how a droplet can form through phase separation, but it doesn’t explain how these membrane-less organelles are able to do complex jobs. Organelle functions, such as ribosome assembly (see figure above), often involve several steps, and they benefit from a complex structure that can separate and organize these steps. Clifford Brangwynne, a biophysicist at Princeton University, and his colleagues found that the surface tension of droplets made of different mixtures of proteins may explain how membrane-less organelles self-organize to do even the most complicated jobs.
Studying the nucleolus, Brangwynne and his team discovered that each layer of proteins and rRNA formed its own droplet, with one nested inside another like a set of Russian matryoshka dolls. One layer did not mix with the others, even when the researchers removed the proteins from cells and tested them on microscope slide cover slips. The different droplets acted like oil and water, co-existing but not actually mixing.
The researchers then learned that the interactions between protein molecules in each layer helped determine each droplet’s surface tension. When a nucleolus forms, the center layer has the greatest surface tension, and each surrounding layer has progressively lower surface tension relative to its surroundings. Using a device that shuttles liquids through millimeter-sized channels and a new technology they developed called optoDroplet that uses light to induce phase transitions inside living cells, Brangwynne and his group will continue to uncover details about how the proteins in membrane-less organelles undergo phase separation so effectively and how precise protein interactions can be derailed in some diseases.

A new tool, the optoDroplet, lets scientists control the formation of membrane-less granules in living cells using light. As shown here, granules are slow to appear. Then as the light is increased, the number of granules grows dramatically, as if a switch has been turned on. The scientists are using this technique to study what happens when healthy granules appear and dissolve as well as how the process may change when the proteins gather into gels or solids, as they do in diseases such as ALS. Credit: Clifford Brangwynne lab.

 Disease Implications

As scientists learn how sensitive membrane-less organelles are to the changing conditions in a cell, they have become interested in these structures’ potential roles in disease. For example, if some proteins found in membrane-less organelles are altered, they can form a more gel-like droplet with less fluid structures. This may affect how well the organelles function, and how easily they can be disassembled, potentially contributing to heart and neurological conditions. Also, cancerous cells often contain bloated and oddly shaped nucleoli that overproduce ribosomes and contribute to cell growth and division that races out of control. Learning more about membrane-less organelles may lead to new ways to influence their function to treat such health conditions.
This research was funded in part by NIH under grants: R01GM115634, R01GM083159, R01GM066833, DP2GM105437, F32GM113290, T32GM007276, 7DP2GM119137-02, R01CA082491, DP2EB024247, U01DA040601, S10RR027425, P30CA021765, R35NS097974, R01AG047928, and R01NS056114.

Could This Be How Life First Took Shape?

Droplets of chemicals within a primordial soup can stretch and split (top row). The process can repeat (bottom row) to create new generations of droplets, in a process that mimics reproduction and reveals a possible way by which life on Earth first took shape. Credit: David Zwicker et al., Nature Physics, 2016.

In the early 2000s, scientists began to identify membrane-less organelles and describe how they form droplet structures. These discoveries reinvigorated a hypothesis put forth by Russian biochemist Alexander Oparin in 1924 that the first protocells—the forerunner of the first modern cell-like structures on Earth—were naturally forming liquid droplets rather than membrane-bound compartments. Oparin’s hypothesis received another boost in 2016 when German scientists reported “chemically active” liquid droplets, which cycle molecules in and out of the surrounding fluid and also grow to near cell size and divide, just like cells.

Zebrafish Scrapbook

Thu, 2017-12-07 14:29
Name: Danio rerio
Hometown: Freshwater ponds and rivers of India, Nepal, and neighboring countries
Occupation: Research
Long-term goal: Solving the basic mysteries of life
Work site: More than 600 science labs worldwide
That’s me and some other zebrafish, swimming in a tank in one of the more than 600 labs around the world that use us to study embryo development, genetics, and all kinds of human diseases. Credit: Wikimedia Commons, Azul.

Apart from the tell-tale stripes that give me my nickname, zebrafish, I look a lot like your standard minnow swimming in the shallows of any pond, lake, or river. But I like to think I’m more important than that. In fact, researchers around the world have turned to me and my extended family to understand some of the most basic mysteries of life. From studying us, they’re learning about how embryos develop, how cancer works, and whether someday humans might be able to rebuild a heart, repair a spinal cord injury, or regrow a severed limb.

Why us? Because zebrafish are pretty special and researchers think we’re easy to work with. First, unlike your standard lab mouse or rat, we lay lots of eggs, producing baby fish that grow up fast. We develop outside our mothers and go from egg to embryo to free-swimming larva in just 3 days (check out this video of how we grow, cell by cell, during the first 24 hours). Within 3 months, we’re fully mature.

Not only do zebrafish moms have many babies at the same time, and not only do these babies grow up quickly, but our eggs and embryos are see-through, so scientists can literally watch us grow one cell at a time. We stay mostly transparent for a few weeks after hatching. That makes it super easy for scientists to monitor us for both normal and abnormal development. In fact, scientists have learned how to turn off the genes that give our skin its color. These zebrafish, named casper, after the “friendly ghost” of cartoon fame, stay semi-transparent, or translucent, through adulthood.

And last, but certainly not least, did I mention that we can regenerate? If parts of my body are damaged, even to a significant degree, they can regrow. This holds true for my heart, fins, spinal cord, and even brain tissue. Our regenerative capacity is seemingly unlimited; my caudal fin, for example, can grow back dozens of times.

We don’t look much like humans. But we aren’t as different as you think. We’re both vertebrates, with a central spinal column, and we have the same major organs and tissues. And we have lots of similar genes. Seventy percent of human genes have a least one close match to our genes.

Although a few researchers in Oregon started working with us in the 1970s, we really skyrocketed into science labs in the mid-1990s, when a huge study of my cousins identified 4,000 genetic mutations—small changes in different genes that could alter how those genes work. Researchers like working with organisms with mutated genes because this lets them more easily understand normal genes. They can compare fish with an abnormal copy of a gene with fish that have a normal copy. We became even more popular when, in 2013, scientists sequenced all of a zebrafish’s genes .

I hope you enjoy this scrapbook. It shows some of my favorite pictures of my kin hard at work in the lab. These snapshots demonstrate just how important we are to research that can promote human health and potentially help treat and prevent human disease.

Click on an image below to launch slideshow.

“Selfish” Gene Enhances Own Transmission at Expense of Organism’s Fertility

Tue, 2017-11-21 11:25
These glowing images of yeast (Schizosaccharomyces kambucha) reproductive cells show an example of a selfish gene at work. Here, the selfish gene boosts its chances of being passed to the next generation by producing both a toxin (stained cyan) and an antitoxin (stained magenta). Cells with a copy of the selfish gene are protected by the antitoxin, left and bottom ovals. Those without the selfish gene are destroyed by the toxin. Scientists suspect that selfish genes could be operating throughout many organisms’ genomes, possibly having a major impact on how genetic material is inherited over generations. Credit: Image courtesy of María Angélica Bravo Núñez and Nicole Nuckolls.

There’s an old saying that rules are meant to be broken. In the 1860s, Gregor Mendel found that each copy of a gene in an organism has an equal chance of being passed to the next generation. According to this simple rule, each version of a gene gets passed to offspring with the same frequency. The natural selection process can then operate efficiently, favoring the genes that produce an advantage for an organism’s survival or reproductive success and, over successive generations, eliminating genes from the gene pool that bring a disadvantage.

Of course, the way organisms inherit genes is not as straightforward as Mendel’s work predicted. In natural systems, inheritance often fails to follow the rules. One culprit scientists are identifying again and again are what are called “selfish genes”: one or more genes that have evolved a method of skewing inheritance in their favor.

Scientists refer to these selfish genes—which are often complexes of multiple genes working together—as “selfish” because they enhance their own transmission to the next generation, sometimes by killing off any of the organism’s reproductive cells that lack copies of those genes. Using a variety of techniques, the genes are effective at passing themselves on to future generations. However, their methods set up a conflict within the organism by damaging its fertility; overall, fewer reproductive cells or offspring survive to produce a new generation.

Selfish genes are a challenge for scientists to identify, but researchers say that knowing more about these genes could help explain a range of genetic mysteries, from causes of infertility to details on how species evolve. The methods these genes use could also be harnessed to help control the reproduction of certain populations such as mosquitos that spread disease.

One recently described selfish gene system is found in the yeast cells pictured above. Sarah Zanders and her colleagues at the Stowers Institute for Medical Research in Kansas City, Missouri, and the Fred Hutchinson Cancer Research Center in Seattle, Washington, study selfish gene systems in yeast to understand how common they are and how they affect a species’ fertility and evolution. “Usually we think about infertility stemming from the good guys failing. For example, a gene that normally promotes fertility could be mutated so that it can no longer do its job,” says Zanders. “But selfish genes are another potential source of infertility. Learning general principles about selfish genes in simple models will guide future searches for selfish genes that could be contributing to human infertility.”

Recently, the scientists discovered a single selfish gene, wtf4, that encodes both a toxin and an antitoxin protein. When yeast produce their reproductive cells, called spores, the wtf4 toxin protein is released into the immediate vicinity, but the antitoxin remains inside spores that contain a copy of wtf4. The toxin destroys all the spores that don’t have the antitoxin protein. Although the yeast has fewer spores—and therefore reduced fertility—each spore carries wtf4, ensuring that the gene will be passed to the next generation of yeast.

Yeast reproductive or gamete cells (called spores) show how selfish genes can influence inheritance. Spores that don’t carry the wtf4 gene are killed when the wtf4 poison protein is released into the area around them. Those with a wtf4 copy (the selfish gene) are protected against the toxin by the antidote protein. Credit: Sarah Zanders laboratory, Stowers Institute for Medical Research.

Researchers have found that selfish gene systems such as wtf4 crop up in many other species. They use a variety of mechanisms to ensure that they survive from generation to generation. In bacteria, some selfish genes can even be beneficial to their hosts. For example, some bacteria have figured out a way to incorporate into their genomes selfish gene systems to respond to stresses such as infection, starvation, or treatment with antibiotics. The selfish elements include toxins that are chemically bound to antitoxins. When the bacterium is exposed to stress, it produces enzymes that cut the bond between the toxin and antitoxin. The enzymes also degrade the antitoxin. The released toxin then stops the bacterium from making other proteins, which sends it into a dormant, or hibernation-like, state until conditions improve.

Selfish genes, scientists are beginning to realize, influence many aspects of inheritance. For example, genes located near a selfish gene in an organism’s genome may be passed to the next generation simply because of proximity, even if they are damaged or produce traits that are not helpful to the organism. For example, researchers found that a selfish gene system in fruit flies causes a large piece of DNA to be passed along unchanged, even though that piece causes sterility in female flies, which inherit two copies of this genetic material. This “selfish-by-association” mechanism may help to explain how a genetic disorder persists in a population.

Sometimes the presence of selfish genes masks how genes actually function. Leonid Kruglyak and his colleagues at the University of California, Los Angeles (UCLA), recently described a selfish element in nematode worms (Caenorhabditis elegans) that causes 25 percent of embryos to die when certain strains of the worms are mated. Researchers had thought a certain gene, pha-1, was an essential regulator of development, because mutant worms lacking a working copy of pha-1 would fail to develop the feeding organ, or pharynx. In fact, the pha-1 protein only suppressed the effects of a toxin, sup-35. This selfish gene system, the scientists found, hijacks a developmental pathway to kill the embryos that do not inherit sup-35/pha-1.

Caenorhabditis elegans. Credit, iStock.

The scientists believe that other genes thought to be essential to development may turn out to be elements of selfish gene systems. Eyal Ben-David and Alejandro Burga, lead authors of Kruglyak’s study, said that their finding points out the importance of studying natural genetic variation in a species. “Most researchers use a single genetic background [that is, they study organisms that all have exactly the same genetic code] because it increases reproducibility,” Ben-David says. “You will get most things right, but you will also miss many important characteristics that make individual organisms and populations unique. In our case, by studying C. elegans from diverse locations in the world, we were able to identify wild worms that lacked pha-1, which helped us solve the puzzle.”

Because selfish genes reduce fertility, any species that finds a way to suppress these genetic elements would have a fertility advantage, because more of its offspring would survive. Indeed, organisms do appear to evolve the ability to suppress their selfish genes. Scientists believe that selfish genes must themselves change rapidly across generations to evade such suppressors, setting off a kind of arms race of evolution between selfish genes and the organism’s adaptations to stop them. For this reason, organisms may have many, very diverse families of selfish genes, making it hard for scientists to identify them.

Knowing how these genes sabotage reproduction is important. For example, selfish gene systems could offer a means for controlling or minimizing the harm caused by disease-carrying or crop-destroying insects. Insects could be developed that carry the selfish genes, which, in turn, would reduce the number of insects produced over time. However, many scientists warn that because so little is known about how selfish genes interact with the natural environment, it is impossible to project the full consequences of releasing these altered insects into wild populations. According to Ben-David and Burga, the effects that selfish elements have on inheritance may help drive the formation of new species among the plants or animals that they affect. Gaining a better understanding of selfish genes will enable scientists to avoid unanticipated consequences of using selfish genes as a tool—for the organism, for its future generations, and for our environment.

Zanders’s research on yeast was funded in part by NIGMS under Grants R01GM031693, R35GM118120 , R01GM74108 , and R00GM114436 . Kruglyak’s research on nematodes was funded in part by the NIH under Grant R01HG004321.

Taking the Guesswork Out of Pain Management

Tue, 2017-11-07 11:02

How do you measure pain? A patient’s furrowed brow, a child’s cries or tears—all are signs of pain. But what if the patient suffers from severe dementia and can’t describe what she is feeling or is a young child who can’t yet talk? Caregivers can help read the signs of pain, but their interpretations may differ greatly from patient to patient, because people have different ways of showing discomfort. And when the patient is unconscious, such as during surgery or while in intensive care, the caregiving team has even fewer ways to measure pain.

Patients can point to one of the faces on this subjective pain scale to show caregivers the level of pain they are experiencing. Credit: Wong-Baker Faces Foundation.

Assessing pain is an inexact science. It includes both subjective and objective measures. A patient might be asked during a subjective assessment (performed, perhaps, with a caregiver showing a pain-rating scale such as the one in the figure), “How much pain are you feeling today?” That feedback is coupled with biological markers such as an increased heart rate, dilated pupils, sweating, and inflammation as well as blood tests to monitor high levels of the stress hormone cortisol. Combined, these measurements can give doctors a fairly clear picture of how much pain a patient feels.

But imagine if members of the surgical or caregiving team could actually “see” how the patient is feeling? Such insight would let them select better drugs to use during and after surgery, tailoring care to each patient. That tool could be put into service in the operating room and by the bedside in intensive care, giving nonstop reports of pain as the patient experiences it.

An objective measure of pain also has uses beyond the operating room and intensive care unit. Given the high risk for opioid misuse, such a measure could take the guesswork out of pain management and give doctors a more accurate indication of pain levels to prevent over-prescribing opioid pain relievers.

Top Down Look at Pain

Researchers are studying several tools to see if any can reliably measure pain in an objective way. One promising technique is functional near-infrared spectroscopy (fNIRS). This noninvasive tool lets researchers measure, in real time, how the brain is responding to certain conditions, such as painful stimuli.

This top-down approach gives scientists a “window” into the brain by detecting changes in oxygen activity in the cerebral cortex, the area of the brain responsible for recognizing and synthesizing signals from across the body.

When the cortex’s activity increases, the oxygen levels also rise as a result of greater blood flow and volume to that area of the brain. In particular, changes occur in the amount of oxygenated and deoxygenated blood cells—indicating how the brain is responding to a wide range of sensations, including pain, cold, and heat. Those changes are then mapped to a chart or displayed as numbers to show the brain’s activity. Other imaging techniques can be used to measure brain activity in this same way, including magnetic resonance imaging (MRI). The chief advantage to fNIRS is that it relies on mild infrared (heat) signals rather than strong magnets or radiation, and it can be used continuously without danger to the patient or to others in the room.

David Boas (of Boston University) and David Borsook (of Boston Children’s Hospital and Massachusetts General Hospital) have developed a portable fNIRS-based device that can be wheeled to the operating room or bedside. This device is now being tested to identify patients who may need more, or a different kind of, pain reliever during surgery.

Scientists are working on using fNIRS technology to track pain. This illustration shows responses to pain in the prefrontal cortex (colored region on bottom right, near the stars). The goal is to alleviate patients’ pain before it registers in the brain. This has practical applications during surgery in patients who are unconscious and also in patients who cannot communicate, such as infants or people suffering from stroke.

In their research, Borsook and Boas have used fNIRS to confirm a specific biomarker for assessing pain. That is, they found that placing optodes (or small sensors) on the patient’s skull above the prefrontal cortex yielded consistently accurate measures of pain (see figure). Because this is the area of the brain that determines how pain will be interpreted and what the response will be, in a sense, it “decides” what is pain. Their next step is to use the prefrontal cortex biomarker in different clinical settings with a variety of types of anesthesia and to further refine the biomarker by filtering out any background “noise” from other interfering signals. Their research team includes fNIRS specialists, pain specialists, and physicians.

Being able to assess and manage a patient’s pain during general anesthesia, when the patient is fully unconscious, is an important advance. If doctors can assess the patient’s pain load and address this pain during the surgery itself, the patient could awaken from surgery with pain already under control. There would be less need for more or additional types of painkillers to make the patient comfortable.

Borsook also believes that better pain management during surgery can help in reducing chronic pain over a patient’s lifetime. He notes that, “43 million surgeries take place each year, and 15 to 30 percent of those patients end up with chronic pain after surgery.” According to Borsook, this pain is not the result of the surgical procedure. Rather it stems from the inability to control pain while the surgery is taking place.

Patients awaken with those pain signals already hard wired into the brain, and it can be difficult to play catch up with medications to ease pain after surgery. A better approach is to squelch the signals that trigger long-term pain before they register in the brain. Taking the guesswork out of pain management during surgery then could reduce the numbers of patients who experience chronic pain, long after the initial healing is complete.

Borsook and Boas are working now to further simplify their fNIRS machine. States Borsook, “It would be ideal to have the device show a green light when the patient’s pain is being managed and a red light when pain signals are reaching the brain.” The team also is looking at ways to better evaluate ongoing pain. This is important because once the initial pain signals are generated, a wide range of inflammatory responses ensue, making nerve endings more sensitive and sometimes causing them to fire spontaneously.

Managing Opioids

An objective measuring of pain has other uses as well. Using fNIRS, researchers are exploring if it can be used to examine how opioids work to relieve pain in healthy men and women. Borsook notes, “Some drugs produce desensitized states” and may not work as effectively in a given patient over time. This is especially true with opioid use. This class of drug actually alters the prefrontal cortex, changing the way it perceives pain and how the brain responds to it. The result is that the drug either doesn’t work as well in the same doses as before (tolerance develops), or the pain seems greater than it was previously (a result of the brain interpreting it differently than before). Using an objective measure could give a clearer picture of how pain is registering in the brain and how best to respond to those pain signals.

fNIRS machine. Credit: National Library of Medicine.

Other scientists are testing fNIRS for measuring dental pain, back pain, and migraine pain.

It should be noted, too, that fNIRS is not the only high-tech tool that holds promise for assessing pain. A recent report compared three imaging techniques used in monitoring pain in infants: NIRS, functional magnetic resonance imaging (fMRI), and electroencephalography (EEG). All of these tools look for clues to the patient’s pain levels by detecting changes in the brain. Although each tool had merit for monitoring pain, the researchers found that EEG had the most consistent results. The drawback with this technique is that electrodes cannot pinpoint the location of the pain signal in the brain to the same extent as fMRI or NIRS. The report authors noted that EEG and other imaging techniques are most effective when combined with existing pain-detection methods, such as monitoring changes in body movements, grimaces, and cries.

More research will help scientists determine how best to blend these high-tech tools with tried-and-true methods of pain assessment, offering patients the best chance at pain relief, both during surgery and beyond.

This research was funded in part by NIGMS under grants: 4R01GM104986-04 and 1R01GM122405-01A1.

Sepsis: The Body’s Deadly Response to Infection

Thu, 2017-11-02 10:56

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Although not as well-known as other medical conditions, sepsis kills more people in the United States than AIDS, breast cancer, or prostate cancer combined. Sepsis is body-wide inflammation, usually triggered by an overwhelming immune response to infection. Though doctors and medical staff are well-aware of the condition—it is involved in 1 in 10 hospital deaths—the condition is notoriously hard to diagnose. In this video, sepsis expert Sarah Dunsmore, a program director with the National Institute of General Medical Sciences (NIGMS), describes what sepsis is and how to recognize it, what kinds of patients are most at risk, and what NIGMS is doing to reduce the impact of this deadly condition.

How I Spent My Summer Vacation

Mon, 2017-10-23 09:43

One of NIGMS’ primary goals is to provide support to train the next generation of biomedical research scientists. In pursuit of this goal, NIGMS aims to enhance the diversity of the scientific workforce and develop research capacities throughout the country. NIGMS-administered training programs at the undergraduate level provide support for trainees underrepresented in the biomedical sciences to develop skills to successfully transition into doctoral programs. Three unique NIGMS-administered undergraduate-focused programs are highlighted below.

  • Building Infrastructure Leading to Diversity (BUILD) grant awards help undergraduate institutions implement and study ways to engage and retain students from diverse backgrounds in biomedical research. The program aims to help these students on the pathway to becoming scientists. Primary institutions eligible for BUILD awards have fewer than $7.5 million in total NIH research project grant funding and a student population with at least 25 percent Pell Grant recipients. BUILD is part of the Common Fund Diversity Program Consortium, a national collaborative dedicated to enhancing diversity in the biomedical research workforce.
  • Maximizing Access to Research Careers Undergraduate Student Training in Academic Research (MARC U-STAR) awards provide support for undergraduate trainees from underrepresented backgrounds to gain skills and improve their preparation for high-caliber graduate training at the doctoral level. Awards are made to colleges and universities that offer the baccalaureate degree.
  • The Research Initiative for Scientific Enhancement (RISE) program aims to help reduce the existing gap between underrepresented and well-represented students in completing doctoral degrees. RISE supports institutions that award the baccalaureate, master’s, or doctoral degree in biomedical science fields; programs include well-integrated developmental activities designed to strengthen students’ academic preparation, research training, and professional skills.

Although BUILD, MARC, and RISE offer a variety of activities at more than 100 supported institutions during the school year—including laboratory research opportunities, faculty mentoring, seminars, and workshops—the programs also provide training experiences throughout the summer. The slideshow below gives a quick peek into what several students participating in MARC, RISE, and BUILD activities did over the summer.

Click on an image below to launch slideshow.

Contact Information:

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