Phage hunters

A unique genomics class offers motivated freshmen the opportunity to do first-hand research

Professor Manuel Ares works with students Georgia Pollard (on his left), and Hilary Hoffman (to his right), during a class. Class size for the course is kept small, with only 14 students. Inset: Students analyze their phage DNA sequence.
Student Adrian Ruiz works on his DNA sequence.

Professor Grant Hartzog lectures a class; at right is the "Phage Hat," an inspirational charm constructed of foil, cardboard, and good vibes. (Photos by Jim MacKenzie)

After shaking out small strips of paper from test tubes, the phage hunters bend over the table in concentration, moving pieces around until the strings of A’s, C’s, G’s, and T’s that form DNA start matching and overlapping. Under the fluorescent lights of the laboratory, the phage hunters are solving this puzzle on their path to tackling greater mysteries in the biomedical world.

This is the Phage Genomics class, and the phage hunters—freshmen just beginning their college careers—are already conducting original investigations. ” Phage hunting” is the art, science, and adventure of finding phages (viruses that infect bacteria) in the wild, breaking down and studying their DNA, and figuring out what genes they hold.

Along with 11 other universities, UC Santa Cruz has offered the three-quarter Phage Genomics course for three years as part of the Science Education Alliance, developed and funded by the Howard Hughes Medical Institute (HHMI). Molecular, cell and developmental (MCD) biology professors Grant Hartzog and Manuel Ares lead the lab, where freshmen learn laboratory skills, independence, and critical thinking, but most of all, a love of meaningful research.

“It’s hard for motivated undergrads to find research opportunities,” Hartzog says. Phage genomics is a good entry into research because the technical manipulations at the beginning are quite simple, he says, but as students get deeper into the project, the techniques and questions grow in sophistication.

On this day in mid-February, the students have just received data from a DNA sequencing center and are about to start analyzing their phage DNA sequence. The exercise using paper strips with letter strings—representing bases, the building blocks of DNA—gives them a chance to work through the process computers undertake to combine the many DNA fragments obtained by the sequencing center into an entire phage genome sequence.

The class is studying mycobacteriophages, viruses that infect mycobacteria. An infecting phage can kill the bacteria or it can integrate its DNA into the host chromosome. Once integrated, the phage can stay inside the bacteria without causing harm; in this way, phages can be used to manipulate bacteria. Although the students are studying a harmless mycobacterium that lives in soil, it is related to a mycobacterium that causes tuberculosis; understanding mycobacteriophages has been a key to understanding tuberculosis genetics. Phages are abundant in nature, but their genetic diversity and complexity have only recently been recognized. The contributions of this class of phage hunters will add to the growing bank of phage, mycobacteria, and possibly tuberculosis knowledge.

“This helps people understand the genome of the bacteria, and has applications in bacterial infections,” says student Julia Froud, 19, of Cowell College. ” I like the idea of finding out something no one in the scientific community has ever seen.”

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Gene finding

Phage Genomics gives freshmen the chance to go out into the field and collect soil samples, use powerful lab tools such as electron microscopes to view their samples magnified many thousands of times, and analyze phage DNA to find genes and their possible functions.

“Gene finding is a bit of an art,” says Hartzog. ” Just because a student sees their gene prediction matches that for a related gene in a database doesn’t mean either prediction is necessarily valid. They need to critically evaluate the data, and not just trust [the database].”

The students and professors from the inaugural class of the 12 participating schools coauthored a paper published this January in academic journal PloS ONE, presenting the 18 new mycobacteriophages isolated by freshmen. Their work indicated that, among other things, mycobacteriophages are still under-sampled, since the students had found phages with genomes completely unrelated to known phages.

Every year, Hartzog and Ares invite incoming freshmen who have done well in high school biology to apply for the class. There is a written application, then an interview, during which the professors look out for the spark that tells them that student will succeed.

“All the applicants are smart, but the interviews help us see who’s motivated, who’s interested in the world,” Hartzog says.

Ares believes research universities provide a different flavor of education than schools focused solely on teaching: professors at research universities are practitioners of their field, and can expose students to the roots of how we know what we know.

“If we produce students who know fixed facts, their knowledge is static and stagnant. But if we incorporate an experimental basis of understanding, now we’ve produced students who can continue to learn and teach themselves,” Ares says.

Such self-directed learning can be challenging. For enterprising phage hunters, when the going gets tough, the tough use the Phage Hat. A wearable talisman Hartzog made to inspire stymied students, the Phage Hat is an impressive contraption of foil, cardboard, and good vibes. No one has failed to isolate a phage yet, so the Phage Hat must be working. On the other hand, perhaps it is simply dedication and hard work at play.

Draw for the science-minded freshman

Victoria McElroy collected more than 45 soil samples before finding success, even driving off campus with her mother on her search. At the beginning of the course, she hadn’t known what to expect and found it rather nerve-wracking. She jumped on the learning curve from day one, picking up basic lab techniques such as pipetting. Now such skills are second nature, and she’s found herself in the lab at midnight, putting in hours for her favorite class.

“I can’t wait for Tuesdays and Thursdays,” says McElroy, 19, a Crown College MCD biology major.

Courses like Phage Genomics are a draw for future UCSC science-minded applicants. “Most other colleges don’t have the opportunity for freshmen to do research,” says Froud. The chance to conduct undergraduate research was a large factor in Froud’s decision to come to UCSC.

The UCSC course has been so successful that, although the three-year HHMI grant is ending, it will continue under UCSC (and possibly National Science Foundation) funding. From next year, it will be a two-quarter class offered to sophomores, reaching out to students early in their college education, but after they have taken basic biology and writing courses. Phage Genomics will add a scientific writing component, a musthave skill in the research world.

Phage expert William Jacobs of HHMI developed the original phage class for young students (“Phage Phinders”) when he worked with his local high school. Phage hunting, he says, is “a lifechanging experience even if you don’t go into research. You learn that you, a high school kid, can discover something new and unique.”

In his pioneering research, Jacobs used phages as tools to genetically manipulate mycobacteria, a technique that enabled a greater understanding of tuberculosis and other bacterial diseases.

Of the UCSC phage hunters, Jacobs says, “Anybody sequencing a phage is fine in my book. Just by using phages, we’re developing all the tools we need to manipulate TB. The trick to overcoming every obstacle, I found in a phage.”

Two years after taking Phage Genomics, junior Kimberly Davis, 20 (Cowell, biochemistry and molecular biology), looks back on the experience as giving her a leg up in her science education. “For once I felt that what I was learning was important,” she says. Without the class, “I wouldn’t be where I am now, doing my second year of research.”

Hartzog and Ares guide their students even after the course has ended, helping them find research opportunities on campus and hoping they go on to productive scientific careers.

“It’s fun to do science!” Ares says. “We do it because we like it. And we want to give them the same feeling.”

Jane Liaw is a freelance writer and UC Berkeley research scientist. She graduated from the UCSC science communication program in 2008 and is now based in San Francisco.