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[Real Science]

It’s a lucky thing that Emily Fisher‘s parents were both scientists.

A lecturer in the School of Arts and Sciences’ biology department whose doctoral work at the University of North Carolina explored Pseudomonas bacterial diseases in plants, Fisher retains a not-so-rosy memory of one of her first lab experiences as an undergraduate. “We were put to work rolling balls down ramps to measure the rate of gravity,” she recalls. It was an experiment with a predetermined outcome teaching an essentially “cookbook” approach to science: do this, then this, measure carefully, and your results will be the following. “If I hadn’t known differently from my parents, I would have thought that all research was doing boring experiments and keeping careful records,” she says. “So I never valued lab courses as an undergraduate. They were a huge disappointment.”

It is in part to spare future generations of aspiring scientists from similar disappointment that Fisher is so enthusiastic about a new course she will begin teaching Johns Hopkins freshmen in the fall. Come September, two dozen students will embark upon a yearlong practical science odyssey in which they will hunt, discover, identify, classify, genetically sequence, and eventually name a bacteriophage, which is a class of viruses that infects bacteria. But more than simply classifying new viruses, the inaugural genome class will be blazing a new path, up-ending traditional cookbook laboratory research training and replacing it with an experience that is challenging and engaging, unpredictable, and at times frustrating—in other words, everything that is common to true scientific inquiry. “What if you look and you don’t find anything?” muses Fisher, recipient of the 2010-2011 Excellence in Teaching Award for the Krieger School. “What if the gene you test for gives a false positive? Sometimes you can do a lot of experiments and come up with nothing. That’s all part of learning how science really works.”

Failures and false positives and unexpected outcomes are all risks worth taking, says biology professor Joel Schildbach, who directs the department’s undergraduate studies program and will co-direct the class with Fisher. He believes an approach that focuses on true discovery through problem solving can help tear down the silos of knowledge that so often seem to arise in students’ minds, a situation he’s experienced many times over in his years of teaching introductory courses in biochemistry.

“I will find myself talking to another biology instructor who teaches a follow-up course and I’ll hear the question, ‘How come you didn’t cover that?’ And I’ll say, ‘What do you mean I didn’t cover that? I spent 45 minutes in class on that precise topic.’ But the students say they never heard it.” What’s missing—and what Schildbach and colleagues have spent years kicking around and trying to figure out—is a method that makes clear how all the pieces fit together. “We want an organization that gets students drawing connections between things.”

The search for novel viruses provides a near-perfect opportunity to integrate teaching across disciplines including biology and microbiology, biochemistry and genetics. Bacteriophages—typically called by their shortened name “phages”—are abundant, important and not well understood (see “Phage Phacts”). Schildbach and Fisher are excited about what the new freshman genomics class will do because it is a new class that comes with a track record, relying on a template created by the Howard Hughes Medical Institute’s Science Education Alliance. Johns Hopkins is one of 12 colleges and universities nationwide in the newest cohort selected by HHMI—a Chevy Chase, Maryland-based nonprofit medical research organization that has been supporting the phage research classes at the rate of a dozen a year since 2008. Among the inaugural universities to offer the class was the University of Maryland Baltimore County.

“The first thing that strikes the students is that the experiments don’t usually work—maybe not the first time, and sometimes not the second, third, or fourth time,” says course instructor Steven Caruso, senior lecturer in the Department of Biological Sciences at UMBC. “One of the key elements students gain is persistence in the face of frustration. I love that student who recognizes that what you have to do is keep working at it and make whatever changes are necessary to keep working.”

Funding support from HHMI for the class lasts three years and includes not only course planning and development, but also training of faculty and teaching assistants, reagents and essential equipment, computing support and network infrastructure, sequencing services for identifying the viruses discovered, and an annual research symposium in which students present the results of their research to faculty from all participating institutions. At the end of the funding cycle, HHMI anticipates that the schools will continue to fund the program themselves.

Schools have considerable latitude to set their own parameters for the class. At Johns Hopkins the class will be open to all freshmen, regardless of intended major. Students enrolled in the new class will spend their fall term doing “wet lab” bench work—isolating and purifying bacteriophages from local soil and characterizing them using a variety of techniques including electron microscopy and DNA analysis. Then through a process of discussion and consensus the class decides to focus on just one of the phages collected, and during winter break its purified DNA sample will be sent to the Joint Genome Institute (JGI) in California for sequencing. In the spring term, the students will download the genome sequence from the JGI and use bioinformatics tools to annotate it—a process of identifying the locations of genes and all of the coding regions in a genome and determining what those genes do. Annotation is a necessary step in studying any genome; in this process the students will essentially be trying to make sense of how their phage works.

But before that can happen, the students begin by actually rolling up their sleeves and getting their hands dirty

“Really this starts with students getting environmental samples to look for these viruses,” says Schildbach. They are provided with 15 ml. plastic tubes and told to collect moist, loamy soil—which should be naturally rich in bacteria and the phages that accompany them—in locations of their own choosing. Since the Homewood campus fronts the Stoney Run tributary stream system, there are abundant locations to find suitable samples; students will go off on their own to take their sample. Then it’s back to the lab to begin the process of isolating and identifying what they have collected. The soil is buffered and filtered, and the filtrate (the water that comes through the filter) is then plated onto agar dishes and incubated. In a bacteria-rich sample a microbial lawn forms on the plate; phage particles are revealed as “plaques”—small round areas of clearing less than a millimeter across where cell death has occurred. These are then collected and further purified to begin the process of identifying the phages. To reinforce ownership of the project, Schildbach and Fisher will encourage students to name their new viruses.

Says Schildbach, “We’re going to start the course by telling the students, ‘OK, you are going to discover a phage, you are going to characterize it. You are definitely going to contribute in some way to scientific knowledge.’ So they all go out, they all collect samples and get to work. One of the goals is that by Thanksgiving they get to go home with the electron micrograph image of a phage that they purified. They can show Mom and Dad, this is what I’ve done.”

The names selected by the students are permanent, and will remain with the virus in all future scientific discussion and analysis. Professor Graham Hatfull, chair of the Department of Biological Sciences at the University of Pittsburgh and creator of the first phage-hunting course on which the HHMI program is modeled, believes that allowing the students to “own” the science is a large part of the program’s success. “We didn’t really understand how powerful that would be when we started,” he says. “The beauty of this approach is that it engages any student in learning how science is done. You don’t have to be destined for grad school.”

To date, nearly 1,700 students have enrolled in the HHMI’s phage-hunting classes in 40 different programs across the country. They have collected more than 1,300 phages and sequenced the genomes of 185 of them. In the process they have contributed significantly to the scientific body of knowledge about bacteriophages. Even more importantly, perhaps, a new generation of young people has discovered the excitement of hands-on scientific research.

“At Johns Hopkins we’ve always been good at teaching the fundamentals and the rigors of science,” says Vice Dean for Science and Research Infrastructure Greg Ball. “But as the cutting edge in science moves farther and farther out, it’s an increasing challenge to get undergraduate students involved at that level. What this program does is it allows us to capture the creativity and excitement of real scientific research right from the get-go.”

Ball, a professor of psychological and brain sciences and director of the Krieger School’s undergraduate neuroscience program, is eager to find new ways to enhance how science is taught. “We’re proud of our research excellence and we like to think we do everything here well,” he says, “but my goal is for us to be just as good at teaching as we are at research.” He notes that the new class is part of a broader effort across the university to improve and sharpen introductory science labs across all disciplines.


If that unusual word, phage, is clattering at some cobwebbed memory in the back of your mind, take heart—you may well have read occasional references to phages in the past in the realm of history, foreign relations, or nontraditional medicine.

These viruses are enormously abundant, with an estimated 1031 total particles in the biosphere, making them by far the majority of all biological entities on Earth. Yet for all their astonishing ubiquity they are in fact not well understood, in part because they represent a dynamic population (it is estimated that phages infect bacteria at the rate of 1023 occurrences every second) of enormous genetic diversity. The 600 or so sequenced phage genomes completed to date have included great numbers of novel genes. Ongoing efforts to characterize new phages are expected to provide important insights into the evolution and function of viruses and may lead to new ways of usefully employing them against bacterial infection.

Prior to the discovery of antibiotics, phages were one form of anti-bacterial therapy that had a brief popularity in the West. However, medical trials were often disappointing, sometimes seeming to work and sometimes not, probably having to do with the viruses’ great specificity (certain phages will only infect certain bacteria) and the inability of early 20th-century science to readily discern these differences. Phage therapy essentially disappeared from European and American medicine and journals with the discovery of penicillin. But use and research continued in the Soviet Union (Red Army soldiers were often treated this way during World War II) and continues to the present, particularly in the former Soviet republic of Georgia, where today increasing numbers of Westerners are seeking out phage treatments for conditions ranging from bedsores to drug-resistant infections. Meanwhile, in 2009, the medical journal Clinical Otolaryngology reported the first controlled clinical trial of a therapeutic bacteriophage preparation showing efficacy and safety in chronic otitis, or inflammation of the ear. In medicine, as in so many things, what is old may one day become new again.

But better lab courses by themselves will not afford students a complete understanding of the world of research. In order to do science you have to be able to talk and think science as well. Even more than a means of exciting students about lab work, Schildbach sees the course as an effective way of teaching what might best be described as the sociology of science. “There is a mentoring component to this where we are going to be talking to the students about research,” he says. “How do you go about doing this? How do you read original journal articles and identify somebody you want to work with? How do you present yourself and let somebody know you’re interested in what they do? How do you talk science?” Among the skills he sees the students gaining is the ability to read the primary scientific literature, identify scientists whose research is of particular interest, and then present themselves and interview to work in their labs. “You move them from somebody who’s thinking like a high-schooler into someone who starts to be in charge of his own education,” is how he describes it.

For both Schildbach and Fisher, this is the thing that really excites them. A couple of self-described “lab rats” who thrill not only in scientific discovery but in the whole world of science as well, they have spent much time talking about how they could motivate more students to pursue paths of scientific exploration. Because it’s challenging. Because it’s needed. And because it’s just—well, so cool.

“For six years in my graduate education I loved waking up in the morning really looking forward to discovering something new,” recalls Fisher. “And when you make a discovery, for a while you are the only person in the world with this insight, with this new understanding. And then you get to tell people and publish it and in some way expand human knowledge. How cool is that?!”