Interviewer: Lydia Morrison, Marketing Communications Writer & Podcast Host, New England Biolabs, Inc.
Interviewee: Tom Evans, Ph.D., Executive Director of Research at New England Biolabs (NEB)
Hi everyone, welcome to the Lesson from Lab and Life podcast. I am your host, Lydia Morrison, and I hope our podcast offers you some new perspective. Today’s lesson focuses the advantage of maintaining a well-balanced research program. I am joined by Tom Evans, who is the executive director of the Research Department at New England Biolabs. If you think the purpose of a research department at a biotechnology company seems quite obvious, I urge you to listen on… I think you might be surprised by the goals of the unique research department at NEB.
Hi Tom, thanks so much for joining me today.
Thanks Lydia, it’s great to be here.
So, I was wondering if you could tell us, what is the mission of the NEB research program?
That’s a great question, I suppose in a very broad sense I feel that the mission of research at NEB is to generate knowledge. Knowledge about the amazing world around us. However, that is only a part of our goal, simply knowing something is not enough, that information needs to be disseminated.
And how do NEB scientists go about sharing that information?
Well, we share our information in a number of ways, we publish in peer reviewed journals, that’s probably our biggest and most important route, but we also present posters at scientific conferences, and when appropriate through turning the information into cutting edge or superior products. I suppose the short answer is that we do research to learn and then pass along that information to the general community, which, of course, is the goal of many research programs.
Actually, perhaps the most interesting aspect of that question is not what the mission is. Our mission is not confined to short-term R&D to create products. In fact, it is not even confined to long-term R&D to create products. Of course, product-related research is pursued and is vital to being competitive in the market landscape of biotechnology, but we also do research from which we do not anticipate immediate commercial upsides.
Can you think of an example, where research has not led to a product for the company?
Well, an important area for us, and an example I would like to use in the case, is in the 1980’s, when NEB had been profitable for a number of years, our founder Don Comb felt very strongly that he wanted to give back to the general community a part of our success. He chose to do this by not only by donating to charitable organizations, which NEB did and still does, but also to generate knowledge that would magnify the effect. Rich Roberts, currently our chief scientific officer, helped organize discussions on areas that NEB could do research that would have the greatest impact. They chose to do research in the area of filarial nematodes. These worms cause terrible diseases such as river blindness and elephantiasis in areas of the world that can least afford either the research investment or the impact of these diseases. Our hope is that someday these parasites will be brought under control, but the goal was not just to generate a product.
What does having a successful research program offer a biotech company?
Well, a successful research program, especially one that is not simply laser focused on the current market leading product, offers a number of advantages; some obvious and some not so obvious. Some of the obvious advantages are a direct product improvement pipeline, staying current, creating intellectual property. Product improvements are critical in a competitive market place and understanding enzymes and protein engineering methodologies allowed us to improve upon our already excellent product offerings.
Can you give a couple of examples of how enzyme-based research led to product improvement?
Two examples that come to mind are our line of high fidelity restriction enzymes and Luna reverse transcriptase. Another aspect of product development is the insight that we gain as not only producers of reagents, but also as consumers of those reagents for use in our own research programs. Firsthand experience with our reagents gives us a better perspective on how to improve them. Or what new enzymes or workflows would make our research more effective, if makes our research more effective, it will probably make other research programs more effective too.
That makes a lot of sense. So, what are the less obvious benefits of a research program?
That’s a good question. I think some of the less obvious is the benefits of a diverse and publication-oriented research program is that it allows us to develop something entirely new and without a specific commercial directive. Such discoveries or technology advances allow a strong IP position and allow NEB to be first to market. Furthermore, basic research has a much higher potential to create whole new areas of research and therefore new markets.
So, beyond the product portfolio benefits… are there any other benefits to the company or the community?
Well, outside of the standard commercial implication that by benefit you mean profit there is significant benefit that is even more valuable because it results in an innovative and exciting place to work. For example, basic research has a significant and positive impact on the company culture. Thinking broadly and creatively, as is needed to do basic research, generates a culture of innovation and of asking the big questions. This results in a company that is adaptable, not only being able to change with changing technology, but thriving on change. There is also the satisfaction of contributing to the world. As we already discussed, we have an entire research program focused on understanding the biology of filarial nematodes. NEB’s goal, is to learn about these worms so that more effective treatments can be developed. The overarching mandate is to generate knowledge, do basic research that we publish, that we hope will help millions of people. It makes me excited to work for a company that wants to give back.
I completely agree, and it’s good to know that the research department actually has loftier goals than product development… but, does the research program help drive product development?
Well, the quick answer is yes. Our research program helps in three general ways: by making new discoveries and having some of those discoveries have commercial potential; by technology development; and by having a large and diverse set of experiences that can directly advise or assist in product development.
And that makes sense, but we’ve just been discussing NEB’s non-standard research department… are there any non-standard products that have been developed as a result of the unique NEB culture?
Oh, I think there have been quite a few. But I feel our Enzymes for Innovation initiative really fits that bill. For much of its existence NEB has sold a small number of interesting enzymes that did not have a clear commercial application. Some of these were purchased by scientists and used to create new workflows or enzyme-based technologies. Whether the enzyme stimulated that scientist’s creativity, or whether it filled in the final missing bit in bringing an idea to fruition doesn’t really matter. The point is that science is accelerated by having unique and interesting enzymes activities easily available. We wanted to build upon this success by having a group of enzymes, Enzymes for Innovation, that have interesting properties, but no current commercial application. We have a number of these available already and welcome suggestions for new enzymes that fit these criteria.
Can you provide a couple of high level examples of research projects going on at NEB?
The difficult part of that question actually is choosing only a couple of projects. About a fourth of the company is involved in research and that translates into scores of projects. As examples, I’ll choose two which you might expect a company like NEB to be working on and one that you might not.
Ok, so what’s the first?
The first is an on-going project to understand how T4 DNA ligase joins DNA. When we started this project about five years ago, there was a great deal is known about DNA ligases, but even so there was a lot more to be learned.
So, where do you start making improvements on something so well understood?
Well when you start on a new enzyme, you start by asking the foundational questions such as how fast does it react with ATP, what is the rate limiting step, does it prefer to bind DNA ends… We published what we learned. At some point we asked a simple question, how well does T4 DNA ligase tolerate mismatches in a 4 base pair overhang ligation. Simple question, difficult to answer.
So how did you go about it?
Well, we applied the unique properties of a PacBio sequencing instrument and performed a ligation reaction containing DNA oligos with all possible 256, 4 base overhangs we were able to determine the preferences and mistake profile of T4 DNA ligase. Basic enzyme information, but information that has significant impact on DNA assembly reactions and by extrapolation synthetic biology and pathway engineering.
The second project involves identifying unknown open reading frames (orfs). We have all heard that about a quarter of all the orfs in E. coli don’t have a known function or activity, even less for less well studied organisms. A short time ago we constructed a metagenomics library and it was one of these instances where everything fell into place and the diversity ended up being excellent.
What is a metagenomics library?
A metagenomics library of genomic DNA taken from a particular environment. For our library, to give it a test drive we screened for two activities an exosialidase and an AP-endonuclease. Two very different activities, but we ended up finding enzymes that belong to previously unknown protein families. Hopefully, this is only the beginning.
Wow, that’s really interesting… so what is the final and unexpected project?
The final project feels a bit retro to me, but also quite current. Retro because NEB has been selling restriction enzymes, proteins that are prevent phage infection, for decades. They constitute, really, a bacterial immunity system. The project is to look not at the restriction enzymes in bacteria, but instead the phage responses to them; specifically, modifications in the phage DNA that allow them to become immune to the immunity system. Phages are amazingly diverse and when we looked, we found two new base modifications in phages that infect Pseudomonas or Salmonella. What made this particularly exciting was that the researchers involved reconstituted the pathway that generates one of the modifications, thus identifying more proteins that were previously unknown open reading frames. One of these proteins, 5-hydroxymethyluridine kinase, is being sold as an enzyme for innovation.
Oh, that’s cool. So, you mentioned earlier that one of the goals of the research department is to disseminate information… Does that mean that NEB researchers actively publishing?
Absolutely. In fact, we have published over 1100 peer-reviewed articles since our inception. You know, we also have Master’s students, Ph.D. students and post-doctoral associates. These scientists are expected to perform research that will lead to publications.
So, as the director of NEB’s research program, where would you like to see the program in the next 5 years?
NEB’s core strengths have been enzymes and enzyme-based technologies. We need to find new enzyme activities, characterize our enzymes more fully, and engineer enzymes when needed to fit the ever-changing requirements of life science research. We spoke about some of our initiatives to find new enzymes, but we are also investigating how machine learning and deep learning can accelerate enzyme discovery.
Wait—how does machine learning or artificial intelligence apply to biological discovery?
It will lead to better and importantly, higher throughput analysis methods and will allow us to extract more information from the volumes of data currently being generated. The T4 DNA ligase project we talked about is just an example of how improved understanding of even a core enzyme can have dramatic effects. There is no perfect enzyme, but knowing the capabilities of an enzyme will permit far more effective workflows to be developed. Finally, what we learn can be harnessed to engineer ever faster, more stable, and reliable enzymes. As we learn we will publish our findings and also use this knowledge to expand the repertoire of enzymes available to the scientific community.
Thanks so much for joining me today, this has been a really informational conversation for me and I’m sure for our audience as well.
I hope so, and it’s been a lot of fun, thank you for the invitation.
I hope you enjoyed this episode of our podcast. And be sure to tune in next time, when I will be joined by Aaron Pomerantz, a Ph.D. candidate in the Integrative Biology Department at UC Berkley, and a lover of entomology, genetics and field research, who wants you to get out there and get your hands dirty.
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