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Interview With a Scientist – Rommie Amaro: Computational and Theoretical Model Builder

Wed, 2018-08-15 14:21

Many researchers who search for anti-cancer drugs have labs filled with chemicals and tissue samples. Not Rommie Amaro . Her work uses computers to analyze the shape and behavior of a protein called p53. Defective versions of p53 are associated with more human cancers than any other malfunctioning protein.

The goal of Amaro’s work is to find ways to restore the function of defective p53 protein in cancer cells. Her research team at the University of California, San Diego, discovered how to do just    that—according to their computer models, at least—by fitting small molecules into a pocket in malfunctioning p53 proteins. Amaro founded a biotechnology company to bring this computational work closer to a real cure for cancer.

She also explained her research in the 2017 DeWitt Stetten Jr. Lecture titled Computing Cures: Discovery Through the Lens of a Computational Microscope.

NIGMS has supported Amaro’s work since 2006 under P41GM103426, U01GM111528, R25GM114821, and F32GM077729.

Americans Fighting the Opioid Crisis in Their Own Backyards

Wed, 2018-08-01 14:39

Credit: New York Times article, Jan. 19, 2016.

The United States is in the midst of an opioid overdose epidemic. The rates of opioid addiction, babies born addicted to opioids, and overdoses have skyrocketed in the past decade. No population has been hit harder than rural communities. Many of these communities are in states with historically low levels of funding from the National Institutes of Health (NIH). NIGMS’ Institutional Development Award (IDeA) program builds research capacities in these states by supporting basic, clinical, and translational research, as well as faculty development and infrastructure improvements. IDeA-funded programs in many states have begun prioritizing research focused on reducing the burden of opioid addiction. Below is a snapshot of three of these programs, and how they are working to help their communities:

Vermont Center on Behavior and Health

Because there are generally fewer treatment resources in rural areas compared to larger cities, it can take longer for people addicted to opioids in rural settings to get the care they need. The Vermont Center on Behavior and Health works to address this need and its major implications.

“One very disconcerting trend we’re seeing with this recent crisis is that opioid-addicted individuals are being placed on wait lists lasting months to a year without any kind of treatment,” says Vermont Center on Behavior and Health director Stephen Higgins. “And it’s very unlikely that anyone who is opioid addicted is just going to abstain while they are on a wait list.”

In urban areas, buprenorphine—an approved medication for opioid addiction that can prevent or reduce withdrawal symptoms—is generally dispensed by trained physicians at treatment clinics. Unfortunately, many rural communities don’t have enough physicians and clinics to serve patients in need. While waiting for treatment, patients are at risk of premature death, overdose, and contracting diseases such as HIV.

Stacey Sigmon, a faculty member in the Vermont Center on Behavior Health, has developed a method to help tackle this problem: a modified version of a tamper-proof device that delivers daily doses of buprenorphine. The advantage of using the modified device is that it makes each day’s dose available during a preprogrammed 3-hour window within the patient’s home, eliminating the need to visit a clinic.

During a study, participants in the treatment group received interim buprenorphine from the device. They also received daily calls to assess drug use, craving, and withdrawal. Participants in the control group didn’t receive buprenorphine. They remained on the waiting list of their local clinic and didn’t receive phone calls. The results, published in the New England Journal of Medicine (NEJM), indicate that the device works. Participants who received the interim buprenorphine treatment submitted a higher percentage of drug test specimens that were negative for opioids than those in the control group at 4 weeks (88 percent vs. 0 percent), 8 weeks (84 percent vs. 0 percent), and 12 weeks (68 percent vs. 0 percent). Sigmon and colleagues are currently testing the device with a much larger group of participants.

“This tool is now available to other rural states that are also being devastated by this crisis and are not so far along in beefing up treatment capacity,” says Higgins.

Vermont Center on Behavior Health’s Stacey Sigmon with the tamper-proof buprenorphine delivery device she used in her NEJM study.

In another attempt at alleviating the crunch in treatment capacity, the Vermont Center is preparing to launch a pilot experiment to deliver medication-assisted treatment in the emergency department. Patients presenting opioid misuse issues—e.g., overdose, swelling from using contaminated needles—would get immediate treatment and continue returning to the ER for treatment until a slot opens up at an opioid clinic.

In a different study, Higgins and Sigmon, along with University of Vermont colleagues, addressed another problem associated with opioid misuse—in utero exposure. Nearly 80 percent of all pregnancies in opioid-addicted women are unintended. Higgins and Sigmon found that financial incentives paired with strategies that reduce barriers to introducing contraception—providing contraception without requiring a physical exam and supplying it during the initial visit—greatly increased birth control adherence.

West Virginia Clinical and Translational Science Institute

The West Virginia Clinical and Translational Science Institute (WVCTSI), funded by an IDeA Clinical and Translational Research (CTR) award, strives to bring the best care possible to residents, many of whom live in rural communities. WVCTSI concentrates on five priority health areas, including addiction and resultant emerging epidemics such as hepatitis B, C, and HIV.

Because opioid overdoses have hit West Virginia particularly hard in recent years, WVCTSI has placed a special emphasis on the study of opioid use disorder (OUD), medically assisted treatment for OUD, and emerging epidemics resulting from OUD.

Age-Adjusted Resident Drug Overdose Mortality Rate in West Virginia and United States, 2001-2014. Credit: WV Health Statistics Center, Vital Surveillance System, and CDC Wonder.

“The IDeA-CTR is a major stimulus to build research infrastructure that will impact health outcomes in West Virginia, including individuals with OUD,” says WVCTSI director Sally Hodder, M.D.

WVCTSI takes a broad approach to studying opioid addiction, with research in the following areas:

Public health. Approaches include using large databases of electronic medical records to model overdose risk and factors that predict overdose deaths. The CTR has also funded focus groups in five communities across West Virginia. The sessions have hosted up to 20 community stakeholders to discuss underrecognized insights about the opioid crisis and to share deeper strategic concepts that might not otherwise come to the surface. “The idea is that opioid addiction may take a slightly different form in every community,” says Hodder. “And it will be interesting to see what similarities and differences there are among these communities, and what we can learn from them.”

Laboratory science. The CTR has been working with a group of multidisciplinary investigators to shift treatment standards for OUD toward precision medicine. Ongoing studies include investigating opioid misuse in pregnancy as well as genetic variants in mothers and newborns that inform the health of babies born with neonatal opioid withdrawal syndrome (NOWS). In an effort to understand the long-term effects of prenatal opioid exposure on cognition, language, and emotional regulation, CTR researchers at Marshall University School of Medicine perform psychiatric evaluations and cognitive testing of children born with NOWS. (To learn more about NOWS, read this story from the PBS NewsHour that was funded in part by NIGMS’s Science Education Partnership Award (SEPA) program.)

In deep brain stimulation (DBS), electrodes implanted in the brain can deliver electrical stimulation to specific regions to fine-tune brain activity. Credit: Wikimedia Commons, Hellerhoff.

Clinical science. The CTR supports novel strategies to treat OUD. In collaboration with Ali Rezai, a neurosurgeon at West Virginia University, the CTR is gearing up to assess deep brain stimulation (DBS) for treatment-resistant OUD. DBS has previously been used to successfully treat neurological conditions such as Parkinson’s disease, epilepsy, obsessive-compulsive disorder, tremor, and dystonia. In this case, Rezai and his team would implant stimulating electrodes in the brain to modify activity in the nucleus accumbens, a region heavily involved in the brain’s reward circuitry.

Northern New England Clinical and Translational Research Network

Managed by Maine Medical Center Research Institute and the University of Vermont, The Northern New England Clinical and Translational Research (NNE-CTR) Network is a group of academic institutions with portfolios that include research on health issues in rural populations. The network collaborates with the University of Southern Maine, and its partners include Dartmouth Synergy and Tufts University School of Medicine.

Projects funded by the NNE-CTR will place special focus on addiction research. “The center-wide goal is investigating and addressing health care disparities in rural populations,” says NNE-CTR co-director Cliff Rosen.

One way that the NNE-CTR plans to support research into improving the health of opioid-addicted people in rural populations is through various pilot projects, the most successful of which may receive additional funding. “We were a little concerned about whether we would be able to get a significant number of applications for these projects,” says NNE-CTR’s other co-director Gary Stein. “We were hoping, initially, to be able to get 10 or 15 good proposals. We received 35, eight of which focus on the opioid crisis in New England. We were absolutely amazed, and to us this is real validation of an interest in engagement.”

The Vermont Center of Behavior and Health is funded by NIGMS grant P20GM103644. The West Virginia Clinical and Translational Science Institute is funded by NIGMS grant U54GM104942. The Northern New England Clinical and Translational Research Network is funded by NIGMS grant U54GM115516.

To learn more about the opioid crisis in America, visit the PBS NewsHour website to watch segments and read stories on various aspects of the epidemic. The videos and stories were funded in part by NIGMS’ Science Education Partnership Awards (SEPA) program.

Broadcast videos

A community overwhelmed by opioids (10/2/17) 
The overwhelming problems faced by Huntington, West Virginia, where the opioid crisis has produced first-responder burnout and overflowing courts, hospitals, and foster care networks. Medical school professor Dr. James Becker told the NewsHour he is seeing rare disease complications and alarming overdose rates.

Understanding the science of pain, with the help of virtual reality (10/4/17) 
The mechanics and science of addiction and the multidisciplinary approach—including hypnosis and virtual reality—being taken by those at the University of Washington, the first institution to treat pain as a problem, not just a symptom of something else.

Synthetic opioids are driving an overdose crisis (10/11/17) 
The catastrophe of fentanyl, a synthetic opioid that’s roughly 50 to 100 times more potent than morphine and that everyone from clinics to the DEA’s special testing lab in Northern Virginia are trying to get a handle on. Fentanyl was responsible for 80 percent of the overdoses in Massachusetts in 2016.

How an opioid addiction can eat your heart alive (4/30/18) 
The heart valve problems of addicts who often face repeat surgeries if they can’t stop taking opioids, as seen from the perspectives of surgeons and a bioethicist.

Website stories

Saving the babies of the opioid epidemic (10/2/17) 
The problems faced by addicted newborns who end up in NICU facilities, dosed with methadone and clonidine to get them past their withdrawal. The focus of this segment is the neonatal therapeutic unit at Cabell County-Huntington Hospital in southern West Virginia.

How to safely dispose of pain medication (10/4/17) 
A reminder of how NOT to dispose of opioids and alternative safe-disposal methods.

How treating opioids with more opioids has divided the recovery community (10/5/17) 
The division among professionals who want to treat addicts with suboxone and other medication assistance and those who insist on a drug-free recovery, as played out in Naples, Florida.

How a brain gets hooked on opioids (10/9/17) 
A detailed look on how a brain gets hooked on opioids and how chronic pain patients who deal with mood disorders are at high risk.

Interview with a Scientist: Julius Lucks, Shape Seeker

Wed, 2018-07-18 09:34

While DNA acts as the hard drive of the cell, storing the instructions to make all of the proteins the cell needs to carry out its various duties, another type of genetic material, RNA, takes on a wide variety of tasks, including gene regulation, protein synthesis, and sensing of metals and metabolites. Each of these jobs is handled by a slightly different molecule of RNA. But what determines which job a certain RNA molecule is tasked with? Primarily its shape. Julius Lucks, a biological and chemical engineer at Northwestern University, and his team study the many ways in which RNA can bend itself into new shapes and how those shapes dictate the jobs the RNA molecule can take on.

In this video, Luck describes a sequencing technology, called Shape-Seq, that he has created to help identify the shape of any given molecule of RNA. With this information in hand, Lucks’ lab can figure out how certain RNA molecules may impact various aspects of human health, and may inspire the development of new treatments for disease.

Dr. Lucks’ work is funded in part by the NIH under grant 7DP2GM110838.

Interview with a Scientist: Elhanan Borenstein, Metagenomics Systems Biology

Wed, 2018-07-11 09:05

Cataloging the human microbiome—the complete collection of bacteria, fungi, archaea, protists, and viruses that live in and on our bodies—is an enormous task. Most estimates put the number of organisms who call us home on par with the number of our own cells. Imagine trying to figure out how the billions of critters influence each other and, ultimately, impact our health. Elhanan Borenstein, a computer scientist-cum-genomicist at the University of Washington, and his team are not only tackling this difficult challenge, they are also trying to obtain a systems-level understanding of the collective effect of all of the genes, proteins, and metabolites produced by the numerous species within the microbiome.

In this video, Borenstein describes the models of the microbiome he and his team create, and how they can be used to predict impacts on the microbiome resulting from a number of conditions, including dietary changes. His goal is to use these models to design synthetic microbiomes composed of certain species at certain abundances that can be transferred to a person to confer specific health benefits.

Dr. Borenstein’s work is funded in part by the NIH under grant 5R01GM124312.

Molecular Fireworks: How Microtubules Form Inside Cells

Tue, 2018-07-03 09:03
       Microtubules sprout from one another. Credit: Petry lab, Princeton University.

The red spray pictured here may look like fireworks erupting across the night sky on July 4th, but it’s actually a rare glimpse of tiny protein strands called microtubules sprouting and growing from one another in a lab. Microtubules are the largest of the molecules that form a cell’s skeleton. When a cell divides, microtubules help ensure that each daughter cell has a complete set of genetic information from the parent. They also help organize the cell’s interior and even act as miniature highways for certain proteins to travel along.

As their name suggests, microtubules are hollow tubes made of building blocks called tubulins. Scientists know that a protein called XMAP215 adds tubulin proteins to the ends of microtubules to make them grow, but until recently, the way that a new microtubule starts forming remained a mystery.

Sabine Petry and her colleagues at Princeton University developed a new imaging method for watching microtubules as they develop and found an important clue to the mystery. They adapted a technique called total internal reflection fluorescence (TIRF) microscopy, which lit up only a tiny sliver of a sample from frog egg (Xenopus) tissue. This allowed the scientists to focus clearly on a few of the thousands of microtubules in a normal cell. They could then see what happened when they added certain proteins to the sample.

Petry and her team knew already that a special tubulin known as gamma-tubulin is necessary to form a new microtubule. However, it was only after they added XMAP215 as well as gamma-tubulin to the sample that they saw new microtubules form and grow, as shown in the video. It turned out that XMAP215 plays two roles in microtubule development—helping form new tubules and helping them grow longer. Petry’s co-author, Akanksha Thawani, a Princeton University graduate student, noted that understanding XMAP215’s double role may give scientists a way to precisely target errors in cell division and cytoskeleton assembly that underlie diseases such as cancer.

In parallel to Petry’s research, Fred Chang and his colleagues at the University of California, San Francisco, recently found that XMAP215 is critical for microtubule formation in living yeast cells, an important independent confirmation of XMAP215’s importance.

Petry’s research is supported in part by NIGMS through grants 1DP2GM12349301, 1F32GM119195-01 and 1F32GM119195. Chang’s research is supported in part by NIGMS through grants R01GM069670 and R01GM115185.

Interview With a Scientist: Andrew Goodman, Separating Causation and Correlation in the Microbiome

Wed, 2018-06-27 09:13

You’ve likely heard some variation of the statistic that there are at least as many microbial cells in our body as human cells. You may have also heard that the microscopic bugs that live in our guts, on our skins, and every crevice they can find, collectively referred to as the human microbiome, are implicated in human health. But do these bacteria, fungi, archaea, protists, and viruses cause disease, or are the specific populations of microbes inside us a result of our state of health? That’s the question that drives the research in the lab of Andrew Goodman , associate professor of microbial pathogenesis at Yale University.

In this video, Goodman talks about how he uses a variety of traditional microbiology tools, as well as computational and systems biology approaches, to separate causation and correlation with regard to our microbiomes. These tools allow Goodman and his colleagues to selectively turn on and off microbial genes to understand how the timing and expression levels impact host/microbiome interactions. One goal of this research is to learn these interactions influence how people respond to drugs. Along similar lines, Goodman thinks his research can help clinicians choose the most effective medications for patients given their microbiomes or even alter a patient’s microbiome to make certain drugs more effective. 

Dr. Goodman’s work is funded in part by the NIH under grants 4DP2GM105456 and 5R35GM118159.

Best Documentary: Cells Record Their Own Lives Using CRISPR

Wed, 2018-06-20 09:14

Suppose you were a police detective investigating a robbery. You’d appreciate having a stack of photographs of the crime in progress, but you’d be even happier if you had a detailed movie of the robbery. Then, you could see what happened and when. Research on cells is somewhat like this. Until recently, scientists could take snapshots of cells in action, but they had trouble recording what cells were doing over time. They were getting an incomplete picture of the events occurring in cells.

Researchers have started solving this problem by combining some old knowledge—that DNA is spectacularly good at storing information—with a popular new research tool called CRISPR. CRISPR (clustered regularly interspaced short palindromic repeats) is an immune system feature in bacteria that helps them to remember and destroy viruses that infect them. CRISPR can change DNA sequences in precise ways; and it’s programmable, meaning that researchers can tell CRISPR where to make a change on a DNA strand, and even what kind of change to make. By linking cellular events to CRISPR, researchers can make something like a movie that captures many pieces of information in the form of DNA changes that researchers can read back later. These pieces of information include timing, duration, and intensity of events, such as the turning on of a specific protein pathway or the exposure of the cell to pathogens (i.e. germs). Here, we look at some of the ways NIGMS-funded research teams and others are using CRISPR to capture these kinds of data within DNA sequences.

An audio recorder stores audio signals into a magnetic tape medium (left). Similarly, a microscopic data recorder stores biological signals into a CRISPR tape in bacteria (middle). An enormous amount of information can be stored across multiple bacterial cells (right). Credit: Wang Lab/Columbia University Medical Center.

Round and Round: mSCRIBE Creates a Continuous Recording Loop

MIT bioengineers, led by Timothy Lu, have devised a memory storage system illustrated here as a DNA-embedded meter that records the activity of a signaling pathway in a human cell. Credit: Timothy Lu lab, MIT.

CRISPR uses an enzyme called Cas9 like a surgical knife, to slice both strands of a cell’s DNA at precise points. A cut like this sends the cell scrambling to repair the damage. Often, the repair effort results in changes, or errors, in the repaired strand that pile up at a known rate. Timothy Lu and his colleagues at the Massachusetts Institute of Technology (MIT) decided to turn this cut-repair-error system into a way to record certain events inside a cell. They call their method mSCRIBE (mammalian synthetic cellular recorder integrating biological events).

With mSCRIBE, researchers can link Cas9 activity to an event in the cell they want to know more about. In one test, for example, Cas9 only becomes active when a protein pathway that responds to inflammation turns on. Only when the inflammation pathway turns off will mSCRIBE’s cut-and-repair loop stop. By looking at how long the loop ran, Lu and his team were able to measure how long the inflammation response lasted as well as how intensely it was activated.

Roll ‘Em! CAMERA 1

Instead of letting cells’ repair systems make changes to DNA, as happens in mSCRIBE, David Liu and Weixin Tang of the Broad Institute of MIT and Harvard coupled CRISPR-Cas9 with other methods that also take advantage of DNA’s ability to act as an event recorder. Their tool called CAMERA 1, adds numerous copies of two plasmids—short strands of DNA—to cells. As in mSCRIBE, Cas9 is linked to an event in the cell. As the event occurs, Cas9 begins destroying copies of one type of plasmid. Researchers can then look at the ratio of the two types of plasmids in the cell to determine how often the event took place.

MEMOIR Uses CRISPR and Imaging Technology to Record Cells’ Histories

MEMOIR enables cells’ histories to be recorded in their genomes and then read out using microscopy. Here, MEMOIR cells have recorded information in response to a signal with the help of the CRISPR DNA-editing system (light blue cells). Credit: Elowitz and Cai Labs/Caltech.

When studying the changes that cells go through in a living tissue or embryo, researchers ideally want to capture what happens in individual cells without removing them from their surroundings, so their findings more closely relate to real-life events. Many of the CRISPR recording techniques, however, must read the DNA sequence that Cas9 has changed to get their results. This means using at least a few cells and removing them from their tissues to extract the DNA.

Long Cai and Michael Elowitz at the California Institute of Technology in Pasadena blended CRISPR with imaging technology to build a recorder called MEMOIR (memory by engineered mutagenesis with optical in situ readout). MEMOIR allows the team to find and identify CRISPR-caused errors without removing the cell, its tissue, or the larger colony.

According to Cai, using imaging to read MEMOIR’s results allows all the cells to remain in the tissue or embryo scientists are studying. This is especially important in research on embryos, where small numbers of cells move around to form new tissues and organs during development.

With TRACE, Adding Short Sequences Records Cellular Events
Harris Wang and colleagues at Columbia University Medical Center in New York developed another technique to better track cellular activity. They’re refining a system called TRACE (temporal recording in arrays by CRISPR expansion) to convert bacteria into tiny devices that record what happens when they travel through the human gut, for example. Like Liu’s technique, their system relies on specially designed small loops of DNA. Instead of cutting DNA, however, Wang and his team use CRISPR-Cas to add two different, short sequences to the loop’s genome. The researchers add one sequence—the timekeeper—at a steady rate. They can then monitor the length of the DNA loop. The longer it gets, the more time has passed. The other sequence is tied to an event in the cell. It’s added to the loop only when the event occurs. The resulting strand shows what happened and when, just like a movie.

As CRISPR becomes more precise and easier to use the hope, says MIT’s Lu, is that eventually these systems will be able to give scientists a very complex view of what happens inside cells over time. This knowledge can then be useful for fixing cells when they break down in the course of normal aging and disease.

Lu’s research is funded by NIH grants DP2OD008435 and P50GM098792. Liu’s research is funded in part by NIH grants RM1HG009490, R01EB022376, and R35GM118062. Cai’s research is funded in part by NIH grants R01HD075605 and K99GM118910. Wang’s research is funded in part by NIH grant 1DP50D009172.

Teens Explore Science and Health through Game Design

Wed, 2018-06-13 09:04

Educators often struggle to teach teens about sexual and reproductive health. Hexacago Health Academy (HHA) , an education program from the University of Chicago, leverages the fun activity of gameplay to impart these lessons to young people from Chicago’s South Side community. Funded by the Student Education Partnership Award (SEPA), part of the National Institute of General Medical Sciences (NIGMS), in 2015, HHA assists teachers in their goal of helping teen students gain awareness and control over their health and also learn about careers in STEM and health fields.

Melissa Gilliam, founder of Ci3. Credit: Anna Knott, Chicago Magazine.

Genesis of HHA

HHA was cofounded by Melissa Gilliam , a University of Chicago professor of Obstetrics/Gynecology and Pediatrics and founder of the Center for Interdisciplinary Inquiry & Innovation in Sexual and Reproductive Health (Ci3) . During a 2013 summer program with high school students, Gilliam and Patrick Jagoda , associate professor of English and Cinema & Media Studies, and cofounder of Ci3’s Game Changer Chicago Design Lab , introduced the students to their STEM-based alternate reality game called The Source , in which a young woman crowdsources player help to solve a mystery that her father has created for her.

From their experience with The Source, Gilliam and Jagoda quickly learned that students not only wanted to play games but to design them too. What followed was the Game Changer Lab’s creation of the Hexacago game board, as well as the launch of HHA, a SEPA-funded project that the lab oversees.

Hexacago Game Board

At the core of HHA is the Hexacago game board , which displays the city of Chicago, along with Lake Michigan, a train line running through the city, and neighborhoods gridded into a hexagonal pattern.

HHA students not only play games designed from the Hexacago board template, but also design their own games from it that are intended to inspire behavior change in health-related situations and improve academic performance.

Credit: Ci3 at the University of Chicago.

In this way, HHA is much more than just game design and play. “Students have no idea that what they’re doing is learning. In their minds, they’re really focused on designing games,” says Gilliam. “That’s the idea behind Hexacago Health Academy: helping people acquire deep knowledge of science and health issues by putting on the hat of a game designer.” Moreover, through the process of gameplay and design, students practice all the rich skills that result from teamwork, including collaborative learning, leadership, and communication.

Gilliam says that the Game Changer Lab is also interested in what happens after playing a completed game. The team seeks to create game-based youth interventions for urban health issues (e.g., drugs, alcohol, reproductive health) through the Hexacago games. A May 2018 article from the Journal of STEM Outreach reveals promising data. From the 24 teens that participated in the 2015 summer session of HHA, results showed that the initial session succeeded in expanding understanding of health science among participants, as well as developing critical thinking skills, inspiring teamwork, and encouraging risk-taking in education.

Credit: Ci3 at the University of Chicago.

In addition to the HHA games, the Game Changer Lab has a number of digital games under development, including two funded by Phase 1 Small Business Technology Transfer (STTR) grants from SEPA. The first, Caduceus Quest, follows young protagonists as they solve medical and science mysteries. The second, Prognosis, is a resource management game in which the player considers the policy and resources needed to keep disease frequency low in the city. SEPA has been crucial to the work of the Game Changer Lab and the young people it serves.

Student Game Design

The HHA program provides a sound structure for student groups, delegating roles for them to learn and perform during game design. For example, some students in the group are tasked with further research while others work on game mechanics, and yet others create game questions and answers. This well-orchestrated process yields thoughtfully designed games produced with a quick turnaround time so that students can see and enjoy the results of their hard work.

A benefit of the Hexacago game board is that it doesn’t require that students work in computer code or have very advanced skills. Still, HHA teens do gain experience in areas such as coding or sound design, and they walk away knowing that what they’ve learned can translate into the career world if they want to become video game designers.

Games in the Hexacago Suite

Credit: Ci3 at the University of Chicago.








HHA students have helped design the following Hexacago games with the goal of attaining positive behavioral outcomes in young people.

  • Smoke Stacks: This board game allows students to role-play as a tobacco executive to uncover strategies tobacco companies use to market to consumers. A student group in California is currently testing Smoke Stacks along with a facilitator who has provided constant feedback about the project as the Game Changer Lab continues building its curriculum.
  • Infection City:  Intended for use in Chicago public school health classes, this board game pits a team of players taking the role of epidemiologists against a single player taking the role of a meningitis outbreak. Another version now exists for chlamydia and gonorrhea.
  • Hearsay:  In this card game, players work with a randomly selected college character, forming a story with the dealt cards. Players win by inserting cards into the character’s story that define different methods of contraception or STD prevention.
  • Clinic Quest: This board game resembles the system of Trivial Pursuit®. Players collaboratively “research” sexually transmitted diseases, as well as their prevention and treatment.
HHA Students with Clinic Quest. Credit: Ci3 at the University of Chicago.

In addition to playtests of Clinic Quest and Hearsay in the U.S., teens in Delhi, India, also playtested and further developed both games during a 2017 week-long workshop.

Current SEPA funding will support HHA as it brings its program in game design and application to students in schools and other academic scenarios. “This is terrific because there’s a lot of teachers involved in curriculum development and implementation, giving us feedback,” says Gilliam. “It’s been a gift that continues to give because we’re able to use Hexacago in so many different settings and test it in different environments.”

Interview with a Scientist: Michael Summers, Using Nuclear Magnetic Resonance to Study HIV

Wed, 2018-06-06 09:22

For more than 30 years, NIGMS has supported the structural characterization of human immunodeficiency virus (HIV) enzymes and viral proteins. This support has been instrumental in the development of crucial drugs for antiretroviral therapy such as protease inhibitors. NIGMS continues to support further characterization of viral proteins as well as cellular and viral complexes. These complexes represent the fundamental interactions between the virus and its host target cell and, as such, represent potential new targets for therapeutic development.

In this third in a series of three video interviews with NIGMS-funded researchers probing the structure of HIV, Michael Summers, professor of biochemistry at the University of Maryland, Baltimore County, discusses his use of nuclear magnetic resonance (NMR) technology to study HIV. Of recent interest to Summers has been using NMR to investigate how HIV’s RNA enables the virus to reproduce. His goals for this line of research are to develop treatments against HIV as well as learning how to best engineer viruses to deliver helpful therapies to individuals with a variety of diseases.

Summers also talks about the importance of providing research opportunities to undergraduate students and high school students from underrepresented populations. He partners with Baltimore-based Youth Works to give up to 40 or 50 students summer research experience in his lab, working directly alongside graduate students and postdoctoral researchers.

Dr. Summers’ work is funded in part by the NIH under grants 5R01GM042561 and 5R25GM055036.

Interview with a Scientist: Wes Sundquist, How the Host Immune System Fights HIV

Wed, 2018-05-30 09:28

For more than 30 years, NIGMS has supported the structural characterization of human immunodeficiency virus (HIV) enzymes and viral proteins. This support has been instrumental in the development of crucial drugs for antiretroviral therapy such as protease inhibitors. NIGMS continues to support further characterization of viral proteins as well as cellular and viral complexes. These complexes represent the fundamental interactions between the virus and its host target cell and, as such, represent potential new targets for therapeutic development.

In this second in a series of three video interviews with NIGMS-funded researchers probing the structure of HIV, Wes Sundquist, professor of biochemistry at the University of Utah, discusses his lab’s studies of how HIV uses factors in host cells to replicate itself. In particular, Sundquist focuses on the ESCORT pathway that enables HIV to leave infected cells and spread infection elsewhere.

Sundquist also talks about the University of Utah’s Center for the Structural Biology of Cellular Host Elements in Egress, Trafficking, and Assembly of HIV (CHEETAH). This center uses computational and experimental methods to analyze HIV molecular complexes and determine how they interact with and commandeer cellular machinery to move themselves throughout cells and tissues. By visually reconstructing virus particle assembly and trafficking, CHEETAH aims to develop HIV into a leading model for understanding how human viruses interact with cellular hosts, and to provide a platform for designing new therapeutic strategies.

Dr. Sundquist’s work is funded in part by the NIH under grants 5R01GM112080 and 2P50GM082545.

Interview With a Scientist: Irwin Chaiken, Rendering HIV Inert

Wed, 2018-05-23 09:04

For more than 30 years, NIGMS has supported the structural characterization of human immunodeficiency virus (HIV) enzymes and viral proteins. This support has been instrumental in the development of crucial drugs for antiretroviral therapy such as protease inhibitors. NIGMS continues to support further characterization of viral proteins as well as cellular and viral complexes. These complexes represent the fundamental interactions between the virus and its host target cell and, as such, represent potential new targets for therapeutic development.

In this first in a series of three video interviews with NIGMS-funded researchers probing the structure of HIV, Irwin Chaiken, professor of biochemistry and molecular biology at Drexel University College of Medicine, discusses his lab’s efforts to interfere with the envelope protein (Env) on the surface of HIV. Env is responsible for recognizing cells of the host organism and figuring out how to disrupt its function may lead to strategies for rendering the deadly virus inert.

Dr. Chaiken’s work is funded in part by the NIH under grants 4R01GM111029 and 5P01GM056550.

CLAMP Helps Lung Cells Pull Together

Wed, 2018-05-16 09:04
Cells covered with cilia (red strands) on the surface of frog embryos. Credit: The Mitchell Lab.

The outermost cells that line blood vessels, lungs, and other organs also act like guards, alert and ready to thwart pathogens, toxins, and other invaders that can do us harm. Called epithelial cells, they don’t just lie passively in place. Instead, they communicate with each other and organize their internal structures in a single direction, like a precisely drilled platoon of soldiers lining up together and facing the same way.

Lining up this way is crucial during early development, when tissues and organs are forming and settling into their final positions in the developing body. In fact, failure to line up in the correct way is linked to numerous birth defects. In the lungs, for instance, epithelial cells’ ability to synchronize with one another is important since these cells have special responsibilities such as carrying mucus up and out of lung tissue. When these cells can’t coordinate their functions, disease results.

Some lung epithelial cells are covered in many tiny, hair-like structures called cilia. All the cilia on lung epithelial cells must move uniformly in a tightly choreographed way to be effective in their mucus-clearing job. This is a unique example of a process called planar cell polarity (PCP) that occurs in cells throughout the body. Researchers are seeking to identify the signals cells use to implement PCP.

In one recent study, NIGMS grantee Brian Mitchell and his colleagues at Northwestern University’s Feinberg School of Medicine in Chicago, Ill, looked at a protein called CLAMP/Spef1 and its role in facilitating PCP signaling between cells. CLAMP/Spef1 molecules stick to microtubules, small structures that form the cell’s skeleton. These structures are important in helping the cell orient itself with other cells in PCP. In addition to forming on the microtubules, CLAMP/Spef1 can be found along the roots of cilia and within the membranes of cells near where they touch other cells. When Mitchell’s team depleted the normal amounts of CLAMP in frog embryo cells, the cells lost their PCP orientation, and their cilia did not coordinate and move in a single direction. Based on those findings, the researchers believe CLAMP is involved in cell-to-cell communication. Their next step will be to determine exactly how CLAMP aids in that communication.

Mitchell’s research is funded by NIGMS grant R01GM089970.

Interview with a Scientist: Jeramiah Smith on the Genomic Antics of an Ancient Vertebrate

Wed, 2018-05-09 09:16

The first known descriptions of cancer come from ancient Egypt more than 3,500 years ago. Early physicians attributed the disease to several factors, including an imbalance in the body’s humoral fluids, trauma, and parasites. Only in the past 50 years or so have we figured out that mutations in critical genes are often the trigger. The sea lamprey, a slimy, snake-like blood sucker, is proving to be an ideal tool for understanding these mutations.

The sea lamprey, often called the jawless fish, is an ancient vertebrate whose ancestor diverged from the other vertebrate lineages (fish, reptiles, birds and mammals) more than 500 million years ago. Jeramiah Smith, associate professor of biology at the University of Kentucky, has discovered that lamprey have two separate genomes: a complete genome specific to their reproductive cells, consisting of 99 chromosomes (humans have 23 pairs) and another genome in which about 20 percent of genes have been deleted after development. Using the lamprey model, Smith and his colleagues have learned that many of these deleted genes—such as those that initiate growth pathways—are similar to human oncogenes (i.e., cancer-causing genes).

Humans (and most other organisms) have a different way of handling growth-related genes after they are no longer needed. Rather than deleting unwanted genes, we wrap them up in special proteins that essentially hide them away within our cells. Our evolutionary strategy, though, is not as foolproof as that of the lamprey. Sometimes the tucked-away genes accidentally get turned on, resulting in out-of-control cell growth that we know as cancer.

In this video, Smith discusses his research with the sea lamprey and how it relates to human health.

To learn more about Smith’s research on the lamprey, tune into the archive of his recent Early Career Investigator lecture. At the end of the lecture, Smith spoke with NIGMS director Jon Lorsch about careers in basic biomedical research. Smith also fielded questions about his research and career from undergraduate students.

Dr. Smith’s research is funded in part by NIGMS grant 5R01GM104123.

Pericytes: Capillary Guardians in the Brain

Wed, 2018-05-02 12:58
The long arms of pericytes cells (red) stretch along capillaries (blue) in a mouse brain. Credit: Andy Shih.

Nerve cells, or neurons, in our brains do amazing work, from telling our hearts to beat to storing our memories. But neurons cannot operate alone. Many kinds of cells support and regulate neurons and—like neurons—they can come under attack due to injuries or disorders, such as stroke or Alzheimer’s disease. Learning what jobs these cells do and how they respond to disease may show researchers new ways to treat central nervous system disorders. One type of support cell, the pericyte, plays some key roles in brain health. These cells are readily adaptable, even in adult brains, and can support a variety of functions.

Pericytes help with blood flow to nerve cells in the brain. They lie wrapped all along the huge networks of capillaries—the tiniest blood vessels—that both feed neurons and form the blood-brain barrier, which filters out certain substances from blood to protect the brain. Pericytes have a body that appears as a bump protruding from a capillary surface. Pericytes also have long thin arms that stretch along each capillary like a snake on a tree branch. These arms, called processes, reach almost to where the next pericyte process begins, without overlapping. This creates a pericyte chain that covers nearly the entire capillary network.

Pericytes are critical for blood vessel stability and blood-brain barrier function. They’re also known to die off as a result of trauma and disease. Andy Shih, Andree-Ann Berthiaume, and colleagues at the Medical University of South Carolina in Charleston, set up an imaging technique in mouse brains that allowed them to see what pericytes do under normal conditions as well as how these cells respond when some are damaged.

Over a period of weeks, Shih watched normal mouse capillaries and their pericyte attendants. The mice had been engineered so that their pericytes glowed fluorescent. Images showed that pericytes’ processes reached out and shrank back periodically by small amounts. As one process grew along a capillary the next pericyte process in the chain retracted. This ensured that the two cells never overlapped.

Using heat, Shih and his team then destroyed several pericytes to see whether their neighbors could compensate for the loss. They did, growing their processes quickly, typically within the first 10 days after the injury to fill the gap. The capillaries that were uncovered when the pericytes were eliminated still functioned, but they became larger. Capillaries need to be slightly constricted to perform well. These same capillaries returned to normal once the neighboring pericytes grew over them. Pericytes’ ability to compensate for losses like this could be an important way that the brain maintains its health. Figuring out a way to exploit this ability may help in developing future treatments for neurological disorders.

This research was supported in part by NIGMS grant 5R25GM113278, 5P20GM109040, and 3T32GM008716.

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