Synthetic Biology

16 May 2010
Presented by Chris Smith, Diana O'Carroll.

We explore synthetic biology in this Naked Scientists Show, finding out how to learn from, and improve on, the structures and systems we find in nature. We'll meet the team of students who designed a biological sensor to win the international genetically engineered machine competition, or iGEM, and find out how to build bespoke proteins. In Kitchen Science, we feed an egg to some enzymes to find out how biological washing powder works. Plus, what the brain does when it sees a familiar face, genetically modified crops boost resistant bug numbers, how to create hair cells, essential for hearing, in the lab and how Tibetans living the high life have different genes to their lowland neighbours!

In this episode

01:18 - Brain scans to recognise facial recognition

This week a group of researchers from California have been able to spot the moment at which your brain recognises a face. They’ve done this using the brain scanning technology known as fMRI...

Brain scans to recognise facial recognition

This week a group of researchers from California have been able to spot the moment at which your brain recognises a face. They've done this using the brain scanning technology known as fMRI - or functional magnetic resonance imaging.

The team, led by Jesse Rissman, had their test subjects look at hundreds of faces from an image database. They were then shown a new set of faces, some of which had appeared in the database. As the subjects looked at each of these new pictures the researchers scanned their brains to see if anything happened.

When the subjects did recognise a face there was an identifiable pattern of neural activity in their brains. According to the journal PNAS, where this was published, the team used software to recognise this pattern as there were quite a few neurons to consider. They found that this so-called 'neural signature' when a brain recognises a face was consistent across all the test subjects. So it's likely that whenever any of use recognises a face, the same bits of our brain 'light up'.

There was one problem, however, in that sometimes the test subjects recognised a face even when they hadn't seen it before. Their brain activity was the same as with a genuine recognition so if you wanted to take an fMRI of someone examining a police line-up it wouldn't be able to rule out any false-positives. The scanning software can tell you if someone believes they recognise a face but one of the key findings here is that the researchers have been able to pinpoint what happens when memories are triggered.

04:03 - GM boosts bug populations

Scientists have found that cultivating pest-resistant GM crop strains can paradoxically create a whole new breed of bugs...

GM boosts bug populations

Scientists have found that cultivating pest-resistant GM crop strains can paradoxically create a whole new breed of bugs!

Writing in Science, Beijing-based researcher Yanhui Lu and colleagues show that after ten years of growing GM cotton in northern China, a previously low-level pest, called the mirid bug, has now risen to prominence and become a serious problem.

Lygus pratensisThe cotton plants in question have been engineered to produce a toxin made by the bacterium Bacillus thuringiensis (Bt), which kills off susceptible pests that try to devour the cotton plants, including one notorious nuisance, the cotton bollworm, Helicoverpa armigera.

In China, the modified plants account for over 95% of the cotton grown.  This has, in turn, translated into a dramatic reduction in pesticide use, but therein lies a problem.

Prior to the introduction of GM Bt cotton, farmers sprayed regularly against bollworm, which also had the effect of killing off other low-level pests like mirid bugs.  But with the introduction of the GM cotton strain, and the cessation of spraying, the researchers found that the mirid bugs, which are actually not affected by the Bt toxin, have increased their numbers dramatically.

But more significantly, they don't remain confined to the cotton field.  Being fairly unfussy eaters, they also spread to and infest other local crop species nearby.

This shows, say the scientists, that "area-wide cultivation of transgenic crops may bring various (direct and indirect) effects on ecological status of different organisms, which should be assessed or anticipated in a comprehensive fashion."

07:06 - Why mice don’t smell the fear but fear the smell...

Researchers have found the chemicals that make mice scared stiff if they smell a predator, such as a cat, rat or snake...

Why mice don’t smell the fear but fear the smell...

Researchers have found the chemicals that make mice scared stiff if they smell a predator, such as a cat, rat or snake.

Publishing in the Journal Cell, a team from California wanted to know what it was about these predators that caused stress hormone levels in mice to rise and why they'd flatten themselves against the floor - even if the predator wasn't visible.

Rattus norvegicus, the Brown Rat.Lisa Stowers and colleagues discovered that the trigger was a group of proteins, found in urine, known as MUPs (major urinary proteins). These are secreted by just about every vertebrate on the planet but they are very species-specific. And one section of the mouse's nose is very sensitive to these proteins.

The researchers already knew that the mouse vomeronasal organ could pick up pheromones from other mice but the idea that they were sensitive to those of other mammals is new. In their tests they placed mice which had an inactive vomeronasal organ close to an anaesthetised rat (so it wasn't going to eat them!). And because the mice couldn't smell any of these MUPs they showed no signs of fear. One even curled up and went to sleep next to the rat. So it shows that the visual spectacle of a rat on its own doesn't play a part in predator recognition.

The fear of cat, rat and snake smell must therefore be hardwired, since these mice have been bred in labs for nearly eighty years and very few would have met Mr Tibbles in that time.

09:30 - Now hear this: scientists make new hair cells

Scientists have discovered how to coax stem cells to become hair cells, the structures that turn soundwaves into brainwaves in the inner ear...

Now hear this: scientists make new hair cells

Scientists have discovered how to coax stem cells to become hair cells, the structures that turn soundwaves into brainwaves in the inner ear.

Stanford researcher Stefan Heller and his colleagues, writing in Cell, first converted mouse skin cells into stem cells by adding four genes, Oct4, Sox2, Klf4, and cMyc.  The resulting cells were then exposed to a host of different growth factors to chemically fool them into believing they were in certain parts of a developing embryo.  This encouraged the cells to specialise or differentiate in a highly specific way.  Finally the cells were grown next to a different batch cells taken from the inner ear region of a chicken, which pursuaded them to turn into fully-fledged hair cells that were mechanically sensitive in the same way as their genuine counterparts.

The organ of Corti (or spiral organ)These cells, of which there are about 15,000 in each human ear, carry thin hair-like projections at one end of the cell.  In the intact ear, these hairs, known as stereo cilia, vibrate in sympathy with soundwaves entering the inner ear to produce nerve signals that are transmitted to the brain's hearing areas.

Unfortunately, the relative scarcity of these cells, coupled with the difficulty scientists have experienced in trying to grow them prior to now, means that they are only poorly understood.

Yet one person in three is set to develop hearing problems in later life as a direct result of the loss or dysfunction of these cells because humans and other mammals, unlike birds, can't regenerate the cells if they are lost or damaged.

But now, say the scientists, the ability to produce large numbers of them means that it will become much easier to study how these cells can be protected chemically from age or sound-related damage, and even how to replace them.

"Perhaps the most promising strategy for taking advantage of this new source for hair cells is high-throughput screening for drugs to awaken mammals' lost ability to regenerate hair cells in the way that other animals can," says Heller.

11:53 - Ten genes help Tibetans thrive over 10,000 feet

Researchers have discovered why Tibetans who have a taste for the high life are much better able to tolerate low oxygen conditions that you find at higher altitude and that’s compared with...

Ten genes help Tibetans thrive over 10,000 feet
with Tatum Simonson, University of Utah

Chris -  Also in the news this week, researchers have discovered why Tibetans who have a taste for the high life are much better able to tolerate the low oxygen conditions that you find at higher altitude, compared with their lowland living counterparts.  It turns out that they carry at least ten unique genes that enable them to do it.  To tell us more, from the University of Utah, is Tatum Simonson.  Hi, Tatum.

Tatum -  Hi. 

Chris -  If you could tell us first of all, what was the reason for doing this study?  What were you aiming to find out?

Tatum -   We were interested in identifying the genetic basis for high altitude adaptation, what's interesting is that several research groups have done an excellent job characterising sets of physiological traits that are unique to native high altitude inhabitants.  These studies have suggested that populations have adapted to this extreme environment, but the genetic basis wasn't entirely known.Mount Everest from Rombok Gompa, Tibet

Chris -   So in other words, by living at high altitudes for many generations, these individuals must've accrued some kind of genetic changes that made them much better adapted to living there than say, me.

Tatum -   That's exactly right.

Chris -   So, how do you approach that problem?

Tatum -   It's only recently that we've been able to actually look at our genetic code, or DNA, and by looking at single changes in the DNA sequence, we can identify regions that have been subject to what we call natural selection - the idea being that these variants have been beneficial for some particular reason in a particular environmental setting, and have been passed on through the generations, and allowed individuals to survive.

Chris -   The thing is there are three billion letters in the human genetic code.  How do you home in on the bit that you think might be important in this instance?

Tatum -   So what we used was an approach that looks at what we call Single Nucleotide Polymorphisms (SNPs) or tags across the entire genome and we identified blocks or regions of the genome that exhibit a certain signature.  The signature that we see with natural selection is that basically, you have a whole region that's increased rapidly in the population.  That leaves behind a certain sign that we can look at and compare it with the rest of the genome.  It really stands out as a striking signal for us to then go in and analyse.

Chris -   So in other words, if you take people who live at high altitude in Tibet and have done for many generations and you compare them with the rest of the world who don't live at those kind of altitudes, and you're looking for specific hot spots in their DNA that keeps cropping up time and time again in the Tibetans but not in other people.  This points you towards thinking in that region of the genome, there must be some beneficial change that helps these people to survive where they do.

Tatum -   That's exactly right and we were able to do that by comparing the Tibetans with publicly available information on both Japanese and on Chinese populations.

Chris -   Those populations presumably being significant because they're going to be relatively closely related in terms of human ancestry to the people you're studying.

Tatum -   Right.

Chris -   So you can iron out a lot of other changes.

Tatum -   Exactly and they've typically lived in lowland regions which is key for our study.

Chris -   And when you did this, what did you find?  Did you home in on some genes that you do think enable these people to survive where I would struggle?

Tatum -   Yes, so as you mentioned, we have at least ten genes that we've identified and what's interesting is that two of those genes were actually correlated with a certain physiological trait which is unique to Tibetans.  That is the fact that Tibetans exhibit haemoglobin concentration which is similar to somebody say, living in London - so somebody at or near sea level.  Yet, they're all the way up at 4,000 metres.  Any non-adapted individual would increase their haemoglobin to compensate for the oxygen-deprived environment.  So, when we compared two of our selected regions of the genome to the haemoglobin levels we measured, we found that two of them actually are associated with this decreased haemoglobin level.

Chris -   So, in other words, if I went up to a very high altitude, I would compensate for the low oxygen by increasing the amount of haemoglobin.

Tatum -   Right.

Chris -   This helps me to get more oxygen around my body but has negative consequences because my blood's going to become thicker, stickier, gloopier.  Therefore, I'm more likely to have consequences like high blood pressure and heart attacks, and strokes.

Tatum -   That's right.  That's exactly right.

Chris -   But the Tibetans don't?

Tatum -   But the Tibetans don't, yes.  This area definitely needs more research.  We know that this isn't happening but it also could be a side effect of something else that's been advantageous and selected for - so that they don't need to increase their haemoglobin because they're already so efficient, perhaps through some other mutation.

Chris -   And I guess, just to finish off, the benefit of doing this kind of work is that there are situations where people who don't live in Tibet above 4,000 metres nonetheless have very low levels of oxygen in the bloodstream; I'm thinking people who have lung problems, lung infections, blood clots on the lung, maybe their whole body is exposed to low oxygen because of drowning or carbon monoxide poisoning or something.  Understanding therefore how people cope naturally in these environments might provide a clue as to how we develop medical therapies to help people who are acutely in that situation.

Tatum -   Yes, that's exactly true.  So, this information can definitely help researchers develop therapies or even drug targets for people who have various amounts of oxygen-deprived disease or that sort of a thing.

Chris -   Is that where you're going next with this?

Tatum -   We do.  We do hope to go forward.  The idea being if we understand why people do well then perhaps we can help those who aren't doing as well at high altitudes.

Chris -   Including one or two climbers perhaps.

Tatum -   Yes, that's true.

Chris -   Tatum, thank you very much.  That's Tatum Simonson.  She's from the University of Utah and she's published that work this week in the journal Science.

18:09 - What is Synthetic Biology?

What do we mean when we talk about Synthetic Biology? What does it involve? Dr Jim Haseloff from Cambridge University explains...

What is Synthetic Biology?
with Dr Jim Haseloff, Cambridge University

Diana -  So Jim, what do we mean by synthetic biology?

Jim -   Well, synthetic biology has quite a broad, some might say ambiguous meaning, and if you'd look up synthetic in terms of the dictionary and its definition, you've got two accepted meanings for synthetic and that's mirrored in the activities in the field.  So synthetic can mean artificial, something derived and unnatural, and there are many people looking at systems which are artificial and used in biology in the sense that they don't come from the natural world.  But as well as this, you've got the original meaning of the word synthetic, derived from its root which is - that it's pertaining to construction and that's really, one would argue, is one of the primary efforts in synthetic biology is to build new techniques for constructing or rearranging biological systems.

Diana -   So, if we're building things with biology, what kind of disciplines are involved in that?

Jim -   Well it's highly interdisciplinary because you've got the understanding of the biological systems that's required, as well as these formalisms that come from engineering.  So the idea that you can construct biological systems is based on the idea of modularity and having individual components that you can put together  - in a crude sense, like Lego blocks, in that they're modular pieces that can be put together.  But also, the complexity of biological systems which work in a very different way from normal man-made artefacts where a man-made artefact might be designed from the top down and things are connected from one to the other, but in a biological system, things are emergent, things have simple bases, but it's the interactions that build the kind of complexity that we see inside our biological systems, and that applies to artificial ones as well.  It's there that computational science plays a major role in our understanding of these systems and is required not just for understanding but also design.

Diana -   Can you give some examples of what synthetic biology has been used for so far?Salt

Jim -   Well it's a very nascent field, a very early field and in fact, in a way, the iGEM competition, this Genetically Engineered Machine competition that you'll be talking about in a minute is one of the major inputs into the field.  It's unusual because it's essentially a student driven competition and it's driven by this conception of people coming together and sharing components or modules.  The idea that you can take these simple functional elements and put them together into more complex systems is something that's quite new in biology.  We've been doing genetic engineering of systems for something like 35 years now as a field and there's been this relative huge growth in our ability to manipulate the basic systems.  An anecdotal way of looking at that, for example, is if you use the kind of understanding that we do have, you could ask any two biologists on the planet to put something together.  Any two molecular biologists could assemble a system if you defined it for them.  But they'd do it in a completely different way.  Each individual would use bespoke techniques to construct this and that's quite unlike any other form of engineering at this point.  And so, what synthetic biology is all about is putting in place the kind of rules and components that allow you to formally assemble systems in a regular routine way which every other form of engineering adopts.

Diana -   So, this isn't just biochemicals.  It's bio systems as well.  You're combining lots of different systems to give one outcome.

Jim -   Absolutely and I guess it's those lifelike properties that we take for granted, the fact that things can organise themselves and maintain themselves, and repair themselves.  They're the kind of properties that people need to deal with the major challenges in sustainable resources and things like sustainable agriculture where you've got a biological basis.  And to be able to re-engineer systems, you require this very different approach.

Diana -   One thing that science fiction likes writing about are biological computers.  How are computer scientists looking at this at the moment?  What's been done so far?

A light programmable biofilmJim -   The main approaches have been to take the idea that you can have simple components and there's this concept of emergence  - you can take simple underpinnings and they don't just mean parts that you can put together, but also the interactions that underlie systems which might be comprised of simple elements.  When it comes down to it, the kind of biology that we're talking about here, there are more similarities with social systems and economic systems.  We have complex behaviour and complex phenomena coming out of local interactions.  In the synthetic biology case, its interactions between genes and gene products in wider, say social situations - interactions between individuals.  You have simple drivers like in a society if you're hungry, you go and get food, and someone fills that because they need to get food themselves so they will provide food for other people.  And you have the kind of complex social systems you get around food and consuming food and society, which are driven by this very simple basic interactions.  It's a crude analogy, but in biology, you need to be able to think of how you could assemble those kind of systems - these complex systems, from these simple interactions.  Computer scientists have the tools which allow one to address these complex interactions and to look to engineer self organisation.

Diana -   So, they can use these tools to look at the organisation, but has anyone actually built something that can store bits, data, binary information?

Jim -   Well, there's a number of crude attempts to put together systems which will retain information, have genetic memory for example and information processing.  So essentially, all genetic systems are based around this idea of taking inputs and providing outputs.  So it's essentially like a cellular or genetic computer.  There are many small examples  - bio sensors for example, where one can take a simple input which might be the concentration of a chemical and produce a genetic response which produces some output, for example a pigment that you can see.

Diana -   And what do you think is next?

Jim -   The concept of synthetic biology and this idea of having more formal engineering approaches of manipulating genetic systems is not so much application oriented but it's a whole new process, a whole new way of looking at biological systems and being able to manipulate them.  And those of us in the field see that it may all make a major contribution to the kinds of things that we're moving towards in terms of sustainable technologies which will be based on biological feed stocks and replacing some of the rather damaging ways that we deal with the environment at the moment and to move towards sustainable technologies.

Diana -   Well, a little bit of plant fertiliser certainly sounds better than the 600-watt power unit that I've got on my computer at the moment!

25:36 - Do airline pilots have more haemoglobin?

Do airline pilots have more haemoglobin?

Chris - Airlines pressurise their airliners to about 7,000 feet worth of altitude, so slightly higher than ground level, and therefore, there will be a slight augmentation in haemoglobin, but not a huge one. Probably not a physiologically (in other words, bodily) significant effect.

If those planes weren't pressurised and they were flying at the kind of altitude they did, everyone onboard will be dead, of course. Most airliners are flying at more than 30,000 feet. That's the equivalent of the top of Mt. Everest where if you don't have supplemental oxygen there and you're not acclimatised, then you'd be dead very, very quickly.

So the answer is, when you go to high altitudes, you get a little bit more haemoglobin to compensate for the reduction in oxygen in the bloodstream, but it is proportional to how long you spend at altitude, and how high you go. And because those planes are not flying very high - equivalently speaking because of the pressure in the cabin - and the exposure is limited, there won't be a very dramatic effect, but there might be a small one.

26:49 - iGEM - the international Genetically Engineered Machine Competition

Meera Senthilingam catches up with members of a team from Cambridge University that took part in the iGEM 2009 project, fusing biological and engineering knowledge to solve real-life...

iGEM - the international Genetically Engineered Machine Competition
with James Brown, Alan Walbridge, Vivian Mullen

Chris -  Every year since 2003, teams of university students around the world - including from Cambridge University - have been taking part in a synthetic biology competition called iGEM.  That stands for the International Genetically Engineered Machine.  The teams who take part are actually given a kit of biological bits and pieces which include DNA and some gene sequences, and they have to use those to solve a bigger biological problem and then make their solution work in real living cells.  In previous years, the teams have made bugs smell like bananas or even wintergreen, which smells nice, and they've even built a bacterial arsenic sensor.  Meera Senthilingam has been along to talk to last year's Cambridge E. chromi team.  They built colour changing E. coli and actually won the competition and she's been finding out how they got into it and what they got out of it.  Graduate student James Brown was one of the supervisors involved.

James -   iGEM is an educational initiative that started about five years ago out of MIT, and it really is about bringing together students of different disciplines, typically biological science students and engineering students to think about some of the new challenges we're facing in the 21st century.  The teams vary in size from 6 to 12 undergraduates typically.  They're given a set of biological parts.  That's pieces of DNA that they're shipped at the beginning of the summer and that's made up of a series of switches and fluorescent proteins from coral and jellyfish.  All of the basic components that have been designed and built by previous teams over the summers gone by and then their challenged to not only create their own ones, but use those basic components to piece together and build modular biological systems.

Meera -   Thank you, James.  The E. chromi team consisted of four biologists, two engineers, and one physicist.  And with me is one of the biologists, Vivian Mullen.  Now Vivian, tell me about E. chromi then.  So what is it and what does it do exactly?

Vivian -   So E. chromi was our project that we developed over the summer.  Basically, it's a bacterial biosensor.  We built a bacteria to be able to sense the presence of a pollutant for example, heavy metal and then change colour depending on the concentration of that chemical.

Meera -   What is this biosensor made up of?E coli evolving in the lab

Vivian -   So it consists of three parts which are DNA parts.  The first part is the heavy metal sensor and which basically involves a protein that binds to the DNA when the chemical is present.  Then when it does, as it causes an output, so in a simple system, it would directly cause the output of colour.  But on our system, we also had a thing called a sensitivity tuner.  We had the heavy metal sensor then cause the expression of a protein which then bound to another piece of DNA and then made the colour output.  So basically, using different combinations of this protein and the other piece of DNA, we were able to change the thresholds of the output from the original heavy metal sensor.

Meera -   So essentially, you'd be able to test for different concentrations of certain chemicals.

Vivian -   Yes and then you would actually have a visible output and multiple different colours depending on how you design the system.

Meera -   And what bacteria was this all inserted into?

Vivian -   So this was an E. coli which is a standard host that we used.

Meera -   The main aim of iGEM is to bring together biologists, engineers, so people of different scientific areas.  So also here is Alan Walbridge who was one of the engineers on the team.  Alan, what was your contribution to this project?  So what would you say your key role was to look at when this E. chromi was being developed?

Alan -   So we brought numerical analysis to this project.  So we're looking at gene expression and an easy way to measure this is using a fluorescent protein and because we know that that doesn't decay very quickly, if we look at the rates of change of fluorescence, we can be fairly sure that corresponds to the rate of production of fluorescence and that then is the gene activity at that particular point.  And so, by doing large scale analysis, over different concentrations we're able to work out this gene activity.

Meera -   Essentially, you were kind of looking at the data and the actual kind of numbers involved with the project in order to see how effective it was.

Alan -   Yes, that's right.

Meera -   And how Vivian, would you summarise the biological contributions to the project?

Vivian -   So we were able to do the lab work and then bring some biological incites to interpret the data set the engineers had put forward.

Meera -   What would the aims then of this type of design be?  What would be some hopeful or potential applications of this?

Vivian -   A member of our team is actually - she's graduating this year and is staying on to move some of these parts into a different host so we were working in E. coli, but possibly, other hosts would be more useful for applications of this design, and then other members of the lab are working on moving it into plants.Child drinking from water pump

Meera -   What would be some potential real world applications if this was developed even further?

Vivian -   So the point of our project was to solve a problem of water contamination.  We wanted to develop a really accessible user friendly technology that anyone could use to test whether or not the water is contaminated and safe to drink.

Meera -   And just lastly, I guess a key part of the project is just to mix the disciplines up as well.  So, what would you say you both learned about each other's disciplines?

Vivian -   So I learned how to think like an engineer which is not to think of what this does in its natural environment, but how could we use this in a system with other parts and how can we piece them together.  That was really interesting.

Meera -   And Alan?

Alan -   Like I said, I entered this with very little biological experience, but I learned an awful lot about how the bacteria work and through some intensive lab work over the summer, I feel I've become a little bit of a biologist now.

Chris -   I'd like to take part myself.  It sounds like fantastic, fun.  That was Alan Walbridge and before him, Vivian Mullen.  They're both students at Cambridge University and the winners of last year's iGEM competition.  You also heard the team supervisor and a graduate student, James Brown.  He was talking at the beginning and they were all chatting with Meera Senthilingam.  And looking at the iGEM website, it looks like they're expecting 180 teams around the world to take part this year, so it's certainly flourishing. 

33:00 - Improving Enzymes

One of the main aims that scientists have for synthetic biology is to be able to take what nature has already made and make it even better for doing certain jobs, and Dr. Ross Anderson at...

Improving Enzymes
with Dr Ross Anderson, University of Bristol

Chris -  One of the main aims that scientists have for synthetic biology is - rather than relying on nature to come up with all the answers, instead, we want to be able to take what nature has already made and make it even better for doing certain jobs, and Dr. Ross Anderson at Bristol University is trying to do just that.

Ross -   Essentially, what I want to do is create an enzyme from scratch.  So enzymes are a class of protein.  Proteins, being a polymer of molecules we call amino acids.  They're protein catalysts.  They perform and accelerate chemical reactions and there's a huge diversity of enzymatic catalysis, so photosynthesis for instance, hydrogen production.  There's a huge range of reactions which would be exceptionally good for us to actually tap into and harness the power of like solar power to generate hydrogen for instance.  That'll be very, very attractive.

Chris -   So these are nature's catalysts...

Ross -   Yeah.

Chris -   ...without them, the chemical reactions that keep us alive just couldn't happen.  It sounds like nature's doing a wonderful job.  Why do we need you?  I mean that in the nicest possible way.

Ross -   We still, after all these years working with proteins, have a fairly tenuous understanding of how to build function into them.  So we have a relatively decent understanding of how enzymes work, but so far, we've been unable to actually make one from scratch.  I think that there's a big gap in our understanding - if we can't make something from scratch, how do we truly understand it?  So that's really where I'm coming from and I think that if we can harness nature's tool kit then there's a whole variety of possibilities available to us.  The other thing is that through evolution, how these proteins have actually evolved and have been put together by nature, we have to some degree lost that history, and we don't have the benefit of seeing the selective pressures that these proteins were under through the course of evolution.

Chris -   In other words, we're seeing the finished product rather than the product being developed and that makes it much harder to get to the nub of how these things, these micro machines, work in the first place.

Ross -   Exactly.  So we see a protein that's been evolving for several billion years and then we want to change it in some way to match our own needs, and the problem we have is that it would be like, for instance, taking a Ferrari and trying to make it into a bus.  The essential elements are the same; an engine, wheels, but you know, it's going to be quite complicated to approach that in that particular way.

Chris -   So go on, give us some examples of things you've been working on.Haemoglobin

Ross -   So an example is an oxygen binding protein.  We've called it an artificial myoglobin or neuroglobin and what we did there was start with a very generic sequence, so we started with a protein that was made up of 100 amino acids, but it was only three different amino acids that made up these 100.  So we know it folds into a particular structure which is useful for us and then we sequentially added functions, so we took a molecule which is present in haemoglobin and myoglobin.  It's called haem and we inserted that into the protein interior.  And then what we did after that was change the sequence of the protein so that oxygen could actually access the haem molecule and reversibly bind.  This was actually the first example of a protein built from scratch that could do this particular function.

Chris -   Is this all done in vitro?  In other words, you make these things artificially in a dish, or are you actually at the stage where you can say, "Well that's the protein I want so I can work out what the gene sequence would be and then I can make that gene sequence and say, put it into E. coli or yeast or something to get that to make it for you."

Ross -   It's a little bit of both at the moment.  What usually happens is that we start with a protein sequence that we quite like and then we would synthesise it in vitro.  There's fairly decent systems now that are kind of almost like a robot which will build up your protein sequence for you.  They're quite expensive though and so we tend to prefer ordering an artificial gene which are now very, very cheap.  Then we get something like E. coli or as you say, yeast to make the protein for us.  So, generally, the proteins I work with, I get E. coli to make them which ends up exceptionally cheap in the end.

Chris -   Are there any risks associated with doing this kind of thing?

Ross -   With my work, I would say no.  the gene that we insert into E. coli is completely benign and certainly, it doesn't change how toxic the E. coli is to us.  So in that sense, no, there really are no risks with what I do personally.

Chris -   And looking to the future, say we can build bespoke proteins, would there be both therapeutic and industrial applications here?  Could you take some of these diseases that people suffer from because one of their own proteins is the wrong shape and build one that works better for them and put it in?A Prostate Cancer Cell

Ross -   Yeah, absolutely.  This is really what's going to happen in the future.  We're really at the beginning of this whole field even though it's been running for about 10 - 15 years.  There's not been a huge amount of progress.  Primarily, just because there's not really that many groups who've been working in it.  But what we could definitely see in the future is targeted therapies for improperly folded proteins in the body.  Also, directed therapies against cancer for instance, we can make antibody silent proteins to go in and perform a reaction which kills cancerous cells for instance.  Industry is really where my work would be more applicable to. In the future, in the absence of crude oil, we're going to have to look for other sources of fuel and a big area of interest is making methanol from methane.  Again, nature does this fairly well in the bug, but when we try and work with the proteins outside the particular bug, they're not so amenable to industrial processes.  So what we're really trying to strive for is a cheap form of catalyst that we can just grow, essentially.

39:13 - Dissolving eggs - the power of enzymes

Dissolving eggs - the power of enzymes

45:52 - Could synthetic biology be used for nefarious purposes?

Could synthetic biology be used for nefarious purposes?

We put this question to Dr Jim Haseloff, from Cambridge University:

Jim - Well I think, like with many technologies, there are different applications and certainly, as one can see with existing concerns about terrorist activity and other potential dangers, people are very concerned about the misuse of technologies. For example, recently the field has highlighted the fact that these synthetic biology technologies can produce different types of, and more extreme, risks which need to be guarded against,

Chris - I remember about seven years ago, someone decided to reassemble the genome of a polio virus using bits of genetic material they bought on the internet to prove that this was a genuine possibility that could be done. I suppose, taking that a step further, you could do some fairly nasty things, given how easy it is to do some of this stuff these days.

Jim - Yes. In fact, DNA synthesis has been identified as one of the main potential dangers - that people can reconstruct elements which might be pathogenic for example. Recently, there's been an agreement, an international agreement among the major DNA synthesis companies. So every sequence that are submitted for synthesis is now vetted. So it would be - I wouldn't say impossible, but probably very difficult to deliberately engineer a new DNA sequence for pathogen at this point.

Chris - But if you made those sequences really short, they're not going to know, are they? If you ordered them from lots of different companies and got lots of little bits to stitch them altogether. It would take you a long time but these people are dedicated. They want to do what they want to do and if they want to bypass the system, they're going to find a way of doing it.

Jim - Well I think the size of DNA elements that is unique is very small and it would be essentially impractical to make any large scale, even the smallest virus would be extremely difficult to construct that way.

48:08 - How are plants modified to be pest resistant?

How are plants modified to be pest resistant?

We put this question to Dr Jim Haseloff, from Cambridge University:

Jim - Organic farmers actually use bacteria - the Bacillus thuringiensis bacterium which has a protein which affects the gut of specific insects and that protein, of course, is encoded in the gene and that gene can be then transferred to plants using genetic engineering techniques. So it's essentially a surgical procedure of isolating the particular gene using a natural bacterium to transfer that into a plant and then once it's in there, it's used as a gene that's for breeding.

Chris - So presumably, with synthetic biology, what one would do is to say "rather than take that toxin from a bacterium, what would be better would be to study the organisms that we want to make the plant resistant to, and then find our own way of making the plant resistant" and put some kind of specific thing into the plant that will be even better than what a bacterium toxin could do for us.

Jim - That's certainly feasible in the longer term. I think most of the emphasis at this point is on better engineering using existing systems, existing parts from what we know in the biological world and rearranging their delivery inside say, for example a crop system, where you might get around some of the issues we're talked about earlier in the program where you've got some insects which are immune to these very specific toxins and can escape. So you can imagine a second element that would deal with that for example.

49:47 - Can plant mutations be transmitted to people?

Can plant mutations be transmitted to people?

We put this question to Dr Jim Haseloff, from Cambridge University:

Jim - I think it's safe to say no. The process of transfer - horizontal transfer from plants to humans requires some kind of vector, some kind of way of transferring it and I'm certainly not aware of any way of doing it,

50:14 - Why should GM seeds be sterile?

Why should GM seeds be sterile?

We put this question to Dr Jim Haseloff, from Cambridge University:

Jim - I think it's an extremely interesting question and with synthetic biology, a lot of us are struggling with this idea that are shifting towards modified biological systems that are based on parts, and that those parts might be open-source and the technology is very cheap, so there's certainly a potential for allowing access in developing countries to technology which can dial straight into important sustainable technologies. The current model for biotechnology involves protecting elements and preventing other people from using them except under license. So, this idea of protecting or removing fertility in seeds can have a bio-safety aspect, but it also can have an aspect of limiting use. So, I think this is a question not for scientists but for society.

51:22 - What do we know about oil-degrading bacteria?

What do we know about oil-degrading bacteria?

We put this question to Dr Jim Haseloff, from Cambridge University:

Chris - A very pertinent question with what's going on in the Gulf of Mexico of course.

Jim - Yes and one of the first patented organisms (and that's another controversial issue, whether you can patent things) was a microbe that had improved oil degradation properties and so, clearly, the appeal of synthetic biology approaches is that you can take some of the diversity that you find in the natural world and transfer that into organisms for more specific purposes.

Chris - In other words, to turn bacteria into things that can eat oil and therefore help with their clean up.

52:03 - Why do we have blood types?

Why do we have different blood types? Did they evolve due to some advantage, or are they simply a complication?

Why do we have blood types?

We put this question to Dr Kenth Gustafsson, reader at the UCL Institute of Child Health in London...

Kenth - There are a number of different blood group systems, or histo blood group systems as it should be called, however, the one that we normally think of as the main human blood group system is the ABO system. These days, I think it's safe to say that most people in the blood group fields think that the ABO system has developed in the course of our interactions with pathogens, in other words, bacteria and viruses. The genetically controlled ABO blood groups are in most people, present in the stomach and the intestines.

Diana - So the same ABO antigens found on blood cells will also be found on some cells in the intestines.

Kenth - And this has led to some bacteria using them as receptors - to simply hang on perhaps, or even accessing into the body by that route, therefore developing a preference for some of these. Some examples would be cholera, campylobacter, E. coli 157 as well as also some viruses, for example norovirus which gives you gastroenteritis. But not all bacteria or viruses of one species or kind will necessarily bind to the same type of ABO - different strains within the same bacterial species may bind with different affinity to different ABO blood group structures. It's certainly clear that other primates, other than humans, also have the ABO blood group system, so it probably developed before the primate group diverged. And also, there are very similar looking blood group systems in other mammals as well, it's known for example that cows have a number of different blood group systems.

Diana - So, having certain blood types can provide you with some protection against certain strains of pathogen. Kenth also added that some bacteria and viruses will pick up the blood type of their last host so that when they invade a new host with a different blood type, their new host's antibodies recognise it and attack it.

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