Hughes Mentor:  Andrew Clark

Department: Molecular Biology and Genetics

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Meet a Cornell Researcher: Dr. Andrew Clark

Dr. Andrew Clark began researching in his undergraduate years. He attended Brown University in Providence, Rhode Island. At Brown University, his interest in math led him to become a math major. He also developed an interest in biology during his college years. He wanted to combine the subjects of biology and math and examine the interface between both of them. This was his inspiration for pursuing a modeling project in Drosophila as an undergraduate. Dr. Clark decided to pursue more theoretically as opposed to experimentally focused research for his graduate studies. He attended Stanford University for graduate school. Although theoretical, his graduate research in population genetics did have an experimental component as well. After receiving his Ph.D., Dr. Clark went on to do postdoctoral research at Arizona State University, as well as postdoctoral work in Denmark. Before joining Cornell University, he was a professor at Penn State University.

There are several different projects that are going on in the Clark lab at Cornell. One of the themes of Dr. Clark’s research involves examining how variable phenotypes are caused in organisms. For example, there is variability in an organism’s ability to fight infection. It is not understood how exactly variable immunity is caused. One of Dr. Clark’s research projects focuses on understanding immunity variations in drosophila. In addition to innate immune responses, he also looks at variability in metabolism and obesity in flies.

There are several undergraduates carrying out research in Dr. Clark’s lab. These undergraduates are involved in different projects that use Drosophila as experimental organism. One undergraduate looks at microRNAs in drosophila that may be involved in immunity defense. She examines the levels of different microRNA pre and post infection to see which microRNAs may be involved in the infection. Another undergraduate studies sperm displacement, also known as sperm competition, in Drosophila. When a female mates with multiple males, the males sperm compete to fertilize the females’ eggs. There is some variation in the males that determines whether they will be better than the other males at convincing the female flies to accept their sperm.

Dr. Clark has a deep understanding of genetic research. There is a broad range of research that goes on in his laboratory, from fat metabolism to immunity defenses. Various research projects are also being carried out by undergraduates in the Clark group. Dr. Clark’s enthusiasm for population genetics is an inspiration to undergraduates aspiring to work in this field of research.

A Day in the Life of an Undergraduate in the Clark Lab

My name is Nandita Garud and I work in Dr. Andrew Clark’s lab. I am studying how microRNAs may be implicated in the innate immune response in Drosophila. I became interested in this topic because I had been studying the function and regulation of microRNAs in plants at Cold Spring Harbor Laboratory in the summer of 2006. MicroRNAs are newly discovered regulatory elements that have been found to play an incredibly important and diverse role in many species. I wanted to continue studying microRNAs when I returned to Cornell for the academic year. When I contacted Dr. Clark, he was interested in working on a microRNA project in his lab, so we decided to design a project on microRNAs in the context of the innate immune pathway.

Prior to working in Dr. Clark’s lab, I had done wet work at New York University, Cambridge University, the Boyce Thompson Institute at Cornell, and at Cold Spring Harbor. However, as a computational biology student at Cornell, I wanted to have more experience in the “dry lab.” I decided to engage in both computational and experimental work in Dr. Clark’s lab. Having the advantages of both approaches at the tips of my fingers puts me at an exceptionally powerful advantage to better grasp the problems that I ask in the lab.

One of the challenges I confronted when beginning my computational work was learning to program. I had learned how to code a bit in MATLAB in my Dynamical Modeling in Biology course (BioEE 362), but I was unfamiliar with Perl, the language most bioinformaticists use. My first task was to independently work through exercises in the “Learning Perl” book. This was, by no means, an easy task for me. I often became frustrated with the bugs in my code and I took a long time to figure out how to read in big data files and parse them. Bit by bit, however, after consulting grad students and the internet, I started to learn how to write code in Perl. I am still a beginner with much to learn, but I am now starting to use my skills to do some data analysis.

While learning to write code, I have also been working on an experiment. I recently completed a pilot experiment looking at the levels of two microRNAs pre and post infection in Drosophila. I infected D. melanogaster with Gram negative bacteria by poking a thin needle dipped in bacterial culture into the fly’s thorax. I froze the flies after three hours of infection and extracted total RNA. Then I assayed levels of microRNA 34 and microRNA 276b. Since microRNAs are very small compared to normal coding mRNA transcripts, there is special technology to assay microRNA levels. I used stem-loop TaqMan, a quantitative technology that is highly specific to the microRNA of interest. My preliminary experiment shows that microRNAs 34 and 276b are up regulated in response to an infection. I am now in the process of designing another experiment to take these results further.

It was very exciting to see statistically significant results in my first experiment in the Clark lab. However, these results come after lots of careful planning and design. In my previous research experiences, I felt frustrated and rushed while working on my experiments. However, this time I knew that I needed to be patient, and indeed, this has been fruitful experience. I am grateful to be working with Dr. Clark on this project, as it is very exciting and promising. I would highly encourage other students to consider a combination of computational and experimental research as there is much to learn in both areas.

A Day in the Andy Clark Lab

I guess one could consider it lucky to be located in a private room with all undergrads, working on your own laptop, free internet access, a portable fridge, the works. For me, 250 Biotech was a blessing and a curse. On one hand, it was a convenient place to set up shop and read papers, formulate my research proposal, do work that needed to be done. However, being that it was separate from the main lab, with nary a professor or graduate student to be found, there was definitely a shortage of guidance when guidance was needed. Though I would always start my day in 250, I would sometimes find myself running back and forth to Dr. Clark’s office with questions and problems as they arose. Sometimes it’s good to have your PI in sight.

That’s not to say that my days in the Andy Clark Lab were totally academic. That cubical, windowless fly-room and its many inhabitants definitely took a lot of my time this summer. To be honest, I rather enjoy working with fruit flies. They are small, innocuous, not completely hideous, and occasionally amusing. The lab tech Sean and I would sometimes take turns narrating their behavior, which, rather often, included some fly mating. On the serious side, one thing I learned is that fruit fly genetics is all about timing. How long you can expect a new generation of flies to be ready, when will pupae become adults, how long can females remain virgin when they first emerge. These things are crucial in planning a fly breeding experiment. If you need to make a cross, you need to have virgin females available for that cross, which means you need to collect these females, which means you need to order food for them and clear their bottles at 8 hour interviews. Timing.

Another thing I learned in my daily life at the Clark Lab is to pay attention to where everything is. Things you’ll just pass over, like the large sharps container, or that bottle of industrial strength Windex could just come in handy when, say, you drop a glass bottle filled with old, rotting fly food and hundreds of fruit flies in the elevator. Now that was terrible. A typical day will also include transfers, which is the fly lab equivalent of flipping burgers, consisting of moving thousands flies from old vials to new ones. On occasion, my job would consist of pooting. A pooter is an interesting device, consisting of a plastic tube attached to a pipette tip, but between the pipette tip and the tube is a sheet of porous cloth. This allows you to inhale through the tube and suck up flies into the pipette tip so that they rest gently on the cloth, and then exhale them back out into a different location. Believe it or not, this is a very efficient way to get flies to go where you want them, and mate with who you tell them.

All in all, a day in the life of the Clark Lab is not quite full of surprises, but perhaps sprinkled with them.

David Lawrie

My name is David Lawrie and I am an undergraduate researcher in the Hughes Scholar program. I work in the Clark lab in Biotech and my project studies the evolution of humans from chimpanzees. The work I do is computational - all of the “wet lab” work, in this case the sequencing of human and chimp genomes, was already done by the Celera corporation. Much of my computational work has been data mining followed up by statistical analysis of the reorganized data. All of the information is present in a raw form, but needs to be reassembled into a much more usable data set. The ultimate goal of my project is to tease out the evolution of gene regulation between humans and chimps. This would affect how often a gene gets expressed to protein and may have been key in the development of humans.

As my work is computational in nature, my hours and locations of work are fairly flexible in the sense that I don’t rely on access to lab equipment. I work 40+ hours a week and I thoroughly enjoy the work that I do. I was already a competent programmer, but I had never done computational work in biology, nor did I know many of the statistical techniques that I now use regularly. Learning techniques by actually doing research is a lot more interesting than learning the same material in a classroom. I was lucky in that my academic advisor, Prof. Andrew Clark, gave me a research lab position and I will continue to work in the lab over the next school year.

A Hughes Scholar Guide to Doing Research in the Clark Lab

Undergraduate research was my first real opportunity to apply what I learned in the classroom, and was essential in gaining a complete understanding of computational biology, my program of study. For me, it was particularly difficult to see how biology and computer science are related, since none of my freshmen or sophomore courses combined the two disciplines.

I emailed Professor Clark, and arranged to meet with him to discuss his research. The meeting was much less intimidating than I thought it would be—Professor Clark was engaging and really sparked my curiosity in several of his projects. We talked about my background—Genetics 281 is definitely a useful course for this lab—and my interests, and he gave me several papers that were relevant to his work.

Summers in the Clark Lab are extremely busy, because this is when we have the time to carry out large-scale experiments. When I first started, I mostly helped other researchers in the lab with their experiments, so that I could get a feel for different projects. As soon as I developed a strong interest in one, Professor Clark arranged for me to work closely with a graduate student on my own project.

I am studying variation in immunocompetence in Drosophila melanogaster. Drosophila have an innate immune system that allows for a rapid and generalized response to invading pathogens. There are more than 300 candidate genes involved in the immune response. My project focuses on how natural genetic variation in the third chromosome contributes to differences in immune response.

We constructed 95 D. melanogaster lines, each homozoygous for a different third chromosome and otherwise isogenic, such that only third chromosome loci contribute to genetic variation. The flies were infected with Gram-positive and Gram-negative bacteria; this was done by pricking them in the thorax with a dissecting pin dipped in bacterial culture, as shown in the picture. The flies were homogenized, or ground up, and plated to measure bacterial load as an indication of immunocompetence.

Next, an expression screen of candidate genes was done to examine which immunity genes are differentially expressed in high versus low immunocompetence lines. At 8 hours post-infection, the flies were homogenized, RNA was isolated, and then hybridized to a BeadChip that was custom designed by the Clark Lab. Gene expression levels were measured by fluorescence intensities.

My summer in the Clark Lab was both challenging and exciting. It was overwhelming at first because of the new information and new laboratory techniques, but everyone in the lab was more than willing to talk to me about their projects and teach me how to do different experiments. In just nine weeks, I learned a lot about the Drosophila immune system, how to plan experiments, how to analyze data and generate interesting questions, and how to communicate ideas to a general audience. It was a summer filled with hard work, and I enjoyed every minute of it.

A Hughes Scholar Guide to Doing Research in the Clark Lab

I started working in the Clark Lab the second half of my freshman year. As you can imagine, at that time I didn’t know the first thing about doing research or working in a lab. But the wonderful, patient people in our lab taught me everything I needed to know. I spent my first two semesters assisting with others’ experiments, but now I am working independently on my own project, which is quite rewarding.

The Clark Lab is a population genetics lab and does a lot of work with Drosophila, also known as fruit flies. Additionally, there are people in the lab who work on the exciting field of human genomics, but my project is strictly fly work. On a typical day, I’ll spend the morning checking on my stocks and doing fly chores. Vials containing isogenic populations need to be transferred to new food every two weeks, which can be a time-consuming affair. I might also need to collect virgins, set up crosses, or empty parents from matings. I will also collect and score experimental flies that pertain to my project. For example, currently there are progeny emerging from 100 matings I set up a few weeks ago; I am now scoring the males based on their eye pigmentation. From working on this project, I became fast and skilled at positioning flies so that I can take nice pictures of their eyes (no small task). Then I had to analyze those images, and created a program to help me do that. Additionally, I rapidly became an expert fly decapitator.

My project looks at how natural variation of the second chromosome affects chromatin structure (which is represented in the eye pigmentation of my variegating lines). So when I’m done in the fly room, I usually come into the main lab to work on the molecular aspects of my project. I might spend an afternoon extracting DNA from dead flies, designing and ordering primers, or running PCR or a gel. Or I might clean up those PCR products and sequence them. These molecular processes all require the ability to follow a ‘recipe’ closely and carefully, all the while keeping an organized record in my lab notebook. I am also learning to troubleshoot these processes when they don’t work. Moreover, I can count on spending several hours on the computer, cleaning up and aligning my sequences and looking for polymorphisms.

Spending time in our lab, I have learned so much about how to actually do biology research. It is much different than simply learning about science from a textbook and, to me, it is much more enjoyable. In fact, I really enjoyed doing research in the summer because, without classes, my work was so much more efficient. For example, during the semester practically all my available time would go toward fly work; the only molecular work I ever did was maybe one or two PCR reactions. But in just the first week of summer, I learned and performed not only PCR but also the extraction and sequencing protocols I have been using continuously all summer. Now that my efforts are yielding data, I see that I have a lot to learn about data interpretation, statistical analysis, and presentation. I have come to realize that there are infinite challenges in scientific research and there is an infinite amount of literature that describes them!