It’s Pay Dirt

Graham Hatfull, Ph.D., is clearly pleased when presented with a film canister brimming with soil dug from a Penn Hills back yard. Common, every day dirt.

An odd gift, to be sure, but one often suggested to anyone meeting the head of the University of Pittsburgh’s Department of Biological Sciences for the first time. “Beautiful,” he says, accepting the gift. And he means it.

Look closely enough — we’re talking microscopically close — and you’ll find in that handful of dirt the heart of Hatfull’s work as a researcher and teacher: millions of microorganisms, viruses known as bacteriophages, whose most notable attribute is their ability to infect bacteria. Their genomes represent the largest reservoir of unexplored genetic information on the planet, and Hatfull has spent years mining that vast frontier, where cures for stubborn human diseases, even answers to antibiotic-resistant infection, are glimmering possibilities. He also finds in that virgin terrain a way to give science deeper meaning to high school and undergraduate students, recruiting them by the dozens into an army of “phage hunters” and entrusting them with research responsibilities significant enough to earn them the prestige of being listed as co-authors of scientific papers published in peer-reviewed journals.

Hatfull, 49, thinks a lot about how to make the world of science more engaging and better understood. He worries about things such as how the image of the scientist as a distant, “snooty professor who if you are lucky will give you five minutes of his time to explain something to you” can be a big turn-off. For the record, he comes off as anything but. In his Langley Hall office, he is jeans-and-Oxford-shirt casual, unassuming, soft-spoken and patient enough to walk a scientifically challenged visitor through such entry-level stuff as recombinant DNA. And the nature of his work suggests he has little appetite for celebrity. His is the kind of behind-the-scenes basic science that explains what things are and how they work — not the stuff of headlines, but essential if sexier high-profile discoveries, such as cures for disease, are to be made.

One measure of how others view the importance of his work is the millions of public and private dollars Hatfull has received to support it, including more than a decade of steady money from the National Institutes of Health and more than $3.5 million from the Howard Hughes Medical Institute, a private foundation that supports biomedical research and science education.

That might seem like a lot of money to spend on understanding something that is probably as old as life itself. But consider the bacteriophage’s talent: it can penetrate bacteria cells, become one with them and either kill them or alter them. And in the never-ending battle against bacterial infection, you can never have enough soldiers. Add to that the fact that, despite the intriguing prospect of harnessing the abilities of phages, scientific interest in them has been slow to boil. The Russians have pursued phage therapies since the days of Stalin. But interest in most Western nations flagged early, in part because the 1941 discovery of antibiotics gave doctors an effective way to treat bacterial infection, while too little was known about the basic biology of phages for them to be considered reliable therapy.

At the time Hatfull started looking at bacteriophages 18 years ago, the genetic makeup for only two or three phages had been determined out of the 10 million trillion species of phages estimated to exist on earth. Much of what makes them tick was a mystery. It still is. And that’s what has him hooked. “The phage population is so large it suggests that bacteriophage particles are the majority of all living things in the universe, which is astounding,” he says. “If we are the least bit curious about what is going on in the natural world, shouldn’t we be looking at what nature has done most successfully?”

Much of his time in the lab is spent doing just that: isolating, identifying, sequencing and analyzing the genetic profiles of bacteriophages and investigating their intimate relationships with bacteria. Hatfull and his colleagues at Pitt and elsewhere are particularly interested in mycobacteriophages, a group of phages that infect mycobacteria. Mycobacteria are responsible for some nasty human diseases, including tuberculosis, which, according to World Health Organization estimates, continues to kill between 2 and 3 million people a year worldwide.

Some discoveries Hatfull has been involved in have been real eye-openers to those familiar with the field, if not the general public. Take the demographics of the phage population. In 2003, after isolating the DNA of 10 phages and comparing them to one another, Hatfull and William R. Jacobs Jr., a researcher at Albert Einstein College of Medicine in New York, reported in the journal Cell evidence that revealed the phage world to be incredibly diverse. They identified more than 1,600 genes and found only one to be common among any two phages. And half of the genes couldn’t be found in any existing genomic database. So, for example, if it’s a never-before-seen gene you’re after, you have a fair chance of finding one among the phages living in your garden bed.

Hatfull and colleagues also discovered phages to be a promiscuous bunch. In the cells of higher organisms, cell division usually involves the recombination of similar chromosomes, which carry the genes that convey hereditary characteristics. But phages, the researchers found, randomly swap genes. That helps to explain how viruses can drive the evolution of their bacterial hosts. No longer should anyone be surprised when a bacterium picks up a strange gene from somewhere. The phages that infect it do it all the time.

One of the easier-to-grasp examples of why investigating phages is important is Hatfull’s recent revelations about biofilm, the antibiotic-tolerant extra cellular gunk that helps bacteria resist treatment. Last year, Hatfull and Jacobs reported that the lack of a single protein prevents the bacterium that causes tuberculosis from forming a hardy biofilm defense — a finding that suggests interrupting the gene that produces that key protein might help treat or even prevent the disease. Their investigation began after Hatfull’s postdoctoral fellow, Anil Ohja, saw that a phage-infected cousin of the tuberculosis-causing bacterium was unable to form proper biofilms.

Another facet of Hatfull’s research is developing the tools that enable scientists like himself to fool around with these microorganisms in ways that help explain how they work. One such tool is a process that allows you to hack out one piece of DNA and replace it with another to see what happens. Says Hatfull, “If you want to know how something works, you take it apart.”

He is emphatic about getting out the word — to students, in particular — that being a science prodigy isn’t a prerequisite for mastering this kind of work. In fact, Hatfull says, he was “just an average kid” while growing up in Stafford, England. “Academically, about as average as you can get.” His father worked for the county as a public food analyst, “making sure there was enough meat in the sausages and the milk was not watered down.” His mother was a housewife. He enjoyed playing the piano and church organ but concluded that his chances of earning a living at music were slim. He did better in science than in other subjects in school and leaned toward biology, in part, because it was taught with more discussion and interpretation of observations than the other sciences.

But the hook wasn’t set until after his freshman year at the University of London, when he took a summer research job that involved using an electron microscope to study how varying amounts of oxygen affected the cell growth of blue-green bacteria. It was a turning point. After earning a bachelor’s degree in biology, a doctorate in microbiology from the University of Edinburgh and doing postdoc work at Yale University, Hatfull joined the faculty at Pitt, where he received the Chancellor’s Distinguished Research Award, was named department head and was awarded the Eberly Family Professorship in Biology. “It was great,” he says of the summer research project that started it all. “I realized the thing I enjoyed doing was this kind of research and I wanted to continue doing it.”

Andrew Hryckowian, a sophomore microbiology major at Pitt, knows the feeling. He grew up in the Westmoreland County coal town of Whitney and, like Hatfull, he waded through his classes at Latrobe Area High School with no particular interest in any subject or career path. “Then,” he says, “it just clicked.” Science was his calling. What led him to that conclusion was a chance to do real scientific research, courtesy of Hatfull’s program aimed at exposing high school and undergraduate students to hands-on, meaningful biology in the lab — biology that involves bacteriophages.

By his sophomore year in high school, Hryckowian was hunting phages in soil, isolating them and learning the details of their genomes. “It isn’t the science you usually encounter in class. It’s not cookbook science. You’re actually contributing to the pool of scientific knowledge out there. As a high school student I was making those sorts of findings.”

Hands-on science may still be hard to come by in our schools, but the concept is nothing new. Hatfull simply uses what worked for him — doing meaningful research — to give students a taste of what science is all about. For it to succeed, he says, the research can’t be too technically difficult and has to carry some importance and be motivating. Students also need to feel the work is theirs, that they are not just lab assistants for those snooty academics that Hatfull fears young people may, rightly or wrongly, see scientists as. Phage discovery and classification satisfies all of the above. Another essential ingredient, funding, is provided by the Howard Hughes Medical Institute, which gave Hatfull $1 million for his education program in 2002, then extended the grant this year.

Hryckowian’s high school biology teacher, Deborah Jacobs-Sera, is now coordinator of Hatfull’s phage hunters education program. The sister of Hatfull’s New York collaborator, she turned to the Pitt scientist when looking for ways to get two of her better students started in their senior research projects. “I thought I’d go and just listen to this great English accent for an hour,” she says. “Then, he laid in our laps the ability to find bacteriophages. We took it, whole hog.”

Her students were two of the earliest recruits into Hatfull’s army of phage hunters and among the first to find themselves co-authors of a published scientific paper. Their phages were among the 10 mentioned in Hatfull’s and Jacobs’ 2003 Cell article that reported the incredible diversity found within the phage population. For his part, Hryckowian is co-author of a paper published this year in the journal Public Library of Science Genetics, which details the genomes of 30 bacteriophages, including one of his, catera, which he named after a friend’s dog. Allowing students to name the phages they discover is a popular feature of the program.

Each year, Jacobs-Sera takes the program on the road, visiting more than two dozen high school classrooms nationwide to introduce teachers and students to phages, show them the initial steps of isolating phages and, generally, “try to communicate that we need to do science, not just talk about it.” She’s reached more than 3,000 high schoolers this way over the past two years. Another 135 area high school students have participated as full-fledged phage hunters, which requires them to scoop up dirt and work in Hatfull’s Pitt lab with undergraduate students to isolate and identify the phages they find and purify and sequence their DNA. This year, the phage hunter brigade includes 37 high school students and 28 undergrads.

Hatfull has a few reasons for doing this. At the very least, he wants students to come away from the program with a better understanding of science and, more specifically, the process of doing research: asking questions, establishing a hypothesis, testing the hypothesis and thinking critically about the interpretations. He worries that is something that is too often lost on the general public. For example, he describes as “quite incredible” the public debate over evolution and whether intelligent design is a valid science-based alternative. “Science, the process of how we learn about things, is based on experiments and testable hypotheses. Simply claiming things are too complicated for us to understand is not based on scientific method at all. The fact that intelligent design has had legs in society — it is easy to think of that as a failure of education, a failure to understand what science is and how we address questions scientifically.”

Just how many of Hatfull’s phage hunters actually pursue science in college and as a career is unclear. An evaluation to help answer that question is just now being designed. But Hatfull is hopeful that phage research will excite and capture some students who might otherwise not consider themselves science material. This, he says, is important not only for increasing the number of scientists, but for promoting diversity. If science, at its core, is about asking and answering questions, it stands to reason that it benefits when those questions come from a pool of scientists with diverse experiences, education and ways of thinking that make them, as a group, more likely to see possibilities beyond the obvious.

Swelling the ranks of America’s scientists is also a critical economic issue. More than ever, nations around the world are seeking competitive advantage by building indigenous science and technology infrastructure, the key ingredient of which is scientists and engineers. But several trends are running against the United States, according to the National Science Foundation report, Science and Engineering Indicators 2006. The number of young Americans earning degrees in the natural sciences and engineering has slowed to 6 out of 100, ranking the United States 32nd among 90 nations surveyed. Meanwhile, some traditional laggards, such as China, are aggressively picking up the pace. Overall, the forecast for the U.S. science and technology workforce is one of slow growth and rising retirements.

Hryckowian, for one, is doing his part to improve those trends. A pharmacy major during his freshman year at Pitt, he recently switched over to microbiology. “Once I actually got here and was working in the lab, I realized microbiology is amazing and that I want to be a part of it,” he says. “It’ll be a fun ride.”

The terrain spread before him is both expansive and largely uncharted. Everything science has looked at in terms of the genetic makeup and behavior of bacteria and viruses represents a mere fraction of what nature has managed to create. “The exciting thing,” says Hatfull, “is that we have the tools to address, essentially, every medical and biological problem we can think of.”

At least for the moment, the possibilities seem limited only by our willingness to explore them.