Interviewers: Lydia Morrison, Marketing Communications Writer & Podcast Host, New England Biolabs, Inc.
Interviewees: Professor Jim Collins, Ph.D., Termeer Professor of Medical Engineering and Science, Massachusetts Institute of Technology
Lydia Morrison:
Welcome to the lessons from Lab and Life Podcast, brought to you by New England Biolabs. I'm your host, Lydia Morrison and I hope this episode will offer you some new perspective. Today, I interview Professor Jim Collins of Massachusetts Institute of Technology, about how his work in synthetic biology has helped drive SynBio-based diagnostics, to detect SARS-CoV-2, both in the CLIA lab setting, as well as in the wearable device arena. We'll talk about how synthetic biology has helped us detect and mitigate the current COVID-19 pandemic, and how it can help prevent future pandemics. Hi, Jim, thanks so much for being here with us today.
Professor Jim Collins:
Thanks for having me, Lydia.
Lydia Morrison:
I wanted to jump right in and have you tell us how your research uniquely positions you to join the fight against COVID-19.
Professor Jim Collins:
We've been working in two broad areas, where I think we were very well-positioned to jump into the fight against the pandemic. One is our area and work in synthetic biology, and second is our area and growing work around using artificial intelligence for discovering antimicrobials. With regards to synthetic biology, for now over two decades, we've been really looking to see to what extent can we use engineering principles in molecular biology, to model, design and build synthetic gene circuits and other molecular components, and to use these to rewire living cells and cell-free systems, endowing them with novel functions for a variety of applications.
Professor Jim Collins:
Most of our effort has been focused on developing new classes of diagnostics and therapeutics. Of relevance to the listeners, we were actually involved, over a decade ago, in one of the earliest demonstrations that synthetic mRNA could be used for biomedical application. So we had teamed up with Derrick Rossi and George Daley to show that you could use synthetic mRNA for reprogramming and redifferentiation of stem cells. In this paper, that was in Cell: Stem Cell, back in 2010, actually became the paper that launched Moderna. So, Derrick Rossi went off and founded the company, and in the piece, we noted that you could use this for therapeutics and vaccines, and had no idea that this could eventually help contribute to the pandemic. But, more specifically to my lab, most of our effort in synthetic biology, relevant to the pandemic, has been around diagnostics.
Lydia Morrison:
Can you tell me a little bit about that?
Professor Jim Collins:
So it's really in two general categories under the banner of synthetic biology. One is around CRISPR-based diagnostics and the other is broadly around wearable synthetic biology. So, in the context of CRISPR diagnostics, going back five years ago, we demonstrated, in the midst of the Zika pandemic, that one could use synthetic biology in a cell-free freeze-dried manner. In the context of paper-based diagnostics, we showed you could open up a living cell and take the machinery out, or in fact use NEBpure, which in fact was our choice. Where, what you have is the inner machinery of the cell DNA, RNA, ribosomes, molecules like ATP and nucleotides. And we showed you could freeze dry these on paper and sometime later rehydrate them, reactivate them and have them function as if they were in a test tube or in a living cell.
Lydia Morrison:
That's pretty amazing.
Professor Jim Collins:
We'd use this initially to get after antibiotic resistance. This was back in 2014, but showed that you could actually extend it to viral pathogens. In 2014, we addressed the Ebola crisis, but, we were in a very strong position to create diagnostics for Zika back in 2016, leading to paper based diagnostics. They were actually deployed as part of the crisis in six different countries, as both surveillance tools and research tools. In that context, we used both synthetic biology sensors of the viral RNA, but also introduced the first use of CRISPR as a diagnostic component, specifically showed how you could use CRISPR-Cas9 to differentiate between different strains. That led to an interaction with Feng Zhang, my colleague at MIT and the Broad Institute, and CRISPR fame, to collaborate on using not CRISPR-Cas9, but Cas13, which is a crisper enzyme that will target RNA, not DNA. When it's brought to its targets by its guide, it will not only degrade its target, but will also exhibit collateral activity and degrade other RNA structures in its environment.
Professor Jim Collins:
We used the latter to then create a highly sensitive diagnostic platform called SHERLOCK, that was set up so that you could have quenched fluorophores, that were held near the quencher by RNA linkers, that would be degraded in the face of a detection molecule. Feng Zhang and I showed you could use this to detect antibiotic resistant, bacterial pathogens, viral pathogens, like Zika and dengue, and we launched a company called Sherlock Biosciences three and a half years ago, to advance this platform and related synthetic biology platforms, to really address challenges in molecular diagnostics, including infectious diseases and at home use. But, in the midst of the pandemic, the company where I'm very active as a science advisor, pivoted toward COVID-19. Starting in February 2020, advanced an effort to create a CRISPR based diagnostic test, that was for CLIA lab use, and by early May, had actually the first FDA approved CRISPR based diagnostic test.
Lydia Morrison:
Wow, that's amazing. Was that a paper based test as well?
Professor Jim Collins:
It was elements of freeze-dried, so it was actually utilized in CLIA labs. In fact, it did not need to be paper based though it could have been. In fact, it was based in labs and notably, we were a strong view at the company that it wouldn't be appropriate to profit from the pandemic, so we actually set up the 221b Foundation, named after Sherlock Holmes' fictional address in Baker Street.
Lydia Morrison:
I love that.
Professor Jim Collins:
Where we made available our CRISPR IP for any group around the world that wanted to develop a COVID diagnostic, on the condition that they make their profits available to the foundation. We as a company, made all of our profits available from our CRISPR diagnostic, to the foundation, which is using those profits to advance STEM efforts for underrepresented minorities.
Professor Jim Collins:
Notably we've now teamed up with five global diagnostic companies through Sherlock and the foundation, who are now on pace to run 10 million tests per month using this CRISPR-based diagnostic.
Lydia Morrison:
Wow, that's amazing. I do know about the Sherlock Biosciences team, because I did an earlier interview with Feng Zhang, Omar Abudayyeh and Jonathan Gootenberg. So, our audience should definitely go listen to that podcast and get a little bit more background on how that technology works too, because it's a great technology. Although, I hadn't heard how quickly the team there had been able to pivot, to focus on COVID-19 diagnostics, so that's really wonderful to hear.
Professor Jim Collins:
I think it speaks to one of the key advantages of synthetic biology, one of the key advantages of the related CRISPR technology, which is its programmability. Meaning that, because it's sequence-focused, in this case RNA or DNA or in the nucleic acid world, it's very easy to change up the components of the diagnostics so that you can target a new pathogen and/or target a new variant of the pathogen. We advanced, in the midst of the pandemic, a platform called minimally instrumented SHERLOCK (miSHERLOCK), the work we just published a couple months ago in Science Advances, that involves a very low cost 3D-printed handheld device that can be used at home. It costs only a few dollars. It can give an output in under an hour that rivals lab based RT-PCR, but that also is relevant to the emergency variants and can be readily reprogrammed to detect variants.
Professor Jim Collins:
To note how fast this pandemic can change, going back just a few months ago, when we were very active on that effort, we were targeting the original UK variant, South African variant and Brazilian variant. Had the piece go through, when it was published, just as the Delta variant was ravaging the world. It speaks to how quickly one can change up these diagnostic elements, and going back to the mRNA vaccines, I think also their programmability is very attractive and that they too can be changed up. Unfortunately, the regulatory path has not kept pace with the programmability, and I think the booster shots that we all will get will actually be targeting the Alpha variant and not the Delta variant. Although, it would be very straightforward for those teams to reprogram the RNA vaccine, but the question is, would the FDA accept that, or would you need to run new trials?
Lydia Morrison:
That makes me wonder if there needs to be a new pathway in the regulatory system, such that you approve a vaccine's backbones, if you will, you approve the structure of the vaccine, but allow for some exchange of those variable regions of the variants that you're trying to detect. Do you think that's feasible?
Professor Jim Collins:
I do think it's feasible. I'm not a vaccine expert and I'm certainly not an FDA expert, but my understanding is that the system you just outlined is one that's in place for the flu vaccine. The flu vaccine, which I just got my shot at MIT yesterday, changes each year, depending upon what the calculation is the immersion variants. I guarantee you that they're not running new clinical trials every year on the basis of whatever five or six strains that they're putting into the mix. You would think that we could take advantage of that precedent for other viral pathogens and even bacterial pathogens, including, in this case, SARS-CoV-2.
Lydia Morrison:
I absolutely agree. Maybe they just haven't made it there in terms of COVID yet. Obviously, COVID-19 hasn't been around as long as the flu has. Hopefully they're headed that way, because certainly we need to be able to turn around new diagnostics to detect specific variants on a much quicker timescale, to be able to protect the community.
Lydia Morrison:
So I heard that you developed a face mask that can actually detect COVID. Can you tell me about that?
Professor Jim Collins:
This was also in the context of our work around synthetic biology. So, when we uncovered that it was possible to freeze-dry cell-free extract systems, along with synthetic biology constructs onto paper, we also uncovered that this wasn't limited to paper, that it could also be extended to other porous substrates, including clothing and/or textiles.
Professor Jim Collins:
Going back two, three years ago, we're advancing efforts, and showed that you could use over a hundred different fabrics that could wick up a cell-free system along with synthetic biology construct, be freeze-dried, and be programmed to be a wearable diagnostic. We were advancing efforts of detecting viral and bacterial pathogens, as well as physiological and environmental small molecules in addition to nerve agents and various toxins, in wearable diagnostic form, that could be used by healthcare workers, first responders, military personnel.
Professor Jim Collins:
We're advancing things such as the lab code of the future, the idea that a healthcare personnel could have patches or a wearable set of components into their lab code, as they make rounds around the hospital, to indicate, had they been exposed to a pathogen and/or is there an outbreak of note in the hospital, and tracing it back to sources. Like, Sherlock Biosciences, when the pandemic hit our team at the Wyss Institute at MIT, we pivoted and thought, "okay, as we're actually revising a paper for Nature of Biotech", which has since recently come out, "how could we best utilize this platform to get after the pandemic"?We had the idea that we would create a wearable face mask diagnostic, and the idea was quite simple. Could we create a paper based in this case, and/or cloth-based insert that could be added to any face mask? The notion would be, you'd wear this, and the normal act of talking, breathing, coughing, sneezing, would give off water vapor, that if you were infected would contain the viral particles.
Professor Jim Collins:
We developed then, a very simple, foldable, lateral flow assay component, that could be added to any face mask, that had a collection zone, a lysis zone, an amplification zone, a detection zone, and an output zone. Programmed it with CRISPR sensors to go after various elements of the spike protein of SARS-CoV-2, and demonstrated a highly sensitive, highly specific, wearable face mask diagnostic, that could give a read out in anywhere from 10 minutes to 30 minutes, down to about 500 particles. We wouldn't view it as a diagnostic test, but really more as a surveillance test. So, if you're suspecting that or wondering what my flu, my cold-`like symptoms, is it COVID or is it just a cough, or possibly the flu being there.
Lydia Morrison:
I wonder that on a weekly basis.
Professor Jim Collins:
I'm sure there are millions of people around the country that are wondering that. If you could just put it in your face mask, as you go on shopping, the insert, and then come home and get some comfort or indicate, "okay, this is it turns green".
Lydia Morrison:
How long would you have to wear the face mask?
Professor Jim Collins:
Our estimate is anywhere from 10 minutes to say an hour, depending upon how much do you talk, how much do you breathe, how much do you cough, back and forth. On a relatively small amount of timing, given that we have mask mandates or mask advisory, still in significant portions of the country, as we should with Delta going on, I think it could be a nice way to help better contain spread. In that, it's not easy to get to a site to get a test, frankly, the at home tests aren't as good as they should be, and not as easy to use, but if you could just add this in, go about your business, as you get to work or to school or go shopping or just out for a walk, it'd be nice to get a read out and then say, "maybe I now need to go and confirm, or I'm just going to play it safe. I'm going to self isolate for five to 10 days".
Lydia Morrison:
I think that's really interesting. I think there would be a big demand for something like that. Certainly, I know the adoption of the home tests has been really strong. I know we have some in our cabinet for when someone's like feeling questionable, when someone's throat starts to tickle or nose starts to run or something like that. So, it's really nice to have that assurance, and I could definitely see how a predictive mask insert could be really helpful and sort of be part of the every day.
Professor Jim Collins:
Again, as a surveillance tool, similar to these at home tests, I think they're good to give some additional information or insight, and then one makes the decision either take it, isolate, or get a confirmatory PCR antigen test at a CVS MinuteClinic.
Lydia Morrison:
What role do you see synthetic biology playing in decreasing the threat of future pandemics?
Professor Jim Collins:
I think synthetic biology's going to play a major role, really on two counts to start. One is in the diagnostics. I think that synthetic biology, with its programmable nature, will be a big part of the sensor component and the device-implementation component of future diagnostics, where,` in a matter of hours or days, we can have systems put in place. There still is a lot of work outside of the synthetic biology on device implementation, sample prep, ease of use, that has caught people's attention in the midst of the pandemic. The second is around vaccines. I think synthetic biology underlies, at least game changing synthetic mRNA vaccines. I think those will be quite important moving forward. I think we got lucky with the very clear targets in SARS-CoV-specifically the spike protein. I don't think it's as clear for many other pathogens, of what you would target, and so there'll be additional work.
Professor Jim Collins:
The area that I think has come up short in our response, has been therapeutics. I mentioned earlier our efforts around artificial intelligence, I think that there were a lot of well-meaning efforts, including some in our lab, on trying to get after therapeutics. We're all focusing on repurposing, to get around the challenges of getting clearance, regulatory approval. I think they were wrong-headed in two counts. One is that, I think we really need, in most cases, novel chemical, these novel molecules, to go after pathogens. Second, it's likely we need combinations. Most antivirals that have been the most successful, many have involved combination therapies. I think deep learning approaches to artificial intelligence approaches will increase our capacity. So, outside of synthetic biology, but still around biological engineering and harnessing these advanced technological efforts, are going to significantly enhance our ability to discover and or design novel molecules to stop a pathogen, including viral pathogens, and to design combinations of either existing molecules or novel chemical entities. To stop a pathogen.
Professor Jim Collins:
The challenge, probably in combinations, is that they very quickly can explode combinatorially, in terms of the number of tests you would need to run experiment, those tests still can be quite challenging if you're going to even run it in silico in a computer. But, if you have a computer based-model around deep learning, that was trained on actual data, it's our hope that with the right experiments to collect the key types of data, you could develop much more efficient screening methods to get after more effective combinations.
Lydia Morrison:
I think that's really exciting to hear. I feel like we're just starting to hear about therapeutics in the mainstream news. For COVID, certainly there's been research going on, I'm sure, throughout the pandemic, to try to find those therapeutics. But, I really haven't heard much talk about it from scientists directly, so I think that's really exciting to hear that there's a lot of ways that synthetic biology could help power the identification of those novel compounds.
Professor Jim Collins:
A few points to that. One is I do think synthetic biology's role will likely be in helping to create efficient screening assays, that could have meaningful outputs for new emerging pathogens, coupling those then with the artificial intelligence type computational platforms. On recent therapeutic developments, Merck just came out with a small molecule that appears to be promising. There's another small biotech that just also announced a small molecule. So, we're seeing now, this 20 months into the pandemic, some promise.
Professor Jim Collins:
Earlier, you saw repurposing of various molecules like Remdesivir and biologics including antibodies, and the antibodies have been quite promising, though difficult to produce. So, again, I think the therapeutics come up short, but now we're starting to catch up. I think it will likely point to valuable lessons of how we can be in a much better position for the next pandemic, and unfortunately, the next pandemic is coming. We don't know when, we don't know from where, but it's coming, and hopefully we don't grow complacent as we now come out of the current one, and learn as much as we can to be in a much better, stronger position for the next one.
Lydia Morrison:
What's the coolest thing that you're working on right now?What's the project in your lab that you're most excited about?
Professor Jim Collins:
Well, we have many, and like a parent, I'm careful not to use superlatives with my kids or my projects, but I'll present a cool project.
Lydia Morrison:
All right. I'll accept that.
Professor Jim Collins:
We've become really excited about RNA therapeutics. I think in part from the success of Moderna, in part from now efforts that are coming out of Flagship Pioneering, where we work quite a bit with, and others, are really excited about what RNA holds as promise. We think that synthetic biology offers tremendous possibilities for control. So, can we better control how that RNA is expressed through interaction with other nucleic acid, or with small molecules? We have a new paper coming out in Nature Biotech, where we actually showed you could engineer mRNA elements to function in human cells, that are kept in a tight off-state, that then could be flipped on in the presence of specific RNA molecules that might be in a cell-specific, tissue-specific standpoint, and/or from an infection standpoint, or an endogenous trigger standpoint.
Professor Jim Collins:
We're very excited about what that opens up from both kind of an mRNA therapeutic standpoint a la Moderna, and/or an mRNA control standpoint from a gene and cell therapy standpoint. We now are advancing efforts to see to what extent can we engineer mRNAs, to similarly being a tight off-state, that can be flipped on with various small molecules. This again, would open up rate-control possibilities, and we have some really nice early advances in that count and are now also seeing, to what extent we could harness AI in this synthetic biology context to better infer design principles, so that we could design from the bottom up, specific control elements for a target small molecule.
Lydia Morrison:
Interesting, I mean, that sounds like an incredibly powerful tool, to sort of have the ability to turn those triggers on and off, once they're already present in the system. Can you give me some examples of the applications of that kind of therapy?
Professor Jim Collins:
The ones that would respond to specific RNA molecules, you can envision in this case, that it would be tissue-specific, that you'd only have the RNA therapeutic turn on in a particular tumor cell, or in a particular cell type, that might be a muscle or a neuronal cell. In terms of the small molecule control, you can envision now having this, where you could widely deliver your mRNA therapeutic. In this case, now turn it on temporarily, and/or spatially, with the small molecule, and/or dose, use the small molecule to dose the response.
Professor Jim Collins:
One of the challenges at present, is that without control, how do you control for dose levels? So, the Moderna vaccine was very, very high dose on expression. So, your dose, the expression level was very high compared to Pfizer, that ended up giving a much stronger immune response, but you can envision now on a therapeutic that you might be needing every day, for weeks, months, if not many years. You'd want to make sure that you could tune it, so that you get within the right therapeutic window, both for efficacy, safety, tolerability, and having a small molecule and/or a nucleic acid control element, could really change significantly the clinical applicability of these systems.
Lydia Morrison:
That's really interesting. How far away do you feel like those therapeutics are from being publicly available, or let's say, being ready to submit to regulatory bodies?
Professor Jim Collins:
I don't think it's far off. I primarily function in my academic lab at MIT, the Beason student and the Bruin student there. We're getting after early proof of concept demonstrations in cell lines and animal models, not humans. So, it's taking the most promising ones, likely moving them into startups, and we are excited on this RNA therapeutic space of startup possibilities. There, you want to advance to non-human primates to demonstrate, and then move into humans, but given the extreme and growing interest in RNA therapeutics, again, speaking to Moderna's great success in this case, in the COVID vaccines, but they have many therapeutic programs, we are really excited about the possibility. So, I don't think it's far off, relative to other advances, but it's certainly not something that's going to happen next week.
Lydia Morrison:
That's interesting. Well, we'll all stay tuned and be excited to see the progress of those therapeutics and look forward to science helping everybody live longer, happier, healthier lives.
Professor Jim Collins:
I as well. I do think that synthetic biology and artificial intelligence, separately and together, are going to be amongst the defining technologies of the century. I think each are incredibly well positioned to dramatically advance our ability to address challenges at human health.
Lydia Morrison:
I absolutely agree. Thanks so much for joining me today, Jim.
Professor Jim Collins:
Thanks for having me Lydia. It was good talking with you.
Lydia Morrison:
Thanks for joining us for this episode of the lessons from Lab and Life podcast. Catch our next episode, when we interview Dr. Neville Sanjana, a core faculty member at the New York Genome Center, about his recent publication entitled "Chemically modified guide RNAs enhanced CRISPR-Cas13 knockdown in human cells." Hope you'll join us for some new perspective.
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