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Trial by PHIRE

Harini Barath, IndiaBioScience


Does the classroom really prepare students for a research career? An early, hands-on exposure to research intuitively seems a better introduction to real science. Most importantly, it would give students a chance to find out for themselves whether they really have a flair for research. The Phage Hunters Integrating Research and Education (PHIRE) program provides high school and undergraduate students just that. Started by Graham Hatfull,  A professor of biotechnology at the University of Pittsburgh, the program provides a platform for students to participate in the discovery of novel bacteriophages – viruses that infect and replicate within bacteria. Students who isolate previously unknown phages from the environment get to add their own personal touch to the discovery by naming them. Many of them go a step further and characterize the phages through genomic sequencing. Advanced students also do their bit to sustain the program and mentor students who are new to the program.  

Graham Hatfull talked to IndiaBioscience at length about the program, the challenges it presents and what the future holds...

What motivated you to start the PHIRE program? 

I think the idea that we can prepare people for successful research careers by putting them in a classroom and teaching them how to remember stuff, is misplaced. We all know, instinctively, that people think in different ways. They think about problems in different ways. And I believe that science progresses best, and fastest, and most productively when you have communities of people that think differently. We hear about thinking outside the box. Well, doing well in the formal academic setting, the classroom, as a qualification to doing well in research is the epitome of constrained thinking inside the box. The question is, how do you break that? You have to find other ways in which students can find out for themselves whether research is an area that they can contribute to and have an opportunity for people to explore. To find those who will mentor and support future researchers, who has good strong capabilities and intuition for doing research, you can only do that by having people do research and see whether they have the aptitude for it or not. To me it makes perfect sense, but I think often it is a poorly utilized priority.

 How does PHIRE address this problem?

I think it's relatively common in the States to have undergrads doing research in labs.  Only usually, it happens in a non-programmatic kind of way. So it's not uncommon for an undergraduate student to end up in a lab, perhaps working under the supervision of a graduate student. But it's not that it happens with every lab or with every student. So one of the things that we did that was different was to explore whether we could find ways, to engage not just one or two undergraduates in a lab but to do it in a more programmatic way.  So it was really that, coupled with the recognition that today's students are going to be tomorrow's professors. And doing research requires skills that people can develop, which is very different from doing well in the classroom in an academic setting. Whether it is undergraduate students or high school students, I would put them in the same cadre as novice scientists – people who may be curious or interested, but who are doing science or doing research for the first time. There are obvious challenges to being able to do that: thinking about the numbers that one might like to engage, thinking about the kinds of projects that would be suitable and dealing with a group of people who have no prior experience in the lab. 

Did your research interest lend itself easily to this kind of an approach or did you have to change your research a little bit so that students could get involved in the program?

I would argue that the directions that we have gone in were motivated strongly by the research questions that we already were broadly interested in addressing. It is not being molded just so it works for education. In fact, I'd go beyond that and say that if anybody is thinking on how to use their research lab to advance the education mission, to engage novice students in science research, then it is critical that it addresses an important research priority. Otherwise it becomes something less than doing science. In my experience, students have a keen nose for figuring out whether what they're doing is some kind of an exercise or whether it is genuine discovery. And the consequences of that are really, really big. When students know that they're engaged in doing important research, they get fired up and put in lots of hours in the lab. They motivate themselves. In our experience, we really were motivated by addressing important scientific questions and really getting lucky in finding out that some of these questions were a particularly good fit to advancing this broader education mission as well. So the whole program is not by well-thought out design, but by serendipity and getting lucky, really, with the fact that the research interest that we had was just tailor-made for undergraduate research initiatives. 

So high school and undergraduate students search for an answer to a research question. That can be quite overwhelming for a beginner, right? 

The question that we always start with and introduce students to, is the research question of trying to understand the genetic diversity of the bacteriophage population and to gain insights and to learn about the evolution mechanisms that give rise to this phage population. So that's really the starting point. Students I think can recognize relatively early on that that is something which is a broad question for which there is not clear and complete answers but that it's something that they can contribute to. The next part of the articulation is the approach by which they can address the question. And that is what excites and motivates them. That if they go and take a sample for anywhere they choose, they can isolate a bacteriophage that's new, that they will discover. Then they go on to name and characterize and then sequence its genome and understand how the phage that they have isolated and named relates to all of the other phages that have been characterized. The opportunity to do that, I think, is often received as being interesting and stimulating and the idea of being able to isolate one's "own" virus de novo from the environment is kinda cool! It is sort of the equivalent of naming your own star, except, you actually get to go isolate the phage and work on it. That sense of project ownership is clearly very important. It doesn't mean that all students will get fired up by this phage discovery project, but clearly, many do. And they get a relatively quick and easy chance to discover whether this type of research is something they want to do or not. Whereas, many of us who have taught students in lab classes know that if we just tell them to mix things together and see if they get the "right answer", it's no more exciting to them than taking a math test. 

What percentage of students go on to the more advanced levels of sequencing and beyond?

We have implemented this general platform in a number of different subcontexts. The answer to your question depends on the particular context of the program and it changes as a matter of time as well. In Pittsburgh, we just have high school and undergraduate students enter the lab and join the research. In the second configuration, the same idea is formulated as a two-term course for first year undergraduate students across the US. For the last five years, we've had a third configuration of the program – an intense two-week workshop in Durban, South Africa. The specifics across these platforms are different.  

When we first started the programs in 2002, it was genome sequencing was relatively expensive. Additionally, the students had to do all of the sequencing by themselves and it was a significant investment of time and effort. So the proportion of students that would do that efficiently and successfully was small. Now, sequencing technologies have advanced, so it's cheaper and quicker and easier to sequence genomes. On the plus side, a very high proportion of students can have their genome sequenced and they can move quickly on to the annotation and comparative analysis, and actually progress beyond that to addressing particular questions of interest. The downside is that sequencing has really come down to the preparation of DNA and handing it to somebody else and getting the sequence back, so there's more of a divorcement from the actual process. I think it is educationally rich to learn what is actually going on and they miss out on it.

In the configuration where the general platform is being offered as a course for first year undergraduate students, in about 70 schools and colleges across the US, in their first term, the students will go and isolate the phages and almost everybody in the class will succeed in isolating a phage sample from the environment. However, typically only one or two of those genomes will get sequenced and then annotated during the next term. The issue there is mostly overall cost. I suspect that just as we had changed and developed the configurations as the technologies advanced, in a few years' time, the technology will advance yet again, and the numbers of genomes that can be sequenced and annotated will be reconfigured once again. So I don't see these as fixed end points. We're on a process that is parallel to a lot of other technological advancements and we just need to keep in step with them and utilize them in the most effective way possible. 

What about experiment design? In the more advance stages, do the students get to design their own simple experiments or do they merely follow a prescribed protocol?

A lot again depends on the specifics of the context. In the broader program at other schools and universities, the principal opportunity is to have students do the phage discovery course in the first year, but in their subsequent years, they could conceivably take a more advanced course that could involve part of the bacteriophage research or alternatively they could do the equivalent of an independent project and pursue their goal. In Pittsburgh, definitely, one of the goals that we've worked on in the past couple of years is trying to figure out how best to train and position students to think about how they can come up with their own ideas to address a specific question, which can then be tested experimentally. That's still a very, very challenging process for students, but a critical and an important one. I'm not sure that we've figured it out yet. But I think that providing some structure, encouraging and showing students how to read and understand the literature and to try to help them figure out how scientists come up with ideas, is really part of the goal. 

What are some of the key scientific results that have emerged from the program?

We've been able to define the genetic complexity of a group of bacteriophages that share a common host. Some of that could be seen superficially as stamp collecting. We don't know what they are, and we're trying to find out. I think that the strategy of isolating and characterizing phages of one particular host gives us a unique insight into what the population looks like. And it wouldn't have happened without having this disseminative, joint research and education initiative. That has provided us a way of thinking about broader aspects of the phage population. How do the phages switch from one bacterial host to another? What are the forces that drive that? How does what we learn from the genomes reflect on the dynamics of the broader population?

We have focussed on the mycobacterial phages in particular because they can provide insights into understanding the hosts, mycobacterium tuberculosis, perhaps, being the most prominent and important species among the hosts. I think that it's clear that the phages are telling us a lot about the host and they're also contributing tools that can be used to manipulate the host. And so, from a very practical point of view, development of tools for mycobacterial genetics and using phages to gain an insight into the physiology and the genetics of tuberculosis is clearly an important area.

Additionally, because of the diversity of the phage population, – meaning just lots of different types, with genes that we don't know what they do, and probably 4 billion years of evolution and a large and dynamic population – they're full of biological novelty. It's a very rich system for anybody to study and we have barely scratched the surface. One of our more recent papers, for example, describes how, in one of these, the bacteriophage immunity systems work, in terms of genetic regulation. 

Are there other research problems that lend themselves as easily to similar student initiatives? Has this program inspired others that you know of?

Absolutely! We got kind of lucky in that the phage discovery genomics project really does have some attributes that make it well-suited to our program. It would be arrogant for me to suggest that that's the only project of that kind. I'm sure that's not true. In fact, much of what we've thought about and analyzed is whether one can dissect and tease out the attributes that are most useful. That should be helpful for others to think about how their research might be able to tap into some of those attributes and therefore make it as effective as possible for such an effort. There are several good candidates for thinking in that context. But I'd also say that finding other projects that satisfy all the attributes that make this program work has turned out to be a little bit more difficult than one might think. 

There are some similar projects that I'm aware of. There's a colleague at Yale, Scott Strobel, another HHMI professor. He has been running a project that involves going with students to tropical rainforests in South America where students isolate endophytes, which are bacterium of fungi that live under the bark of plants and trees. They do this in the context of having a guide that's knowledgeable about the local biology as well as knowledgeable in the traditional uses of medicines. The students isolate these endophytes and then they take them back to Yale where they then work on isolating, characterizing and studying them. Many of them are strains of unknown species and they make lots of interesting things like anti-microbials, antibiotics, anti-fungals and so on. The link to what we've been doing is that Scott has very much taken advantage of this concept of project ownership, which is important in motivating students.  Another project involves students in characterizing worm genomes. 

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