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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.

Optogenetics Sparks New Research Tools

Tue, 2018-04-24 08:56

Imagine if scientists could zap a single cell (or group of cells) with a pulse of light that makes the cell move, or even turns on or off the cell’s vital functions.

Scientists are working toward this goal using a technology called optogenetics. This tool draws on the power of light-sensitive molecules, called opsins and cryptochromes, which are naturally occurring molecules found in the cell membranes of a wide variety of species, from microscopic bacteria and algae to plants and humans. These light-reacting molecules change their shape or activity when they sense light, so they can be used to trigger cellular activity, such as turning on or off ion flow into the cell and other regulatory pathways. The ability to induce changes in cells has a broad range of practical applications, from enabling scientists to see how cells function to providing the basis for potential therapeutic applications for blindness, cancer, and epilepsy.

Opsins first gained a foothold in research about a decade ago when scientists began using them to study specific electrical networks in the brain. This research relied on channelrhodopsins, opsins that could be used to control the flow of charged ions into and out of the cell. Normally, when a neuron reaches a certain ion concentration, it is triggered to fire, but neuron firing can be changed by inserting opsins in the membrane. Neuroscientists figured out how to incorporate light-sensitive opsin proteins by inserting the opsin gene into the host’s DNA. The genetically encoded opsin proteins in the neuronal membranes could be turned on or off by shining light into the brain itself, using optical fibers or micro-LEDs, to switch on or off the flow of ions and neuron firing.

Since those early studies in the brain, the optogenetics field has come a long way. But the leap from brain cells to other cells has been challenging. Scientists first needed to find a way to deliver light into tissues deep in the body. And, unlike stationary brain cells, they needed a way to target cells that are on the move (such as immune cells). They also needed to develop a way to study not only cell networks but also individual cells and cell parts. The NIGMS-funded researchers highlighted below are among the scientists working to overcome these obstacles and are using optogenetics in new and inventive ways.

Illustration shows how “bridges” can be built within a cell through the use of light-reacting molecules. The light triggers proteins to line up within the cell, making it easier to shuttle molecules between the membranes of two subcellular organelles. This optogenetic strategy is helping scientists to control cell function with a simple beam of light. Illustration courtesy of Yubin Zhou.

Building Bridges

Yubin Zhou of Texas A&M is using optogenetics to control the way cells communicate and to study immune cell function. In one line of research, Zhou is using light to make it easier for calcium ions to enter cells. The ions carry instructions for the cell and also help tether small cellular structures (called organelles).  Those inter-membrane tethers allow for the movement of  proteins and lipids back and forth across the cell, and are critical for sending chemical messengers to communicate information (see illustration). When this process is disrupted, it can lead to extreme changes in cell function and even cell death. Using this technology to “switch on” normal pathways enables the scientists to better understand how such processes can be disrupted.

Going Wireless

In another line of research, Zhou and his collaborator Gang Han at the University of Massachusetts Medical School are combining optogenetics with nanotechnology to establish a way of remotely controlling immune cells. This technology helps to overcome a key obstacle in optogenetics by allowing the scientists to reach deep within tissues using tiny light-switchable particles (called nanoparticles).

This wireless technology is made possible because the nanomaterials can absorb near-infrared light far away from outside the tissue and then convert it into visible light locally. Because nanoparticles can move within the body, they can be targeted to specific cell types or tissues in the living body to provide the light needed to activate optogenetic proteins.

As noted by Zhou, “The potential impact of this wireless nano-optogenetic technology is likely to be broad and profound.” He further added that one tangible therapeutic application of this technology may be combining it with immunotherapy to fight cancer. Using this technology, the particles could be dispatched to activate T-cells—the immune system’s prominent tumor attackers—at a desired time and location.

Tracking Movement

Over time, additional light-reacting proteins have joined channelrhodopsins as scientists look to expand the uses for optogenetics. For example, cryptochromes, which are important in sleep and wake cycles, have helped usher in a distinctly different type of optogenetics that researchers are using to control processes at the subcellular level and to study individual cell behavior.

Researchers are now applying subcellular optogenetics to better understand how cells move as well as how they divide and multiply. Narasimhan Gautam and colleagues from Washington University-St. Louis are using optogenetic strategies to control cell communication (signaling activity) and the mechanical forces at play when cells invade surrounding tissues. Specifically, Gautam’s group is examining whether cells move from the front by crawling forward, or move from the back, like rolling up a toothpaste tube. They activated molecules either in the front or back by selectively focusing light. By simultaneously monitoring the molecular and cellular activity using live cell imaging methods, the researchers can see how this migration occurs and can even direct migration at will.

Example of a macrophage cell undergoing optogenetically driven cell migration. Credit: O’Neill et al., Mol Bio Cell, 2016.

Said Gautam, “We anticipate this approach will help us to identify how dynamic interactions between signaling activity, cytoskeletal changes, and plasma membrane mechanics govern cell migration and, in the long term, help us to apply this knowledge to inhibit pathological migration [seen in cancer].”

Expanding the Optogenetic Tool Kit

Today’s optogenetic research is effective but also hampered by the limited numbers of proteins available for use in these studies. Researchers now are looking for ways to generate synthetic light-regulated proteins. Michael Lin and colleagues at Stanford University are developing FLIPs (or fluorescent light-inducible proteins) that they can use in place of any protein.  According to the researchers, FLIPs offer advantages over traditional optogenetic methods; they’re generalizable, meaning they can work in place of a variety of protein targets without needing to be modified. The proteins are 100 percent genetically encoded, so they don’t require help from enzymes (or cofactors) to activate them. They also feature built-in “reporters” that enable scientists to easily track them and to see their activity throughout the body. Finally, these new proteins are useful at lower levels of light, making them a good choice for deep tissue locations.

Chandra Tucker and colleagues at the University of Colorado-Denver are developing additional tools for today’s optogenetics toolkit. They are combining light-responsive plant-based photoreceptors with custom genetically engineered proteins. When flashed with light, the custom proteins link together. This ability to make proteins link and to stay connected for extended periods is a first step in being able to control proteins that must link together to function including membrane receptor signaling and gene expression. And it should help to show how specific proteins and protein pathways work, both in health and in disease.

Zhou’s research is supported by NIH under grants 5R01GM112003-04 and 1R21GM126532-01; Gautam’s research is supported by NIH under grants 1R35GM122577-01; Lin’s research is supported by NIH under grant 5DP1GM111003-05; Tucker’s research is supported by NIH Grants 5R01GM100225 and 1R21GM126253-01.

The Skull’s Petrous Bone and the Rise of Ancient Human DNA: Q & A with Genetic Archaeologist David Reich

Wed, 2018-04-11 09:17
The human petrous bone in the skull protects the inner ear structures. Though it is one of the hardest, densest bones in the body, some portions (such as the area in orange, protecting the cochlea) are denser than others. Possibly because the petrous bone is so dense, DNA within the petrous bone is better preserved than in other bones. In some cases, scientists have extracted more than 100 times more DNA from the petrous bone than other bones, including teeth. Credit: Pinhasi et al., 2015, PLOS ONE.

For the past few decades, new evidence about ancient humans—in the form of skeletal remains, tools, and other artifacts—has trickled in, inching us closer to an understanding of how our species evolved and spread out across the planet. In just the past few years, however, knowledge of our deep past expanded significantly thanks to a series of technological breakthroughs in sequencing of ancient human genomes. This technology can be used to find genetic links among populations of human ancestors dating back hundreds of thousands of years.

In addition to advances in genomic technology, another factor is driving the explosion of new discoveries—an inch-long section of the human skull. Found near our ears, this pyramid-shaped portion of the temporal bone is nicknamed the petrous bone. The bone is very hard, possibly because it needs to protect fragile structures such as the cochlea, which translates sound into brain signals, and the semicircular canals, which help us maintain our balance. Perhaps because the petrous bone is so dense, it also is the bone in the body that best preserves DNA after a person dies. As a result, archaeologists are scrambling to study samples taken from this pyramid-shaped structure to unlock the mysteries of our species’ formative years.

Here’s a sampling of headlines declaring new findings about ancient peoples from around the globe that were based on genetic information obtained from the petrous bone (NIGMS-funded research indicated in black):

“How the introduction of farming changed the human genome” November 2015

“Fourth strand’ of European ancestry originated with hunter-gatherers isolated by Ice Age” November 2015

“Scientists sequence first ancient Irish human genomes” December 2015

“Genetic studies provide insight into ancient Britain’s diversity” January 2016

“The world’s first farmers were surprisingly diverse” June 2016

“Study reveals Asian ancestry of Pacific islanders” October 2016

“Ancient DNA solves mystery of the Canaanites, reveals the biblical people’s fate” July 2017

“Ancient DNA data fills in thousands of years of human prehistory in Africa” September 2017

“European Hunter-Gatherers Interbred With Farmers From the Near East” November 2017

“Surprise as DNA reveals new group of Native Americans: the ancient Beringians” January 2018

“Ancient DNA reveals genetic replacement despite language continuity in the South Pacific” February 2018

“Stone Age Moroccan Genomes Reveal Sub-Saharan African, Near Eastern Ancestry” March 2018

“Some early modern populations in Britain may have had dark skin” March 2018

To learn more about the petrous bone and its use in archaeology, as well as other advances in the field, I spoke with NIGMS grantee David Reich , a genetic archaeologist from Harvard Medical School and the Howard Hughes Medical Institute, and one of the world’s leading experts in ancient human DNA.

Credit: Howard Hughes Medical Institute.

Chris Palmer:
How would you characterize the current state of research about ancient humans?

David Reich:
We’re going through a gold-rush phase in ancient DNA. It’s a technology-driven boom like those in the past, such as the development of the microscope and telescope in the 17th century, and radiocarbon dating in the 1950s.

The first ancient human genomes were published in 2010. Just a couple of months ago, the 1,000th was published. The number has been multiplying by about 10 every two years and that trend seems to be continuing. What this means is that it’s possible to ask and answer questions about how our ancestors all around the world are related to each other. Some of these questions were just not answerable even a few years ago.

The first studies of ancient DNA were published in 2010. Since then, the number of ancient DNA samples that have been sequenced has grown exponentially. Credit: David Reich.

Chris Palmer:
Which technologies are fueling this “technology-driven boom”?

David Reich:
The first technology is next-generation sequencing, which became available at the end of the 2000’s and made sequencing literally 10- to 100- thousand times cheaper.

Another innovation was an extraordinary increase in the efficiency of methods for extracting DNA from biological samples and the ability to turn that DNA into a sequenceable form. Most of these improvements were developed by Matthias Meyer and Svante Pääbo at the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany.

Yet another important innovation has been improvements in methods for separating out human DNA from microbial DNA, which tends to dominate the DNA extracted from most ancient biological samples.

Chris Palmer:
What is so special about the petrous bone, and what role has it played in advancing research in this field?

David Reich:
Bone powder taken from the petrous bone yields on average up to 100 times more DNA than powder from other, softer bones. Also, because it’s so dense, when the rest of a skeleton has crumbled into dust, the petrous bone often still remains. So, it’s been a real game changer for the field of ancient DNA.

Using the petrous bone as the source for ancient DNA has made it possible, for the first time, to begin to regularly extract DNA from older biological material, and from biological material that does not preserve very well, such as samples found in hot tropical environments.

Chris Palmer:
Can you pinpoint when scientists realized the value of the petrous bone?

David Reich:
In 2014 to 2015, a group in Ireland led by Ron Pinhasi published a paper that clearly documents how much better this type of bone was than other types of bone as a source for ancient DNA.

Chris Palmer:
What role has petrous bone had in advancing the work of your own research team?

David Reich:
Our first big finding based on petrous bone work was a paper in late 2015 where we reported the first ancient DNA from that population of farmers in Anatolia (present-day Turkey) who went on to populate Europe.

Then, in 2016 we published a paper that reported DNA from four individuals from islands in remote Oceania. We were able to show that those people, who lived between about 2,500 and 3,000 years ago, contributed very little to many of the people who live in those places today, suggesting that there must have been at least one later wave of migration into the region. That was really a big surprise.

A third finding was published a few months ago. We obtained DNA from an approximately 3,000-year-old herder from Tanzania and a little girl. The girl turns out to be from a keystone population that left East Africa and moved in all directions around that time.

[Each of these papers was done in collaboration with the Pinhasi group.]

Chris Palmer:
In response to repeated requests, you recently published a book [“Who We Are and How We Got Here” ] that aims to make ancient DNA research accessible to anyone. Tell me about the book.

David Reich:
It’s a manifesto of the ancient DNA revolution and what its significance is, what it does and doesn’t show, and how it can be used and integrated with our current understanding of ancient humans.

While ancient DNA has already changed our views of the past, it hasn’t yet taught us much about human biology, such as how adaptations and traits spread through populations. We just haven’t yet had enough high-quality data. But the recent innovations, including the use of the petrous bone, are bringing us closer to being able to learn about the biology of ancient humans.

One of the big new findings that has emerged from the ancient DNA revolution—and that I emphasize in my book—is that human populations today are, almost without exception, highly mixed. Populations today almost never descend directly from the populations that existed in the same place even 10,000 years ago. I think that’s a very profound insight, and it should change the way we see our world.

David Reich’s research is funded in part by NIGMS under grant 5R01GM100233.

To learn more about what ancient DNA is telling us about our origins, read NIGMS program director Dan Janes’ Biomedical Beat story “Field Focus: High-Quality Genome Sequences Inform the Study of Human Evolution.”

Cellular Footprints: Tracing How Cells Move

Wed, 2018-04-04 08:38
An engineered cell (green) in a fruit fly follicle (red), or egg case, leaves a trail of fluorescent material as it moves across a fruit fly egg chamber, allowing scientists to trace its path and measure how long it took to complete its journey. Credit: David Bilder, University of California, Berkeley.

Cells are the basis of the living world. Our cells make up the tissues and organs of our bodies. Bacteria are also cells, living sometimes alone and sometimes in groups called biofilms. We think of cells mostly as staying in one spot, quietly doing their work. But in many situations, cells move, often very quickly. For example, when you get a cut, infection-fighting cells rally to the site, ready to gobble up bacterial intruders. Then, platelet cells along with proteins from blood gather and form a clot to stop any bleeding. And finally, skin cells surrounding the wound lay down scaffolding before gliding across the cut to close the wound.

This remarkable organization and timing is evident right from the start. Cells migrate within the embryo as it develops so that body tissues and organs end up in the right places. Harmful cells use movement as well, as when cells move and spread (metastasize) from an original cancer tumor to other parts of the body. Learning how and why cells move could give scientists new ways to guide those cells or turn off or slow down the movement when needed.

Glowing Breadcrumbs

Scientists studying how humans and animals form, from a single cell at conception to a complex body at birth, are particularly interested in how and when cells move. They use research organisms like the fruit fly, Drosophila, to watch movements by small populations of cells. Still, watching cells migrate inside a living fly is challenging because the tissue is too dense to see individual cell movement. But moving those cells to a dish in the lab might cause them to behave differently than they do inside the fly. To solve this problem, NIGMS-funded researcher David Bilder and colleagues at the University of California, Berkeley, came up with a way to alter fly cells so they could track how the cells behave without removing them from the fly. They engineered the cells to lay down a glowing track of proteins behind them as they moved, leaving a traceable path through the fly’s tissue. The technique, called M-TRAIL (matrix-labeling technique for real-time and inferred location), allows the researchers to see where a cell travels and how long it takes to get there.

Bilder and his team first used M-TRAIL in flies to confirm the results of past studies of Drosophila ovaries in the lab using other imaging techniques. In addition, they found that M-TRAIL could be used to study a variety of cell types. The new technique also could allow a cell’s movement to be tracked over a longer period than other imaging techniques, which become toxic to cells in just a few hours. This is important, because cells often migrate for days to reach their final destinations.

Eventually, Bilder believes M-TRAIL could be used to trace the first movements of metastatic cancer cells in humans from a primary tumor out to a blood vessel and surrounding tissues. Learning how cancer cells take these first steps could uncover new ways to stop their migration.

Feet, Fans or Waves? Changing Cellular Modes of Motion In this photo, cells move by creating a fan shape at their front edges and pulling forward. Each color represents a different photo taken one minute after the last. Credit: Peter Devreotes lab, John Hopkins University School of Medicine.

Besides tracking where cells go when they migrate, scientists need to know what cues set them in motion and what controls their movement. NIGMS grantee Peter Devreotes and colleagues at the Johns Hopkins University School of Medicine, Baltimore, MD, are studying a network of connected signaling proteins inside cells. Their findings show that this network is key to controlling cell movement.

Once it’s turned on, this protein network starts up the cell’s movement machinery, including its cellular skeleton, called the cytoskeleton. In response to signals from the network, the cell begins to change shape, an early step in cell migration.

The movement network can start up at random, but it also responds to cues from outside the cell. Devreotes and his team tested this by putting the amoeba cells in a dish of swirling water. Amoeba cells need to be able to respond to liquid moving around them as well as to other signals coming from the surrounding environment. The researchers found that the network proteins within the cells responded to the swirling water in the same way that they respond to other environmental cues. Devreotes thinks the network gives the cell a sophisticated way of interpreting and adjusting to real-world situations.

Once on the move, different cells use different techniques to propel themselves forward. Some, like amoeba or our own white blood cells, reach out with bumps called pseudopods, cellular “feet” that pull the cell forward. Others create a large fan-shaped bulge all along the leading edge of the cell that drives it along, and still others make waves from their centers that ripple through the cell, pulling them forward.

Scientists had thought that each kind of cell used only one of these modes to move. Instead, when Devreotes and his team changed the proteins in the movement network inside cells they found that amoebas altered their movement behavior, switching from pseudopods to fans to rippling waves and back again. So, the network Devreotes studies might be both powerful and universal. It may be similar across many kinds of cells from different species, coordinating signals from outside and determining what mechanism the cells will use to move. Further defining this network could help reveal ways to tweak cell movement when it goes awry.

Saving Resources: Every Cell for Itself Bacteria in a biofilm move together in ordered columns across a surface. Credit: Scott Chimileski, Nick Lyons and Roberto Kolter of Harvard University Medical School.

Understanding how individual cells move tells only part of the story. Cells often move as a group, and when they do, they can do complex jobs that you might not expect. For example, instead of using an every-cell-for-itself approach, bacteria can coordinate their behavior to move the entire colony in an orderly way. Scott Chimileski, an NIGMS-funded research fellow and imaging specialist in the laboratory of Roberto Kolter at Harvard University School of Medicine, uses time-lapse photography to observe how bacteria do this.

Moving as a group has benefits for bacteria, but it is also expensive. For example, making and secreting surfactant, a substance that reduces the tension of the surface and makes it easier to slide across, takes a lot of energy for each cell. So, bacteria want to make sure that none of their competitors can use the surfactant they make for a free ride. Bacteria have evolved many methods for telling their close relatives from their enemies. They even release antibiotics that they are immune to but that will kill bacterial cells not related to them. Kolter and his team believe that the weapons bacteria use to compete successfully also make them into close-knit colonies and promote cooperation. Learning about the balance between cooperation and competition in bacterial colonies, Chimileski said, will help clarify what happens in places like our own gut microbiomes, which, we are learning, are highly complex microbial environments very important to our health.

Dr. Bilder’s research is supported by NIH Grants 5R01GM068675-13 and 5R01GM111111-04. Dr. Devreotes’s research is supported by NIH Grant 5R35GM118177-02, and Dr. Kolter’s research is supported by NIH Grant R01GM058213-20.

Genomic Gymnastics of a Single-Celled Ciliate and How It Relates to Humans

Wed, 2018-03-28 08:37

Credit: Denise Applewhite. Laura Landweber
Grew up in: Princeton, New Jersey
Job site: Columbia University, New York City
Favorite food: Dark chocolate and dark leafy greens
Favorite music: 1940’s style big band jazz
Favorite hobby: Swing dancing
If I weren’t a scientist I would be a: Chocolatier (see “Experiments in Chocolate” sidebar at bottom of story)

One day last fall, molecular biologist Laura Landweber surveyed the Princeton University lab where she’d worked for 22 years. She and her team members had spent many hours that day laboriously affixing yellow Post-it notes to the laboratory equipment—microscopes, centrifuges, computers—they would bring with them to Columbia University, where Landweber had just been appointed full professor. Each Post-it specified the machinery’s location in the new lab. Items that would be left behind—glassware, chemical solutions, furniture, office supplies—were left unlabeled.

As Landweber viewed the lab, decorated with a field of sunny squares, her thoughts turned to another sorting process—the one used by her primary research subject, a microscopic organism, to sift through excess DNA following mating. Rather than using Post-it notes, the creature, a type of single-celled organism called a ciliate, uses small pieces of RNA to tag which bits of genetic material to keep and which to toss.

Landweber is particularly fond of Oxytricha trifallax, a ciliate with relatives that live in soil, ponds and oceans all over the world. The kidney-shaped cell is covered with hair-like projections called cilia that help it move around and devour bacteria and algae. Oxytricha is not only bizarre in appearance, it’s also genetically creative.

Unlike humans, whose cells are programmed to die rather than pass on genomic errors, Oxytricha cells appear to delight in genomic chaos. During sexual reproduction, the ciliate shatters the DNA in one of its two nuclei into hundreds of thousands of pieces, descrambles the DNA letters, throws most away, then recombines the rest to create a new genome.

Landweber has set out to understand how—and possibly why—Oxytricha performs these unusual genomic acrobatics. Ultimately, she hopes that learning how Oxytricha rearranges its genome can illuminate some of the events that go awry during cancer, a disease in which the genome often suffers significant reorganization and damage.

Oxytricha’s Unique Features

Oxytricha carries two separate nuclei—a macronucleus and a micronucleus. The macronucleus, by far the larger of the two, functions like a typical genome, the source of gene transcription for proteins. The tiny micronucleus only sees action occasionally, when Oxytricha reproduces sexually.

Two Oxytricha trifallax cells in the process of mating. Credit, Robert Hammersmith.

What really makes Oxytricha stand out is what it does with its DNA during the rare occasions that it has sex. When food is readily available, Oxytricha procreates without a partner, like a plant grown from a cutting. But when food is scarce, or the cell is stressed, it seeks a mate. When two Oxytricha cells mate, the micronuclear genomes in each cell swap DNA, then replicate. One copy of the new hybrid micronucleus remains intact, while the other breaks its DNA into hundreds of thousands of pieces, some of which are tagged, recombined, then copied another thousand-fold to form a new macronucleus.

Following up on the work of earlier researchers who provided the first glimpse into the unique nature of sexual development in Oxytricha, Landweber’s lab sequenced the complete genomes of Oxytricha’s two separate nuclei, figured out how the organism tags its tiny pieces of DNA, and deciphered how this marked DNA is guided to the right spot in the new macronucleus.

Oxytricha is not the only unusual research organism Landweber has worked with over the years. Below is a sampling of some of the exotic, and more mainstream, organisms to have spent time under her microscope.

Click on an image below to launch slideshow.

Biology, but also math

Growing up in Princeton, New Jersey, as the daughter of academics, Landweber says her career trajectory almost felt like a foregone conclusion. Early on, her parents fostered a fondness for science, subscribing her to mail order science kits and giving her a microscope for her birthday. In particular, she recalls getting excited about biology around age 10 thanks to a human anatomy coloring book.

Landweber says that, while her “gut instinct” drew her to biology, she also “always loved the mathematical side of things.” She has explored many different ways to combine the two disciplines and often uses math and computer analogies to explain complex biological concepts.

Landweber stayed close to home for college, receiving a degree in molecular biology from Princeton. She then went to graduate school at Harvard University, where her research centered on how errors in RNA are corrected before the molecule is translated into proteins. She likens this process, called RNA editing, to correcting text using a word processor. “Imagine you’re editing a text document and you find a typo,” says Landweber. “You can just go in and fix it before printing.”

The first course Landweber taught at Princeton was “Jurassic Park: Myth or Reality?”—just one year after the dinosaurs-run-amok blockbuster had dominated movie screens. The controversial topic was a wonderful way to get students excited about reading scientific journal articles—plus they could watch a movie then talk about the real science behind it, Landweber says. Credit: Flickr, Ian Welch.

After her time at Harvard ended, Landweber returned to her roots, landing a faculty position at Princeton at the remarkably young age of 26. Initially, one research project focused on building computers based on RNA and DNA. For a few years, her lab even held the record for the most powerful molecular computer. But she abandoned the field before too long, convinced that it had no future as a serious competitor to silicon-based computers.

Ciliate Sex

The next field Landweber latched onto, and the one which dominates her current research, was ciliate genomics. She first learned about Oxytricha’s genomic anomalies from a talk she attended by biologist David Prescott, who initially discovered the ciliate’s tiny chromosomes. Right away, Landweber was hooked. “It seemed to fit right into my interest in biological computation, because, when you think about it, ciliates—which scramble, shuffle and reassemble their genes—really are cellular computers,” she says.

Like any typical nucleus, Oxytricha’s macronucleus contains all the DNA it uses to make the RNA and proteins required for everyday life. But the way the DNA in the macronucleus is organized is anything but typical. Humans have 23 pairs of chromosomes. In 2013, Landweber’s team discovered that Oxytricha’s macronucleus contains roughly 16,000 unique chromosomes—nearly 700 times more than we have!

Oxytricha’s micronucleus supplies the pool, or reservoir, of genetic material that it can exchange with another Oxytricha cell. During mating, the micronuclei provide all the drama—they divide by meiosis, discard unneeded material, exchange DNA with the partner cell, shatter into thousands of pieces, shuffle and scramble their DNA. Meanwhile, the macronuclei completely degrade.

Oxytricha reproduction, Credit: NIGMS.

The entire process is quite complicated, but here’s the basic idea (see illustration for a simplified version). Two Oxytricha cells fuse, creating a connecting structure that bridges the insides of both cells. About one half of the DNA in each cell’s micronucleus travels across this bridge into the partner cell. In each cell, the fresh DNA combines with existing DNA to create a hybrid micronucleus.

The two cells split apart, and the hybrid micronucleus in each makes a copy of itself. In each cell, one of the two new micronuclei remains intact, while the DNA in the other one breaks apart into nearly 250,000 disordered pieces.

Then, Oxytricha spends two days discarding about 95 percent of the DNA from shattered micronucleus. The remaining 5 percent of its DNA rearranges (sometimes scrambled or turned upside down), and reassembles to construct the creature’s new macronucleus.

At this point, the macronucleus contains about 16,000 different nanochromosomes—some of which are just a single gene in length, or about 3,000 letters. These nanochromosomes are then amplified another thousand-fold, yielding about 16 million nanochromosomes in the completed macronucleus, which explains its larger size.

At the end of the process, which can take three or four days, the micronucleus and macronucleus of both Oxytricha cells are genetically rejuvenated, incorporating DNA from each cell’s original cache as well as new bits from its partner.

Landweber digs deeper into Oxytricha genomics

While Landweber and her team initially thought the discarded, or leftover, DNA of the shattered micronucleus was “junk,” they later discovered that a substantial chunk of this DNA encodes enzymes called transposases, which are partly responsible for shuffling and reordering the genes of the micronucleus and stitching them together into the new macronucleus.

Landweber and her colleagues subsequently learned a few additional details about the process that harken back to her early interest in RNA. They discovered that small, non-coding RNAs called piRNAs play the role of Post-it notes, flagging the 5 percent of micronucleus DNA to keep for Oxytricha’s macronucleus. In addition, Landweber’s team discovered that long, non-coding RNAs help steer the tagged DNA to the right location in the remodeled macronucleus.

Given the rather convoluted nature of Oxytricha sex, one question Landweber is often asked is “Why does such a complicated system exist?” Landweber offers a few possibilities. First, encrypting its DNA may protect Oxytricha against viruses that attempt to take up residence in its genome. Second, the ability to come up with new combinations of DNA can be used to create new genes, but this happens rarely enough that she thinks it’s something of a side benefit. Instead, Landweber leans more toward the idea that the system evolved as an error-correction mechanism that relies on RNA to ensure the precise transfer of genetic information across generations.

No matter what the ultimate reason turns out to be, Landweber continues to be enthralled with Oxytricha. “It is just truly marvelous that nature has invented such a clever mechanism,” she says.

Bringing Oxytricha to the clinic

While Oxytricha can provide insights to the burgeoning field of genome editing, particularly relevant to human health is the observation that so many human cancers are defined by fairly drastic chromosome reorganization. One extreme example is chromothripsis—a rare occurrence linked to a variety of cancers, in which a single catastrophic event triggers thousands of chromosomal rearrangements.

Oxytricha can teach us a lot about the possibilities of maintaining genome integrity in the face of destructive forces that can corrupt it, including cancer,” says Landweber.

Landweber hopes that her lab’s discoveries in Oxytricha will help improve our understanding of events that can lead to cancer. “It’s as though Oxytricha’s process of rebuilding its chromosomes runs the clock in reverse, starting from a shattered genome and restoring integrity,” she says. “We need to tap into that.”

Within a short walk of her new lab overlooking the Hudson River at Columbia University Medical Center, Landweber has found many potential clinical collaborators. “I’m now actually surrounded by a lot of people studying problems of cancer biology,” she says.

As Landweber prepares to apply her knowledge of ciliate biology to combating cancer, she plans to continue seeking to understand exactly how Oxytricha can manage the chromosomal chaos that would be catastrophic to human cells.

Experiments in Chocolate

Like Landweber herself, Landweber’s three daughters with husband Steven Gubser, a theoretical physicist at Princeton, are growing up in a household steeped in academia. However, while conversations around the dinner table might revolve around science, Landweber says her and Steven’s best collaborations occur in the kitchen.

“That’s where he can be an experimentalist,” Landweber adds, “And we absolutely do like to experiment with making things like what we claim to be healthy chocolate cakes.”

While the healthiness of her cakes may be in question, Landweber’s bona fides as a chocolate lover are not. Just after graduate school, she served as Chocolate Steward of the Harvard Society of Fellows.

“Among other things, being steward meant that I had a little bit of clout when I’d walk into a chocolate shop,” says Landweber. “I would get a few more tastings and a few more tips, and I learned a lot about chocolate.”

She poured most of what she learned into one of the first online guides to chocolate in Boston, which, to her surprise, was for years the number one page resulting from a Google search of “chocolate” and “Boston.”

Landweber’s research is funded in part by NIGMS grant R01GM059708.

Have Nucleus, Will Travel (in Three Dimensions)

Tue, 2018-03-20 12:41
These two human cells are nearly identical, except that the cell on the left had its nucleus (dyed red) removed. The structures dyed green are protein strands that give cells their shape and coherence. Credit: David Graham, UNC-Chapel Hill.

Both of the cells above can scoot across a microscope slide equally well. But when it comes to moving in 3D, the one without the red blob in the center (the nucleus) stalls out. That’s sort of like an Olympic speed skater who wouldn’t be able to perform even a single leap in a figure skating competition.

Scientists have known for some time that the nucleus is involved in moving cells across a flat surface—it slides to one side of the cell and “pushes” from behind. However, scientists have also shown that cells with their nuclei removed can migrate along a flat surface just as well as their brethren with intact nuclei. But they had no idea that, without a nucleus, a cell could no longer move in three dimensions.

This discovery was made by UNC-Chapel Hill biologists Keith Burridge and James Bear and their colleagues. These NIGMS-funded researchers also observed that cells whose nuclei had been disconnected from the cytoskeleton could not move through 3D matrices. The cytoskeleton is the microscopic network of actin protein filaments and tubules in the cytoplasm of many cells that provides the cell’s shape and coherence. It has also has been thought to play a major role in cell movement.

The gray, stringy background of these videos is a 3D jello-like matrix. The cell in the top half of this video has a nucleus and can migrate through the matrix. Both cells in the bottom half have been enucleated (a fancy term for having its nucleus removed) and cannot travel through the matrix. Credit: Graham et al., Journal of Cell Biology, 2018.

The researchers speculate that the reason cells without nuclei (or those whose nuclei have been disconnected from the cytoskeleton) don’t navigate in 3D has to do with complex mechanical interactions between the cytoskeleton and the nucleoskeleton. The nucleoskeleton is a molecular scaffold within the nucleus supporting many functions such as DNA replication and transcription, chromatin remodeling, and mRNA synthesis. The interface between the cytoskeleton and nucleoskeleton consists of interlocking proteins that together provide the physical traction that cells need to push their way through 3D environments. Disrupting this interface is the equivalent of breaking the clutch in a car: the motor revs, but the wheels don’t spin, and the car goes nowhere.

A better understanding of the physical connections between the nucleus and the cytoskeleton and how they influence cell migration may provide additional insight into the role of the nucleus in diseases, such as cancer, in which the DNA-containing organelle is damaged or corrupted.

This research was funded in part by NIGMS grants 5R01GM029860-35, 5P01GM103723-05, and 5R01GM111557-04.

Carole LaBonne: Neural Crest Cells and the Rise of the Vertebrates

Thu, 2018-03-08 09:30

The stunning pigmentation of tigers, the massive jaws of sharks, and the hyper-acute vision of eagles. These and other remarkable features of higher organisms (vertebrates) derive from a small group of powerful cells, called neural crest cells, that arose more than 500 million years ago. Molecular biologist Carole LaBonne of Northwestern University in Illinois studies how neural crest cells help give rise to these important vertebrate structures throughout development.

Very early during embryonic development, stem cells differentiate into different layers: mesoderm, endoderm, and ectoderm. Each of these layers then gives rise to different cell and tissue types. For example, the ectoderm becomes skin and nerve cells. Mesoderm turns into muscle, bone, fat, blood and the circulatory system. Endoderm forms internal structures such as lungs and digestive organs.

These three layers are present in vertebrates—animals with a backbone and well-defined heads, such as fish, birds, reptiles, and mammals—as well as animals without backbones, such as the marine-dwelling Lancelets and Tunicates (referred to as non-vertebrate chordates). Unlike cells in these layers, neural crest cells, which are found only in vertebrates, don’t specialize until much later in development. The delay gives neural crests cells the extra time and flexibility to sculpt the complex anatomical structures found only in vertebrate animals.

Scientists have long debated how neural crest cells manage to finalize their destiny so much later than all other cell types.

Using the frog Xenopus as a model system, LaBonne and her colleagues performed a series of experiments that revealed the process and identified key genes that control it.

In this video, LaBonne describes the power of neural crest cells and how they can be useful for studies of human health, including how cancer cells can metastasize, or migrate, throughout the body.

Dr. LaBonne’s research is funded in part by NIGMS grant 5R01GM116538.

Computational Geneticist Discusses Genetics of Storytelling at Sundance Film Festival

Thu, 2018-03-01 11:03

About 10 years ago, University of Utah geneticist Mark Yandell developed a software platform called VAAST (Variant Annotation, Analysis & Search Tool) to identify rare genes. VAAST, which was funded by NHGRI, was instrumental in pinpointing the genetic cause of a mystery disease that killed four boys across two generations in an Ogden, UT family.

NIGMS has been supporting Yandell’s creation of the next generation of his software, called VAAST 2, for the past few years. The new version incorporates models of how genetic sequences are conserved among different species to improve accuracy with which benign genetic sequences can be differentiated from disease-causing variations. These improvements can help identify novel disease-causing genes responsible for both rare and common diseases.

Yandell and his colleagues in the Utah Genome Project recently took part in a panel at the Sundance Film Festival called the “Genetics of Storytelling” to discuss film’s ability to convey the power of science and medicine. Yandell told the audience his story about his efforts to use VAAST to trace the Ogden boys’ genetic variation back to their great-great-great-great-great grandmother.

Below is a blog post published on January 30 by University of Utah science writer Julie Kiefer about the event.

Finding the Story Within: Utah Genome Project at the 2018 Sundance Film Festival

When Helen’s two sons died before they were a year old, she thought she had terrible luck. But when her grandsons died as babies, she knew that something was horribly wrong. In 2011, University of Utah geneticists uncovered the reason for the boys’ deaths. They all had a genetic mutation that caused a serious condition, now known as Ogden syndrome , named after the Utah town where they lived.

Knowledge is nothing if not power. Armed with this information, Helen’s extended family and others like them can make informed decisions about whether or not to have children, and what to expect if they do.

Mark Yandell, Ph.D., a computational geneticist and Utah Genome Project (UGP) investigator, relayed the tale as part of the “Genetics of Storytelling” panel last Friday at the Sundance Film festival in Park City, Utah. A collection of artists and scientists, the panel discussed film as a dynamic medium for conveying the power of science and medicine.

“We hope to discover new narratives in our heart, our history, and our genes which is where the story lives,” said moderator Geralyn Dreyfous.

Within the UGP, those stories abound. Already, The Atlantic has explained how the 14-generation story of a pilgrim family led to discoveries that are preventing modern descendants from dying young of inherited colon cancer. These “previvors” are outliving their ancestors.

“The research has progressed to the point that people with this disease no longer need to fear cancer,” said UGP and Huntsman Cancer Instituteinvestigator Deborah Neklason, Ph.D.

UGP investigator and cardiologist Martin Tristani-Firouzi, M.D., described his team’s work searching for families who have no idea that their heart could seize unexpectedly. Giving them a simple treatment of beta-blockers could prevent them from becoming the casualty of a misspelled gene.

There is no need to invent stories when telling a true tale can fill a valuable role, said film director Christian Frie. That job could be to raise awareness, bolster support, or stir conversation.

His movie “Genesis 2.0 ” fills the latter category by depicting legendary geneticist George Church’s ethically dicey efforts to resurrect the wooly mammoth that has been extinct for over three millennia. “Our job as artists is to turn science into a language people can understand,” he says.

The Ogden syndrome story is one that’s ripe for the telling, but it’s far from over.

With sophisticated algorithms, Yandell is tracing the boys’ genetic variation back in time. Born in 1807, their great-great-great-great-great grandmother also carried the mutation.

Consider what it could mean to go back even further, he mused. We rarely think about the effects that genetic disease had on our caveman ancestors. “When we can extrapolate data, it has a huge impact on understanding human health and death.”

Group picture: Martin Tristani-Firouzi, Mark Yandell, Vineet Mehra (Ancestry DNA), Deborah Neklason, Christian Frei, Geralyn Dreyfous. Credit: Charlie Ehlert

These aren’t just stories of despair. There are many stories of hope. “It’s natural to think about the bad side of knowing your genetics, particularly when you have family dying around you,” said Yandell. “Genetics can also bear good news. It might say that no, you don’t have the mutation, and you never have to worry about it again.”

Utah Genome Project is all about understanding the narrative that lives within us. Along with drama, intrigue, and glory, there is a story that continues to unfold.

Sounds like the making of a good movie.


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