Timothy Lu is an Associate Professor of Biological Engineering, Electrical Engineering, and Computer Science at MIT and founder of Senti Bio, a synthetic biology start-up that is developing a platform technology to advance cell and gene therapies. Senti just announced $53M in Series A funding and a move toward advancing its research towards the clinic. Lu is also a co-founder of Synlogic, Tango Therapeutics, Sample6, Eligo, BiomX, and Engine Biosciences. He spoke with SynBioBeta's Kevin Costa on the eve of Senti’s Series A announcement.

Congratulations on Senti’s Series A funding announcement!

Thanks! We’ve been working on this since 2016, when the company was founded and we got initial seed funding. Over the past year and a half we've been scaling up and getting more data to support fundraising. It’s been a fun time so far, but we have a lot more work to do.

In your own words, what is Senti?

Senti is a start-up company focused on using synthetic biology tools to build next-generation cell and gene therapies that can adapt, sense, respond, and have a greater range of effects than current cell and gene therapies are capable of.

It sounds as if the promise of being able to use synthetic biology to build complex cellular logic for therapeutic applications is finally coming of age. How does that feel?

Yes, that’s right! Well, it’s been a long time coming. Since the early 2000s, there have been a lot of questions like, are we just playing with toys, or is this really going to have an impact? I’ve been working in this field for the past fifteen years, and it’s exciting to be at the point where we feel like the tools are robust enough to be implemented in a human cell context. I think the other thing we’re benefiting from is a renewed external interest in cell and gene therapies, and the recognized need for this sort of technology. So it's a nice confluence, these two factors coming together.

Just how complex are these circuits that we're talking about?

With Senti, we've pulled together work from a bunch of different labs, not just my own group: Jim Collins, Martin Fussenegger, Wilson Wong, Mo Khalil, Michael Andreeff, Chris Voigt, and others. We aim to bring in best-of-class technologies, and collectively these labs have shown that you can program sophisticated logic with multi-input, multi-output (MIMO) types of systems.For example, we published a paper last year about sensing two different promoters that were selective for cancer and only triggering four different therapeutic outputs when those promoters were both active. So in terms of sophisticated MIMO systems, seven or eight components is doable. Now, just because it's doable doesn't mean that's what we are going to do for our first program. There is a translational issue here which is: the simpler you can make these things, the more likely you will be able to translate these systems successfully. So for our first internal programs we’re trying to simplify as much as we can. But the ceiling in terms of what's possible over time is increasing, and we're super excited about the longer term potential.

Senti will apply its technology in both genetic and cellular therapies. Can you elaborate on that?

With gene therapies, we're talking about in vivo treatments, where you deliver a genetic circuit through a virus or other non-viral approach, and it goes into certain cells to have a specific activity. Relevant applications include, for example, oncolytic viruses, where you can program the cells with one or more payloads, and also increase their specificity by putting sensors that are highly specific to cancer cells and averse to non-cancer cells. Other applications in this area are in vivo gene therapies where you do not want to simply over-express the gene without control; maybe the expression level of a gene or the cells in which it expresses matters in terms of safety and/or efficacy. So that's an area where our technology can certainly play a role. In the cellular therapy context, we're talking about the ex vivo cell engineering strategy of taking cells out of a patient or donor, putting the genetic circuit into the cells, growing those cells, and then delivering them into the patient where the circuits then endow that cell with enhanced therapeutic capabilities.

I imagine the Senti team you are working with is quite amazing.

Yes, and we're continuing to recruit great people, so hopefully through SynBioBeta and elsewhere we'll get more amazing people to join. We have a team of outstanding scientific advisers and founders. Jim Collins is one of the early pioneers in this area and continues to advance the field in building new genetic circuits. Martin Fussenegger is one of the most prolific researchers in terms of engineering mammalian gene circuits and putting them into a variety of disease models to show therapeutic effects. Wilson Wong at Boston University has done a lot of work on next-generation CAR-T strategies. We're also working with Mo Kalil, also at Boston University, who has done a lot of very useful work on synthetic transcriptional regulators and epigenetic regulators. Chris Voigt at MIT is pioneering high-throughput and computational strategies for designing genetic circuits. And most recently we've been working with Michael Andreeff, a physician at MD Anderson Cancer Center, who has been pioneering the use of off-the-shelf cells for cancer therapies, so we have a very nice translational link there.

At what point when you were sitting there at MIT did you say yourself, "I have just got to make a company out of this!"?

The idea for Senti evolved over time, and the company’s genesis was triggered by the confluence of several key events. I had been talking to Jim for quite awhile about the use of these technologies. We were seeing the progress being made with the first generation of CAR-T treatments and gene therapies. So we felt that it was an opportune time to do this, if we could pull together the right team. Jim played an integral role in that aspect. Fortunately, I also had been in touch with Ed Mathers, a partner at the venture firm NEA. Jim and I worked with Ed before on a company called Synlogic, which is pursuing engineered microbiome therapeutics and is now in the clinic. Ed encouraged us to think about starting a company and mentioned that NEA would be interested in supporting such an effort. So that was great and encouraged us to further put together a business plan. Then the third component that really brought it together was when I reconnected with my former classmate from MIT, Philip Lee, who's a co-founder of Senti. Philip went to UCSF and Berkeley for his PhD, started a company (CellASIC), sold it to Merck KGaA, and then spent time within Merck looking at the cell therapy space. So we came together and started to dig into whether there was a business there and what the approach would be. After we had the confidence that we could do it, we went back to the investors, got the round together, and pulled together the amazing scientific team and advisors.So I would say it was definitely a process. There wasn't a single “aha moment,” but I do think it started with the realization that those first-generation cell and gene therapies were going to make it out of the clinic, and that there was a real need for better technologies to go on top of them.

What’s it been like watching your academic research make it into the commercialization pipeline?

Yes, it’s been awesome to work to translate the field’s collective advances towards the clinic. As you know, a decade ago there was a whole down-cycle in the field of gene therapies where few people thought that gene therapies would ever make it into real-world use. And now we're in a sort of different world where people are open to these new cell and gene therapies. There are still a lot more challenges ahead of us, of course, but we're excited about the prospects and feel like we have much to contribute to this burgeoning class of medicines.

Do you have advice for other entrepreneurs wondering what to do with their promising technology?

Well, when starting Senti, we quickly realized that it was one thing to have technology, but it was another thing to have an actual market or a specific application. So we spent about six months just talking to a bunch of clinicians, industry veterans, and KOLs trying to figure out the best fit for the technology. So my advice would be to find the right use cases for your technologies. We found that it was important to define the clinical applications with unmet needs and then figure out which technologies we needed to pull together to address them.

Do you have a favorite application of this technology?

Well, we definitely see this as a platform, so we want to use it as broadly as possible so we can realize its full potential. Internally, we're extremely excited about the use in tumor immuno-oncology. This is obviously a hot area of research right now, but most existing approaches are limited in that they have trouble concentrating the activity of these immunotherapies to specific areas to avoid off-target side effects. It's also becoming pretty clear that you're likely going to need multiple mechanisms of action to get really good efficacy. So, immuno-oncology is a really good fit for our genetic circuits because it enables therapies that achieve controlled, localized stimulation of multiple pathways. I’m particularly excited about that use case, although I don't want to give short shrift to the other applications!

What would a home run for Senti look like, say, five years down the road?

A home run for us would be, first, if we could advance our internal programs into the clinic and see evidence that these therapies work in patients. That in itself would be pioneering and a tremendous outcome for us. And second, I would really like us to be able to work with partners and incorporate this technology into therapeutic indications beyond our internal programs. Those are our team’s two major goals.

Are there other areas of synthetic biology that you feel are particularly ready or in need of investing that you expect will outperform in the coming five to ten years?

Outside of what we’re doing, I think there's a lot of exciting stuff happening in the diagnostic space, for example with cellular biosensors and CRISPR, that have real potential. However, diagnostics can be challenging to commercialize, so the field will need to work creatively to achieve success. Nonetheless, from a technological perspective, these advances are really, really exciting in terms of what they enable in terms of sensitivity, specificity, time-to-result, and the environments in which they can operate. And we certainly need better diagnostics if we're going to fully achieve precision medicine, for example.I think the microbiome continues to be an attractive application space for synthetic biology, and we're now starting to see technologies make it into the clinic. I am really bullish on that. I think we're just at the beginning of having the tools to precisely engineer microbial communities and achieve new therapeutic functions. In many cases, the technologies for manipulating microbes are much more advanced than for manipulating human cells. So I'm super excited to see what can happen in that area and I think we’ve only begun to scratch the surface.

What personally motivates you to pursue this technology and build a company out of it?

Everyone at Senti -- and probably everyone we know -- has been touched by diseases like cancer in some way. From a personal perspective, knowing family and friends who have had cancer and gone through some of the terrible side effects of existing drugs, it makes you wonder why we can't have better treatments. Thus, I think everyone at Senti is driven by some personal story and really wants to bring a new kind of adaptive therapy to the world.From a scientific perspective, I'm just super excited that, as a field, synthetic biology is on the edge of achieving real-world applications. Collectively over the last two decades, we’ve been playing around with the technology and figuring out how to program cell circuits. Some great applications have grown out of the biomanufacturing and diagnostic spaces, but we really haven't realized the full promise of the technology yet. So if Senti can contribute a success in this one narrow slice of what synthetic biology can do, I'll be really satisfied. Personally, that's what gets me up in the morning.

Will we see you in SynBioBeta 2018?

Yeah, I would love to have an opportunity to participate!