NEB Podcast #37 -
Interview with Professor Karmella Haynes: Synthetic Biology and the future of epigenetic medicine

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Transcript

Interviewers: Lydia Morrison, Marketing Communications Writer & Podcast Host, New England Biolabs, Inc.
Interviewees: Professor Karmella Haynes, Ph.D., Associate Professor, Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University


Lydia Morrison:
Welcome to the Lessons from Lab and Life podcast from New England Biolabs, I'm your host, Lydia Morrison. And I hope this episode offers you some new perspective. Today we interviewed Professor Karmella Haynes of Emory University, whose work focuses on using chromatin based systems to control gene expression and how these methods can be used to improve the accessibility of DNA during CRISPR-Cas directed gene editing. Dr. Haynes, thank you so much for joining me today.

Karmella Haynes:
Hi, thanks for inviting me.

Lydia Morrison:
So I wanted to jump right into it and talk about, now that there's broad acceptance of mRNA therapeutics, how can synthetic biology help advance the next phase of this technology?

Karmella Haynes:
Oh man, that's a great question because I'm personally, I've gotten really excited about the role that messenger RNA technology has played in helping to stem this current pandemic. And it's super exciting to kind of see it in action and being distributed and tested. So that's going to provide a huge sort of a boost for application. So it's basically going to allow us to continue to work on something that is now based on sort of a proven field testing, with the early voluntary trials. And then after it was shown to be safe, folks then sort of signing up to get the vaccine and just showing the actual efficacy as well as some of the shortcomings is definitely going to actually help synthetic biology.

Karmella Haynes:
So then in turn, I think synthetic biology is going to help advance mRNAs as therapy by going in and figuring out what features can be customized that appear in messenger RNA. So the most recognizable feature that folks are probably already familiar with is the fact that messenger RNA can produce, whatever protein you encode in the messenger RNA sequence by adding specific sequences of codons. But there are other features that give you even more control over how the messenger RNA is used once it gets into yourselves.

Karmella Haynes:
For instance, if you want that messenger RNA to be turned off in certain cells, right so the cells in your body are very genetically and epigenetically diverse. And so some of them actually produce smaller RNAs, called micro RNA or miRNAs for short, and those miRNAs, if they find a match, a matching messenger RNA, they'll turn that messenger RNA off. So the current COVID vaccine messenger RNA does not have that, right? It gets fully expressed in the cells that it gets delivered to. But let's say we wanted to develop an mRNA-based cancer therapy, and we want that mRNA to be on in cancer cells and off in healthy cells. You can actually customize the messenger RNA so that it gets shut down by the micro RNAs in healthy cells, right? So that's through a pathway called RNA interference or RNAi.

Karmella Haynes:
And then another really cool feature of messenger RNAs is the little, little bit of sequence at the beginning that tells your ribosomes where to land and to start producing proteins. That bit of sequence is actually pretty diverse if you look at different messenger RNAs in nature, you'll see different combinations of those ribosome start signals. And then so those can be chosen so that the messenger RNA can be translated at different magnitudes and in specific cell types. So I just think there's a lot of, given what we know and what we've learned from basic biology, about the molecular biology of messenger RNAs and the ability of some techniques like synthetic biology to go in and sort of mix and match and tune those things. I think there's a lot of potential there for using messenger RNAs for different healthcare applications.

Lydia Morrison:
Yeah. I think that's really interesting. You gave some great examples. It sounds like one of the great applications is going to be that you can basically use synthetic biology to really fine tune the specificity of mRNA therapeutics and how they're applied and controlled and where.

Karmella Haynes:
Yes, absolutely.

Lydia Morrison:
We know that epigenetic modifications are central to regulating chromatin structure. How can synthetic biology enable a future where chromatin structure can be selectively manipulated?

Karmella Haynes:
Right. So that's a topic that's near and dear because my lab group actually focuses on that. So our primary goal is to... Again, synthetic biology in general uses this approach where we take information from basic research, right? So, through basic research, what do we learn about some specific mechanism? And then a synthetic biologist looks at that information and asks, okay, well, how can I take what I know about these different components that interact with each other? How can I rearrange them to generate some sort of useful behavior in the cell? So there is a lot of effort. There are quite a few scientists other than myself who are curious about that, we're sort of inspired by that question. And gosh, there's lots of examples so far. So initially very few people were working on that and now there is the community engaged in chromatin or epigenetic engineering has grown.

Karmella Haynes:
So in terms of healthcare, one topic that we focus on specifically is what role chromatin-mediated epigenetics plays in cancer cell behavior, right? So there's been some really exciting research done that has revealed how misbehaving chromatin in cancer cells can drive higher rates of proliferation, metastasis, drug resistance. And then, so what that tells us is that chromatin in general acts as, or it helps the cancer cell to become more aggressive, to take on these phenotypes that are associated with poor prognoses and resistance to drugs. First, you have to pinpoint specific proteins or specific interactions in the chromatin system that you could actually disrupt or drug, and sort of the approach that folks sort of outside of the synthetic biology community use is okay, well, let's find a small molecule, right? Lets find some small compound that can go and attach itself to some problematic chromatin protein, and then that should then sort of disrupt that mechanism in cancer cells.

Karmella Haynes:
So, as successful as it has been for drug development, historically it's still has limits. Based on what we know about how chromatin proteins are produced, and they can even mutate, you can have variants that develop resistance, they no longer attach to these small molecules. So I think that there is an opportunity for synthetic biology to provide some complimentary tools. This was synthetic biology, where you can go beyond small molecules and build proteins, that we regulate chromatin and the epigenetic machinery, you could probably even go in and engineer RNAs, because RNAs also play a role in epigenetics.

Karmella Haynes:
So there's lots of potential there, and it's not to say that that would replace the small molecule approach, because that's definitely got advantages. But I think that as long as we focus on, sort of this basic approach where you're taking a small molecule and trying to find one that binds to a protein, that's going to be very limited. And I think that therapy would benefit greatly from the sort of more rational design around chromatin, sort of using that approach.

Lydia Morrison:
I hadn't heard of synthetic biology approaches to monitoring epigenetic modifications before or altering epigenetic modifications. Seems like a really interesting approach. Do you know potentially what the timeline on seeing some of these approaches in trials is looking like at this stage?

Karmella Haynes:
Well, it's really hard for me to put a number on that because so much of it's just so experimental at this stage.

Lydia Morrison:
Mm-hmm (affirmative).

Karmella Haynes:
However, I am aware that thanks to a lot of basic research technology, if you have the resources, you can quickly start testing things in mice. And in in vivo models, so I would say that however much time it takes for you to move from a mouse up to clinical trials, that that would basically be that timeline, because there's all sorts of different angles that people are investigating now, like my lab, we're... Actually, also I want to mention that another sort of a challenge that has to be addressed early on in the experiment and design process is delivery.

Karmella Haynes:
The epigenetic approach relies a lot on customized proteins, right? So, that seems to be the most common tool used for that approach. So yeah, just in general using proteins, and they would fall under this umbrella of biologics, so they'd be described as biologic. Getting those to the right place in the body and into the right cells is very challenging. They're much bigger than small molecule drugs. Yeah, the delivery aspect... That I think would really sort of influence how soon we're able to see these engineered epigenetic approaches being applied clinically.

Lydia Morrison:
Yeah. It's definitely interesting to hear about them and hopefully we'll continue to hear more about them in the future. I'm sure your work has changed a lot in the last year and a half. You know, many scientists were out of the lab for months or longer. How has your work been affected?

Karmella Haynes:
Yeah, thank you for asking. So decisions had to be made to sort of balance risk against dampening research effort that could actually help to address the pandemic. So then a lot of institutions, including my own program, allowed research continue as long as it was contributing to researching and fighting COVID. Unfortunately for my group, being that we were only about two years old, I moved from Arizona State University to Emory University in 2019. So I'm officially still in startup phase. So the entire second year, pretty much of my startup was under... It was during the pandemic. We couldn't pivot to COVID specific work, so we had to shut down. So we're basically not doing any experiments in the lab for about three months, and my personnel could only go in and do things like check on freezers and check on our liquid nitrogen to keep the cell lines. So, yeah, it really unfortunately put a damper on our work, and now we're just trying the best that we can to keep everything on track.

Lydia Morrison:
Yeah. I'm sure that was so tough at the beginning of setting up your lab. So I'm glad that you guys are back in there now, and hopefully ideas will start flowing and experiments will all come together, and I'm sure there's lots of headway to make. So I wanted to ask you, what role do you see synthetic biology playing in decreasing the threat of future pandemics?

Karmella Haynes:
Right. So, what was interesting for me as I'm witnessing all of this unfold, like the trying very rudimentary approaches to stuff. I mean, theoretically it should have been effective, but the role of human behavior in completely thwarting any of your approaches to just stop the virus from spreading, it didn't work out so well, because of pushback and then also the pressures of life, and it's hard. It's like, we're not robots. We can't just park ourselves in a closet and wait for something to be over and then come back out again, try as we might, because I do appreciate all of the effort, we actually, we gave it a shot. So to me, it seems obvious that the answer is technology like medicine.

Karmella Haynes:
We can't... We're not going to be able to beat anything like this without medical intervention, like a vaccine. So I think that... Yeah, so synthetic biology, I do remember some conversations from five, 10 years ago, this idea of quickly synthesizing nucleic acids in order to protect folks from diseases and whatnot, that idea has been floated around for a very long time. So what was really striking to me with like, the recent development of the Pfizer, Moderna vaccines was just the fact that it was actually happening. It was kind of like one of those things to where for 10 years, or a bunch of people saying, gosh, I wish we could do this because it would be so easy to just... Instead of having to isolate virus and then make vaccine out of that, we just synthesize nucleic acids!

Karmella Haynes:
We've been doing that to make DNA primers and all sorts of short pieces of DNA, and it seemed like such an obvious thing to do awhile ago, and finally here we are! So I would say that already... And I don't want to give the impression that synthetic biology is solely responsible for the genesis of that idea, but I think there was a lot of advocacy for it. One person that I remember talking about that idea a lot was Craig Venter, right?

Lydia Morrison:
Mm-hmm (affirmative).

Karmella Haynes:
Oh, well, we need a platform to where as soon as we isolate virus sequences genome, then make a nucleic acid and then get that distributed as a vaccine, rapid development and turnaround. So that idea was very popular in the synthetic biology community, and now we're finally seeing it start to happen

Lydia Morrison:
Yeah, now we're living it.

Karmella Haynes:
Yeah.

Lydia Morrison:
It's pretty amazing.

Karmella Haynes:
Yeah. It is.

Lydia Morrison:
Do you have any stories as you sort of reflect back on the last year and a half, do you have any sort of silver linings that have come out of it or stories about your time in quarantine or what you've done with yourself in the last year?

Karmella Haynes:
Yeah, so I do want to take a moment to mention or to reflect on how the pandemic has sort of brought more light to inequities, racial and social, and then how that kind of intersects with science. Because I know that you were asking earlier about, okay, what's the future look like? How is synthetic biology going to make our life better? And I think what's important to think about along with that growth and along with sort of dreaming up all of these other developments... I think it's really important to keep in mind, well, how do we not basically... Go about business as usual and keep repeating history and developing these ideas in these silos where folks who are historically more privileged than others are always the stakeholders and always the ones that have access to the job opportunities in the sector?

Karmella Haynes:
So ever since I, even... Since I moved to Atlanta, I've been dreaming about, gosh, wouldn't it be nice to have some biotech company that also had like a training campus where you don't necessarily need a PhD to jump into biotech? So, that's something that I do plan on seriously pursuing. A training program where entry-level is high school. If you're really serious about a career in biotech, you can get training over a short period of time and then be offered, for instance, a position with the company, the associated company, some sort of epigenetics engineering company. I haven't come up with a name yet.

Karmella Haynes:
What really broke my heart was in sort of seeing this disproportionate impact on what we're calling frontline workers. So a lot of those frontline worker jobs are taken by folks who are traditionally marginalized in STEM, in the research sciences. The types of jobs where people had the option to work remotely or not, didn't belong to folks who were traditionally marginalized. So I really think that the pandemic has shed light on a disparity in career opportunities. So I'm really hoping that my efforts in sort of establishing some sort of company, I'm kind of thinking about dipping my toes in the industry, the waters of industry, to build something that is very responsive to the disparities in career opportunities we're seeing.

Lydia Morrison:
I think you're absolutely right. It's been so difficult to see the disparities in education and access that have really been made more prominent by the pandemic, but it is good to see the recognition of those things. And it's especially nice to see someone helping to address that by dipping their toes in the wells of company waters and trying to figure out how to bring those programs to underserved populations. We wish you all the best in your future endeavors, and we can't wait to see what synthetic biology holds in the world of mRNA therapeutics, as well as in the world of regulating chromatin structure. Thanks so much for joining us.

Karmella Haynes:
Alright. Thanks Lydia, and I'm also excited and I'm looking forward to following what I'm sure to be fantastic and really helpful developments.

Lydia Morrison:
Thanks for joining us for this episode of the lessons from lab and life podcast. Join us next time when we interviewed Professor Jim Collins of the Massachusetts Institute of Technology, we'll discuss his projects using synthetic biology to enable SARS-CoV-2 detection, and how synthetic biology can help us decelerate future pandemics.

 

 

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