Programming Proteins by Deep Sequencing and Design
Kent Simmons:
Welcome, everyone to this Cambridge Healthtech Institute podcast presented in conjunction with the planning for the 13th annual PEGS Boston, which will be held May 1st through the 5th, 2017 at the Seaport World Trade Center in Boston. I'm Kent Simmons, I'm a program director with CHI and with me today is Dr. Tim Whitehead, an assistant professor in the department of chemical engineering and material science at Michigan State University, and the presenter of the 2017 young scientist Keynote at PEGS Boston. The young scientist Keynote recognizes a rising star in the field of protein science who has completed a post doc in the last five years. Dr. Whitehead was selected from the field of 26 candidates from leading industry and academic research labs in the fall of 2016. Thanks for joining us today, Dr. Whitehead.
Tim Whitehead:
Thank you for inviting me, Kent. It's quite an honor to be selected for this Keynote presentation.
Kent Simmons:
In considering your nomination for this role, I know our reviewers were impressed by your work on the correlation of protein sequences and biomolecular function of potential therapeutic antibodies. Could you tell us a little bit more about your research in this field?
Tim Whitehead:
Absolutely. I'd be delighted to. For several decades, researchers and scientists have been able to evaluate effective individual point mutations on function. You can make a single point mutation in a DNA sequence, you can produce that protein, and you can evaluate the mutational effect on that function. What my lab has been able to do is develop a platform to evaluate the functional effect of tens of thousands of mutations in a single experiment and in many cases in a single test tube. We can do this in the context of proteins that bind other proteins like antibodies and cytokines, as well as for enzymes. We're also extending these techniques for membrane proteins.
Kent Simmons:
A lot of the people watching your talk at PEGS will be from industry research groups. What are the implications of your labs work on the discovery and development of next generation bio-therapeutics?
Tim Whitehead:
There are several straightforward applications of our methods for the discovery and developmental cycle. For example, in antibody engineering we have shown that the type of functional analysis we can do for thousands of point mutations at once, we can identify rare single point mutations that confer acidity as well as specificity for a given antigen. This is powerful because it allows you to rapidly identify very specific antibodies for closely related targets such as many cytokines. In the discovery vein we have also extended these techniques to knock conformational epitopes recognized by an antibody, and these can be used at a typical characterization pipeline to identify, for example, neutralizing antibodies. Where exactly do they target? This is in the case for antibody discovery and may also be extended for design of structure based vaccines which we're looking forward to getting into. We've also extended this to enzymes and looked at rapid ways to tune specificity, affinity and stability in enzyme sequences. This can be both from a diagnostic as well as a therapeutic vein.
Kent Simmons:
Seems like this field is moving along very very quickly. What are the next steps for you and your colleagues, and how do you see this work evolving over the next couple of years?
Tim Whitehead:
On the one hand we want the same as for any technology. We want to make it faster, cheaper, better, more usable and a greater utility for the end user. We're working in different ways along with other labs who are across the world in doing that. In terms of the science, another portion of my lab is really focused on computational design to design proteins from scratch with intended functions. A medium term, I hope it's a medium term goal, it may be a long term goal, but the goal of ours is to use the data we get from these experiments of thousands of point mutations to be able to design proteins better from scratch. We'd like eventually to design and optimize a protein for any specification directly on the computer.
Kent Simmons:
What new research technologies are being applied in your lab and have these contributed to your ability to develop understandings of structure and function relationships at this level?
Tim Whitehead:
Sure. The biggest drivers for techniques are reading DNA very quickly and cheaply and writing DNA very quickly and cheaply. We use next generation DNA sequencing and keep abreast of new advances in the field. On our own we've had to develop a couple of new technologies. For example, for writing DNA we developed a saturation mutagenesis method that allows the end user to construct libraries containing all possible single amino acid substitutions, in a single day, in a single test tube requiring only a plasmid that en-quotes your nucleic acid sequence. For reading DNA, many of the problems with commercial sequencers is they give short read that do not cover full gene sequences. We've had to invent new library preparation methods to read longer [inaudible 00:04:24] DNA with accuracy and fidelity.
Kent Simmons:
Considering the instruments and software that are available to you now off the shelf, how do you see these evolving in the coming years and what capabilities would you like to see developed by supplier companies and labs that are working on new technologies?
Tim Whitehead:
I think the cost of reading and writing DNA will continue to fall, which will help us out tremendously. In terms of instruments outside of my expertise area, my group relies heavily for antibody and cytokine engineering on fluorescence activated cell sorting using commercial flow [inaudible 00:04:56] and these are used to screen our antibody mutants. I would love for the microfluidics community to develop commercial cell sorters on microfluidics platforms, so we can develop, do cell sorting in massively parallel microfluidics devices.
Kent Simmons:
What are you looking forward to in attending and participating in the PEGS meeting?
Tim Whitehead:
In particular I'm honored to be speaking in the same session with Sir Greg Winter. More generally I'm fascinated by the fast moving cellular immunotherapy field including all of the really exciting work on [inaudible 00:05:25] cells. I look forward to seeing the most recent science at PEGS.
Kent Simmons:
Thank very much Tim. This has been very interesting. In closing I'd like to congratulate you on your recognition as our young scientist keynote for 2017. I've really enjoyed working with you on this process over the last couple of months, and we're all greatly looking forward to your talk at the meeting.
Tim Whitehead:
Thank you again Kent. I'm quite looking forward to attending PEGS Boston in 2017.
Kent Simmons:
Thank you everyone for listening today. This has been an interview with Dr. Tim Whitehead, an assistant professor in the department of chemical engineering and material science at Michigan State University, and the presenter of the 2017 young scientist keynote at PEGS Boston. If you would like to register for PEGS or learn more about the more than 350 scientific presentations at the event please visit www.pegsummit.com. This has been another Cambridge Healthtech Institute podcast. I'm Kent Simmons and thank you for listening.