Author: Emily Carlson

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Knowing Networks

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Artist's rendition of a network diagram. Credit: Allison Kudla, Institute for Systems Biology.
Artist’s rendition of a network diagram. Credit: Allison Kudla, Institute for Systems Biology.

Networks—both real and virtual—are everywhere, from our social media circles to the power grid that delivers electricity. The interactions of genes, proteins and other molecules in a cell are examples of networks, too.

Scientists working in a field called systems biology study and chart living networks to learn how the individual parts work together to make a functioning whole and what happens when these complex, dynamic systems go awry. For example, the network diagram here depicts yeast cells (superimposed circles) and the biochemical “chatter” between them (lines) that tells the cells to gather together in clumps. This clumping helps them survive stressful conditions like a shortage of nutrients.

Network diagrams provide more than just hub-and-spoke pictures. They can yield information that helps us better understand—and potentially influence—complex phenomena that affect our health.

Read more about network analysis and systems biology in this Inside Life Science article.

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How Cells Take Out the Trash

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Proteins entering the proteasome. Credit: Office of Biological and Environmental Research of the U.S. Department of Energy Office of Science.
When proteins enter the proteasome, they’re chopped into bits for re-use. Credit: Office of Biological and Environmental Research of the U.S. Department of Energy Office of Science.

As people around the world mark Earth Day (April 22) with activities that protect the planet, our cells are busy safeguarding their own environment.

To keep themselves neat, tidy and above all healthy, cells rely on a variety of recycling and trash removal systems. If it weren’t for these systems, cells could look like microscopic junkyards—and worse, they might not function properly. Scientists funded by the National Institutes of Health are therefore working to understand the cell’s janitorial services to find ways to combat malfunctions.

Read more about how cells take out the trash and handle recycling in this Inside Life Science article.

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Basic Research Fuels Medical Advances

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Genetic defect that causes myotonic dystrophy type 2 and used that information to design drug candidates to counteract the disease. Credit: Ilyas Yildirim, Northwestern University.
Scientists revealed a detailed image of the genetic change that causes myotonic dystrophy type 2 and used that information to design drug candidates to counteract the disease. Credit: Ilyas Yildirim, Northwestern University. View larger image

This image may look complicated, but it tells a fairly straightforward tale about basic research: Learning more about basic life processes can pave the way for medical and other advances.

In this example, researchers led by Matthew Disney of the Scripps Research Institute’s Florida campus focused on better understanding the structural underpinnings of myotonic dystrophy type 2, a relatively rare, inherited form of adult-onset muscular dystrophy. While this work is still in the preliminary stages, it may hold potential for someday treating the disorder.

Some 300,000 NIH-funded scientists are working on projects aimed at improving disease diagnosis, treatment and prevention, often through increasing understanding of basic life processes.

Read the complete Inside Life Science article.

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Meet Jeff Shaman

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Jeff Shaman
Jeff Shaman
Field: Climatology
Works at: Columbia University’s Mailman School of Public Health, N.Y.
Favorite high school subject: Biology
First job: Guide at the Franklin Institute in Philadelphia, Pa.
Alternative career: Opera singer
Credit: Anne Foulke

Before he wrote any scientific papers, Jeff Shaman wrote operas. At the premiere of one of his operas, an 80-minute story about psychoanalysis, reviewers said the work “crackle[d] with invention.”

After 4 years of training to become an opera singer, Shaman realized that the work wouldn’t offer him career stability. He started thinking about his other interests. After college, where he majored in biology with a focus on ecology, he had volunteered to help with HIV clinical trials and developed a fascination with understanding infectious diseases. He wondered if the quantitative tools and methods used to study the physical sciences—another interest area—could inform how contagions spread and possibly even lead to systems for monitoring or predicting their transmission.

So Shaman returned to school—this time, for advanced degrees in earth and environmental sciences. He now studies the relationship between soil wetness and mosquito-borne diseases such as malaria in Africa and West Nile in Florida.

“I love science—probing questions, thinking about problems, finding solutions, pursuing my ideas,” says Shaman.

His Findings

A few years ago, Shaman took some of his scientific compositions in another direction by focusing on seasonal flu outbreaks. For more than 60 years, researchers have linked seasonal flu outbreaks with environmental data like humidity and temperature. Shaman analyzed this work and figured out that absolute humidity, rather than relative humidity, was the best predictor of outbreaks. Now he’s applied state-of-the-art mathematical modeling and real-time observational estimates of influenza incidence to predict when outbreaks will likely occur.

His forecasting technique mimics that used by meteorologists to predict weather conditions like temperatures, precipitation and even hurricane landfall. Shaman’s version incorporates variables like how transmissible a virus is, the number of days people are contagious and sick, and how much humidity is in the air.

The flu forecasts build on a series of studies in which Shaman and his colleagues used data from previous influenza seasons to test their predictions and improve reliability of their model. The work culminated with real-time predictions for 108 cities during the 2012-2013 influenza season. The forecasts could reliably estimate the peaks of flu outbreaks up to 9 weeks before they occurred.

For the 2013-2014 flu season, the researchers continued to make weekly predictions. But instead of first publishing the results in a scientific journal, they posted them on a newly launched influenza forecasts Web site  where the public could view the projections.

“People understand the limitations and capabilities of weather forecasts,” says Shaman. “Our hope is that people will develop a similar familiarity with the flu forecasts and use that information to make sensible decisions.” For instance, the prediction of high influenza activity may motivate them to get vaccinated and practice other flu-prevention measures.

As he waits for the start of the next flu season, Shaman continues to tweak his forecast system to improve its reliability. He’s also beginning to address other questions, such as how to predict multiple outbreaks of different influenza strains and how to predict the spread of other respiratory illnesses.

Learn more:
Influenza Forecasts Web Site 

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What Students Want to Know About Cells

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Cell Day 2014

During a live online chat dubbed “Cell Day,” scientists at NIGMS recently fielded questions about the cell and careers in research from middle and high school students across the country. Here’s a sampling of the questions and answers, some of which have been edited for clarity or length.

What color are cells?
While cells with lots of iron, like red blood cells, may be red, usually cells are colorless.

How many different types of cells can be found inside the human body?
There are about 200 cell types and a few trillion total cells in the human body. That does not include bacteria, fungi and mites that live on the body.

Is it possible to have too many or not enough cells?
The answer depends on cell type. For example, within the immune system, there are many examples of diseases that are caused by too many or not enough cells. When too many immune cells accumulate, patients get very large spleens and lymph nodes. When too few immune cells develop, patients have difficulty fighting infections.

How fast does it take for a cell to produce two daughter cells?
Some cells, for example bacterial ones, can produce daughter cells very fast when nutrients are available. The doubling time for E. coli bacteria is 20 minutes. Other cells in the human body take hours or days or even years to divide.

Do skin cells stretch or multiply when you gain weight?
The size of cells is tightly regulated and maintained so they do not stretch much. As the surface area of the body increases with weight gain, the number of skin cells increases.

Why do cells self-destruct?
The term for cellular self-destruction is “apoptosis” or “programmed cell death.” Apoptosis is very important for normal development of humans and other animals as it ensures that we do not have too many cells and that “unhealthy” cells can be eliminated without causing harm to the surrounding cells. For instance, did you know that human embryos have webbing between their fingers and toes (just like ducks!)? Apoptosis eliminates the cells that form the web so that you are born with toes and fingers.

In what field is there a need for new scientists?
I would say that there is a need for scientists who can work at the interface between the biological and biomedical sciences and the data sciences. Knowing sophisticated mathematics and having computer skills to address questions like ‘what does this biomedical data tell us about particular diseases’ is still a challenge.

What is a scientist’s daily work day like? Is all of your time spent in a lab testing or like in an office throwing ideas around?
There are lots of different kinds of jobs a scientist can have. Many work in labs where they get to do experiments AND throw ideas around. Working in a lab is a lot of fun—you learn things about the world that no one has known before (how cool is that?). Other important jobs that scientists can do include writing about science as a journalist, helping other scientists patent new technologies they invent as a patent agent or lawyer, or working on important scientific policy issues for the government or other organizations.

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Capitalizing on Cellular Conversations

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Fat cells
Fat cells such as these listen for incoming signals like FGF21, which tells them to burn more fat. Credit: David Gregory and Debbie Marshall. All rights reserved by Wellcome Images.

Living things are chatty creatures. Even when they’re not making actual sounds, organisms constantly communicate using chemical signals that course through their systems. In multicellular organisms like people, brain cells might call, “I’m in trouble!” signaling others to help mount a protective response. Single-celled organisms like bacteria may broadcast, “We have to stick together to survive!” so they can coordinate certain activities that they can’t carry out solo. In addition to sending out signals, cells have to receive information. To help them do this, they use molecular “ears” called receptors on their surfaces. When a chemical messenger attaches to a receptor, it tells the cell what’s going on and causes a response.

Scientists are following the dialogue, learning how cell signals affect health and disease. They’re also starting to take part in the cellular conversations, inserting their own comments with the goal of developing therapies that set a diseased system right.

Continue reading this new Inside Life Science article

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Resetting Our Clocks: New Details About How the Body Tells Time

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VIP in time-keeping brain cells
Boosting doses of a molecule called VIP (green) in time-keeping brain cells (blue) helped mice adjust quickly to major shifts in light-dark cycles. Credit: Cristina Mazuski in the lab of Erik Herzog, Washington University in St. Louis.

Springing clocks forward by an hour this Sunday, traveling across time zones, staring at a computer screen late at night or working the third shift are just a few examples of activities that can disrupt our daily, or circadian, rhythms. These roughly 24-hour cycles influence our physiology and behavior, and they’re driven by our body’s network of tiny timekeepers. If our daily routines fall out of sync with our body clocks, sleep, metabolic and other disorders can result.

Researchers funded by the National Institutes of Health have spent decades piecing together the molecular mechanisms of our biological clocks. Now, they’re building on that basic knowledge to better understand the intricate relationship among these clocks, circadian rhythms and physiology—and ultimately, find ways to manipulate the moving parts to improve our modern-day lives.

Continue reading this new Inside Life Science article

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Meet Ravi Iyengar

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Ravi Iyengar
Ravi Iyengar
Fields: Systems pharmacology and systems biology
Works at: Mount Sinai School of Medicine, New York, NY
Favorite sports team: Yankees
Favorite subject in high school: Math
Recently read book: The Signal and the Noise by Nate Silver
Credit: Pedro Martinez, Systems Biology Center New York

Ravi Iyengar, a professor at Mount Sinai School of Medicine, stood in an empty lecture hall, primed to tell thousands of students about systems biology, a holistic approach to studying fundamental life processes. To prepare for this moment, he had spent 4 months reading hundreds of scientific papers and distilling the research into understandable nuggets. But that day, his only student was a videographer.

Together, they recorded 15 different lectures about systems biology—many related to Iyengar’s own research—that thousands of people would stream or download as part of a MOOC, or massive open online course.

Trained in biochemistry, Iyengar built his research career around studying molecules and developing a list of all the parts that help nerve, kidney and skin cells to function. As he obtained more information, he realized he needed to know how all the components worked together. To achieve this comprehensive understanding, Iyengar turned to computational techniques and mathematical analyses—cornerstones of systems biology.

For more than a decade, he has been using and developing systems biology approaches to explore a range of biomedical questions, from very basic to translational ones with immediate relevance to human health.

Iyengar’s Findings

In his earlier work, Iyengar used mathematical analyses to show that molecules within cells connect with one another to form switches that produce cellular memory. This may allow, for instance, an immune cell to remember a foreign object and secrete an antibody. In recent work, he and his team developed a mathematical model showing that the shape of a cell influences the flow of information across the membrane, possibly contributing to disease states and offering a way to study and identify them under the microscope. In another study, they analyzed a database of drug side effects to find combinations of medications that produce fewer adverse reactions and then created a cell biology interaction network that explains why a certain drug pair had this beneficial outcome. The approach could point to other combinations of FDA-approved drugs that reduce serious side effects and thereby guide clinical practice.

“Systems biology is a powerful way to explore important biological and medical questions, and it’s relevant to many fields of science,” said Iyengar. But he added that the majority of educational institutions, including liberal arts and community colleges, don’t have systems biology courses. So, Iyengar teamed with colleagues to create a series of MOOCs.

The first course, offered last summer and taught by Iyengar, presented all the facets of systems biology. The syllabus included lessons on genomics and bioinformatics, fields that have contributed to systems biology; gathering and integrating data; and the use of modeling in drug development.

“My goal was for the students to get the general gestalt of systems biology,” explained Iyengar, who directs an NIH-funded center focused on the systems-level study of medicine and therapeutics.

In total, more than 12,000 participants watched at least one video lecture, 3,000 submitted one or more of the weekly quizzes and 1,800 took a mid-term or final exam. The online discussions forum included nearly 400 topics with about 5,000 posts. The students, most enrolled in a graduate program or working full-time, had some training in the biological, biomedical, computer and information sciences.

“The stats tell me that many people are in fields adjacent to systems biology and don’t have access to more traditional systems biology courses,” concluded Iyengar. “Through the MOOC, we can reach them in a substantial way.”

The second course, which covers network analysis, wrapped up in early December, and the third course, which covers dynamical modeling methods, began in January. Iyengar plans to offer the intro course again in late March.

Learn more:
MOOC Systems Biology Courses Exit icon

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Local Flu Forecasts Posted on New Web Site

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Incidence of influenza during the week starting 12/29/2013 (top); influenza incidence forecasts for selected cities (bottom). Credit: Columbia Prediction of Infectious Diseases.
Incidence of influenza during the week starting 12/29/2013 (top); influenza incidence forecasts for selected cities (bottom). Credit: Columbia Prediction of Infectious Diseases.

News articles this weekend reported an uptick in flu cases in many parts of the country. When will your area be hardest hit? Infectious disease experts at Columbia University have launched an influenza forecast Web site that gives weekly predictions for rates of flu infection in 94 U.S. cities. The predictions indicate the number of cases in Chicago; Atlanta; Washington, D.C.; and Los Angeles will peak this week, with New York City, Boston, Miami and Providence peaking in following weeks. The forecasts are updated every Friday afternoon, so check back then for any changes.

The forecasting approach, which adapts techniques used in modern weather prediction, relies on real-time observational data of people with influenza-like illness, including those who actually tested positive for flu. The researchers have spent the last couple of years developing the forecasting system and testing it—first retrospectively predicting flu cases from 2003-2008 in New York City and then in real time during the 2012-2013 influenza season in 108 cities.

“People have become acclimated to understanding the capabilities and limitations of weather forecasts,” said Jeffrey Shaman, who’s led the flu forecasting project. “Making our forecasts available on the Web site will help people develop a similar familiarity and comfort.” Shaman and his team are hoping that, just as rainy forecasts prompt more people to carry umbrellas, an outlook for high influenza activity may motivate them to get vaccinated and practice other flu-prevention measures.

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

Learn more:

Columbia University News Release

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Detailing Key Structures of HIV

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Structure of Env. Credit: The Scripps Research Institute.
This model shows a birds-eye view of the structure of Env, a protein on the HIV surface that enables it to infect cells, bound to neutralizing antibodies. Credit: The Scripps Research Institute.

In a statement on World AIDS Day 2013, NIH leaders wrote, “In the 25 years that have passed since the first annual commemoration of World AIDS Day, extraordinary scientific progress has been made in the fight against HIV/AIDS. That progress has turned an HIV diagnosis from an almost-certain death sentence to what is now for many, a manageable medical condition and nearly normal lifespan. We have come far, yet not far enough.”

One area of progress is in understanding the structural biology of HIV, the virus that causes AIDS. Capturing details about the virus’ shape has helped scientists better understand how HIV operates and pinpoint its Achilles’ heels. Recently, scientists got a closer look at two key pieces of the virus.

In one study, researchers developed the most detailed picture yet of Env, a three-segment protein on the HIV surface that allows the virus to infect cells. The work illuminated the complex process by which the protein assembles, undergoes radical shape changes during infection and interacts with neutralizing antibodies, which can block many strains of HIV from infecting human cells. The findings also may guide the development of HIV vaccines.

In another study, researchers created the best image yet of the cocoon-like container, or capsid, that carries HIV’s genome. Capsids have been difficult to study because individual imaging techniques had not produced high enough detail. By combining several cutting-edge imaging methods, the scientists pieced together the individual polygonal units of the capsid like a jigsaw puzzle to determine its structure in detail. Now that they know how HIV’s inner vessel looks, the research team is searching for its cracks—potential targets for drug development.

Learn more:
Imaging HIV’S Inner Shell Article from Inside Life Science
Key HIV Protein Structure Revealed Article from NIH Research Matters
Interactive HIV Structural Model