Category: Tools and Techniques

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The “Virtuous Cycle” of Technology and Science

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A scientist looking through a microscope. Credit: Stock image.
Whether it’s a microscope, computer program or lab technique, technology is at the heart of biomedical research. Credit: Stock image.

Whether it’s a microscope, computer program or lab technique, technology is at the heart of biomedical research. Its central role is particularly clear from this month’s posts.

Some show how different tools led to basic discoveries with important health applications. For instance, a supercomputer unlocked the secrets of a drug-making enzyme, a software tool identified disease-causing variations among family members and high-powered microscopy revealed a mechanism allowing microtubules—and a cancer drug that targets them—to work.

Another theme featured in several posts is novel uses for established technologies. The scientists behind the cool image put a new spin on a long-standing imaging technology to gain surprising insights into how some brain cells dispose of old parts. Similarly, the finding related to sepsis demonstrates yet another application of a standard lab technique called polymerase chain reaction: assessing the immune state of people with this serious medical condition.

“We need tools to answer questions,” says NIGMS’ Doug Sheeley, who oversees biomedical technology research resource grants. “When we find the answers, we ask new questions that then require new or improved tools. It’s a virtuous cycle that keeps science moving forward.”

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Raking the Family Tree for Disease-Causing Variations

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Silhouettes of people with nucleic acid sequences and a stethoscope.
A new software tool analyzes disease-causing genetic variations within a family. Credit: NIH’s National Human Genome Research Institute.

Changes in your DNA sequence occur randomly and rarely. But when they do happen, they can increase your risk of developing common, complex diseases, such as cancer. One way to identify disease-causing variations is to study the genomes of family members, since the changes typically are passed down to subsequent generations.

To rake through a family tree for genetic variations with the highest probabilities of causing a disease, researchers combined several commonly-used statistical methods into a new software tool called pVAAST. The scientific team, which included Mark Yandell and Lynn Jorde of the University of Utah and Chad Huff of the University of Texas MD Anderson Cancer Center, used the tool to identify the genetic causes of a chronic intestinal inflammation disease and of developmental defects affecting the heart, face and limbs.

The results confirmed previously identified genetic variations for the developmental diseases and pinpointed a previously unknown variation for the intestinal inflammation. Together, the findings confirm the ability of the tool to detect disease-causing genetic changes within a family. Another research team has already used the software tool to discover rare genetic changes associated with family cases of breast cancer. These studies are likely just the beginning for studying genetic patterns of diseases than run in a family.

This work also was funded by NIH’s National Institute of Diabetes and Digestive and Kidney Diseases; National Cancer Institute; National Human Genome Research Institute; National Heart, Lung, and Blood Institute; and National Institute of Mental Health.

Learn more:
University of Utah News Release (no longer available)
Yandell Exit icon, Jorde and Huff Exit icon Labs

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Meet Rhiju Das

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Rhiju Das
Credit: Rhiju Das
Rhiju Das
Fields: Biophysics and biochemistry
Works at: Stanford University
Born and raised in: The greater Midwest (Texas, Indiana and Oklahoma)
Studied at: Harvard University, Stanford University
When he’s not in the lab he’s: Enjoying the California outdoors with his wife and 3-year-old daughter
If he could recommend one book about science to a lay reader, it would be: “The Eighth Day of Creation,” about the revolution in molecular biology in the 1940s and 50s.

At the turn of the 21st century, Rhiju Das saw a beautiful picture that changed his life. Then a student of particle physics with a focus on cosmology, he attended a lecture unveiling an image of the ribosome—the cellular machinery that assembles proteins in every living creature. Ribosomes are enormous, complicated machines made up of many proteins and nucleic acids similar to DNA. Deciphering the structure of a ribosome—the 3-D image Das saw—was such an impressive feat that the scientists who accomplished it won the 2009 Nobel Prize in chemistry.

Das, who had been looking for a way to apply his physics background to a research question he could study in a lab, had found his calling.

“It was an epiphany—it was just flabbergasting to me that a hundred thousand atoms could find their way into such a well-defined structure at atomic resolution. It was like miraculously a bunch of nuts and bolts had self-assembled into a Ferrari,” recounted Das. “That inspired me to drop everything and learn everything I could about nucleic acid structure.”

Das focuses on the nucleic acid known as RNA, which, in addition to forming part of the ribosome, plays many roles in the body. As is the case for most proteins, RNA folds into a 3-D shape that enables it to work properly.

Das is now the head of a lab at Stanford University that unravels how the structure and folding of RNA drives its function. He has taken a unique approach to uncovering the rules behind nucleic acid folding: harnessing the wisdom of the crowd.

Together with his collaborator, Adrien Treuille of Carnegie Mellon University, Das created an online, multiplayer video game called EteRNA Exit icon. More than a mere game, it does far more than entertain. With its tagline “Played by Humans, Scored by Nature,” it’s upending how scientists approach RNA structure discovery and design.

Das’ Findings

Treuille and Das launched EteRNA after working on another computer game called Foldit, which lets participants play with complex protein folding questions. Like Foldit, EteRNA asks players to assemble, twist and revise structures—this time of RNA—onscreen.

But EteRNA takes things a step further. Unlike Foldit, where the rewards are only game points, the winners of each round of EteRNA actually get to have their RNA designs synthesized in a wet lab at Stanford. Das and his colleagues then post the results—which designs resulted in a successful, functional RNAs and which didn’t—back online for the players to learn from.

In a paper published in the Proceedings of the National Academy of Sciences Exit icon, Das and his colleagues showed how effective this approach could be. The collective effort of the EteRNA participants—which now number over 100,000—was better and faster than several established computer programs at solving RNA design problems, and even came up with successful new structural rules never before proposed by scientists or computers.

“What was surprising to me was their speed,” said Das. “I had just assumed that it would take a year or so before players were really able to analyze experimental data, make conclusions and come up with robust rules. But it was one of the really shocking moments of my life when, about 2 months in, we plotted the performance of players against computers and they were out-designing the computers.”

“As far as I can tell, none of the top players are academic scientists,” he added. “But if you talk to them, the first thing they’ll tell you is not how many points they have in the game but how many times they’ve had a design synthesized. They’re just excited about seeing whether or not their hypotheses were correct or falsified. So I think the top players truly are scientists—just not academic ones. They get a huge kick out of the scientific method, and they’re good at it.”

To capture lessons learned through the crowd-sourcing approach, Das and his colleagues incorporated successful rules and features into a new algorithm for RNA structure discovery, called EteRNABot, which has performed better than older computer algorithms.

“We thought that maybe the players would react badly [to EteRNABot], that they would think they were going to be automated out of existence,” said Das. “But, as it turned out, it was exciting for them to have their old ideas put into an algorithm so they could move on to the next problems.”

You can try EteRNA for yourself at http://eternagame.org Exit icon. Das and Treuille are always looking for new players and soliciting feedback.

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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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Understanding Complex Diseases Through Computation

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Scientists developed a computational method that could help identify various subtypes of complex diseases. Credit: Stock image

Complex diseases such as diabetes, cancer and asthma are caused by the intricate interplay of genetic, environmental and lifestyle factors that vary among affected individuals. As a result, the same medications may not work for every patient. Now, scientists have shown that a computational method capable of analyzing more than 100 clinical variables for a large group of people can identify various subtypes of asthma, which could ultimately lead to more targeted and personalized treatments. The research team, led by Wei Wu Exit icon of Carnegie Mellon University and Sally Wenzel of the University of Pittsburgh, used a computational approach developed by Wu to identify several patient clusters consistent with known subtypes of asthma, as well as a possible new subtype of severe asthma that does not respond well to conventional drug treatment. If supported by further studies, the researchers’ proposed approach could help improve the understanding, diagnosis and treatment not just of asthma but of other complex diseases.

This work also was funded by NIH’s National Heart, Lung, and Blood Institute.

Learn more:
Carnegie Mellon University News Release Exit icon

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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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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