Virus Lasers | Spring Into STEM

Virus Lasers | Spring Into STEM

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so the session is being recorded um it will take us a little while to uh transcribe it because we have to um put subtitles on um ai machine learning can help a certain amount with that but it does get very confused with some of the terminology in the name so we have to vet it quite carefully so yes the session is being recorded i'll email you afterwards with a link to that um but if you have any questions please put them in the q a box at any point in the session uh and we'll gather them up towards the end now just as we're ready to get going i've got two polls that i'd really like to share with you first of all is just to find out what level of study you're interested in so if you could fill that in and let us know you'd be very interested to know so it's gasoline whether you're interested in studying a degree or an msc or equivalent or you're not you're not actually here to uh inquire about study so we'll be reading to see your feedback on that very interesting so at the moment it looks like the majority of people are interested in studying a degree um and then a few more interested in doing msu equivalent uh we do an emulation department as well and some who aren't heroes didn't study so i'm going to finish that off thank you very much and the next poll is really about whether you've got an offer already we're just we're just interested to know whether you are an offer holder uh either with us or with somebody else or you don't have an offer so again really interesting most people don't have enough to study so [Music] that that's that's very interesting for us to know um and so about yeah about roughly split between people have been offered to study here and elsewhere thank you very much really appreciate that that helps us get an idea of the audiences that are joining us so now that we've got the admin out of the way and i've told you where all the fire exits are and all these things um i'm going to hand over to dr john hales who is going to give the presentation if my screen goes blank at any point i'm still around i'll just be doing things in the background okay over to you john hi everyone uh thanks for joining us today i'm just going to share my screen can everyone is that is is that good excellent perfect okay so today we're going to be talking about virus lasers which is the subject of my research program so what is a virus laser so virus lasers are a new class of a laser system in which the active component is composed of dire label viruses i'm going to go into a lot more detail later on and exactly what that means but as an analytical technology but we're designing virus lasers for use as tools for making scientific measurements now a big application in the future for virus lasers will be in helping to manufacture biopharmaceutical products such as monoclonal antibodies selling gene therapies and also vaccines so as as i'm sure you can imagine this is a really hot area at the moment and i think that virus lasers can play an important role because at the moment manufacturers are really calling out for new analytical technologies now based on the data that we've collected in in the recent past we think that virus lasers have a lot of advantages over the current analytical technologies available for instance they can be a lot more precise sensitive and can also operate in close to real time so this is potentially high impact research but like most research at the cutting edge is also high risk it's also multidisciplinary in that it bridges laser physics and also molecular biology and also our application space is another field so bio processing that that's one of the reasons why i'm especially happy about being based at the ucl biochemical engineering department so much of the research we do here is multidisciplinary and it's also a great base to form collaborations both with other researchers and also with industrial partners including your other company companies who do manufacturing that helps us keep the research really relevant the department also has a very strong track record in commercializing its research so that the technologies that we develop get into the real world and have a real impact so there's been at least a couple of successful spin outs in the recent years from the department and i recently founded oxygen which is a ucl spin-out and what we're going to do is build a new platform for bioprocess analytics and that will bring in the virus laser technology that we're talking about today and also another technology uh invented by myself and colleagues at ucl called decay associated chromatography and we're not going to be talking about that technology today so to make all this happen i'm currently funded by a ukri future leaders fellowship and that's worth about 1.2 billion pounds okay so before i dive into the the detail now i've got another poll um so this will just help me gauge how to pitch it today so if you don't mind uh you could answer this poll question how much do you know about laser physics uh are you an expert do you just have some knowledge or experience or not much nothing there's no right answers to this question it's just be i'm just curious to know what the results again oh it's up so it just took a moment to get launched ah the results coming through thick and fast okay so um most people voted the majority of people would say well 80 would say not much not nothing and a 17 have some knowledge okay don't have any experts in the audience or people don't feel they're expecting maybe soon after this lecture um okay right excellent okay yes that's just the poll results fantastic okay so i'll crack on them so okay so before going into the more technical detail i thought i'd give you an insight into my background um because i know a lot of you are interested in studying and maybe becoming researchers yourself there is by no means know that you know there are we know people in the department have very diverse research backgrounds this is just mine and i probably say it's probably relatively unusual um so i as an undergraduate i studied physics at oxford and i found that as i progressed through my course i and got closer to the cutting edge i got more and more interested in the course and by the end i felt like my journey with science if you like hadn't quite reached a conclusion yet i wanted to do more in my final year i did a major module on biological physics and i felt like that was where the future was going to be so that's what i wanted to get involved in so i was lucky enough to get a place on a full year welcome funded phd program and uh during my phd at ucl i invented the virus laser which we're going to be talking about today i subsequently joined uh well i joined the biochemical engineering department as a post-doc in paul dorby's group who's also on the call and it was during that time that we invented decay associated chromatography i subsequently had a royal society of edinburgh enterprise fellowship which helped me to consolidate the plans for the company oxygen and i'm currently a ukri future leaders fellow okay so what came before the virus laser um so there's been a lot of excitement around nanotechnology so a nanotechnology is a device or a material where at least one of the lengths one of the functional lengths is less than about 100 nanometers this on that kind of length scale that quantum mechanical effects start affecting the properties of the material of the device so if you if you're building a new uh material or technology you have all of the classical physics up to a certain length scale and then as you reduce those length scales into the nanometer region you can start leveraging these quantum mechanical effects uh you know to make new and exotic types and technologies so one of the yeah so so people are interested in that and then they came the observation that of course molecular biology is already at that length scale so if you look at say a typical protein a protein might have structural features on a sub nanometer scale which actually impact its function so to illustrate that on the left hand side you can see some electron microscopy images of some cadmium sulfide nanorods and you can compare the morphology of that to a tobacco mosaic virus tnb on the right so you can see they both have a kind of similar shape quite rigid tnv really is that rigid they haven't just kind of picked one that happened to be quite rigid and in the bottom left you can see almost kind of spaghetti of carbon nanotubes and on the bottom right you can see m13 phasing which is a type of virus and you see how flexible that is as well so then the question was can you start using biological molecules to start building nanotechnologies and the answer that question was comprehensively um answered as yes you definitely can uh by research through numbers a number of groups i think uh one of the one of the groups that you know whose work i certainly followed and was very interesting was angela belcher's group and what they did is they took m13 bacteriophage which is a type of virus that infects certain strains of e coli bacteria and they're able to use it in its structural properties to make different uh interesting uh materials but where their kind of nano scale aspect was relevant so here on the right side you can see a panel for one of their papers where they used m13 phage to make a lithium-ion battery but as far as we know no one else had the idea of actually trying to use this kind of stuff to make lasers so that's what we're going to be talking about today so this is a photograph of one of the early prototypes of the virus laser um now obviously lasers themselves as the technology have been around a really really long time and i'll just go through some of the uh components that are uh true you know have to be there in all lasers what the key components are so in this photo you might not be able to see this particularly well on your screen but on the left hand side you might be able to see a kind of very thin slightly fuzzy blue line and that's going uh from from left to right can you see my mouse pointer at all or not okay you can okay so so it starts about here and it comes into to here um so that's the first thing you need and that's an energy in so there's no free lunches you need to have energy in to make these devices work and in this case that's coming from something like well a laser-like source so that blue light enters what's called a cuvette which is essentially a four-sided glass container and you can see this liquid via these tubes kind of flowing in and out of that glass cuvette so in this instance this is fluorescein dye which is being flow through into the cuvette now the dye absorbs the blue light that's coming in from the left side and then it emits green light in every direction some of that light is then trapped by what is called resonant cavity so that's the second key component you need in your laser system so the the resonant cavity is essentially two mirrors that are set in opposition to each other so if you've ever been in a bathroom where you have two mirrors on opposite walls and you get that infinite reflection effect that's essentially what the resonant cavity is doing so some of the light that's emitted by the by the dyes will bounce against one of the mirrors and then it will trace back on the long the same path and bounce to the other mirror and it will be trapped between the two mirrors okay so this is this is one of the interesting and maybe unexpected things that makes lasers possible so when some of that green light passes back through the cuvettes it will actually trigger the emission of more green light in the same direction okay so so light will reflect off the mirror come back towards the dye and it will trigger you know more of the more dyes to emit in the same direction and and color so you so you can imagine that this increase in light being emitted will then bounce across against the other mirror bounce back towards the dies and then trigger even more emission of green light and so you have an amplification in the light you have almost like a runaway increase in the amount of green light being emitted that light is then your laser light so the third key component is that you need to have a cuvette with a material that will perform that amplification for you and that's called the gain medium now the final the final component of a useful laser system is that you need to have some way of extracting the energy or the light out of the laser system otherwise it's not very useful so in this early prototype we actually uh used this contraption which is a thin membrane which was partially reflective however in subsequent prototypes we actually removed this part and instead use the light that was transmitted through the back of the mirrors so you can actually see that that's possible in this photo because around the back of this mirror you can see that some of the lights being transmitted so that's a brief overview of how lasers work what's unique about virus lasers so a virus laser in many ways looks quite similar to what we saw before here in terms of the optical configuration but the gain medium is composed of dire labeled viruses in the first manifestation we used m13 bacteriophage so that's the same m13 phage that was used to make that lithium-ion battery that i mentioned earlier so the advantage in using a dye labelled m13 phage as the gain medium well there's several advantages but the two there's two main ones the first main advantage is that you can chemically modify the coke proteins along the surface of the phage so that you can so that you have a diet molecules at specific positions and you can decorate the surface of the phage so that there are dyes along the length of the virus m13 is a long rod like virus which is about one micron long and about six and a half nanometers long but the dyes are only spaced apart by a few nanometers so you can see that they can pack quite a lot of dyes onto one one of these viruses the second big advantage of using a dye labeled m13 is that m13 can be programmed to bind uh so to dark or to connect with other biomolecules so a lot of uh measurements uh other kinds of measurements that we try to make we're trying to measure how much of something is present in a liquid solution and a standard tactic for doing that is that you introduce something into the system which can generate a signal that could also bind that target that you're interested in okay and then that that readout that signal will give you some indication of how much of that target is present so m13 phage can be programmed to bind target biomolecules with similar with a similar spec to the gold standard in this area okay so you have your dye labeled m13 and you have an optical configuration you know flowing through the dye labelled uh virus through the optical configuration how do you know that it's working is it just about a case of just generating a lot of really bright green light and well no there's there's more tests that you have to do there's actually several tests i'm going to focus on one of the more important ones and that's the lasers to be lasers have to show threshold like behavior so this is illustrated in this graph which i'll walk through now so on the horizontal axis this is the intensity of the incoming light so this is the blue light that we were talking about earlier now notice on the on the on this axis the ticks here are actually a logarithmically spaced what that means is that each major axis is actually 10 times larger than the previous one so this is quite a large variation in the intensity of the incoming blue light on the vertical axis here this is the output from the from the laser system so this is the green light that's coming out again it's logarithmically spaced and you can see that there's a very large range in the intensities of the output light now when you so this orange curve here this is a curve for when you introduce fluorescent dye into the optical configuration we know in advance that fluorescent diet is capable of lasing so this is kind of just a check that the system is working so at very low input light intensities you get almost no output from the laser system okay at that point you haven't put enough energy in to make it work however as you increase the energy there comes a critical point which is known as the threshold point above which you have now put in enough energy to achieve lasing and you see an extremely sharp increase in the output of the laser system so a very small change in the input light results in a very large increase in the output light and this is this is characteristic of lasers so if you look at the other curves now these are our diode labeled m13 when that was flown through the optical configuration and you can see a similar pattern there's a sharp change in the output about the threshold point now each of these curves actually represent a different concentration of the dye labeled m13 and and as it goes this way the concentration decreases until you get to a point where you can see that the concentration isn't high enough for you to achieve lasing anymore okay so how would you use that in in the context of an analytical measurement so this is this is something that we demonstrated in our research it was it was quite exciting so quite often what you're really interested in is whether the concentration is above or below a critical number for instance in the context of clinical diagnostics there might be some biomarker and if that biomarker is above a certain concentration that might indicate uh disease um but then if it's below that uh that concentration then there might not that yeah everything might be good likewise in a manufacturing context there might be a level of a contaminant which is acceptable but then above that point then it ceases to be okay and that might result in a failed batch so what we've done here is that we've we've changed things up on the horizontal axis so on the y-axis here you've got the output of the laser system again yeah the green light is coming out but on this horizontal axis now instead of having a change in the input energy the input light we're changing the concentration of the dye labelled m13 or as we sometimes call it the virus lasing detection probes each of these curves then are then at a fixed light intensity so the amount of blue light coming in is equal for each of these different coloured curves this is how it works so let's say that you initially had a low concentration say a hundred picomole per ml of your dye labeled m13 then for this blue curve which is as a fixed energy input you would have a very low output a very low signal generated demonstrated here on the cartoon on the left however if you were then to increase the intensity by just 50 ah sorry increase the concentration of the dye labelled m13 by just 50 then you would increase the signal up here which is a very large intensity so you can see that now a 50 increase has resulted in a large signal in fact a 50 percent change here from 100 people more per mill to 150 mole per mil results in an over 10 000 fold increase in the signal now this is the largest responsibility ever observed in this kind of measure in any kind of measurement system like this that we've ever certainly we're aware of so if your critical concentration will say between 100 and 150 pick a mole per mil as you as the concentration move beyond that critical point that would be readily obvious because this very large change in the laser signal this is very unambiguous result okay so to try and give you a little bit of a flavor of what research can be like sometimes i wanted to kind of give you uh tell you a little bit about what it took to invent virus lasers so the picture on the photograph on the right here is a much later prototype of the virus lasers you can just see by the density of the optics around the game medium now that a lot more stuff has been added to try and refine its properties so uh in developing a superior optical configuration we introduce components to control the intensity of the incoming light and also that the beam profile of that incoming light in terms of the output from the virus laser which uh now the light comes out of this mirror here through the back is transmitted through uh we we introduced it we introduced optics to enable us to measure the light levels over a very large range so we were able to measure uh a dynamic range of over 100 million fold to put that into context if you have a 30 centimeter ruler the dynamic range the difference between the largest and the smallest measurement that you can make is a factor of 300 300 millimeters to one millimeter here we were able to measure over 100 million so aside from developing the optical configuration there was also a lot of work involved in developing the the dye labeled m13 phage themselves uh in terms of the the chemistry and also the the growth and purification of the phage and so even after doing all of the work to develop the biology then also the optical configuration yeah at that point where we're starting to generate lots of data actually it was so new that we didn't you know the the the models to actually fit and interpret the data didn't really exist so there so after doing all the work in the lab there was then a substantial period of time where i developed essentially crunch fuel the algebra to develop new models to then fit that data to interpret it okay so i touched on the an important application for the virus laser being in manufacturing biopharmaceutical products so i wanted to briefly give you a little bit of an insight into how biopharmaceutical products are manufactured to put that into context now i'm certainly not the number one expert on this in in the department but i'll do my best to give a very quick and maybe slightly crude explanation of how it works so in terms of biopharmaceutical products we're talking about monoclonal antibodies selling gene therapies vaccines in this example uh i'm imagining your product is a monoclonal antibody as illustrated here so this is the actual medicine that you're going to inject into someone's arm is you know hopefully going to treat them so you start with a genetically engineered cell which is capable of expressing this uh this product you then have to create an environment for those cells and supply them with the raw materials that they need in order to for them to express that product now having done that you then have your product but you also have the rest of the cell and all of the rest of the culture medium so lots of different contaminants now some of them know some of those are potentially harmful to humans so then your next step is to try and remove all of the contaminants and leave your product and it's in that phase the downstream processing that we think that the virus laser can have an impact so why do you think that's the case well currently the industry is calling out for new analytical technologies now one of the reasons for that is partly because biopharmaceutical products are getting more and more complex over time they're also getting more powerful we can treat many things that are maybe previously untreatable but they are getting more complex and maybe some of the old technology that we were using to make these measurements aren't you know aren't really performing in the way we'd hope aside from that there's also a question of trying to optimize the manufacturing process so we think so our data uh suggests to us uh that virus lasers have a lot of advantages over the current state-of-the-art technologies give you uh well so we've already spoken about how the responsibility of virus lasers uh you know and that's an ideal output if you want to integrate the output of these measurements into say a software control system for your manufacturing process you're either lazy or you're not lazy that's a binary output a zero or one and that's exactly the language that the computer system might understand aside from that though you always you also need to make it very straightforward to make these measurements and in this other this this different set of experiments now we showed how easy it is to make these measurements so we demonstrated what we call was called a mix and measure uh measurement so i'll talk through this graph now so in this experiment you start with your dye labeled m13 phage and you then we we then at different time points so on the horizontal axis that's time we added uh a antibody similar to the one in the in the drawing i showed previously and then having added those antibodies those antibodies and the dye labeled m13 actually bound to each other they form binding complexes now the impact of that was to change the laser output so that changed the laser signal so if you look at the purple curve you added the antibody and then there's a very sharp decrease in the laser output and that was indicative of the presence of the antibody that then plateaus out and then as you add more antibody to the system you then see it never drop in the output now if you don't put enough energy in to achieve lasing then you get what's shown in this green trend so here the output doesn't really change even even when you've added the antibody and the time scale here for this change is about at the max is at the maximum rate of which this could possibly be observed this is as rapid as this kind of measurement could have been made so how do we see virus lasers integrating into the manufacturing process so we imagine that between between the different unit operations of the downstream process connecting a virus laser actually outlined to the process itself sampling from the process stream and then mixing that with the dye labeled m13 the resulting signal would then be indicative of the presence of you know the the product or a contaminant depending on what you're trying to measure in this example the virus laser might detect that at the level of contaminant is too high and then prov and then it talks to a software system to then actually change something upstream to prevent the formation of that contaminant to give you some context to how this sort of thing might work at the moment we have industrial collaborators and their experience is actually common across the industry and so between each of the processes between each of the processing steps they extract a sample and they actually have to walk across the road to get to their quality control lab uh where they do a whole suite of uh analytical tests so many of which take several hours they can actually be four to eight hours before the process can start again and proceed to the next stage this is obviously very inefficient uh and you know the manufacturing process would be more productive if you could make these measurements in close to real time which is what we're aiming to do with the virus laser but it's not just about making things more efficient we think that by making these measurements well we think that the virus laser will be able to make measurements actually more sensitive and more precise as well so we think this would potentially make the process safer and more reliable and and and potentially will also enable new modes of manufacturing typically manufacturing happens in so-called batch mode whereas we think that introducing these kinds of new analytical technologies will facilitate a move to continuous manufacturing key point there being that being able to continually make measurements very rapidly and they will enable new modes of manufacturing that are potentially more efficient and will reduce the cost of manufacturing so what the technical milestones for the the project that i'm working on at the moment so at the moment one of the things we're trying to do is uh work out what the limit of sensitivity is for the virus laser we're also very interested to find out how the structure of the laser detection probes the dye labelled m13 in our example impact the laser properties so if you how does changing the number of dyes on the virus affect laser how does changing the chemistry on the code proteins affect lasing i think that's very interesting and from a from a research perspective but also from a practical perspective because it might help us make more effective probes in the future a very big goal for us as well is to actually demonstrate prototype systems in our application in a relevant context it's okay being able to do things in my lab but ultimately we want to be we want virus lasers to work in the labs of our researchers and also within industrial contexts so to make that all happen i was fortunate enough to be awarded a ukri future leaders fellowship that's that's a a a fellowship that lasts four plus three years and first four years are worth 1.2 million pounds so to give you an idea of what that pays for so that will pay for my salary it will also pay for the salary of another researcher to join the project it also will pay for lots of new equipment in order to make these measurements lab consumables and also have a travel budget but suffice to say that hasn't been going down very quickly so i currently have a fairly sparse looking lab in the basement uh on of the department on the ucl campus uh currently buying all the lots of the kit and you know populating that lab i won't be based there for you know for especially long the plan is for me to join the manufacturing futures lab at ucl east so if you haven't heard about this before this is very exciting uh development so ucl is building a new campus on the former olympic site near stratford or in stratford and on level seven uh there will be the manufacturing futures lab the aim is to become a global leader in manufacturing research this is highly multi-disciplinary the biochemical engineering department is is is one of the departments involved but there's several others so that's going to be very very exciting so watch this space on that the last thing i wanted to do is to acknowledge uh the the generosity of all of the funders that i've been that i've had over the years and last of all uh well i also like to thank you all for uh joining us today and lastly before we open up to your questions we have one more question from us and that is did you learn enough today to explain virus lasers to a friend well wallace uh thank you very much john that was great i'd also like to say just a shameless plug that is a slide in the background of the here east image that john showed that slide is great fun and you'll scream a lot going down it um thank you um so whilst uh so the answer coming from that uh john i'm going to end the poll and publish that for you it's great thank you very much for your responses there um we've got quite a few questions coming they uh there's some really good questions come in what i'm gonna do is i'm gonna leave john um and paul if you're available paul if you could have a look through those questions um and between you uh i think who's going to answer them whether you want to group them up into sections um john you may have actually addressed some of them in the presentation because they were the questions were coming throughout but just before we get just just whilst uh paul and john are looking through those i just want to say that we've got um we've got a uc um a biochemical engineering msc q a session uh on friday professor dan bracewell is uh he's going to be available to answer any questions you've got about studying a an msc with us at bike and plunging i also want to let you know that ucl has moved its deadlines to the 31st of may for all its postgraduate talk programs so if you are interested it um because we've been especially popular this year um many people have wanted to study a postgraduate degree um ucl has brought its deadline forward so you're more than welcome to join myself and dan bracewell on friday i'll put a link in the chat so you can sign up to that but do bear in mind that the deadline is fast approaching for that if you're interested in studying a degree or just want to know some more about studying a degree at ucl ucl's undergraduate open day is uh in june myself uh dr brenda parker uh chica nueke um we'll be around in two sessions one at twelve o'clock and one at five o'clock so come along talk to us and talk to brenda about any of the degrees we do any of the questions any questions you've got about studying by the department uh we'd love to talk to you about that we can go into much more detail obviously than we can here i'll put a link to that as well and the final thing that i'll put a link to is a survey to ask how you thought we did we do really appreciate your feedback so what i'm going to do now is i'm going to hand over to uh first of all paul paul you'd like to introduce yourself and then between you and john if you could answer the questions that would be great very quickly so i'm professor paul dolby in the department of biochemical engineering and also as you can see in my that side um logo in the back uh one of the directors of the future targeted healthcare manufacturing hub which is a industry sponsored and partly and also ukri sponsored initiative to look at manufacturing and formulation of therapeutic proteins okay so i guess um john do you want to pick off some of the questions in the q and a first yeah i had i had a quick quick look through so there's no upvoting system here is there it's just so i'll just i'll just i'll just go from top to bottom then there's quite a few so i won't be able to dwell too long on each question so apologies if you think the answer is a bit brief but you know you can always uh you know contact me and we can talk about it more as well um okay so the first question is uh could you give uh some information on the risks you face in your research and how you mitigate manage or avoid these um okay so uh the main the main risk is the laser light itself um so we uh introduce uh various safety mechanisms to prevent the laser light getting into uh into the user's eyes or indeed anyone else who happens to be in the lab uh probably the main safety things we do are we have a special lock on the door um so that only uh people well so if someone comes in without typing in a code maybe they're not aware that the laser's there then it will stop the laser from from working we also have lots of metal shielding to prevent stray light getting into people's eyes we wear safety goggles and so on in terms of the biological risk we don't use uh dangerous biological materials here um so the virus is a bacteriophage that only in fact affects certain strains of e coli that we have in the lab so they don't pose any risk to to to people okay so next question are are viruses able to replace other methods that require the binding of a biomolecule to a ligand if yes how much more effective is the method okay so a good question and we see virus lasers as a platform that will directly compete against uh the most common methods for these kind of ligand assays um so for instance eliza and the big advantage being uh potentially the sensitivity the precision and the rapidity with which the measurements can be made uh uh and also being able to get very unambiguous answers i think anyone who's done eliza before knows that getting an unambiguous answer is usually a bit of a challenge um can you give an example of the analysis that you want to carry out with the virus lasers uh you explain varying the concentration of control light intensity how does that help in the analysis okay right so um typically in these kinds of assays um you let's say you have a target biomolecule so this is this this is maybe a very general simple assay that might be commonly used in labs uh so you have something that generates a signal uh your you know your detection probe that binds the target you then have some way of isolating that complex maybe on a surface or through some methods of purification and then and then you're able to then read off that signal and then the intensity of that signal is going to be proportional um proportional to the uh the amount of the the target that was present what if i might even let me i just want to quickly um just watch you doing that just say i paul's actually answered one of the questions in text i'm just going to read this out because if anybody's watching this recording this they want to see the text but uh somebody else can virus lasers be used to live therapeutics inside uh living systems and uh paul said viruses are fairly stable such as against degradation by heat etcetera um i'll try and publish these things in a in a blog but we'll but um but what we're trying to do is we'll try we'll try and answer these uh verbally because otherwise uh people watching wouldn't have seen paul's great answer there so just to let you know thanks uh so just just quickly finishing off uh that answer so one of the big advantages of blazing is that you can so you remember that graph i showed with the threshold points um so instead of measuring the output of the light intensity which is what you'd have to do during a fluorescence measurement and you can actually measure the position of the threshold point this actually uh blends into this next question as well which is what arguments would you give using this system as opposed to classic fluorescent labeling okay so instead of measuring the output intensity as your signal you can instead measure the position of that threshold point okay and then this graph here shows uh i hope you can all see shows that the position of that threshold point can be related to the concentration of the detection probe and that's significant because typically in say fluorescent labeling the signal is very weak okay so you need really sensitive optics in order to make that measurement it's quite hard to make those measurements very accurately and precisely here though you're essentially measuring the intensity of the incoming light because that's what determines the threshold point right so because the threshold point is either blindingly bright or not there okay you can then vary the input light to see at what point that happens and you can measure that point very precisely so you can measure the threshold point extremely precisely and then infer the the concentration from that i hope that makes sense so that's a slightly different paradigm than for making these kinds of measurements a little bit more technical there's a big advantage of using laser systems instead of using fluorescence systems so there are lots more arguments for you know why you would use lasing instead of fluorescence um it depends obviously it depends on the context if you're doing some kind of microscopy you might use fluorescent um okay so if i stop sharing now yeah i'm sorry good paul can i still ask a quick question i mean when i when um when john joined the department he who's also working with the london center for nanotechnology why what is what is um the context of john's work in relation to biochemical engineering at ucl i think it it's quite interesting to know how it fits in with because you're also the director of research in the department so could you give some context yeah so you know you know i was also collaborating with uh somebody at the london center for nanotechnology and it was kind of all happening kind of in parallel we were doing another project with them and so i was kind of aware of what john was doing at that time um and then as he moves forward usually you're looking for sort of the next thing to do the next grant to write et cetera the next part of the evolution of the project and so at that point it kind of came together we were we were evolving our projects and we brought john in on that project but of course what he's already doing was this phage lazing work as well so you know we kind of allowed that to continue because it obviously had its own part to play and i think it was from what i'm aware it was already connected into the department or into by processing and you know the likes of john ward were kind of involved and had already plugged it in so it was just kind of a continual evolution of that really you know we wanted to support it as much as we could so i'll move on to the next question um so are virus lasers faster than other methods used to determine quality quantity of a biomolecule uh by biotransformation and the answer is yes um so the mix and measure uh assay that i showed that happens as quick yet that the response to that happens as quickly as the binding between the probe and the target you can't get faster than that um you know that's that's the speed limit if you like and if you could do that at line uh which was you know we're very determined to be able to do uh it's our big research focus then that would be a lot faster than the current techniques which require walking across the road to make those tests um would the output continue to decrease once more antibodies are added to the solution yes it would do and uh it would continue to do that until there comes a point where um yeah where there's no more you know you can't put enough energy into the system anymore to observe lasing in the industry have you got an estimate as to how much benefit we could get compared to the cost of the virus laser so you've got to factor in the cost of the analytical testing currently uh which is extremely large uh and you've got to factor in the loss of process intensification because you're pausing the process uh to make some of these tests you're imagining being able to go from one unit operation to the next without pausing because you're confident enough that the virus lasers detecting uh all of the relevant contaminants at that stage and and and the concentration of the product if that's desired as well um so that you so i guess if you're a contract manufacturing organization you are just getting through more processes per year than you would have been doing otherwise if you're interested in moving to continuous manufacturing which i know a lot of companies are very interested in doing but feel like maybe the technology isn't quite there especially on the analytics this is the kind of innovation that we're hoping will be able to make that possible at the moment if you're measuring continuously you know you need to have your analytical team running 24 7 constantly making measurements whereas this is the kind of thing you plug in and you're getting that data data continuously i'll just add to that there's lots of different ways you can measure benefit in terms of money in industry so one one example of that is they say if you're if you haven't got your product on the market it's costing you a million dollars a day because there are other competitors getting things on the market and you lose patent lifetime and that's how much so if you can get even even a day earlier to market you've just made a million pounds so a million dollars rather so you know that that's one way and the other way is cost of goods you know if you can bring down cost of goods on manufacturing by even one percent that's a significant amount of money so it's i think that the value you can bring is is very quickly gained how does it work in terms of scalability of the design i mean is it something which you know what's the cost of actually making the making the kits and is it possible to look at making it more compact and how does that work yeah i mean that's a b a big focus of our research is is you know you we're building prototype instruments uh that will be uh have a compact enough footprint and a robust enough uh profile that you could integrate into a manufacturing context uh you don't want a very delicate liquid handling robot in that kind of context um so so yeah that's that's that's something that we're working with we yeah one of the things i'm funded to work on um what exactly is lazing uh so lazing is uh i don't know if it's an acronym or an initialism anymore you get picked up on that uh but it laser stands for light amplification by the stimulated emission of radiation um so when you have and uh light that's being uh amplified by that stimulated emission process that i discussed remember where you had the green light passing back through the cuvette and then triggering more emission in the same direction the same color uh yeah a a device that's using that mechanism to generate a often intense uh single color beam of light then that that is laser and that is the the lasing mechanism please explain the interaction between the contaminant from the reactors and the virus sorry okay the interaction between the contaminant from the reactors and the virus in the virus laser so i this so i so this is uh this is something that's common to uh a lot of how these measurement systems work and it's a non-covalent uh so it's not a chemical uh bond that's being formed between the two things uh they they they kind of essentially the the uh surface of the probe the proteins on the surfaces of the probe are essentially a sticky for that target molecule um but then not for the other that the other molecules that are present in the system it's a non-covalent interaction between the two uh particles whichever we could talk a lot about i don't think we've got time for unfortunately sorry uh are there other bacteriophages that can be programmed to bind to target molecules uh yes absolutely uh that is definitely possible you explain the use of antigen to bind with m13 virus which then changes light intensity what is the injective of the measurement um so uh let's say that you had a so in fact in that experiment uh we added a liquid solution to the dye labeled m13 and there was no antibody present and then there was no change in the laser output but then you add in a sample that did have the antibody and then you can see that sharp change in the laser output and therefore that change in the laser output means that you just you know added a sample that had the antibody present which is which is the information you wanted to to know what was the greatest challenge so far during the research of prototype manufacturing process greatest challenge um many many many things some of them scientific some of them not um yeah i would i was i would say that some of the biggest challenges were actually around uh the the modeling of the data uh because it was such new stuff we really had to get into the theory and really understand it in depth to really make sure that we understood it uh which we did um but you know i think you know when you start with a blank slate like a blank optical table and start building the instrument uh you know that's an exciting time but that's also extremely challenging as well would a virus laser based i say need a wash step as in eliza uh so no not in every type of assay format so you can use the virus laser in different ways you could use it in a similar way to eliza potentially but you don't have to and you know we have demonstrated an essay where you didn't need any wash steps to get a clear answer are there other virus laser research going on in other universities or other countries how are they different from ucl research uh there are other research groups studying by other biological lasers but as far as we're aware there isn't any active research programs into virus lasers at other universities um it was invented at ucl so i guess we've got a little bit of leads but there are other biological laser groups who do some great stuff as well and their systems tend to be quite different to the virus laser system though how many years would it take to commercialize the virus laser for industry application how big is the potential market size um so we so so we're looking i guess it depends on what stage um but we're looking at a kind of three to four year time scale before we would have systems which could potentially be integrated into manufacturing processes um and how big is the potential market size uh well uh it's it's very large uh you've got to remember that a couple of years ago the the biopharmaceutical market was worth about 250 billion dollars about a third of that money is spent on manufacturing and a large chunk of that is spent on analytics so i'm finally going to jump in here because we're coming quite clean that we are we're just about to finish off but we've got time for two more questions but just before we do that i just want to say i'm going to put a link to i'll just put a link to a um a survey if you could open that and then finish it and let us know afterwards how you found this session that'd be great um but we're coming up to the end so ask john to pick to look at the questions that we have and choose the two that he thinks he's got time to answer between him and paul um and then and then we'll wind it up um i think we've only got two more questions left oh fantastic so why green light for the virus laser so fluorescein diet was an attractive option because it could be excited with blue light shorter wavelengths are harder to generate than blue light so hence fluorescein and fluorescent emits in the green in the antibody example am i right to say they will only work for antibody of m13 virus used in the laser if you want to test another type of antibody then you need to use different viruses in the laser right yeah if you want to bind a different target then you'd need to program uh the virus to bind that different target it will speci it will specifically bind a specific target great thank you we got through all of them that's fantastic i think that that's uh great achievement thank you thank you but thank you very much john and we've got some very kind words in the chat box which you may not have seen but um thank you john thank you paul and and uh a huge thank you to everyone who posted these questions they've been really interesting somebody did actually say are you going to be doing any more any more uh presentations for us respected phd students and we try to get a balance in the taste lectures so we cover things like uh vaccines and surgeon therapy which are core parts of the tort programmes we've also got this and we've got one coming with emily costas and gary ly which is going to be on [Music] bioprocessing of seaweed so there are elements of research we do we're also trying to cover parts of the talk programs as well so um have a look through the program next year we'll see we'll see what what other research we we which other researchers are happy to present in the same way as john has was very very kind of take time out to do this but um just thank you very much um i hope you have a great afternoon and i hope you enjoy the rest of the sessions and for those of you who have an offer we really look forward to welcoming you at ucl and seeing you in person in the future so have a great afternoon and goodbye thanks everyone thanks bye-bye you

2021-06-15 19:13

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