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Genetic Circuit Engineering with Gene Editing

The human body is an amazing machine. Think about all of the cellular programming that went into making you, starting with a single cell. Also, notice how when we talk about biology these days we draw the inevitable analogy with computers and machines. Artificial intelligence is one obvious example, as artificial neural networks attempt to replicate the complex computational power of the human brain. But we can find other places where biology and machines intersect. Specifically, we’re talking about computer circuits, as in those that help computers perform specific tasks, and genetic circuits, which have similar “components” as their inorganic counterparts but drive complex biological processes.

And, like computer circuits, biological circuits can be engineered and programmed. Genetic circuit engineering falls into a broad scientific discipline called synthetic biology that we’ve covered before. For example, there are companies that can genetically modify organisms to create milk and meat proteins using techniques similar to brewing beer with yeast. AI tools such as machine learning and other automation technologies, combined with the low costs of gene sequencing and advances in gene editing, have enabled companies like Ginkgo Bioworks to rapidly design, build and test organisms for specific applications such as organic pesticides or artificial fragrances.

How It Works

Genetic circuit engineering goes even further. Scientists can design genetic circuits and insert them into cells, giving them new functions such as producing drugs when they detect disease in the body. Of course, it’s much harder than it sounds—and it sounds really, really hard. Until recently, only a select few could pull it off, requiring years of design and trial-and-error to get these synthetic circuits to perform as intended, despite the fact we’ve been working on these problems since the 1960s.

Gene circuit research has been around for a while. This image shows work from 1961 from a couple of French scientists who described the genetic circuit in E. coli that senses and eats lactose. Their description of how the appropriate metabolic genes are regulated was the first of its kind.

That was before researchers, particularly some big brains out of MIT and Boston University, figured out a way to automate the process much as chip designers today use sophisticated software to design, test and manufacture hardware. In fact, they use a computing language called Verilog, which is used to design silicon circuits, to create specialized genetic circuits. The user types in commands to design the gene circuit with specific functions. The code is then turned into a DNA sequence using a software program called Cello that sanity checks the design. Below is a little demo that will probably only appeal to the computer scientist geeks among you. You can also get a more in-depth but readable explanation of gene circuit engineering here.

As Christopher Voigt, one of the key minds at MIT behind gene circuit engineering, said: “It’s literally a programming language for bacteria”.

What’s It Good For

Before we do a brief dive into possible applications, let’s get the big caveat out of the way: Gene circuit engineering is cutting edge technology and very few companies (two of which we’ll talk about shortly) are even trying to commercialize it yet. So, at this point, there’s no direct exposure to this technology for the retail investor, which is probably a good thing. As we’ve recently discussed, investing in synthetic biology stocks is still a pretty risky venture, but we’d bet you a million bitcoins that healthcare, agriculture and other industries that rely on understanding and manipulating biological systems will one day be dominated by synbio. That’s why we want you to understand this emerging technology.

Now for the fun stuff: What can we do with gene circuit engineering? One possible application would be to design cells that when they detect a tumor can produce a drug to attack the cancer. It would be like turning the cells in our bodies into nanobots, able to detect, diagnose and treat disease without the hassles or costs of insurance and deductibles.

Maybe we’ll make smarter plants that can respond to droughts or produce their own insecticide. Remember those meat-protein-fermenting yeasts? Those yeast cells, as more than one expert has noted, could be engineered to halt their own fermentation process if too many toxic byproducts build up. Or perhaps we could reprogram cells so people are no longer lactose intolerant or gluten intolerant by helping them digest what was once indigestible.

It’s Not Science Fiction Despite the Name

Those are some of the possibilities that inspired the founding of Asimov last year. The Cambridge, Massachusetts startup raised $4.7 million in Seed funding last December, led by the powerhouse VC firm Andreessen Horowitz. Most of the company’s co-founders, all of whom hail from MIT or Boston University, published a seminal paper on gene circuit automation in the journal Science in 2016. Their research had been funded by the Navy and the shadowy government agency known as DARPA. In other words, these guys are pretty smart, and their business plan sounds like it comes out of the Ginkgo Bioworks playbook: They want to design and sell engineered genetic circuits to other biotech companies for various applications. (By the way, Ginkgo Bioworks became the first synbio unicorn last year.)

Overview of the original Cello platform. You’ll have to trust us: This makes sense to someone. Credit: Asimov

Asimov’s platform can reportedly predict whether or not a biological circuit will work with up to 90 percent accuracy.

It’s a Small World After All

Not surprisingly, the other startup that we found attempting to commercialize gene circuit engineering also has roots in MIT, though Senti Bio is headquartered on the other side of the country in San Francisco. The company, founded in 2016, raised a $53 million Series A last month from about a dozen investors including names like Amgen. It’s also not surprising to find one of the pioneers of synthetic biology, MIT professor Timothy Lu, at the helm. Lu has co-founded a number of biotech companies including Synlogic (NASDAQ:SYBX). Sitting on the company’s advisory board is Voigt, a colleague at MIT and a co-founder at Asimov. No doubt synthetic biology is a small world in more ways than one.

Credit: Senti Bio

Senti Bio is specifically concerned with disease, which in the context of our biology-machine analogy can be thought of as an error in computer code. The company’s technology platform enables it to rapidly design, build, and test various genetic circuits to enhance human cell and gene therapies to fix those errors. The company has pulled together experts in not just gene circuit engineering but therapeutic synthetic biology, immune cell engineering, and engineered cell therapies. It sounds like Senti Bio will target cancer and autoimmune diseases to start.

Conclusion

We only learned about gene circuit engineering a few months ago when Asimov had its high-profile coming out party late last year. And then Senti Bio came out of stealth mode last month. It probably won’t be long before we have to revisit this topic to cover the latest top 10 gene circuit engineering startups on the planet. That’s just how quickly (well, 60 years after gene circuits were first recognized) these technologies are emerging and being commercialized. As long as venture capitalists remain fearless when it comes to investing in synbio—up to $1 billion per year now—we wouldn’t be surprised if another biotech unicorn is born soon. Could it be Senti Bio or even Asimov? It’s just one SoftBank-sized deal away from happening.

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