Bulletin: Powered by Students

illustration by Monica Ramos

Powered by Students

Two HHMI-supported scientists involve undergraduates by the hundreds and thousands in real, published research.

Even after centuries of scientific discovery, there’s a lot of mystery left in our universe. In the last six years, astronomers have found more than 1,000 previously unrecognized planets. Here on Earth, biologists identify over 15,000 new species each year. And today’s biomedical scientists seek clues about human health and disease in genetic data so vast that even computers are having trouble parsing it.

How to make sense of all that? By using technology, of course, but meaningful progress also requires scientists’ discriminating eyes and creative minds.

Educators working to inspire the next generation of scientists are learning that engaging students in research – not one by one, but by the hundreds or thousands on a single project – can drive discovery forward, propelling research in ways that would be impossible without a massive group effort.

This spring, two separate, unusually large teams reported findings on microbial diversity and fruit fly genomics in the journals eLife and G3. The publications represent the work of hundreds of faculty and more than 3,500 students who conducted research through an HHMI program called the Science Education Alliance – Phage Hunters Advancing Genomics and Evolutionary Science (SEA-PHAGES) and the Genomics Education Partnership (GEP). Both involve undergraduates in real research as part of their coursework at institutions around the country.

Delving into genuine research, where outcomes are uncertain and false starts are inevitable, can be both daunting and empowering for students and faculty alike. SEA-PHAGES and GEP faculty say their students gain confidence as the courses progress, and both programs have data demonstrating that the experience boosts undergrads’ academic performance as well as their interest in science. But the students aren’t the only ones who benefit. The young scientists make lasting contributions to the research community – collecting and analyzing data, sharing their findings, and establishing a base of knowledge upon which other scientists can build.

Connecting the Dots

HHMI Professor Sarah Elgin, director of GEP, studies the dot chromosome, a small genetic element in fruit flies, in her lab at Washington University in St. Louis. DNA in the dot chromosome appears to be tightly packaged into heterochromatin, a format that usually restricts the activity of genes, but genes on the dot chromosome work just fine. Understanding how those genes have evolved could help illuminate the relationship between DNA packaging and gene function.

GEP students at over 110 schools have been learning about the power of genomics as they piece together genomic evidence for how the dot chromosome has evolved. Each student or pair of students is responsible for a small chunk of raw sequence data from a fruit fly genome. Their first task is to find and correct errors in the sequence, after which they evaluate several lines of evidence to determine whether genes are present and, if so, how they’re organized.

That divide-and-conquer strategy has enabled Elgin and her colleagues to compare high-quality sequences from the dot chromosome with a second, more loosely packaged piece of DNA across four species of fruit flies. They found most of the dot chromosome’s distinctive characteristics in all species and uncovered evidence that genes on the dot chromosome have been less affected by natural selection than genes in the more loosely packaged DNA. Those findings were reported May 1, 2015, in G3, in a paper coauthored by 1,014 researchers, including 940 undergraduates from 63 institutions who worked on the problem between 2007 and 2012.

“This is not a lightning-like way to do research,” Elgin acknowledges. But without GEP, it might never get done. “When you think about the man-hours that go into careful annotation, there’s just no other way to do it,” she says. “The computer programs are getting better, but they’re not as good as the human mind.”

Breaking Ground

Students in the SEA-PHAGES course are involved in a similar large-scale effort. They are analyzing genomes they isolate from bacteria-infecting viruses that they find in local soils. These viruses, called bacteriophages, thrive just about everywhere, outnumbering all other life forms on the planet. Their impact on ecosystems and the environment is likely profound, but little is known about their astounding diversity.

In fact, relatively few phages have been isolated at all, let alone had their genomes sequenced and made available for comparative analysis. But now SEA-PHAGES students are filling in the missing information, phage by phage. Since SEA-PHAGES was launched in 2008, thousands of undergraduates have sequenced and analyzed bacteriophage genomes and shared their results through a custom-built online database. Pooling that data has allowed a team of scientists led by HHMI Professor Graham Hatfull at the University of Pittsburgh to compare the genomes of 627 different bacteriophages, all of which students had isolated using the soil-dwelling bacterium Mycobacterium smegmatis.

Students Dig Science

Undergraduates characterize bacteriophages found in backyard soil and get hooked on real research.

Researchers had wondered how much genetic diversity exists among bacteriophages that infect a single host. Based on more limited analyses, such phages had been sorted into several clusters with shared genetic features – but with few genomes represented, it was impossible to know whether the clusters were truly distinct.

“You need a sufficiently large collection of sequenced genomes to give you the resolution you need to address the question,” says Hatfull, who is lead scientist for the SEA-PHAGES program, now running on 95 campuses. When he and his colleagues analyzed the vast new dataset, what emerged was a continuum of genetic diversity.

Hatfull’s team found that phages that infect M. smegmatis are related to one another in complex ways that cannot be explained with discrete genetic groups. “We couldn’t have gotten that perspective without getting the data the way we did, as a collective consortium,” he says. The group reported the findings April 28, 2015, in the journal eLife, in a paper authored by 199 faculty and 2,664 students at 81 institutions in the United States and South Africa.

Corndog Mosaic

After participating in real research, students sometimes wonder why all science classes don’t use that approach. But for educators, implementing a shift from traditional lab courses to true discovery requires planning, flexibility, and new resources. SEA-PHAGES and GEP support that effort with training for faculty, as well as by fostering communities where students and faculty can exchange ideas across institutions; both programs continue to seek new schools to join their ventures.

Other efforts to integrate research into undergraduate courses are yielding results, too.

For example, students at the University of California, Los Angeles, have helped identify genes that drive fruit fly development through the Undergraduate Research Consortium in Functional Genomics, run by HHMI Professor Utpal Banerjee. And thousands of students have contributed to the field of synthetic biology, designing new biological circuits and devices, through the Genome Consortium for Active Teaching (GCAT), organized by biology professor Malcolm Campbell at Davidson College in North Carolina.

Meanwhile, Elgin hopes to make it easier for interested faculty to launch their own bioinformatics-based courses, creating opportunities to tie student activities more closely to their own research questions, by driving the development of a new, user-friendly genome browser.

“This is all part and parcel of a whole classroom-based research movement, and I’m hoping that’s a movement that’s really going to grow,” Elgin says. “It’s the ultimate active-learning strategy.”