Paul Freemont - Biosensors hacked yeast

09 December 2015

Interview with

Paul Freemont Imperial College London

Kat - Back in October we visited the world of synthetic biology - using genetic engineering techniques to cut and paste DNA together to create exciting new biological components that can do all kinds of things. Now we're returning to that theme with a look at some of the potential applications being developed using synthetic biology approaches. Paul Freemont is co-director and co-founder of the Imperial College synthetic biology hub in London, and he told me about some of the exciting approaches he and his team are exploring.

Paul - We have all this huge antimicrobial problem and we have a lot of need to have very good, possibly point of care diagnostics that could detect infections, bacterial infections or whatever quickly and cheaply and reliably. So, one of the great projects I think that my lab is working on is to develop a whole series of in vitro biosensors. What I mean by that is that you could use a living cell as a biosensor. But because of the application space, people feel slightly uncomfortable having an E. coli as a biosensor.

Kat - Yeah, bacteria sensing bacteria seems weird.

Paul - And which one is the good one and which one is a bad one, and all that stuff. So, we early on decided, well okay, some people might feel uncomfortable with that. So, let's think about, "Can we use the cell extract which would have all the machinery to be able to run our genetic programmes that we've been designing?" So essentially, what we use is the cell-free extracts. So they're non-living. They don't have any DNA in them. And then we put into that extract our designed DNA which would then make some proteins, which would then detect various signals that are analytes or small molecules or whatever you want to call them - chemical molecules which would indicate the presence of a pathogenic bacteria. And when that molecule bound that little chemical entity, it would then activate the production of some colour or some fluorescent protein or something else. But it's all genetically encoded if you see what I mean.

Kat - So, it's kind of almost the same idea with like pregnancy test stick or something like that where you pee on it, it changes colour but this is a biological system that's changing colour.

Paul - Perfect example, perfect analogy. I think what's exciting about this type of approach is that there's been some recent work from colleagues in the United States to indicate that these cell-free extracts can actually be freeze dried onto filter paper potentially. We've also been working on other kinds of materials that we can sort of freeze dry these extracts. So, it's essentially quite a complicated extract and it's got a complicated piece of DNA in it. But actually, this could end up being an incredibly simple device.

Kat - So, you could just pee on it?

Paul - Yes, theoretically. That's kind of exciting because it would be very cheap, easy to use, and it would be quite safe. It wouldn't be quite safe - it would be very safe.

Kat - So, that's using this kind of technology to detect bacteria, pathogens in the environment. Are there other things that you could detect?

Paul - There are and I think people are very interested in detecting sort of potential diagnostic biomarkers that could indicate if someone is unwell or if they've got a continual condition like diabetes or whatever or if they might have had a heart attack, there'll be some people who are very interested to have early detection systems or whatever. You can imagine the kind of scenarios. So, there are a whole bunch of other people and ourselves working on biosensors that would detect protein biomarkers. So maybe, we'll end up with sensing protein markers and protein markers in the urine or in the blood which could indicate either cancer or some particular early stage physiological dysfunction. So, those are very exciting. And then the other ones I think which are also very exciting is developing sensors that could be used in more global healthcare scenarios. So, one other sensor we're working on in my lab is to detect the schistosomiasis parasite. This is a very debilitating disease. It's a waterborne disease. It affects 200 million people in the world. It's a tiny little parasite that actually uses humans as part of its lifecycle, so it's a really interesting bit of biology. But it would be really good if we could have a very local, very cheap, simple diagnostic sensor to test water samples. Not necessarily to prevent people from going into water but just also to understand the disease, to understand just the epidemiology of the disease, and just also to have a tool that local water management people could use in that kind of area. So, we're working on that as well.

Kat - How about another thing that's really exciting? Tell me about something else that's really cool right now.

Paul - The other really amazing project which we're involved in is called the synthetic yeast project and this is a really, really exciting project because what the project is about is to essentially synthesise chemically all of the chromosomes of Saccharomyces cerevisiae. Now, Saccharomyces cerevisiae is better known as baker's yeast and you use it to make bread and make beer or whatever you ever use it for. And it's also very well-known. It's a very well-studied organism and we've been studying it for hundreds of years, thousands of years, we've been using them. So the idea is that can we replace the natural chromosomes in that cell - and it's a eukaryotic cell, i.e. it's not a bacteria, it's a much more complex cell - can we then replace it with synthetic semi-designed DNA?

Kat - So, can you engineer a yeast to be exactly what you want it to be?

Paul - Yes and also, the great thing about this project and it's a world consortium. It's led out of the US by a guy called Jeff Boker who's in New York and Jeff set this consortium up. So there are people in China, people in Australia, people in Singapore, and in the UK Imperial College working on different chromosomes because there 16 chromosomes. It's a massive project and we're working on chromosome 11 and this is led by my colleague Tom Ellis in our centre. He's a fantastic synthetic biologist. And so, Tom has been leading on the synthesis of this and I've been involved in the project as well. The idea is that not only can you get a yeast cell which has been essentially controlled by designed synthetic chromosomes - that's what we're aiming for - but also, we've built into the designs, bits in the DNA sequence that allow you to essentially scramble it. So, this is the really cool bit. So, we can induce production of a protein in this synthetic yeast cell which will essentially start recombining differentparts of these synthetic chromosomes. So, we could end up scrambling the whole genome and then plating the yeast off and looking for different phenotypes, like a yeast that produces much more alcohol might be interesting or a yeast cell that...

Kat - Woohoo! Or a nicer bread?

Paul - Or a nicer bread or a yeast that grows at higher temperature. From an industrial biotechnology point of view, it's a terribly important project because yeast is a very good cell for manufacturing chemicals or pharmaceuticals or drugs, or whatever. And so, if we can build these kind of interesting yeast strains that have particular properties that are very useful for manufacturing, are very useful for whatever, that could open up a whole plethora of different applications. And finally, we will also learn a lot about biology because by scrambling all these genomes up, we're going to learn all sorts of weird stuff about why is a cell growing at 42 degrees for example. It shouldn't be. It should be dead. The wild type strain doesn't - so, what have we done to create those properties? It's going to be very interesting.

Kat - Does it feel a little bit strange to effectively be evolving yeast or I suppose, to use a terrible phrase, to be playing God to yeast

Paul - Well, I don't consider playing God. I mean, I consider it to be more engineering. As you probably realise, we're very focused on the sort of engineering approach to synthetic biology. Yes, we're exploring accelerated evolution and I think that's right. You were right in saying that. You can't select naturally different strains but it takes a long time. It doesn't always work. This is an acceleration of that process, but it's also something we've never been able to do before which is explore the boundaries of chromosome organisation, how genes are regulated and turned on and off. Just by scrambling everything and then look and see what's happened and what it produces is a really interesting experiment, just on its own right.

Kat - Paul Freemont from Imperial College London's synthetic biology hub.

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