Synthetic Biology: New Tools, New Approaches, New Thinking- Interview with Professor Paul Freemont

Paul Freemont
Contributor: Paul Freemont
Posted: 08/20/2013

Gerald Clarke:           Hello, I’m Gerald Clarke, editor at PharmaIQ. Today I’m joined by Professor Paul Freemont, Chair in Protein Crystallography and Co-Founder and Co-Director of the EPSRC Centre for Synthetic Biology and Innovation at Imperial College London. Professor Freemont, it’s a pleasure to have you here.

 Paul Freemont:           Hi, it’s great to be here.

 Clarke:           So Professor Freemont, could you give a bit of introduction for yourself and give us a little background about how you became involves with synthetic biology?

 Freemont:       I started off life as a protein crystallographer, as a structural biologist, very interested in understanding the molecular mechanisms of proteins involved or linked to human disease, and I spent quite a lot my years studying these proteins and these structures and these mechanisms. I worked for Cancer Research UK London Research Institute and spent a lot of time surrounded by molecular cell biologists interested in understanding cancer and the basis of oncogenesis and cell growth and all the rest of the stuff that goes along with that and came across many interesting proteins and structures and complexes, including the RING finger domain which I first identified and discovered in 1991. But in about 2000 I decided to move my lab over to Imperial College in London and became Director of the Centre for Structural Biology.

 Imperial College is an amazing institution because it has a very strong engineering faculty, very strong physical science faculties and I became, rather than surrounded by molecular cell biologists, as I was in the London Research Institute, I actually turned out to be surrounded by engineers and physicists and chemists, which was a great experience. Particularly I met an engineer called Richard Kidney who prompted us to discuss lots of different things about engineering, about biology, about scale, about all sorts of interfacial activities. Being a molecular structural biologist I was very interested in a scale which is very, very small and Richard, as a biomedical engineer, was interested in a scale which was much larger. And we talked about scales and we talked about how you would bridge all the different scales in biology because we all work at these different levels. And then we started talking about how biological systems are coded, how they’re built, how they’re assembled and we suddenly had a real interesting debate one afternoon actually talking about all this stuff.

 Richard is a visiting professor at MIT and he was over at MIT and he was talking to some of his colleagues over there and they said yes, this is all very interesting because it sounds a bit like this new field that’s coming along called synthetic biology, which was being developed out of MIT from colleagues, Tom Knight, Randy Rettberg and Durandy who were all developing this concept of how you would bring engineering into biological systems, the idea of considering biology to be component led, if you like, DNA as being a code for different components and how you would bring these together and how you would build things.  And so Dick and I were in MIT and we visited them – this was in early 2004 – and we suddenly got very excited by this whole concept and that was really where we started working together in 2005 on thinking about what synthetic biology is, how it would manifest itself in a research scenario and what the different things that would be needed were to achieve the field at that time. This was several years ago. So that’s really how I got into it. It’s a bit of a circuitous route but I think one that was a very interesting route and I think it came about by interacting and being around different colleagues from different disciplines.

 Clarke:           This might seem like a tough question but what’s your definition of synthetic biology?

 Freemont:       Synthetic biology, in my view, because of how I got into it, is essentially bringing engineering directly into molecular biology. So molecular biology has been around for a long time, since the 1970s, and we’ve been manipulating DNA and cells and cloning and all the rest of it for a long time but we’ve never adopted any systematic approach that engineers adopt. So when you bring an engineering framework into molecular biology you end up with this new potential opportunity for how you build and design biological systems. So the definition that we often use and ascribe to really and I think probably most of the people in the synthetic biology field internationally ascribe to is that it aims to design and engineer biologically based parts, devices and systems as well as redesigning existing natural biological systems. So it’s this systematic design that seems to be the big driving feature for synthetic biology which makes it very different than molecular biology, than cloning, than even metabolic engineering and all of these other biotechnology associated technologies. They’ve often not been driven through an engineering framework and I think that’s quite unique actually.

 Clarke:           What are the top three challenges that you face and how can these challenges be addressed?

 Freemont:       If you accept the definition of the field as being one of really merging engineering with molecular biology and using essentially DNA as the vehicle to code for different biological phenotypes, ie building parts, building piece of DNA, putting piece of DNA together, characterising biological parts, therefore the real technological difficulties are going to be around how we develop platforms that would allow this rapid part characterisation, how we treat host cells – synthetic biologists often call them chassis – as vehicles for running different DNA circuits, how do we build communitorial DNA circuits of large lengths, and essentially how would we engineer in a systematic way a design based on in silico modelling which would allow us then to do prediction on the function of the design before we actually implement the design. So it’s very much like an engineering framework and therefore there are a lot of technological barriers to get over that. I suppose the main technological barrier is already happening now, is the ability to synthesise very large pieces of DNA very cheaply and very rapidly and using methodologies to allow us to assemble very, very large pieces of DNA. That technology is now really beginning to mature. There is still a long way to go before it gets towards the base of DNA sequencing which is incredibly mature and incredibly cheap.

 But if DNA synthesis reaches that level then I think we are in a completely different ballpark because we have all of the genomic information and metagenomic information that exists in the world, we have a huge amount of information about how biological systems work and if you combine that with the ability to provide a rational systematic design framework around engineering, around parts, around design, around computer aided simulation and computer aided design, Bio-CAD, then you can just design things, send things off, get potentially whole genomes synthesised but certainly very, very large pieces of DNA synthesised and sent back. That opens up an extraordinary new world, if you like, of opportunity.

 Clarke:           So along with being able to synthesise long segments of DNA, what technologies do you think will change this field the most in the future?

 Freemont:       I think it’s going to be the ability to develop this systemised design framework based on in silico modelling. So engineering is, when you build engineered structures you are usually working with standardised components. And I think technologies to give standardised biological components are going to be important, so measurement technologies, measures tools, what is a standard, developing standards in synthetic biology is really important. But the ability to then do computer aided design and computational design, computational modelling and simulation based on our understanding of biological systems to allow predictability or a robustness of the design to occur in silico is going to be a massive leap forward if we can get that to work. That of course is reliant on the ability of us to understand biological systems at a sufficient level of detail where the modelling becomes predictable and robust, and of course that’s a whole area called systems biology and we’re still working out very good systems models for how biological cells work. So I think getting that simulation and computer aided design seamlessly integrated into platforms that allow testing and characterisation and DNA assembly rapidly is going to be a key driver I think for the field.

 Clarke:           What is the BioBricks Foundation and what do they do?  

 Freemont:       The BioBricks Foundation is a really interesting foundation. So this is a non-for-profit organisation. It was established to allow essentially this new field of synthetic biology, the engineering biology to be conducted in an open and ethical way to benefit all people, so to try and provide a democratisation of the science that we’re developing, if you like. So it’s a new paradise, it’s the idea of ethical and open innovation around biotechnology which has not existed. One of the bases of that will be to provide a BioBricks public agreement which is a way of synthetic biology of some people sharing parts. Because I think, as I mentioned to you earlier, synthetic biology is built upon this idea of building systems using biological parts or components. So the BioBricks Foundation has been working very hard in developing a public agreement, a free to use legal tool that would allow individuals, companies and institutions to make these standardised biological components of parts free for others to use. And that’s quite an important part of our field actually because I think what’s happened up until now, at least in biotechnology, is that there’s never been this idea of sharing, pre-competitive sharing of any information actually. So I think the BioBricks Foundation is trying to find a way forward because one of the great problems with synthetic biology is... As we develop more and more sophisticated designs, more and sophisticated biological parts, one of the things that we’re worried about is some of these parts becoming entangled in intellectual property and preventing, essentially, the field to really push forward. So it’s this sort of open source parallel if you like or analogy that exists and computing is something that’s driving this kind of thinking.

 Clarke:           What are some of the projects in the field that you think are showing the most promise?

 Freemont:       That’s a good question. Clearly this is a new field, it’s early days but there have been some amazing challenges that have been already overcome. I think one of the most interesting projects for me is, well there are a couple of interesting projects actually, is the synthetic yeast project which Imperial College is involved in with my colleague, Tom Ellis, leading that project with myself. And the synthetic yeast project is trying to, and it’s an international consortium led out of Johns Hopkins University with a really amazing yeast genealogist called Jef Boeke and who’s developed this whole concept of trying to re-synthesise or re-factor if you like all of the chromosomes of  yeast. And of course that’s a big project given there are 16 chromosomes in saccharomyces  cerevisiae, it’s a eukaryotic system and the idea here is that we’ll be designing and synthesising these chromosomes and then putting them into yeast cells and essentially replacing the natural chromosome with a synthetic chromosome. I think that’s a very exciting project if that works and I think there’s so much data to suggest that it will work, but that’s very exciting.

 The other very exciting projects which were published this year were the emergence of very well defined and robust genetic logic gates. So this is the idea of information processing because synthetic biology is about building engineered systems, and part of those systems is in information flow, decision making and all the rest of it. So these genetic logic gates are pieces of DNA that have been designed to work in all of the Boolean logic that one would find in a computer. So these would be two inputs gives one output or one output plus one input gives an output plus another input. So there are all of these wonderful logic gates which are essentially useful for designing information flows or genetic circuit control. And so there’s been two lovely papers, one out of Drew Endy and one out of Tim Lu at MIT this year showing that you can make these logic gates based on a very interesting biological enzyme recombinant which will essentially reverse, will cut a piece of DNA and reverse the orientation of that DNA. And through using that simple system they’ve created all of these decision making logic gates, so that’s a fantastic advance in terms of components if you like, the core components that we’re going to use to build and design really complex genetic circuits.

 And then the third project which I think is really showing this amazing field is out of Chris Voigt out of MIT where... He’s got a lot of projects but one project that catches the eye is he’s refactoring the nitrogen fixation operon cluster which is a huge project. So this is like 20 genes, seven operons and he’s trying to bring them together in a refactored cluster which is 23.5 kb. But not only is he just doing one design; what he’s doing is he’s doing multiple, multiple designs, so this very large fragmented DNA and he’s learning rules and principles about the optimisation. He’s got some designs now which are producing good nitrogen fixation results which have got no resemblance to the genomic organisation in nature. So I think that’s a really exciting project and he presented that at the international meeting we had at Imperial College in July at SB6, so suggesting that you can essentially redesign natural systems and get completely unnatural arrangements giving good biological activity.

 Clarke:           As you said, it’s a fairly new field. SB6, as in the name, is only six years old which is very new for science but so far how well do you think the academic research in this field is translating to results in the industry?          

 Freemont:       It’s early days. I think one of the exciting developments that I’m personally involved in with Richard Kidney, my co-director at Imperial College, is the development of an innovation knowledge centre at Imperial College which will be established in October this year. That’s a government funded centre and the aim of that centre is to allow academic research to be translated into industry to address industrial problems in using these new synthetic biology emerging technologies. It is early days. A lot of the big companies are looking at this field as being incredibly important, including pharma and I think we can talk about some of the pharma applications in a minute. But I think it’s clear to everyone in the field and into industry that the toolkits, the technology, the synthetic biology approach, the design, the DNA assembly, the rapidity of designing different genetic circuits and testing them, which we’re beginning to do now in academia, is going to be extremely useful in industrial settings. So the translation I think is going to accelerate over the next couple of years.

 There are quite a few synthetic biology spin-out companies around, there are quite a few start-ups in the US, some have been more successful than others but, like in any new field, some of these start-ups have made great progress but have maybe not made as much as they wanted but that’s been useful for the field and it’s been useful for the investors. So I think there are some really good examples now coming down the pipe of synthetic biology start-ups where I think they’ve got a lot of opportunity. So I’m very optimistic about the translatability of this field. And the other point about it of course is that synthetic biology is very application focused so it’s really applying biology in a way that we’ve never done before by using, again, systematic engineering approaches, using a completely different philosophy on how you build systems to do things and I think that’s very powerful. And biotechnology has been very, very successful to date but it’s never really fully maximised the opportunity I don’t think and synthetic biology will allow biotechnology to really maximise the opportunity.

 Clarke:           You mentioned pharma there. How do you think synthetic biology will influence pharma in the future?

 Freemont:       I think what’s interesting about, if we look at where synthetic biology applications are now, a lot of people are interested in building biosynthetic pathways, pathway building, pathway engineering, essentially metabolic engineering but trying to apply synthetic biology approaches to metabolic engineering as I’ve described. Pharma, for many years, have had a great interest in production strains for either antibiotics or for other therapeutics and these production strains have been developed using traditional selection methodologies. I think they’re extremely interested in trying to apply new synthetic biology processes for maintaining and developing either their existing production strains which have been around since the 1980s, some of them in some of the big pharmas, where some of these production strains will become less robust just through natural adaptation and evolution and mutation. And I think they’re quite interested in developing new chassis, new strains but using a more synthetic biology approach, ie more of a systematic analysis, systematic design.

 And I know that companies like GSK have developed groups that call themselves synthetic biochemistry groups; they’re interested in pathway design but the other major interest I think from pharma, and other chemical companies actually, is in biocatalysis and biotransformation.  So this has been around a while but I think the idea here is that some of the chemical synthesis stats which are, to try and replace those with more biological based synthesis steps which will be a bit greener, probably more efficient, slightly cheaper. So instead of having your chemical reaction being catalysed in some acid with some organic solvent, you just put in a set of bugs to catalyse the reaction, if you see what I mean. So there’s going to be this idea of developing microbial based biocatalystic organisms that will carry out particular chemistry. It’s not going to replace synthetic chemistry but it’s going to add in certain components within the chemistry pipeline which will be biologically based, particularly for complex chiral synthesis or a particular complex stereoisomer separations or whatever where there are some issues in the chemical, in pharma in some of the manufacturing processes.

 So I think in the bio-manufacturing area, I think pharma are very interested in synthetic biology providing new tools, new approaches and new thinking. And also in the biocatalysis world where we can start harvesting the rich biological environment that we have, the metagenomic environment, all of these weird and wonderful organisms around the planet that catalyse all the most amazing chemistry you could think of and trying to harness those and trying to characterise those and trying to get toolkits. So in the future I guess the chemical synthesis production platforms will have strong biological components within them. So I think that’s more an immediate term.

 Now, in the future, clearly in the long term as the field develops into a more systematic engineering field then I think pharma will be looking at more sophisticated and maybe more whacky projects which could be micro-organisms delivering insulin to patients for example and sensing glucose levels in blood and all these more futuristic application things. I know that some of the speculative applications like that or even micro-organisms that would locate cancer cells and do something, all of that more speculative stuff, I know that some of the bigger pharmas are interested in that thinking because it may or may not be relevant now but thinking like that in the future is very, very interesting. And I know that pharma is certainly thinking in some way towards those future therapeutic opportunities.

Clarke:           Thank you very much, Professor Freemont, for sharing your insights and your time with us today. It’s been a very stimulating discussion.

Paul Freemont
Contributor: Paul Freemont
Posted: 08/20/2013

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