Danny O’Hare is Professor of Biosensor Technology at Imperial College London where he and his group research minimally-invasive devices for diagnosis of sepsis, the management of chronic obstructive pulmonary disease and therapeutic drug monitoring. In his inaugural lecture he will illustrate each aspect of biosensor development using examples from his own research into topics ranging from cells-on-chips and the neurochemistry of ageing to host-pathogen interactions. #ImperialInaugural
Yeah sit down here for a minute I’ll be fine in a minute it’s cuz I can’t see great well good evening everybody um what am I doing here I’m I’m a former head of Department of bioengineering and it’s a great pleasure to welcome you um and those online and there are many
People online to this inaugural lecture of Professor Danny oare our good friend and colleague in the event of a fire alarm please follow the emergency exit signs to the assembly point which is on the corner of exhibition Road and Imperial College Road just follow the crowd we’re not planning anything like
That um but in welcoming you I’d particularly like to welcome on behalf of the department and the college Danny’s loved ones um uh past and present research group members um the department of bioengineering family esteemed members of the college um Danny’s broader collaborators where else would you want to be spending the evening
When storm kieron arrives and we can be hunkered down together and this is going to be a bit of a melstone because we’re expecting that it’s Danny aren’t we so just be prepared before we start um this celebration um I’d like to give a few personal and departmental Reflections on Danny’s career to
Date Danny’s Beed Imperial on and off for a very long time since 1981 I think and he completed his PhD in the Forerunner to the department in 1991 um and then he secured his first academic position in Brighton he returned to Imperial in 2001 and has been promoted through the ranks to full
Professor in 2021 I think Danny is an academics academic he’s not an administrator he has a very strong sense of the priorities in the academic life what matters and this is Ed in his focus on I would say te teaching first research throughout everything that you do and service in his own
Inimitable way he’s a great teacher student online evaluation scores are a blunt tool but he always gets well more than average on that but more memorable perhaps are the comments that they write about him most of which I can’t repeat in public they reflect on his style his delivery his
Humor his excellence and his dedication to them a as an old um academic colleague once once mentioned don’t focus on getting the students to like you you focus on learning to like them and this will help you to teach them and for them to learn well and I think he does this
And the students simply do love him and he’s always being nominated for student academic Choice Awards um Etc Dany has served the department in many ways over the years in many different ways um but I think all of them take second place to this specific area that
He’s LED significantly and that is he led the establishment of our intercalated BSE in biomedical engineering for medical students he has always been a proponent of us the department of bioengineering contributing to the development of clinical medicine through making them engineers and the ibsc was born after
This drive and he led it he led it from the start he developed the vision the syllabus and got through the paperwork strong bind from his academic colleagues and from the faculty of medicine at Imperial um and he ran it highly effectively got it off the ground
Since then he he’s done some other things but I just want to highlight that as a key contribution to us here and to all those students and we’re so proud of what we are achieving with the ibsc and so we should be proud to Dany and
Grateful to him for his vision drive and continued leadership in many ways Danny’s going to talk about his research later so I won’t spend much time on that now and he’s going to bring some new results in as well actually so there’s going to be some new stuff here
That we’re all very excited about but I I just want to mentioned that he’s one of bioengineering strong collaborators and it’s evidenced by his long running collaborations with many people with joint Publications joint supervision these are the Hallmarks of a good collaborator and these are international
As well as uk- based and within the department as well and within the college he also supports Enterprise activity and many of his students have gone on to develop spin out companies over the years and before winding up this introduction and truly the show is coming everybody grab hold of your seats
I just want to say he’s part of the furniture here in bioengineering I think there are only three academics three active academics who’ve been in bioengineering longer than Dany but none can trace their pedigree back as far as his if we take into account his PhD Danny truly commits to the life of
The department reports of Staff student parties always end with Dany being the last academic standing or sitting and we’ll all have our me our memories of other people’s inaugural lectures where at the end of the festivities Danny stays and stays like a comfortable old Chesterfield armchair he is committed to his
Colleagues and to the vision of the department he can be relied upon to do the most important things very well and to support his colleagues and students through thick and thin Danny I’m going to hand over to you please come to give your onogo lecture thanks thank you so
Much WoW Anthony thanks for the very kind introduction and thanks to everyone for coming what a fabulous turnout it’s is almost as many as our first year classes in thermodynamics and many many more than we find in the second and subsequent lectures um so tonight I’m going to be
Talking about my research and collaboration some of it’s going to be an overview of the of the of I think some of the more complete pieces of work that I think we can describe in full and much of it is going to be incomplete stories and Ne necessary glosses and I
Apologize in advance for people whose names I’m going to be leaving out so where do I come from born brought up in the English latus where my mother still lives and my big sister down here uh in God’s own country olston in the English Lake District famous for I think the
Saxophone player Jess Gillum uh the nurenberg prosecutor um Norman Burkett and the Navigator um Sir John Barrow but most uh probably famous for Stan Laurel as his as his birthplace in wonderful Countryside and gorgeous Coastal scenery leading up to the these very mountains here that you can see here the highest
Mountains in England the scel massive I was very fortunate to go to a really good comprehensive school the only School in town a proper comprehensive school and I want to give a special shout out to miss Wally who was one of the finest physics teachers in the
History of the world and just was an absolute inspiration and her love of experimental work we’d ask her questions to try and catch her out and she’d say come back at 4:00 and we’ll set up an experiment and we’ll measure it this is this is what you want for a teacher and
And uh and Peter wild ex outstanding chemistry teacher and I we always look back with horror at us washing our glasswar with uh no gloves on in Benzene and amazingly we’re both still alive chemistry has this reputation even in the early part of the 18th century from James gilray and his
Little friends uh right through to more recent cartoons of Nick Kim’s chemist this this cartoon here called chemist attitudes to explosions uh bo this very much describes my early years as my mom and sister will certainly remember it’s an absolute miracle that the house didn’t burn down on more than one
Occasion or be blown to pieces and uh yeah chem is Sinister figure in a white coat who synthesizes chemicals or a friendly figure in a white coat who syn dispenses drugs but what’s not to like smells explosions fireworks drugs all human life is there and chemical industry itself which still has this
Reputation as a large and wicked Enterprise dedicated to the production and dispersal of pollutants and I think David Jones’s column years and years ago in New Scientist the Deus column for coming up with these wonderful terminologies but to be fair I do work a lot with the medical profession and it’s
Important to pick your collaborators carefully always go for the one on the right so my career has been totally unplanned I mean really unplanned and a way that I highly recommend students today do what you’re interested in at any given moment and at least you’ll
Have had some fun if you try and plan it out and think well I’ll grind through this bit Anything could happen next and you could and you could miss out on some great opportunities I read chemistry as an undergraduate at Imperial College fell under the influence of the legendary professor John Albury and
Having fun was certainly a major part of of his approach to doing science as well as being rigorous about the physics and physical chemistry behind it all I was keen on research but I was one of the worst undergraduate from the Department of chemistry’s history and John said to
Me well I know you want to do research and I won’t have you but there’s a couple of interesting if rather eccentric people over in the pfsu Peter win and Kim Parker both of you who are fantastically here tonight thanks both for coming and I fell under their influence Peter theoretical physicist
Cosmologist and legendary cabinet maker and Kim Parker an actual rocket scientist uh who realizes that many of the wave equations also apply to wave propagation in arteries and I had a wonderful time working with them it’s old enough now that those of you might recognize this were actually drawn by
Hand in pen and ink on tracing paper and letter seted or or stenciled letters in my PhD which covered many of the topics that are still very closely related to what I’m working on now so maybe not such a random walk then did a post do brief post do with uh Peter before
Getting a job at what was then Brighton poly Technic teaching analysis to uh environmental chemist Rand to Martin Arendell whose work I’ll be talking about later uh great student of mine there and uh teaching uh physical chemistry to the environmental scientists and biomedical scientists and teaching physical chemistry to The Ungrateful
Pharmacists and I was away for 10 years thought I’d escaped The Event Horizon of Imperial College but no just when you think you’re out 10 years later I was back and uh so this is what I’m going to be talking about I’m going to yeah in in
Honor of my mom I think never miss an opportunity for Te teaching and learning I’m going to make you at least try and understand some of the very basics of electrochemistry there’s two or three people here at least who’ve got to who are going to be absolutely appalled at
My summaries but no matter how much if I applied all of my knowledge on the subject they would still be absolutely appalled so I think a summary is probably what we’re going to be doing I’m going to cover some uh work uh from on the neurochemistry of aging and some
Celles on chips work and some microfabricated devices before I go on to more recent work because I realized when I was halfway through this it sounded as much like a retirement lecture uh and I need to warn everyone it absolutely isn’t I’ve got years left of mad ideas I’m going to waste
Thousands of students lives on for for this so the LA the last two topics that I’m going to be talking about are some some work on on antimicrobial uh uh resistance and our work that we’ve been doing on that and on exhale condens breath and some work we’re doing on
Translating our work finally into into the clinic so uh electrochemistry traditionally thought of as beginning in the late 18th century in Bologna in Italy with the work of galvani and vter originally thought to be a property of animals interestingly when uh the uh when when gavani touched his frog frog
Leg muscles they they they twitched and it was voltero later pointed out that it was the corrosion of the stain of the of the steel in the in the uh ra rather than the actual animal electricity but I think it points to the right direction for electrochemistry which is at the
Interface with Biology and medicine but there are versions of this stuff collect the Smith college Museum Baghdad battery 2 250 BC no one’s entirely sure what this was used for it was used for over 400 years probably for electroplating so they could play plate gold on lead and
Pass it off as the as the real thing uh and John albur again I mean it’s amazing to see how many people turning out for a lecture with the title with the word electrochemistry in the title but there you go and despite writing the book and being the most eminent electrochemist in
The UK for the last 50 years John himself said distaste and disgust are the predominant emotions that the normal student feels for electrochemistry so what is this and how can it tell us what our Mo where our molecules are and most importantly what on Earth they’re up to loss or gain of
Electrons oxidation loss of electrons reduction gain of electrons there’ll be a quiz after the second drinks reception so do pay attention and the um but really the key idea here is that it’s the movement of charge part electricity is the movement of charge particles under under when when you apply a
Voltage and these at the interface between an electrolyte solution and a uh and a u i stand to one side between electrolyte solution and the uh and and a conductor the nature of the charge carriers changes so here for example we’ve got ion losing a couple of electrons to form ion two these
Electrons traveling to another site in the ion reacting with oxygen and the ion itself being further oxidized to create rust this is happening everywhere on campus as we speak now but it’s also uh it so corrosion is certainly at the heart of it we can run this process
Backwards and get electroplating we can use it to make molecules such as the commercial production of hydrogen peroxide or bleach and it’s also of course in batteries and and John goodne enough’s uh uh lithiumion battery which eventually as course I can’t believe I’m about says was eventually good enough
For a Nobel Prize and uh but analytical measurements and that’s where I’ve been coming in so what do these electrodes look like remarkably simple a piece of metal surrounded an insulator these are the commercially ailable devices maybe 3 or 4 millimeters in diameter in in KF or some other installating on these are
Some ring disc electrodes this bar is 100 Micron so these are about the size of the hair on your head that seev Harvey a fabulous PhD student of Mind from back in the day developed a method for building a method built a SP inverted sputter coat to actually make
These damn things and then we measured uh blood flow and and profusion flow with these some microfabricated devices which I’ll be going on to a bit more tiny seven micron diameter carbon fibers which Martin arel here was using in some extraordinarily patient experiments on snail neurochemistry seven microns to
Give you a scale is about the diameter of a human red blood cell and then of course the commercial devices for measuring blood glucose Tony cass’s great invention the exact blood blood glucose analyzer which transformed the lives of type one diabetics and all this technology now in in Wireless form but
The idea here then the energy that we have to apply is somehow through some deep mysterious process related to the identity of the molecule that’s either accepting or donating the electrons so that’s how we identify what there is and how so voltage is one key to selectivity
But we can couple this to perhaps some other molecular recognition such as an enzyme reaction or an or an apoma reaction but how fast it happens depends on the concentration I was told not to put equations in so that Badness here one is the rate at which the reaction
Happens simply scales with the electric current so that’s how we get the quantity and this is just Faraday constant that takes us from electrician’s units into molecular scientists units and back again so we measure the rate of electron transfer and therefore we can get the concentration if we control the voltage
We can control the stivity and we can put other molecular recognition events in the way and that’s pretty much all I’m going to be testing you on later on so it’s the only examinable content so why should we measure chemical concentration well cells only know what’s going on on on their own
Surfaces secondly we want to measure the concentration because the more crowded they are the more energy they have and the faster they react and some concentrations correlate with disease states such as glucose in your urine for example and type 1 diabetes and so if we can come up with a cheap surrogate for
An expensive an extensive medical history taking by a expensive member of the medical profession then we can we can be improving outcomes extending the healthcare and getting good results and also making doctors breath nicer after they’ve just tested a diabetic because they used to have to taste the urine to
Do the analysis the thermodynamics of this okay one more learning opportunity we go from Big molecules to small molecules we get energy in the form of adenosine triphosphate to get the process to run backwards and assemble molecules we have to consume the energy so we go the the biology from the
Thermodynamics of the biology follows this kind of idea and the general idea that people working in this space are because there are no real underlying theories is is to try and measure what we can and then gradually piece it together into networks this last piece last part is a long way from
Complete so the general idea is we need some sort of molecular recognition this might be the voltage or we might link it to enzymes like this one from Bic Patel here where we have glucose oxidase competing with hexokinase to allow us to to measure and detect uh ATP or we have
Aptus which when they’re buying their target change shape and the rate of electron transfer changes this now needs to be transduced into a electri electrical signal so we have different materials the Classic Materials are gold platinum and glassy carbon Carbon Composites like we have here this is a
Lovely image from some work that with Julie mcferson uh when we uh when she set this some of our Carbon Composites up on a fluorescent microscope and did an oxygen reduction reaction as the PH Rose the furosine the die that was in there the fluoresence was switched on so
We could see the patterns of conductivity and the growth of the diffusion fields we also did some nice modeling on this with with Hong XA another very talented PhD student we can also use fancy materials like Boron dope diamond and RAF tan is with us tonight
We be able to tell us a little bit about that then we need to do some electronics and I did some stuff with hying Lim in uh in Taiwan about this we built I came up with some ideas for and put these onto a chip for a tiny potentia stat
Unless I only went I only did this collaboration because it involved molecular imprinted polymers which I’m a bit skeptical about but the main reason I did this is work was because it was in Taiwan and it’s worth going just for the food but we need to produce exotic waveforms measure the current and
Process the data particularly drag the noise out of it and get improved selectivity by doing some of these fancy signal processing routines that Costas anastas you who was watching online tonight uh developed in my lab along with some very fancy numerical modeling along with Chris Bell uh don’t read the small print but
The the key ideas are here why it’s so difficult to do any kind of measurement whatsoever in biology everything is compartmentalized on every length scale so if we think of the human population H sapiens every individual is different you look within that individual every organ is different you look within the
Organ there are regions with the organ that got different cell types within the cell the cells themselves are compartmentalized so trying to Define what you mean by concentration is by no means straightforward at that point so that’s an interesting Challenge and if you have one molecule per cell it’s
Still PCO so we’ve still got you know realistic concentrations down at that level there are the production of the molecules is very localized all the time scales are relevant from subm second neuro neurochemical signaling up to the chemical changes that happening happen over aging uh and in the course of a
Lifetime concentrations are low there’s nanomolar here but really folar and lower can be important as well the lower the more we improve the sensitivity of our devices the the more we uh the more we find we need to be able to measure and we’re trying to do this on something
That’s active so changing it’s complex and it’s typically moving and every single part of every single experiment and experimental subject is different but we nonetheless feel we can make some sort of progress on this so what kind of stuff has been happening these collector generator sensors here meas for
Measuring flow generating hydrogen on one electrode collecting it on the other this is my own hairy arm here because you got to show willing we’re not allowed to just complete ban on self- experimentation Imperial College so I had to go down to the medical school at Southampton and in return for agreeing
To implant my sensor I had to agree to having my collaborator I Shan name in this stage having her dialysis probes implanted in me as well with some numerical modeling alongside all this some work on iridium oxide which we’re still doing Boron dop Diamond Alex Lindsay’s photoelectric chemical senses
Where we light things up and look at the Redux properties of of photoactive species I even against my better judgment did some work on molecular imprinted polymers signal processing that allows us to separate molecules for which the chemistry would seem important different but we’re exploiting the properties of the waveforms to exploit
The differences in kinetics between the rates of electron transfer for different molecules what else neurochemistry of Aging which I’m going to be doing quite a bit about in a minute and these microspike arrays I’ll be talking to about later but there’s some work we did with Alison Willows and and Ivan stov on
Water quality sensors because similar problems uh uh in sensing apply in the complex uh wild environment and I’ll be talking a little bit about some new recognition chemistry and some breath sensor stuff later so into the meat this animation no longer works unfortunately but and it was a bit cheesy anyway so
It’s no worse really for it not working here but one of the key things about getting older is you notice how much harder it is to learn a child learns to ride a bicycle three years old in about an hour maybe less half an hour and there’s probably nothing more comic than
Watching an adult learning to ride a bicycle except possibly watching an adult trying to learn to swim the must be a chemical basis for this and one of the aspects of this was to try and measure what’s happening in the sinapsis so electrical wave comes down this nerve cell here and it needs
To transmit the signal to the next one and how this works is a bunch of chemicals in these little bubbles here fuse with the surface cell surface membrane here burst out and if we position our little electrode here we can see a spike in the current as these
Molecules emerge and then we see them Decay away as they diffuse or taken up by the Target cell or are taken up by the cell that releases and this is what this device looked like and Martin AR here was involved in the design and making of these electrodes so serotonin
Is one of the molecules we went looking for which can be oxidized and we get this kind of raw data when the snails were cooperating which was I think what one time in 20 for a 4-Hour prep and we got about five minutes of data it’s takes a lot of resilience this field
Some sometimes and these tiny signals pamp current and then someone had to go through someone I don’t mean me go through and pick all of these little spikes up zoom in on them and say well that’s a nice looking one that’s a nice looking one but that looks like two vesicles bursting or
Maybe even three so we an so sift the data and then analyze how big they are how much charge has passed is how many molecules how high the current was and then this exponential decay better than a a square root of time Decay showing it wasn’t diffusion but reaction that was
Causing them to move away and the reuptake that was dominating and then when we looked at this we see the young vesicles were smaller the middle-aged ones were larger on average and the old ones were bigger still so different sizes and distribution and this is a we think a compensation mechanism for the
Downstream cells being less responsive as we get older so it’s like my son having to shout to get me to hear properly on the phone you know it’s so so the undergraduates got tiny little visic the postto it’s getting it’s already starting to kick and by the time you get
Made Professor you’re having to massively increase the concentration of your local drug and the same thing seems to happen for nitric oxide as well although the mechanism is different there it involves changing the enzymes so next topic cells on chips uh work from raap Tron Martin arandel Tempest van shik and shua uh
This is the early prototype devices six little micro electrodes insulated and microfabricated on a dual inline chip the more sophisticated version designed by Martin Aral here made on glass so we could still see the cells we apply different voltages we measure different things we can measure oxygen at one
Voltage and nitric oxide n o singly molecule if we put glucose oxidase or lactate oxidase enzymes on we can measure glucose and lactate if we put iridium oxide on there we can measure PH all of the things so we it’s kind of a platform technology and the big
Breakthrough was trying to find out what makes the cells grow so coating the surfaces with poyin sulphonate poly polycin which was supposed to be good for cells turned out to be a bit of a disaster and you can see the cells curling up and dying uh but for B and C
On the fibron ones after 24 hours and 48 Hours look at their little faces they couldn’t be happier so we were able to get biocompatible Cod you two days worth of measurements is pretty good and five days I think was about the record so here’s the protocol we were
Interested in anogenin with the late Su Chang wonderful collaboration that we had go with in with with suck uh starting about 15 years ago I suppose now but andreo Genesis is where new blood vessels grow plainly that’s a good idea if you just cut yourself in wound healing it’s obviously vital in uh
Development and growth uh but it’s a disaster if it’s a tumor that’s run out of that’s grown to a size that can no longer feed Itself by diffusion it recruit it uses those same molecular mechanisms to to draw in blood vessels so an anogenin is one of anogenin here
This this peptide is one of the molecules that is is involved in drawing in blood vessels to feed the tumors and provides a pathway for metastatic cells to provide to create secondary tumors throughout the body and this was suk’s interest here so we wanted to know what does angiogenin do we thought nitric
Oxide might be involved so we plate out the a thousand cells or so on the surface of the of the sensor array uh let them calm down a bit give them the androgenin and we see an increase in the nitric oxide signal now this is numbers and sensors and the biochemist took some
Persuading about this so we needed immunohistochemistry confirmation as well this is the enzyme that’s responsible for this we’re very confident in these results because there a dose response relationship the more we give it the more nitric oxide It produced and we could see the development over time and a Time dose
Response curve is is is generally considered quite compelling data so we then started looking at the pathways so neyin stops uh the phosphorilation and the akt pathway and stops it getting into the nucleus this other drer here blocks IR pathway and this one blocks a
Pi3 kyes pathway so we can see the neomy knocked it back to a control level this one had no effect so the irk pathway wasn’t involved this one the pi3 kyes pathway absolutely was because it goes back to control levels when you put this drug in so we start being able to piece
Together the mechanisms of how angiogenin how anogenin is promoting the formation of nitric oxide signaling the growth of new blood vessels at the very beginning of this process so what else can we use this for well host pathogen interaction it’s pretty cool uh this is one of my early foray into microbiology
Involved a collaboration with d Williamson at dstl Port and down because obviously they’re naturally interested in Anthrax for many of the right reasons as well as the obvious wrong reasons because they do all the vaccine development for this work it’s a very interesting bug it has a two-part toxin
One part is protective antigen and then it needs either aema factor or lethal factor and it does this extraordinary little dance on the surface the protective an comes in bind cmg2 receptor on the cell surface a little bit gets cleaved off once that happens the PA can find six of his little
Friends and create a heptameric pore and drag the lethal factor or EMA factor into the cell but you can work with either protective antigen or either of these two in the Open Lab because they need the other part of the toxin to cause problems so again the same sort of
Idea exposing it to know to increas in concentrations at around the 20 microgram level we start seeing increase nitric oxide production this time both the a irk and the pi3 kyes pathway are involved because it’s a different enzyme it’s the induced nitric oxide en now we’re expecting this because production
Of nitric oxide is involved in killing any invading microorganisms at the very early onset or recognition of disease so this is a really important idea and then by loading the cells with Az the anti-hiv drug we could increase the sensitivity and bring it down to well below the circulating levels you’d find
At the very early stages of infection this is something due to uh Christian Amor the grand Fage of electrochemistry in in France who uh realized that you could actually do this and we got down to essentially 10 so 10 nanograms per per milliliter detection on this so uh
We then looked at engineering different parts of this work that D Williamson did at Porton down so it turns out this domain four which is involved in binding is all you need so this part for gives the same response as though it was the whole Anthrax
Toxin so what we were detecting here was the initial binding event which is absolutely essential for the disease to develop because mice that are deficient in this cmg2 can’t get the full-blown version of Anthrax so we thought we developed a drug screening tool that were for Rapid screening for
Anti-anthrax drugs to prevent infection and we thought when we braced ourselves for the world to throw money at us but we often have that moment in Academia right and then you just wait and there’s a kind of uneasy silence so brief break I’ve always had side hustles in in consult in consultancy and
This is I brought this up because it was kind of interesting and some lovely work with Howard Dodd who at least one person in this room remembers and uh who was my phys cam technician at down at Brighton and I’m only mentioning this I’m only able to mention this because the
Company’s long since got got taken over and out of business and no longer in the UK but the problem was their entire Warehouse full of brro refills upm Market byro refills dve up and they came to us they said do a quality assurance assay on the solvent that these terrible
French Crooks have sold us it’s in really poor quality this must be the problem then we can sue them and everyone’s going to be happy we looked at the solvent and it was over speec better than it had been told for so no problem there at all so what the hell
What what’s going on so we just s we sat in the lab how night in the afternoon thinking what to do and we picked the so let’s have a look at what’s what the dried up bits on the end of the Bros are so we picked these scabs off the end and
Ran thin layer chromatography which almost everyone’s done at school right with you know cabbage red cabbage ink and so on and we separated the ink separate the scab out into three of the pigments but then we looked at the ink itself and there was a missing pigment absolutely fascinating and when we added
Corrosion products ion 3 and Chrome 3 we were able to reproduce this so the corrosion was what was causing it and it was causing precipitation of one of the pigments in the broing so it was electrochemistry after all but the background to this is kind of interesting the six different grades of
Stainless steel in a Buro refill this is insane and someone really hasn’t thought through the supply chainers one of these was a 430 stainless steel which is only available in one steel yard in the UK they didn’t like being dependent on one steel yard for their supply chain so
They thought let’s to hell with the consequences let’s spend all the money we can on the highest grade of stainless steel the world knows which is 316 SL medical grade stainless steel because that’s going to be brilliant and when they told me that we thought we better
Have a look at that how does it corrode and of course it hardly corrodes at all in the normal normal media but put it in birro Inc and it was nearly 10 times higher corrosion current density so we were able to solve that problem and it turned out to be electrochemistry after
All and not actually a side hustle and we didn’t charge them enough why chromatography in that at that point well chromatography in a more sophisticated form as hplc is really the Workhorse technique of analytical chemistry now normally coupled with a mass detector on the end that is pretty
Much the way everything goes so here’s the column where the separation occurs you’ve got a mixture of molecules you wonder how what they are and how many there are of them you inject it into this flow that they interact in different ways with this column and emerge at different times and from how
Much area there is under the curve you can tell how much there is and from how long it takes to come out you can get a reasonable guess as to what they are and that’s the general idea but we W decided to play at trying to miniaturize this
Technology surfing on the wave of the craze for lab chip technology in the early 2000s and with a wonderful student P Ling Lao uh built this beautiful little device but it had instead of having a detector at the end it had detectors all the way down and so we can see at the
Top there’s the mixture all together with one of the one of the molecules these were neurotransmitters this is serotonin leak starting to separate off and we can see further down the column the further it’s separated from the others then this big lump at the beginning starts to separate out into
Dopamine and its metabolic product the metabolic product of Serotonin and noradrenaline until finally halfway down the column there full resolution so we would only ordinarily see this down here but we were able to use this approach to actually look at developing effective separation methods on a tiny scale with
Very small sample volumes but that’s not enough we need to be able to collect the samples and I’m putting this next slide up for series Jen Young’s in the audience here tonight and there also their wonderful animations or not animations but actual movies of uh how do we separate the samples out very
Cunning trick that jiny young got organized here applying oil flow to break up the air fluent that comes off the end of the column so the oil flows in here and here and depending on how how how what the flow rates are you can break them into tiny droplets at several hundred per
Second or to these lovely wobbly droplets and each of these is now isolated and you can the your separated sample is now in a separated single droplets so some really nice work there and beautiful engineering so some more recent work shaon mang and a project here on molecular recognition which uh
Collaboration with the legendary Silvan leam foros from the back over on the right here we both look at each other in a particular way with because it’s a really cool idea that doesn’t work very well but it’s still a cool idea and we’re not giving up we’ve already wasted two
Perfectly good PhD students on this and the postto but there’ll be more to come micro rnas are a newish class of biomarker but unlike the others which are usually proteins they’re nucleic acids so we can exploit Crick Watson pairing the way the the nuclear bases
Line up we can pair with each other we can use this for the molecular recognition and get really good recogn nition on this so this is DNA with a deoxy ribos backbone going down there and the bases that do the recognition and of course the chemistry hanging off
This or RNA has ribos nucleic acid as a backbone but you can do a synthetic version of this with a protein or peptide called PNA down here and this is more stable chemically robust and that’s higher binding constant because it’s not negatively charged so there are fewer electrostatic repulsions and syvan has
Already developed this many years ago into a very reli ible assay so this is the target you have two recognition elements that are brought together by the microrna that we’re trying to measure which is could be a biomarker for cancer for example and the one we’re interested in that we were interested in
With this project is prostate cancer because it’s massively underdiagnosed and it’s typically diagnosed at a late stage and if we could get a screening tool we could get better outcomes for the existing tests particularly if the screening tool could give good results within a minute or two on a single sing
Le visit to a GP surgery rather than having to rather than having to rely on men going to the doctor even once which is often quite a challenge so this is there yes there’s a serious bit behind us but this recognition brings these two head groups together so they can now
Have a chemical reaction and this has being made to work beautifully with fluorescence using a cumarin and a th and and and you really ought to have a look at this but we’d like to adapt this for electrochemical detection because it’s cheaper possibly faster and capable of being miniaturized and and and
Distributed and for Community use and very rapid screening so here’s the schematic again the reaction is kind of quite unusual and quite surprising for people who studied organic chemistry and that was my first love I think as an undergraduate is that you can get this one4 addition of a
Base through this reaction here but if you use a catacol this molecule here with the two o’s on this is unreactive so we can allow the hybridization to occur then wash the hell out of the sample clean it all up wait till we’re ready everything working then we oxidize
The catacol and the reaction can now take place so then what happens here is we can see in this Vol amram first time through all we see is a peak for the catacol oxidation and then when we scan back the red current emerges and we see
A a pair of Peaks emerge for this new species that’s formed only because the target micro RNA biomarker was there in the first place so we’re using the biomarker itself to drive the chemistry and I absolutely syvan needs to get the credit for the templated reaction behind
This and I take absolutely take the blame for this working well enough to keep our hopes alive but not well enough to revolutionize Diagnostics yet I’m afraid so this brings us on to more recent stuff uh I’ve been trying to get stuff into the clinics a little bit more and
Complete devices the ideas are the easy bit the implementation of properly engineer technology into biomedical applications or clinical applications is really where the difficulty arise and I don’t know why I’m looking to do something difficult I really it’s not it’s a break with the habit of a lifetime looking for difficult things to
Do that’s for sure but the motivation for minimally invasive sensing then is to obviously minimize the damage to the patients and as it’s afterthought the damage to the senses but the motivations behind this are primarily demographic you know we’ve got an aging population as we see here look how many people
There are over the age of 90 and look at these bugers going up there are simply not going to be enough people to provide medical care and the medical needs of the elderly greatly increase see three of the four sorry four I can’t count four of
The five graphs here this is the cost of prescriptions increasing as we go with age the cost of primary care generally Community Services which really kicks in on retirement here General and a general medicine cost going up here we see we have a moment of San ity however in the
Mental health here at about my age funnily enough so this is as good as it’s going to get but the it’s simply not going to be possible to manage the health care of the elderly without getting greater increase uh increases in technology and we get better disease management we can get longitudinal
Recordings so for example you know type 1 diabetics out Health outcomes are way better now as a result of glucose monitoring the underlying disease has barely been modified but the their ability to interact with that disease and to manage their LIF in such a way as to minimize the long-term consequences
As transform diabetic treatment without the actual diabetes having to be cured or treated so there’s a real role from biomedical engineering in improving lifestyle uh and outcomes in as a result of all this kind of stuff but there are also applications in well-being Sport and Fitness monitoring where is a bit of
A gray area but also I think in pharmaceutical testing because it’s very rare and very difficult to get more than a dozen people into a phase two trial for where they test actual drugs on actually sick people and they’re testing them in very artificial circumstances and we could massively distribute this
Uh technology and greatly improve drug testing by doing this so the two areas that I’ve been looking at micro needles and the application here is antimicrobial resistance and also lactate in sepsis and also exhale condensed breath for uh uh exacerbations and chronic obstructive pulmonary disease and also for diagnosis of sepsis
In the in community settings where it isn’t normally able normally possible to take blood so if we want minimally invasive sensing where should we go there’s a lovely table from hiken feld’s paper in nature about four years ago and the two that are in red are the ones you
Need to pay attention to because that’s what I’m going to be talking about so traditionally whole blood plasma R serum very welld developed the technolog is very welldeveloped for this because until the Advent of scientific medicine all doctors could do to treat you was draw blood either with leeches or with
Lanets and that’s what they did because that’s how that’s all they understood about medicine so technology for taking blood samples was already very good and since the Advent of scientific medicine the blood samples were there and we know how to deal with these things but it causes there’s an absolute limit on
Volume for everybody but this is a particular problem for example in newborn babies or infants and where it could be genuinely limiting it’s painful you get tissue damage if you have to do repeated measurements so for the management of chronic disease this isn’t great and uh
There’s a risk of infection if you want to implant something it’s worth mentioning I think the continuous measurement really means about one sample a minute we don’t need megahertz collection sampling rates cuz a about a minute is about how long it takes for your entire blood circulation to go all
The way around and back again through the lungs and back to your heart so that’s how long it takes for the solution to get well mixed so we don’t need to do any better than that so the Alternatives I guess that have been used historically urine but again there’s
Variable delay the concentrations need to be corrected for by so you need to measure creatinine at the same time and uh so so that that adds an additional complication and of course it’s rarely acceptable in public and um so interstitial fluid which is the space between the cells in your skin is
Absolutely available and you can recover the device afterwards if it caused problems without an additional surgical intervention and breath well what could be if the patient isn’t breathing then not being able to collect exhale breath is frankly the least of your problems so as I like to do when we talk about
Enterprise and Tech transfer students you’ve always got to start with the problem you’re trying to solve and not the technology even though when your Cold Black Heart it’s the technology you’re really interested in but this problem antimicrobial resistance well nearly half the population died from infections in the
Bad old days before anti antibiotics were around it’s a miserable way to go it’s right up there with metastatic disease but they have resistance the resistance has evolved spontaneous genetic mutation Gene swaps natural selection but it’s accelerated by excessive inappropriate uses and we can see these are the death rates in multi
Multiple different regions of the world and it’s you know maybe five million deaths per year worldwide uh sorry premature five premature death million premature deaths per year that something can be done about so the effective use of existing drugs is the really key idea here obviously we need new drugs and
There are new drugs like seid derol from shogi and there’s been about 10 new antibiotics this Century not many in other words uh but existing and responsible use of the existing drugs means you want the patients to be getting the right dose for the right condition at the right time
And work by uh Jason Roberts and others hgle show that around two-thirds of the patients in hospital when they’re being treated under probably ideal conditions are getting the wrong dose too high just right and too low and too low is the problem because that creates a a a an
Evolutionary selection pressure for the development of resistance so even under idea ideal circumstances where they get therapeutic drug monitoring when they’re measuring blood samples because it takes too long to get the results back there are still more than a third of the patients getting the wrong dose five days in a
Dose that’s too high or too low so it barely improves the situation so what we want is Clos Loop control we want to measure the drug concentration and that’s where our bio sensor comes in sends a error signal generates an error signal here the controller controls an
Infusion pump tops the drug up to a Target level now this target level could be for example a pharmacokinetic or Pham pharmacodynamic level what’s the level that patients traditionally needed for this as a population but our new idea and our more recent and exciting ideas are saying we should be titrating this
Against host factors so we should be seeing is the patient getting better we should be measuring those factors as well like C reactive protein and procalcitonin because you can stop if they’re not getting better after a day and you can stop the treatment if they get better four days into a 7-Day
Treatment so micro needles developed by Tony Cass look a bit like this go just into the viable epidermis so they go through the dead skin at the top of the stratum corneum into the vial epidermis where there are no nerve endings no blood vessels so it doesn’t hurt doesn’t
Bleed there’s minimal risk of infection very small risk of a uh of a um uh allergic reaction so they’re very well tolerated the concentrations of all the important things are very similar to plasma so we can interpret the values rather well so we’d like to get the right do
And our proposed solution is Clos Loop control so how does this how do we get this done on our Micron needles we put an enzyme that catalyzes this reaction the red bits where the action is so it hydrolyzes that amide creates an acid this causes a drop in the pH which the
Aridium oxide detect as a voltage change and we can read this out and this is what the Micron needles look like and this is I think Dave Freeman’s arm yeah he’s nodding patient three I think he was our second legal patient anyway and you can see after the after
The device comes off it looks just like the kind of marks you might get on your leg after your socks have been on too tight so really not you know really and the illumination an hour in obviously has changed because he’s now in the pub but 10 hours later absolutely no
Sign so very well tolerated and you noticed I went straight in with the safety and tolerance here rather than out whether the science was any good so definitely safe to use we validated using liquid chromatography Mass Spec from dialysis samples taken from underneath the skin and Venus blood
Samples taken every 15 minutes this addresses the essential epistemological problem of analytical chemistry which is how do I know I’m right you measure something you got a device you know works but how do you know you’re getting the right result and validating against techniques that have a different physical principle greatly increases the
Chances that you’re not fooling yourself and not making a fool of yourself in public either when you present these data so at the top here we see the three sensor Curves in blue green and red Rising when we were when we swallowed the penicillin dose the blood levels
Leading this slightly by about 15 minutes also oscillating up and down interestingly and the micro dialysis levels from under the skin more or less following what we were able to do measuring just on the surface of the skin and here’s one of our Bland and alment plot where we plot the difference
Between our method and the reference method against the average of our method and the reference method we’d expect a straight line around zero and most of the spots fall in this particularly in the important region where the drug Target concentration actually lies so yeah I’ve actually managed to
Keep more or less the time here the uh sorry I’m I’m more surprised than anybody and certainly anyone anyone who’s ever endured in my undergraduate lectures will be amazed uh the final topic then exhale breath condensate our original Target work on this was on chronic obstructive pulmonary disease
And exacer a working with the people at the national Heart and Lung Institute uh down the road from here um exhale breath we’ve all done it as kids bleeded on a car wind screen or CR or window and seen it steam up and think well what’s in
That mean water obviously but stuff that your lungs are exchanging with that we may be able to find things it’s massively non-invasive everyone breathes we can collect this without hurting anyone without doing any damage to anyone but it remains a bit of a controversial subject the clinical need
Was early detection and management of exacerbations and OPD it’s a remorseless disease goes on there’s no cure if there’s an exacerbation caused by for example air pollution or an infection they get dramatically worse and stay worse and they usually have to be temporarily at least hospitalized as
A result of that now if we could get early warning from that the patients could take their emergency test kits keep out a hospital have generally more improved quality light they could also look back at a longitudinal record if they’re testing themselves regularly and find out which lifestyle factors made
Things worse or better for them is an individual but the there’s a lot of controversy about this and hydrogen peroxide is a pretty good Mark H2O2 but you see here the lovely graphic produced by white by Danny Chen one of my great X PhD students here and you know control
Levels are all lower within any one study the difference between control stable exacerbated and treated was pretty stable but you can see that one study here uh has levels in exacerbation in in in in stable COPD that are lower than somebody else measured in control subjects so that can’t be right and the
Reason for this is if you condense breath you sure as hell need to know the temperature of the breath in and out you need to know what the flow characteristics are and you uh because I I should have been listening to my first year my own first year lectures on
Thermodynamics temperature and heat mass and heat mass transport are important in the partition coefficients the volume that we collect is going to be affected by the temperature the the partitioning of the of any volatile molecules into the condensate when we collect it is going to be affected by the temperature
Of the cond condensate and the temperature of the breath and we need to correct for that and Danny Chen came up with some beautiful solutions for this so we have an impinging jet flow which is very stable and very tolerant to changes in design and changes in breathing pattern with a pelti chip
Condenser temperature sensors on the inlet and outlet and flow measurement so that we could correct for breathing patterns and we this allows the patients to breathe normally which is a really important part for COPD patients so this is the competing technology the r tubes and we see the
The patient blows in here it goes round the bend there’ll be all kinds of helical variable flow here it condenses because this stainless steel sleeve has been in the freezer and I don’t know about you but when H do you really know what temperature your freezer is really
When how long has been last since been defrosted how long has the stainless steel sleeve been on the side there’s no way this could be getting reliable results and this is our device uh since commercialized by Danny Chen and Shia Kai Hong two two of our great students
And they uh set up a company called respire diagnosis so you can now Buy you blow into this it condenses on the Peltier chip at the back we got all the sensors to measure all this stuff we get around three 3 30 to 50 microliters in 2 to five minutes of normal breathing
Which is similar to the r Tube Technology except it works better and it’s properly controlled and we can keep the samples we’ve got a hydrogen peroxide sensor based on Prussian Blue so we’ve coupled the Redux chemistry of ion 2 and ion 3 to the hydrogen peroxide
Chemistry here we have to do look at all the different steps in this and back out all the rates of these reactions and we get limits of detection down in the in the submicromolar level and repeatable measurements this way and we can also measure nitrite as well at the same time
So by combining hydrogen peroxide with nitrite and the flow data because the pattern of velocity in patients with COPD is different from uh normal healthy individuals and combining these into machine learning classifier it turns out to be as potential as a diagnostic which we’re very surprised about as well
Because we’re really just looking at a at a healthcare device that allowing people to manage their own health care conditions and we can couple this to an enzyme to measure lactate in exhale breath as well these are the raw data for those of you who think I’m just
Trying to hide through this stuff and these are the Disposable sensors that we’re manufacturing at scale now and we did some preliminary evaluation in healthy exercise volunteers too damned healthy in the case of Richard Wilson we had to get him up to 210 Watts before he
Produced any lactate at all so don’t use healthy individuals if you’re trying to study lactate ignoring the first point for a moment see when he exercises the lactate on his breath goes up and goes down when he stops cycling we’ve got this intriguing business at the beginning
Though that really made me wonder were we measuring something else as well so we developed an lcms assay with with Allah Zeke and the uh in um uh infectious diseases to some fantastic analytical chemistry for us and know all of these results that our sensor got were all actually correct so this early
Stage fall in lactate when patients are get healthy volunteers are getting ready to exercise we have no idea about we’ve tried all sorts we saw as bugs on teeth what you’ve been eating someone having a sneaky bottle of duest bul be which has got lactic acid beforehand none of these
Are an explanation but the results all fall in line with the mass spec and we can’t argue with that so in conclusion ah if you’re going to get into Diagnostics and bi analysis you need interdisciplinary knowledge so you need to know what you don’t know and then you
Hire the experts to deal with this stuff you build a multidisciplinary team have relying relying on your own sketchy knowledge to actually identify people who have the cor knowledge that can make your project work and this has been a central element to my research throughout my professional life I think
One of my major conclusions is the ideas of the easy bit and the reduction to practice is where things go horribly wrong and where it gets hard minimally invasive technology can address some of these demographic challenges in healthcare deliveries and more importantly get better patient outcomes interstitial fluid is a accessible
Medium low risk we can measure all sorts in with the micro needles an exhale breath condensate we think is a viable potential Source uh but but really my final conclusion valid analytical measurements are difficult to do uh lots of people paid for all of this this is
My favorite quote from one of my favorite books G Travels by Swift he meets the scientists on the flying Island and they take him back to uh to their uh to LOD their uh their Homeland where their labs are and he’s describing the extraction of sunbeams from
Cucumbers and he said you know young students were employed in this labor which might still be improved and much expedited if the public would raise a fund and thank you all for your attention you’ve been a wonderful audience I’m all [Applause] done I’m not going to say thank you and
Congratulations that will come later but but this was absolutely fantastic um we have time for just a few questions from either the audience in in the lecture theater here or online schulin is scanning the online um chat on YouTube to see if anybody wants to make a
Question they’re 20 seconds behind us so that gives us time that was in case I swore right we we weren’t counting Danny um is there a question here in the room Molly so um Danny is amazing and I’m very very ENT thank you mly yeah for the micro needle sensing
What I mean you could do so many other applications as well right where where where are you thinking for the future well the host factors for infection and when what we want to be able to do is titrate antibiotics against the patient’s own response to an infection
So if we could measure those either going down as this treatments being successful or being are not changing as a result of the antibiotic and you know they’re resistant I think that’s a very exciting application so you and that can the same idea could be applied to other
Drugs and we’re actually applying the same concept to not to micro needles but urine samples for uh urinary tract infections as well so you try and measure the drug and the production of nitrite from nitrate by the bugs so that’s that’s definitely an area I’m super excited about I think there are
All kinds of other areas that would occur to anyone else you know you drug testing for example or you know bail conditions stuff I’m not interested in well I I mean I think if you can make a dent in the antimicrobial resistance is huge hugely important I mean it’s
Probably what third existen most serious existential threat to humanity at the moment I think maybe something like that so it definitely seems like a worthwhile activity thanks thanks M any other questions from in the room I know that we have uh Refreshments afterwards so uh you’ll have time to
Caller Danny and ask him those questions that you don’t want to raise in public I can see about a 100 people here dying of thirst Frank there’s one here here we go yeah of Frank were you sitting in on the discussion that shuin and I were having
The other day because when we calculate the levels of lactate that we should find they F five orders of magnitude lower than the ones we actually get so it’s definitely aerosols absolutely aerosol and we don’t know what what this means means and and we we you we’re we’re absolutely open if there’s anybody
On YouTube who’s got an idea respiratory physicians in particular and we’ve been talking to people we obviously we’ve been constantly talking to respiratory Physicians about how to analyze this if we knew where they were coming from it’ be easier to interpret but no absolutely right it’s it it is we think mostly
Aerosols that we’re capturing because you know one tiny droplet of actual liquid is many many more times more molecules than a vapor so yeah absolutely we should get you back in the lab now you’re retired we’re going to take our final question from on CH you
Want to read it out yeah so here is one question in the area of AI how much do we need accurate biomanagement bio managements v as a large number of them oh yeah I mean I I think this is going to be an important field and it’s and
And I would really suggest they talk to somebody who knows about AI about this because it’s not absolutely not my specialty but I think the idea of just looking for patterns and not caring what they are is definitely an important Trend in in Diagnostics uh but it’s not
Something that I have any I would that I would pretend to have any expertise in here there are mercifully however plenty people in the department of bioengineering at Imperial College who do and I would I would encourage them to to get in touch with for example anel
Barth Danny if I could invite you just to take a seat for a moment and invite Peter winoff to come on Peter is Professor of biophysics at exitor um a graduate of Imperial College physics and was here in bioengineering well before it was called bioengineering
For a couple of decades over 20 years I think and you’ve already seen his photo today this is what he looks like in the flesh actually no different I would say um and he clearly overlapped substantially with Danny in his time here and it’s a great pleasure that
Peter is able to be here to give the V of thanks right well I’m sure you all want to join me in saying thank goodness that’s over and that Danny long last has got the the tear that he deserved served for so many years but I’m sure he didn’t invite me
Here to say nice things about him so I thought I might take take you back to the beginning to Where it All Began now around about 1980 Kim and Kim parter my oldest and dearest friend who I’m delighted to see here this afternoon were trying to carry
On the work of a Polish post dot who we convinced was a spy and just doing a little research on this but he left us with the problem of measuring oxygen concentrations in the walls of blood vessels and Tim set about assembling our very first computer and after several long weekends
With the aid of a a real tooreal tape recorder as the data acquisition uh system we were able to record Electro electrod currents of the order of a thousand data points in no more than 10 seconds or so so this revolutionized uh chronoamperometry we realized that but
We also realized we didn’t know any electrochemistry but we as Danny pointed out realized that one of the world’s leading electrochemists was sitting over in chemistry so we beat a path to his door and he was very very understanding he entertained us for many afternoons and really took us under his
Wing and then finally he introduced us to this young chap who was stulting about in his laboratory having screwed up his his final examinations and I often wonder whether that was a joke on his part because this electrochemist was a man of Catholic taste in the widest sense of the word
And I always suspected this was because he couldn’t persuade Dany to join him in some of his more Priestly behaviors uh anyway we had to uh make a special uh appeal to some college board or other to allow Dany to undertake his PhD and despite all of that it worked
Out very well Danny very quickly mastered all the electrochemistry we threw at him the one thing he found difficult was that because we work at the interface between physical biological science and medicine it means you have to interact with people from very different background and work in different people’s labs and
That was something that Danny struggled with for a long long time one of my first experiences was doing with him to to one of the biological facilities here and we were given a lab where for some reason they had a large poster on the wall on how to an the ti a
Pig and it was a very graphic poster and it led Danny and I to a very animated discussion about animal husbandry which we thought was very far reaching and extremely entertaining but unfortunately the the technicians in the lab didn’t share our sense of humor and strong letters were exchanged between heads of
Department which resulted Us in as both being banned from the lab for some considerable time in fact I’m not sure whether that ban is actually being a still there so that was a very good start and Danny’s Pro first project concerned measuring oxygen concentrations in the invertible disc and so it was inevitable
That I brought him into contact with the queen of the intervertebral disc my other friend uh who was a incredibly bright but also very reserved and doesn’t tolerate fools gladly so every student is in in a OFA and so I put it off as long as
Possible before the end of his PhD he and I had to make a a trip up to watsford put his electrodes into an intervertebral dis preparation of hers and we had a a great day but I got very nervous when I realized I had to leave
Drive back to London leaving he and this lady Alone Together and so the next morning I got on the phone to see how things went and I found out that she was even frostier than usual it took me a long while to th her out and it turned out that Dany had
Assured her that he was perfectly equipped not only to solve outstanding problems in the intervertebral disc but also to resolve any inadequacies she may be finding in the marital bed got no idea at all how that conversation evolved anyway there are many more stories I can tell you about Dany but
Most of them would be slightly tasteless so I think they’re probably better better left till later on uh so I shall finish with the observation that when Danny went into Exile in Brighton I thought he really belonged here and tried very very hard to find ways to
Bring him back they all failed and I the only way I could find of bringing him back was to leave myself and I’m sure Anthony and other people in the department will tell you that that’s a a win-win situation but uh before I give him that opportunity I think a day I’ll stop
Talking and just ask you to join me in thanking Dany in a for a great presentation and congratulating him on his position [Applause] 31 I thought he was going to complete the story okay everyone let’s celebrate with Danny yay going to have a drink