Optical Tweezers

Physics professor Mark Williams talks about his research

Mark Williams, Professor of Physics, sits down with the College of Science Graduate Program staff to talk about his research at Northeastern University.

Tell us about your current research.

In my lab we study individual biological molecules such as DNA and proteins to try to understand how they work and what drives their interactions with each other. For example, we have instruments called optical tweezers that allow us to capture a single DNA molecule in between two polystyrene beads. We then use the tweezers to stretch the DNA, which can convert it from the double-stranded helical form (the form that stores our genetic information) to the single-stranded state, a state that is used by our cells to read and copy our genetic information. One new project we are working on is using this method to watch as single molecular motors called polymerases move along our captured single DNA molecule and add bases to one DNA strand using the information on the opposite strand in a process called DNA replication. If we pull on the DNA to oppose this process, we can fool the polymerase into thinking it has encountered DNA damage, so it starts to move backwards and remove the bases that it just added! By measuring how the motor properties depend on force we can work towards understanding how the polymerase detects damage and switches between the states that add and subtract bases. For the polymerase study we are collaborating with the laboratory of Penny Beuning in the Department of Chemistry and Chemical Biology, who is an expert on DNA replication. We are studying polymerases from bacteria, hoping to understand what aspects of bacterial polymerases are different from humans, which in turn may help to develop antibiotics that specifically target bacterial polymerases.

Another project involves the study of HIV-1 replication proteins. It turns out that humans have a set of “innate immune” proteins that combat retroviruses like HIV-1 as well as other pathogens. One of these proteins, called APOBEC3G (A3G), is known to give humans immunity to HIV-1, but HIV-1 fights back by using its Vif protein to destroy the A3G proteins in human cells. We are using our single molecule methods to understand how A3G works so that this information can be used to develop anti-HIV drugs that mimic A3G or enhance its properties. To do this, we take a single DNA molecule in our optical tweezers and monitor how A3G binds to the DNA. We find that over time A3G forms clumps of multiple A3G molecules on DNA in a process called oligomerization. Our measurements suggest that A3G could block HIV-1 replication by forming these large clusters, making it very difficult for the HIV-1 replication machinery to get past them.

We use our single molecule methods (optical tweezers and atomic force microscopy) to study a wide variety of biological systems. These systems range from the DNA interactions of small molecules that serve as models for anti-cancer drugs all the way to proteins that control access to the DNA packaged in human cells (packaged in chromatin – we also stretch single molecule arrays of nucleosomes that mimic DNA packaged in chromatin) to regulate the production of proteins. To understand these systems, we use biophysical tools to probe these diverse and complex biological systems, discovering new physics while helping to understand problems in biology that are important to human health.

What drew you to your field?

I was originally drawn to the field of single molecule biophysics because I really liked the technology. I love building complicated instruments that can be used to do things that seem impossible – like grabbing a single DNA molecule and stretching it! Once I got started in the field, I became really interested in applying all of my physics training to studying really complicated problems, like the behavior of a molecular motor on a DNA molecule. I find these tiny molecular motors fascinating, and I am really excited to understand how we can control their behavior with force.

What do you like most about being a faculty member at Northeastern?

I really like having our energetic students working in my lab, sharing in the discoveries about tiny particles interacting on a single DNA molecule. The co-op program has allowed me to typically have one or two full time undergraduate students working in my lab, and they get to learn how to manipulate single molecules using optical tweezers. It’s very exciting when you catch your first DNA molecule – you know it is there because you see it tug on the bead in the optical trap, but you can’t see the molecule, you can only “feel” it!

What is your favorite part about Northeastern?

I am really happy to be in a dynamic environment that encourages collaboration between faculty members, particularly for interdisciplinary research that crosses over traditional boundaries between scientific fields.

What is your favorite part about Boston?

I love taking the T to and from work every day. I get so much work done while commuting! And Northeastern could not be in a better location, within walking distance of so many cool things to do and great places to eat.

What advice would you give to new and current COS graduate students?

If you are a graduate student, your primary goal is to do successful research, but you should also take advantage of all of the great scientific seminars going on every week. As my former postdoctoral advisor Victor Bloomfield used to say (and it may be a quote from someone else, but I don’t know the source), “an hour at a seminar is worth a week in the library!”

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