Synthetic Biology Primer: In Conversation With Richard Kitney, Part 1

Xconomy National — 

“Synthetic biology” has always been a puzzling term to me. Prosthetic limbs are synthetic. Knee replacements are synthetic. Splicing the gene from one organism into another, a practice that began in the 1970s and gave rise to the biotechnology industry, is also a synthetic act.

But those things are not “synthetic biology” in the way the term is used today to describe… what, exactly? A new cross-discipline of biology and engineering? The transformation of cells into factories under our own control: cells as machines? Well, yes, but the biotech industry has been modifying cells—E. coli bacteria, Chinese hamster ovary cells, yeast—to become engines of production for a long time now.

So what’s the difference? That’s the question I began with last month when I sat down with a pioneer of the synthetic biology field, bioengineering professor Richard Kitney of Imperial College London, on the school’s campus. Along with researchers such as Tom Knight, Drew Endy, Pamela Silver, Craig Venter, and others, Dick Kitney has helped create the field, founding and chairing a veritable tower of academic departments and institutes, and co-authoring hundreds of papers, all of which, judging by the unruly state of his campus office, could easily be within arm’s length of anyone dropping by for a visit.

In the U.K., Kitney has also galvanized government support for synthetic biology, and he is co-director of SynbiCITE, a national translational research center helping to push the basic research into commercial applications with support from government and industry. 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. Xconomy has written about some of these companies here, here, and here, and hosted a discussion on the topic in Boston back in May.

Kitney answered my questions about the underpinnings of synthetic biology, described one example of a possible medical product in development at Imperial College, and told me how he helped convince government officials to back the nascent field to the tune, so far, of about half a billion dollars.

Part one of our interview follows; part two will come next week. The conversation has been edited for length and clarity.

Xconomy: Let’s start with a question about fundamentals. How do you differentiate synthetic biology from genetic engineering? Is synthetic biology a new term for an old technology?

Dick Kitney: There’s a continuum here in terms of the molecular biology revolution. It arguably started with Watson and Crick, and led through polymerase chain reaction and into the initial sequencing of the human genome as published in 2001.

X: We realized we didn’t know right away what the sequence of letters comprising DNA meant, but at least we learned the order of those letters, and how they might fit together into codes for proteins and other things, like instructions to the cell that housed them.

DK: And with the technology that lies behind the sequencing of the human genome—the ability to read the DNA [of naturally occurring genes]—there was industrial development, and that began to be applied to write DNA as well [and create artificial genes]. So a rough date for the start of synthetic biology is around 2001. Look at the situation now. The cost of reading DNA is really low, it’s accurate, and it’s fast. Writing DNA is now quite accurate, pretty fast, but still fairly expensive in relation to reading it.

You’ve now got two paths, reading and writing. At a big lecture in London recently I described the ability to read and write DNA in terms of its potential impact, a bit like Johannes Gutenberg developing the printing press in 1440.

The other key differentiator at the heart of the synthetic biology movement is about the application of engineering to biology. It means applying the engineering principles of modularity, characterization, and standardization, plus systematic design, to biological devices and systems. It’s about designing and building according to engineering science principles. That’s key.

X: In other words, before synthetic biology, one could say that genetic transformation was about taking a known piece of code, such as the human DNA strand that naturally codes for the protein insulin, and putting it into a system that already existed in nature, like a bacterium or yeast cell. But synthetic biology is writing new DNA. It might mimic something that exists in nature, or it might not, plus it needs a lot of additional parts to make it work in a cell.

DK: That’s right. Whereas now, in the large part of synthetic biology, you design a piece of DNA, you put together sections of DNA, this is then synthetic DNA—which is now being built by a lot of companies. You put that into a cell, typically something like E. coli, and you see how the cell responds. Think of the DNA as an instruction set, a computer program driving the cell. You want the cell to produce something you want, rather than what it would do normally.

Two things about that. Typically one designs the DNA and produces it synthetically. But you also have to look at the context of the cell. How does the cell respond? That process is called characterization, that’s where these engineering principles really come in.

X: There is no “right” code in DNA. If you take 1,000 people and one gene, there could be 1,000 variants of that gene. As you write DNA that’s meant to program a cell, how do you find the right sequence?

DK: [With] an electronic circuit, all the components are put together in a linear pattern, and when you build it, it’s all hard wired and typically it works. You don’t have that in biology. You’re putting in a strip of DNA which tells the cell to perform in a particular way. Basically the section of DNA that’s the synthetic instruction set for the cell comprises a whole series of what we call bioparts.

X: Meaning not just the parts of genes that code for proteins, but the code that tells the cell to cut, paste, copy, and do other things with the information?

DK: If you put [the bioparts] into a cell, and it doesn’t achieve what you want it to do, usually the reason is these parts are in the wrong order. They need to be changed around.

Doing this process in a one-off way would take a long time. But with synthetic biology you can produce a whole series of combinations of these instruction sets in parallel, the sort of thing that Twist Biosciences, Gen9, and others can do. Then you run them in parallel and see which ones produces the best results.

X: So if I place an order of synthetic DNA, I’m getting a series of potential combinations, and then it’s my job to test them all to see which one actually works?

DK: Frankly that’s a function of price. You can go to them and say, “I want this single realization of this sequence.” Or, “I want various combinations.” And they’ll do either of those for you.

X: What about the cell itself? Is anyone building new cells from the ground up?

DK: People are trying to do that. Craig Venter is trying. But 99.9 percent of people in synthetic biology use natural cells. That gets us to the next level. The cell is either called the chassis or the host in this field. E. coli and yeast are most common. Within that family of E. coli and yeast, there’s a whole series of different versions, or strains. In addition to doing all these parallel versions of DNA, typically one uses three or four different strains, until you get to a situation where the match between the DNA and the strain of E. coli, for example, is optimal.

X: To someone who has mainly covered biopharmaceuticals for the past decade, this sounds a bit like running a drug discovery screen, whittling down from an array of possibilities.

DK: That’s right, but remember as the field progresses—with thousands of people working on these aspects of synthetic biology—we’re converging on a much more systematic way of designing these synthetic biology devices. People run experiments, where they check the DNA in relation to how the cell responds, and that information is placed into a registry. For a particular type of scenario you can go to a registry and say, “I want a particular biopart that does something.” The information about that biopart has already been characterized in a detailed way.

X: Are you saying everyone working in the field is obliged to contribute their findings to a registry?

DK: We work closely with American colleagues; in the academic community of Imperial, MIT, Stanford, Berkeley, et cetera, there is a strong feeling to share with each other. It’s a whole open source movement on the academic side.

X: Is that what “Biobricks” is?

DK: Biobricks is associated with the iGEM competition, the international student competition in synthetic biology. That registry comprises about 20,000 biobricks—the different components. But they’re not properly characterized. In the field there’s a clear distinction between what’s done for iGEM— we’ve had a team in the competition since 2006, and I’m on the advisory board—and a professional movement where people are building out registries of fully characterized parts.

On the professional side, industrial translation is important. Tom Knight, one of the fathers of synthetic biology, has a company called Gingko Bioworks in Boston. When he gives a lecture, he comes in with a tome, the Texas Instruments transistor handbook from about 25 years ago, which has all these data sheets in it. When TI produced those transistors they had to be completely reliable. That’s the key difference between the iGEM registry and the professional registries.

If you go back to the 1950s, transistor characterization was not very reliable. I remember as a student, we would be in the lab, measuring the characteristics of transistors to find the one that was good. We don’t do that now. Intel is producing chips with billions of transistors. Biology is at the point where electronics was in the fifties. You’ve gotten a professional part out of a registry. Yes, it’s characterized as accurately as possible. But you still go back and check it.

X: Many years ago, I covered tech before I covered biotech. One thing I enjoy much more about the life sciences is the messiness of it.

DK: That will disappear, in my opinion, in the next 70 years!

X: Even with something as complex as the human immune system? It’s hard to imagine components of the immune system, for example, being modularized in that sense. But you feel it’s going to happen?

DK: I really do. It might take 50 or 100 years, but there’s a wave front moving through.

More to come in part two: A biosensor for urinary tract infections, imperfect analogies to automotive plants and electronic circuits, and the minister wants jobs.

Image courtesy of Imperial College London.