Better Brewing Through Synthetic Biology

IRA FLATOW, host:

You're listening to SCIENCE FRIDAY from NPR News. I'm Ira Flatow. Expecting a little bit with our biology dean today. You know, if you've ever built something using Lego blocks or Tinker Toys or even that old shortwave radio, you know that by using a given set of standardized parts, they are parts off the shelf. You pick them up, put it together, you build those Legos, right? You build the radio? Tinker Toys?

You can build a lot of different things. This is how we build the cars and the buildings and the computers that we do today. We all use these standard parts.

And now biologists want to do the same things on a tiny scale. There's an effort known as synthetic biology, which has the similar goal of being able to custom-build organisms using parts selected from a library of standard genetic codes.

But in biology, the parts aren't as - you know, you don't build them as simply as by taking a two-by-eight Lego brick and sticking it onto a two-by-three brick or a, you know, a four brick or something like that. And that's because when you build Legos, you can predict what the finished object is going to look like. But when you build with genetic codes, one section of genetic code may interact with another one or even with multiple or other sections of DNA, making it difficult to predict what the final organism might be like from just looking at the code.

Well, writing this week in the journal Nature Biotechnology, a team of researchers says that they've developed a better way to simulate the outcome of some of these kinds of interactions, making it easier to design customized organisms. And like many a good university student, they turned their attention in trying this all out, they turned it to beer - actually, the yeast that's used to brew beer.

Joining me now to talk about the project is Jim Collins. He's an investigator in the Howard Hughes Medical Institute and professor of biomedical engineering at Boston University. Welcome back to the program, Dr. Collins.

Dr. JAMES COLLINS (Howard Hughes Medical Institute; Professor of Biomedical Engineering, Boston University): Thanks for having me, Ira.

FLATOW: Let's talk about synthetic biology. Is it really like just taking parts of genetic material and hooking it all together?

Dr. COLLINS: It is. It's basically an engineering approach to biology. We're taking genes, promoters, which are on-switches for genes, proteins, other bits of DNA and basically taking a wiring diagram based on those components and then going in the lab and piecing them together.

But as you alluded in the intro, while we often can get the circuit to look the way we want, we rarely can get it to behave the way we want. So whereas it might take a week to come up with our wiring diagram of the different molecular components and, say, a couple weeks to build the initial circuit, rarely does it actually function the way we like. And as a result, it could take us several months and in some cases years of tweaking to get our little biological system to do exactly what we want it to do.

FLATOW: That's because you don't understand how the standard parts interact fully with each other.

Dr. COLLINS: That's right. So we don't have a really good understanding like, say, we do of Legos or transistors and resisters for an electrical engineer or, say, screws or (unintelligible)…

FLATOW: You know when you put a screw in a hole, it's going to hold a certain amount.

Dr. COLLINS: Right.

FLATOW: And you know what that erector set's going to look like.

Dr. COLLINS: That's right.

FLATOW: But you don't know what that's - how it's going to turn out when you do that with the DNA parts.

Dr. COLLINS: That's right. And it's mainly, as you alluded, it's the interaction. So we can get a decent handle on how they might behave in isolation, the biologic components. But once you put them together, we really just don't have that level of understanding yet that, say, the electrical and mechanical engineers do to design these components into networks with some predictability.

FLATOW: So you went ahead to try to figure out how to make it more predictable.

Dr. COLLINS: That's right. So we did two things. One is we recognize that while there may be 30,000 genes in humans and 4,000 genes in bacteria and associative promoters, so a large number of parts out there, they're not standardized or in a kind of a consistent fashion, similar to Legos or transistors that an engineer could use.

So we started with just two promoters or on-switches for genes and made slight tweaks to these to create libraries based on those promoters where we had, in each case, 20 different ones that were - only had slight changes that would still basically have the same function, but slightly different properties.

We then were able to characterize these and - experimentally, and use that information to begin to get some predictability on how they would behave in a network.

FLATOW: So you started to - if I may paraphrase what you're saying, you started to understand how the on-off switches work first.

Dr. COLLINS: That's right.

FLATOW: That was the first thing. Easy way to go?

Dr. COLLINS: You know, it's a decently easy way. It's probably the most common component that's right now being used by synthetic biologists, and you can imagine making switches. You can make blinking genetic circuits or cascades. And so it's - I'd say it's probably the most common component that's out there.

FLATOW: And then you, having figured out how to make the on-off switches work a little better or categorize them better, you then took that to graduate students' favorite place.

(Soundbite of laughter)

Dr. COLLINS: I don't want to get the hopes up for the beer drinkers out there, but we then, after a few steps, we did get over to engineering brewer's yeast to basically control the timing of one of the critical components in fermentation, and so what we focused on was designing genetic timers.

So could we put together two genes and their associated promoters in basically a tug of war, where gene A is trying to shut off gene B, and gene B is trying to shut off gene A. If you have one of the genes a lot stronger than the other, you can, as I say, set this up in a tug of war where now one gene will very quickly overpower the other.

FLATOW: Like an arm wrestle.

Dr. COLLINS: Like an arm wrestle. And if you now set these up, you can create so-called genetic timers, where if you shut off the stronger gene and then allow it to come on, it will take some amount of time, say minutes or hours, before it can overpower the weaker gene. And we used our general synthetic biology approach to create these timers that then controlled a gene involved in flocculation. I'm happy we can say that on the air.

(Soundbite of laughter)

Dr. COLLINS: Flocculation is a process where the yeast cells of the brewer's yeast will clump together and then sediment out, and it's critical to have this in the fermentation process, where you want it to happen after fermentation has occurred, so after all the sugars have been converted to ethanol.

If you can time it nicely, you can actually get very clear, smooth-tasting beer. It's still very much trial and error in the brewing industry, where you'll have add additives to your vat. But we're able to deal with now programmed yeast, using our predicted networks, so we can actually say, okay. This is now going to flip on flocculation at 100 minutes or 150 minutes or 170 minutes. And we were able to select these out of several thousand different timers from our libraries, and very nicely, they behaved just as we predicted.

FLATOW: Wow, that's interesting. So beer, or at least the on-off switches, you're getting to understand the on-off switch parts.

Dr. COLLINS: That's right. You know, it's still a relatively simple circuit.

FLATOW: Yeah.

Dr. COLLINS: There's an awful lot of hype in synthetic biology. We're far away from many of the things that are being promoted, but here it's a two-gene system that, prior to our work, you really had great difficulty making predictions.

FLATOW: But you must be hearing from brewers by now.

Dr. COLLINS: I haven't yet, but I've heard from several of my friends. My lab does a lot of work in therapeutics and medical devices, but to many of my friends, this is probably our most important and least relevant development.

FLATOW: But applicable to other things.

Dr. COLLINS: It is. You know, the fermentation process, in particular, is at the heart of many efforts now in bio-energy, where companies and academic groups are now programming organisms to convert different sugars or cellulose or sunlight into fuels of interest, whether it be ethanol or butanol or diesel. And there's a lot of interest in trying to actually scale this up so that you can have industrial-scale bioreactors, as well as increase the efficiency so that it makes economy sense.

The trouble is is that we don't have the level of control that we need over the different aspects of the process. And this is where synthetic biology is stepping in.

FLATOW: You know, I think many of us haven't got our head around the fact that you can program DNA, you can stick these little links together and make a machine out of them, you know?

Dr. COLLINS: Yeah, and it's basically a wet machine. It's kind of a wet version of what many of us did with radio circuits or with erector sets. And it's exciting a lot of young people in the engineering space who are interested in moving into biology in that we're now getting a level of control over the small circuits, at least. And we can do this in bacteria, we can do this in yeast, and we can actually do this in mammalian cells, also.

FLATOW: But your circuits are not made out of electrical parts. They're made out of DNA pieces.

Dr. COLLINS: They're made out of DNA and RNA. Many of them are inspired by electrical engineering parts. So, for example, the tug-of-war circuit I mentioned was motivated by a digital toggle switch or RS latch that's at the heart of all digital computers, a simple memory element.

And so much of the inspiration is coming from the electrical side, but I think many of us are now recognizing that many of the analogies and motivations fall apart when you move to biology, and we're now increasing, looking to see what are some of the natural circuits that are utilized by organisms that have evolved over millions, if not billions, of years.

FLATOW: But if you can turn a yeast on and off, then you've created a memory device.

Dr. COLLINS: Absolutely.

FLATOW: You've made a DNA memory device which could be used in a biological computer.

Dr. COLLINS: You could. I mean, there remains an awful lot of interest in programming DNA, programming cells, to create biologic computers, but I don't think anytime soon you're going to have a PC on your desk with E. coli inside on the front, and in part it's that these switches are still very slow.

FLATOW: Might be a Mac, though.

(Soundbite of laughter)

FLATOW: 1-800-989-8255.

Dr. COLLINS: It should be an Apple computer.

(Soundbite of laughter)

FLATOW: There you go. Let's go to George from Chariton, Iowa. Hi, George.

GEORGE (Caller): Yeah, hi. Yeah, say I kind of like my beer just the way it is. I don't really want you to be messing around with my beer, for number one. And number two is it seems, you know, in my basement, I've got lots of little electronic circuits I worked on when I was a kid. And, yeah, a lot of them didn't work, but they didn't replicate and get out into the environment and replicate.

It seems to me there's a real danger here of you creating something that you don't understand, and the consequences, you can't fathom. And it's going to get out in the environment, and yeast cells, for instance, are going to be doing things in the environment that we didn't really want them to be doing.

FLATOW: Like the Michael Crichton novel, that…

GEORGE: Oh, I don't know.

Prof. COLLINS: It's initiating concern. So two points now: one is that there are pretty strict regulations that arose in the early days of genetic engineering. Around - it focused on labs, such as mine, where we're quite restricted on what we're allowed to work on to prevent the accidental escape of something from our lab. And coupled with that, we also generally work with neutered organisms, so that organisms that we would engineer and change, if they actually did get outside, they would immediately get beat up by the tougher microbes that are out there.

GEORGE: Well, I'm…

Prof. COLLINS: But it is…

GEORGE: …I'm a farmer and all my neighbors raise genetically modified crops. And those Monsanto, et cetera, were allowed to release these organisms into the environment without thoroughly studying them and without the FDA conducting their own research. They accepted Monsanto's data on those organisms. And now, they're out in the environment and I don't think we know what the consequences of those things are.

Prof. COLLINS: Yeah. I suspect that in the case of the organisms that many of the syn-bio labs are working on, that if we were to put them out, I suspect there would be pretty tight regulations to clear what would be potential consequences that could come out. The second point I want to make on this is that there are efforts now, in synthetic biology, to put natural expiration networks into these organisms, so that if they did go out into the environment, (unintelligible) you might intentionally put them out to create an engineered bacteria, used for example, as a biosensor to sense if there's anthrax or some other pathogen in the environment - that groups, including ours, are now working on circuits where you would have the cells essentially commit suicide after, say, five hours in the environment or two or three days in the environment.

FLATOW: Good call, George.

GEORGE: Okay. Thanks.

FLATOW: Thanks for calling. Do you patent these things?

Prof. COLLINS: We patent some of the circuits. We make all the parts and components freely available to the academic community, but we have pursued some patents. And there has been some interest, including from ag-bio companies who are interested in some GMO aspects of either crops or plants.

FLATOW: Mm-hmm. So what kinds of different circuits are you working on now?

Prof. COLLINS: So we are also working on engineering schemes that could basically link to your earlier speaker as tumor fighters. So we're working circuits that would invade bacteria, that are congregating near a tumor, and that could then produce an anti-tumor agent that could go in and begin to battle the tumor.

FLATOW: So you would program the bacteria that - you put it in the bacteria and the bacteria then makes something?

Prof. COLLINS: So that's one I think that Chris Voigt at UCSF is actually, right now, working on that. We're working on actually engineering the viruses that would infect the bacteria…

FLATOW: I see.

Prof. COLLINS: …that are already at the tumor. We're also now working on a circuit that can learn. So we want to now program the bacteria so that it can learn a situation, learn an environment and make adjustments and actually change the way it's wired in order to alter its output.

FLATOW: Talking about synthetic biology on SCIENCE FRIDAY from NPR News. I'm Iraq Flatow talking with Jim Collins at - who is professor of biomedical engineering at Boston University.

Is that the name you use, do you call them circuits?

Prof. COLLINS: We use - yeah, we say circuits or networks. Again, bringing in the electrical engineering analogs.

FLATOW: Mm-hmm. I interrupted you. What other things are you working on besides those?

Prof. COLLINS: So we're also working on oscillators. So, can we create circuits that would go in and periodically produce a protein? In this case, they could be useful, for example, in mammalian drug therapy. So you could put it into human - in the cases where you need a protein that's produced in a periodic fashion, you could have this as the output.

FLATOW: Why do you call it an oscillator? To me, as an old engineering student, an oscillator was something that made radio waves or sound waves or something like that.

Prof. COLLINS: So the oscillator here would be a system that would produce a protein periodically.

FLATOW: I see.

Prof. COLLINS: You would have it going so that it, for example, might produce a burst every hour or it might actually produce continuously a protein, but it's going to go from a low amount to a high amount, then to a low amount to a high amount.

FLATOW: So you're dosing somebody with something.

Prof. COLLINS: Exactly. You're dosing somebody in a controlled fashion…

FLATOW: Right.

Prof. COLLINS: …where you could now have this implanted in the person.

FLATOW: Mm-hmm. Or you're taking the place of medicine or body function - let me just say, for example, like insulin. You're making it in the body for the body.

Prof. COLLINS: That's right. That's right. And there's efforts in synthetic biology to create glucose sensors that are cell-based, that could then produce appropriate amounts of insulin in response to changes in blood glucose levels.

FLATOW: Mm-hmm. So there's a lot of interest in this, in synthetic biology to make these things.

Prof. COLLINS: There is. You know, as I indicated, there's a number of engineering departments - most of the major research universities in this country are looking to hire and expand in this phase. There are fairly, a growing number of concerns, as was evidenced by the caller, about, are we kind of running amok in these labs, are we out of control and what sort of regulations are needed to make sure that we don't create something that would escape. And I think these discussions are healthy and needed. My sense is that the regulations that were put in place 30 years ago, with genetic engineering developments, are right now, suitable for what we're doing, because we're really just taking baby steps.

FLATOW: Yeah.

Prof. COLLINS: We're effectively genetic engineering on steroids, but we're not yet anywhere close to being out of control or a chapter in a Michael Crichton novel.

FLATOW: Yeah. You're referring to the Asilomar Conference?

Prof. COLLINS: Yes.

FLATOW: Back in '74? Yeah. So are you getting stimulus money for this kind of work?

(Soundbite of laughter)

Prof. COLLINS: Right now, we're very fortunate. Our lab is well funded by the HHMI, Howard Hughes Medical Institute - NIH - so we're now pursuing the stimulus money. We're just trying to recruit as many talented folks as we can into the lab.

FLATOW: And getting corporate partnerships with this?

Prof. COLLINS: Ah, so there has been an awful lot of company interest around the synthetic biology effort. As the Howard Hughes Medical Institute investigator, I'm actually prohibited from taking company money. But we have had a lot of interest, separate than from the sponsorship aspects, for people licensing (unintelligible) companies.

FLATOW: And who owns the intellectual property of what you create?

Prof. COLLINS: So the work that I created up till now has been owned by Boston University. And now, future work will be jointly owned by B.U. and Howard Hughes.

FLATOW: Hmm. And possibly, as you say, patentable, and products made from it later on.

Prof. COLLINS: That's right. That's right.

FLATOW: Sounds good.

Prof. COLLINS: And their interest, the Howard Hughes and B.U. to actually to get it out there and see that it's used.

FLATOW: Yeah. Sounds very exciting.

Prof. COLLINS: Yeah. It is. You know, we're really, really excited to see different things that can happen in this next decade or so, particularly as the young people come in with new ideas.

FLATOW: Hmm. And this is where scientists are going. That's good.

Prof. COLLINS: Yeah.

FLATOW: Better than Wall Street.

(Soundbite of laughter)

Prof. COLLINS: Yeah. Yeah. We got to recruit the better minds back into these labs.

FLATOW: All right, Jim. Thank you very much.

Prof. COLLINS: Thanks, Ira. Thanks for having me.

FLATOW: Good luck to you. Jim Collins is an investigator in the Howard Hughes Medical Institute and a professor of biomedical engineering at Boston University. Interesting stuff there, talking about synthetic biology.

We're going to take a break and talk - still talk about gadgets, not synthetic biology gadgets, but green gadgets that you can make at home, you know, if you want to live Earth Day every day. What kind of stuff is around the house? What kind of things can you do with the junk you might be throwing out? What other useful things, if you want to recycle it into making something else, Cy Tymony is going to be here talking about that.

Stay with us. We'll be right back after this break.

(Soundbite of music)

I'm Ira Flatow. This is SCIENCE FRIDAY from NPR News. Transcript provided by NPR, Copyright National Public Radio.