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From Ambitions To Markets: Richard Kitney And More Synthetic Bio Views

Xconomy National — 

Last week, Xconomy ran the first part of my conversation with Richard Kitney, a bioengineering professor at Imperial College London and a pioneer in the field of synthetic biology. We met in his campus office in November.

Kitney has coauthored hundreds of papers and helped galvanize U.K. government support for synthetic biology. He is also codirector of SynbiCITE, a national translational research center that has support from government and industry in an effort to turn synthetic biology into a major driver for the London region and the U.K. economy generally.

Some of the many products taking shape in the U.K. and elsewhere: medical diagnostics, fragrance and flavor substitutes, and biofuels. And as in any gold rush, many companies are moving aggressively to provide the tools and forge the deals needed to create synthetic biology products, while watchdogs call for a more deliberate pace to debate health, social, and ethical considerations.

Part one of the conversation began with an attempt to clear up my own confusion about the difference between the relatively new practice of synthetic biology and the 40-year-old practice of genetic engineering. To explain, Kitney described some of the technical underpinnings of synthetic biology.

Part two of the Q&A will focus on turning the science into products. Before we rejoin the conversation, however, I think it’s helpful to hear other views and definitions of the field, then briefly describe a few important products that synthetic biology has helped create or that are in development. I reached out to several people in the field to ask them for their thoughts. Perhaps my favorite response wasn’t about a product but was this, from Stanford University professor Drew Endy: “The fact that you want to write about products indicates that you want to describe what can be synthesized via biology, but not (describe) synthetic biology, per se.”

To help explain, he pointed me to an old video, shot by a student, in which Endy explains synthetic biology.

Endy tells the student, “Synthetic biology isn’t making a specific thing. It’s how you make something.” In other words, genetic engineering and synthetic biology are means to a similar end, but synthetic biology adds more steps to the process.

Jack Newman, cofounder of Emeryville, CA-based Amyris (NASDAQ: AMRS), acknowledged that the definition was elusive. “I’ve given up trying to define synthetic biology and [now] use it interchangeably with modern genetic engineering, as both seek to efficiently write DNA code into living organisms,” he said.

I suspect that a couple generations from now, perhaps earlier, we’ll look back and wonder why we were trying to suss out the difference between the two. Here are a few key products:

Artemisinin

If there is a poster child for what synthetic biology can do, it’s from Newman’s Amyris. The compound artemisinin is used in malaria-fighting drug combinations; its precursor artemisinic acid comes from the sweet wormwood plant. But there’s not enough of it to produce a larger, cheaper, more stable drug supply. So Amyris scientists and others set out to engineer yeast to produce artemisinic acid, starting with work from the lab of University of California, Berkeley professor Jay Keasling. Amyris tweaked the yeast’s genes to provide larger yields, and made other improvements, described in a 2013 Nature paper. International drug firm Sanofi took over production in 2008 and reached 120 million doses of artemisinin in October 2014. “Jay analyzed the metabolic pathway from wormwood and worked out how to do it over a 10-year period using sugar as the yeast’s feedstock,” Kitney told me. “That’s the classic example.”

Insect control

The British firm Oxitec has begun to release engineered Aedes aegypti mosquitoes into the wild to stop the spread of dengue fever. Three countries have hosted trials: the Cayman Islands, Panama, and Brazil. Brazil liked it so much it granted commercial approval in 2014, with projects now in two cities. Oxitec’s mosquitoes, all male, are meant to mate with females and pass along a gene that causes the offspring to die as larvae. Trials have shown a sharp reduction in the dengue-carrying mosquito population, but as a Brazilian researcher in this article pointed out, a reduction of mosquitoes doesn’t necessarily equal a reduction of transmission.

An even more powerful mosquito “product” could soon be here, via an extremely controversial technique called gene drive, making a genetic trait of one organism heritable by its offspring all the time, not just half the time—and now possible using the CRISPR-Cas9 gene editing system.

Stanford bioethicist Hank Greely generally resides on the laissez-faire end of the spectrum regarding altering the human genome. But as he described at Xconomy’s biotech forum last month, gene drive—with the power to sweep unalterable genomic changes through a broad population of a species—keeps him up at night, even if those changes are meant to do good, like creating mosquitoes that don’t transmit malaria. No one has proposed commercializing a gene drive organism yet.

Vanillin

The Swiss firm Evolva has re-engineered yeast to produce a form of vanillin. With that product, Evolva is aiming to compete with the widely used artificial vanilla flavor, not the natural flavor extracted from the vanilla bean. There are environmental and fair-trade concerns, voiced here by Friends of the Earth, many of which are rebutted here by a synthetic biologist at Arizona State University.

Evolva’s synbio vanillin came to market in 2014. Jamie Bacher, CEO of Pareto Biotechnologies in San Francisco, is also trying to create flavors using synthetic biology techniques spun out of the Salk Institute. He said Evolva’s form of vanillin was important to the field “because it started a discussion about the role of synthetic biology in the public and in the general press that is now becoming sophisticated.”

My query returned several other examples, including carpet fiber, pain killers, meat and dairy substitutes, and animal feed ingredients. It also prompted thoughts from synthetic biology leaders on what the field needs most in the coming year and beyond. “Broadly educating the public,” said Twist Bioscience CEO Emily Leproust, citing the challenge of “the small minority who carry an irrational fear of science.”

Bacher said education can come by making products that matter: “We’re past the point where technophiles can just say that this sounds cool. The field has to deliver real innovation.”

Endy, meanwhile, also warned against complacency, but from a different point of view. “We need to keep synthetic biology weird and wonderful,” he said. “The field has been mostly captured over the last eight years by an abundance of boring people and programs. Synthetic biology needs to renew its ambitions and capacities.”

Let’s finish with part two of the conversation with Kitney. (It has been edited for length and clarity.) Part one ended with Kitney saying that the perceived messiness of human biology will eventually come to seem far more rational, broken down into understandable parts—or “modularized,” in engineer speak. “It might take 50 or 100 years, but there’s a wave front moving through,” he said.

Xconomy: Besides artemisinin, where has that wave had an impact so far in human therapeutics?

Dick Kitney: One area to single out is biosensors. We and others have built sensors that do things like detect urinary tract infections. In patients with an in-dwelling catheter, the infection starts to build up on the outside of the catheter, spreads into the bladder, and causes a massive infection. A lot of people in hospital are elderly or frail, and the infection kills them. Sometimes the antibiotics kill them.

To get around this you need a biosensor that detects the infection before it gets into the catheter. The bacteria Pseudomonas aeruginosa like to congregate into a colony by releasing a small signaling molecule called AHL. We figured if you could detect the AHL, you would know the colony is coming together. So we developed a [cell that is a] three-stage biosensor: It detects the AHL, amplifies the signal, and [activates] a fluorescent protein.

It works in a lab. Now we’re starting to seek industrial partners to work out a delivery mechanism. In simple terms you can imagine putting the biosensors in some kind of suspension like shaving foam. You then spray that suspension onto the end of the catheter. If you’ve got infection starting, it would fluoresce green to the human eye. A nurse could spray it on and come back 20 minutes later and wipe clean the catheter.

X: A preventive measure?

DK: Sure, you could do it two or three times a day. It takes about 24 hours for urinary tract infection to develop from the end of the catheter.

We and others are also working on a combination of a biosensor and therapeutic device, looking at liver cancer. You can introduce this into circulation, and it will identify malignant cells within the liver, latch on to them, and release cytotoxic drugs.

X: So take the example of the infection sensor and explain the components. How do you build that from the ground up?

DK: You design the synthetic DNA with a section that codes for the green fluorescent protein. [Other parts of] the gene circuitry do the detection of AHL. The circuit also has components like promoters, and we’ve worked on the best type of promoter to make the device work properly. [A promoter is a part of a gene that tells the cell’s machinery to start making a protein based on instructions from the DNA code.] It’s all connected together, and when you put it into the cell, the cell produces the whole device for you.

But to get there, a lot of optimization goes on. At the moment a lot is done in the labs to see what combinations of gene components and chassis [strains of host bacteria for the synthetic genes] works best.

That gets us into what we call foundries. The big thing we’re working on with Jay Keasling at Berkeley is development of foundries to automate what you’d do in a wet lab manually. Taking all the human steps out of it, that’s the objective—get it all done with laboratory robots. Why are we doing that? You can go through every stage of the design and implementation in parallel, the whole work flow, to run through all the combinations of promoters and different cell types. You can test out every single possibility for that device.

X: I’m trying to think of older-world industrial parallels.

DK: You could think of it conceptually as an automotive plant. The whole thing is automated. Except in synthetic biology, the engineering hasn’t been pinned down to the nth degree as it would be in electronics or automotives. So think of a situation where you want the BMW plant producing various versions of a car, trying out different engines, different gearboxes, all in parallel. Of course that doesn’t happen in the automotive industry because the design decisions have already been done.

X: Because this is biology, will there always be a greater amount of uncertainty than in the design of a car to run in a predictable way?

DK: You’d run the foundry to optimize the last bit. You’d ultimately get to a point like in the Toyota production line; the book The Machine That Changed The World years ago analyzed the whole Toyota approach. Instead of letting the car come off the production line then fixing all the problems, every time there was a problem they stopped the production line to fix it. It will be like that.

It gets me into another analogy. A lot of traditional biologists say, “How can you do all this stuff, we don’t understand the biology to the nth degree.” My riposte to that is usually to say, “Well, in 1903 the Wright Brothers flew the first powered flight at Kitty Hawk, NC, and flew for 120 yards.” The whole aircraft industry developed from that. We all fly around the world in all these planes, yet three minutes’ walk from here, colleagues of mine in the aeronautics department are world experts on wing turbulence—which they still don’t understand. It doesn’t stop the aircraft industry from developing. It should be true of synthetic biology. We’re at the early stages but we’re still able to produce stuff.