Cell and tissue surfaces are crucial in the regulation normal body function. They control the passage of a variety of substances and physically separate parts of the cell and tissues which have different functions. As with many crucial processes these borders are disrupted in disease and can represent a crucial ‘battleground’ which determines outcome but also represents diagnostic and therapeutic opportunities.
In his inaugural lecture, Simon will use examples from pathological science to highlight how the cell surface can catalyse enzyme reactions and how dysfunction of this system can lead to tissue surfaces sticking together in the abdominal cavity forming peritoneal adhesions. These are a leading cause of small bowel obstruction and secondary infertility in women.
Professor of Integrated Oral Sciences, Simon Whawell’s recent work has highlighted the crucial role of what was previously thought to be relatively normal tissue or stroma surrounding tumours including those originating from the oral cavity. By reflecting the progress of the ‘battle’, cells within this border may be better diagnostic markers of disease than features of the tumour itself and represent an area where specific interventions may represent a promising therapeutic target.
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Inaugural Professorial Lecture as part of the Public Research Programme.
More on the Public Research Programme: https://www.plymouth.ac.uk/research/public-research-programme
My name is Jun McCall I’m head of the dental school so first thing to say is welcome everybody everybody to tonight’s lecture um I’m in the zone for public speaking having just finished the graduation where I had to read out about 200 names in front of thousand people so
I think this will be a bit easier tonight um I’m sure it’s going to be a fascinating talk um I’ve known Simon and veed from we were all at the East mental institute in London together so in my case it was a fleeting visit I was there
2001 to 2004 uh Simon and veed uh were part of the furniture and I think it’s a bit bit longer than that and I’m sure they will explain that in the process so with that in mind vead is going to do the introduction so we welcome V uh onto
The stage to do the introduction to Simon’s lecture thank you good evening everyone here in devonport lecture theater at the University of Plymouth and as well online welcome I’ll just do a double angle so everyone can see me welcome to this inaugural professorial lecture I’m honored to have
Been asked to introduce Simon and offer a short prey of his academic career and indeed explain why we are here this evening first and foremost I’d like to welcome our University colleagues as well as faculty and dental school colleagues here this evening I’d like to extend an especially warm welcome to
Simon’s close family and uh friends who have also been able to join us welcome to you all I see many students in the audience as well and people we don’t know so that’s fantastic the marketing has worked a quick moment to acknowledge the work and time spent by our colleagues
From the events team please for preparing this evening they’ve worked very hard to ensure that everything runs smoothly and efficiently thank you for your efforts so an inaugural lecture this is a time honored tradition and a key milestone in any academic colleague’s career signifying their promotion to full
Professor by the way the origin of the title Professor for those who don’t know comes from the need to profess or declare publicly one’s knowledge no pressure Simon it evolved in medieval Europe from being a synonym of Magister or doctor denoting someone qualified to teach again no pressure Simon to imply
Distinction within a gradually developing hierarchy of teachers this right was originally possessed by any master or doctor to teach publicly in schools of A Faculty at universities around Europe however that was gradually restricted to an inner circle of teachers and the term Professor became an eventual term to be confined to the
Holders of salaried or endowed teaching offices so they the highest ranking teachers if you like this evolution of titles was accelerated in mid6 Century by King Henry VII when he founded five regious professorships in Divinity civil law medicine Hebrew and Greek tonight is a platform for a new professorial colleague to present his
Research specialty firsthand to colleagues students and the public and it offers a fascinating glimpse into the evolving issues or topics of importance in Simon’s research it brings experts and experts together to showcase the research and ideas that demonstrate the recipient’s academic experiences and we look forward to that here at Plymouth
University excuse me University of Plymouth it is also delivered as part of the University’s public research program we are praising and commending Simon’s work my role tonight is known as the speaker’s introduction traditionally from the Latin latio and I am your La laor this evening and we are lording his
Achievement Latin always raises the bar doesn’t it I would also like to welcome at this point all of the students who’ve made an effort to attend this seminar your presence here de demonstrates your desire to learn and grow this evening presents a chance for us and you to
Question Simon at the end and broaden our own perspectives and knowledge so the first years that started last week I can see sitting in the audience again no pressure but a question from you would be amazing so who is Simon waywell and how did he get here Simon was born in Kingston upon
Tams in Southwest London he obtained his BC with honors in life sciences before going on to gain his PhD um at Imperial College London at St Mary’s Hospital medical school his post-doctoral work took him via research positions within the welcome trust the British Heart Foundation before he landed at the East
M Denis Institute as we’ve already heard well I’ve met him in 1998 we were there for some years five years together uh we crossed paths um at the University College London although we worked in different research groups we shared interests ideas tips and advice in cell culture cell assays
Cricket Mano cheese and had regular intense research discussions in postgraduate room number five well sorry actually known as the lamb just by great Orman Street children’s hospital then in 200 three uh an opportunity arose for him sadly for us at the Eastman to join the oral and Magilla facial pathology group at the
Dental school at sheffel University where his career blossomed and he remained for some 18 or 19 years I believe time in a long time and you earned your academic Stripes his academic administrative teaching examining research roles are numerous and have led to many strategic improvements teaching Innovation book chapters articles and and developments
Both nationally and internationally he also very recently became president of the British Society of oral and dental research Simon we were fortunate to have you join us here at Peninsula dental school last year where you continued to build rapport with both undergraduate and postgraduate students and colleagues
And bring us fresh ideas you are inclusive and Collegiate student focused collaborative and friendly and we are glad you are part of our Dental team so that’s enough from me this evening is about Simon’s main research themes and interests we look forward to hearing your knowledge and expertise sorry your dedication and
Commitment to research teaching and assessment is laudable and we are grateful for the opportunity to learn from you ladies and gentlemen may I introduce Professor Simon waywell thank you very much indeed good evening everybody thank you veid for that fantastic introduction I know veid was probably more nervous about doing
That than I am doing this very generous and and heartfelt and thank you so much for that it means a lot to me that um so um thank you all very much uh for coming and can I add my thanks to the events team they’ve been absolutely fantastic
In arranging this I’ve got as a uh various introductions said quite a mixed audience uh so hopefully you’ll be able to follow everything I say uh obviously as I got dentists in the room I’ll have to turn down the science a bit um joking joking joking joking uh so uh on the
Border is is the theme that I want to uh thread through this presentation and hopefully that will become apparent later so On the Border uh it comes from a sermon delivered by my father who’s a retired Church of England Vicor who unfortunately can’t be with us tonight
Um but he was inspired by the countryside on the top leftand corner so he had a parish um on the Essex suffk border near Colchester uh and literally would look out of the vicarage window and see the next County and so he wrote a sermon uh about being on the border I don’t
Remember the religious side of it but I do remember the sermon and I do remember that the message was when you’re on the border you can see both ways and that’s something I will come back to later um but we’re all on the border aren’t we
Look at the image on the right that will be uh familiar to most of you some of you cross the border every day on the way to work and home again and part of our dental school is across the border as well uh in TR
So we are all on the border um but borders are in the news a lot aren’t they at the moment uh you can see from the images at the bottom uh people risk their lives every day in trying to cross borders uh and other people try to make political careers and statements by
Making borders stronger or taller um but we won’t get into the political side of things today uh but border they they they form an important part of our lives in every sense um but today I’m going to not surprisingly uh talk about biological borders so cells and tissues and organs
Have borders and they perform an important role uh in our normal physiology so first of all I will um briefly describe some of the reasons why we have these biological borders and and then from various stages of my research career I’ll discuss three particular borders uh the last two you will see uh
From my 25 years in oral and dental research so then I will try and conclude and share with you some lessons that I’ve learned along the way uh and last but by very much not least I need to thank some people uh who literally are the reason that I’m stood here this
Evening okay so why do we have cell tissue and organ uh borders well as you can see from the the diagram at the top right hand corner most people if they were to draw a cell would draw a line and maybe a circle in the middle for the nucleus of the cell I
Think most of us have probably done that at some stage but cells are a little more complicated than that they have an ex external uh border around them but they also have borders within them uh so the particular organel that occupy the cytoplasm of the cell uh they have
Borders around them as well and one of the reasons that they have those is to keep things apart that have a different job so for instance inside a cell there are organel called lomes they contain highly potent proteolytic enzymes that if released into the rest of the cell
Would dissolve uh uh the contents so they need to be kept away from the rest of the cell uh the cell membrane itself that surrounds the cell is a very complex structure uh as probably most of you know it’s a a by layer of lipids but within that and all over that it’s
Covered with other molecules that have an important role in the function of that cell and a colleague of mine from Sheffield described this uh in terms of a a rainforest canopy these proteins on the cell membrane they’re covered in sugars so that there literally isn’t any spare space on the cell surface and
That’s how cells interact with each other and with pathogens we’ll see later on uh and are important in its um function of the cell um also you may see uh in the diagram at the bottom uh there are some channels within that membrane so these are border controls if
You like uh they control what goes in and what goes out of the cell and play a very important role uh as well so as uh they had mentioned uh my research career began at St Mary’s Hospital in Paddington Paddington gateway to the Southwest you can see the Gateway there in the middle
Um so um my career started in the academic surgical units at Mary’s hospital where I did my PhD so we had uh some Labs through this Archway in the basement of this building to begin with uh and then we Rose as a department to the Dizzy Heights of this
Is the Queen Elizabeth the Queen Mother Wing uh where we occupy occupied the top 10th floor with panoramic views over London so not much work got done there then um but um the the place has a lot of history uh including uh where sir Alexander Fleming discovered
Penicillin uh and there’s a local public house uh named after him uh where we’ve occasionally had research meetings known by people that work at the hospital as the fleem that I’ll leave you to decide why that might be okay so um apologies for the slightly gory images uh these are the only gory
Images apart from that one of my face at the beginning of the lecture um but this was a first of um many productive collaborations with clinically trained colleagues so F first of all with general surgeons uh and then with Pathologists and dentists uh and this was the first of those
So um you can see from these images here uh and this is our first border so our uh abdominal cavity is lined by a border and so are all the internal organs within it and they serve a purpose in keeping those organs separate from each other but also to lubricate their
Movement within the abdominal cavity um and so I was working with general surgeons that often came across uh the formation of this internal abdominal scarring uh called peronal adhesions so this was a big problem for surgeons um they would be causing them in the first place by performing
Operations uh and then if they tried to um divide those adhesions with further surgery this would lead to more adhesions and is a big clinical problem so these sticky internal scars can get tangled up with your intestine and cause obstruction so prevention of the food going through your intestin it is also a
Big problem in women because the internal reproductive or organs can also be affected uh which can lead to INF infertility so it’s very common after surgery uh or infections known as peritonitis and so this was a a big clinical problem uh that we then set about trying to find out um the
Mechanism by which adhesions form so this was the working hypothesis from our own group but from others working in the field at the same time so it seemed that there was some sort of injury that causes this process to start uh this results an in an inflammatory
Reaction and an exudate uh which is WR in fibrin so fibrin is the protein which forms the basis of blood clots so this is a bit like an internal blood clot to begin with now if that remains within the peronal cavity it becomes organized to form these more permanent uh peronal
Adhesions so the fibrin turns to collagen it’s infiltrated by other cells and becomes more difficult for the body to break down and that’s when it can lead to these subsequent medical problems but the body uh is a fantastic thing and it has a natural mechanism to break down fibin when it’s not needed
And that is fibrinolysis or the fibrinolytic system and you can see on the uh left hand side if the fibrinolytic process is activated then these early deposits of fibrin are broken down and the adhesions don’t f form that’s the theory anyway so we we were tasked with looking with the Fairly limited biochemical
Tools that we had at that time into the mechanism by which um these adhesions form uh and this is the fibrinolytic pathway in a in a simple diagram relatively simple diagram and like many of these enzyme Cascades it involves one enzyme activating another enzyme enzyme and eventually leading to the end result
And you can see in blue those enzymes are plasminogen activators they activate plasminogen as the name suggest to form plasmine and plasmin is the enzyme that degrades this vibrin material uh to soluble degradation products now also what is extremely common in these enzyme Cascades a bit like the clotting system
Uh is that they are really tightly regulated they’re complex systems because it allows lots of different time points to do this regulation and the action of Inhibitors controls the activity of these enzymes so they’re in Black plasminogen activator Inhibitors and anti plasmine they can control uh the function of these
Enzymes so this was the pathway that we thought was leading to adhesion formation and so we investigated different components of this fibrinolytic Pathway to see what might be uh the cause of these periton adhesions and if you look at the top right you can see an overall estimation
Of the peronal fibrinolytic activity in normal tissue or inflamed tissue and if you remember inflamed tissue uh is in a circumstance which likely to lead to aesan formation you may ask how we got hold of normal human tissue obviously with the appropriate permissions but you may be surprised to know how many normal
Appendices are removed during surgery so this was our um normal tissue to compare with the inflamed tissue so you can see from the top right normal tissue has this fibrin clearing activity and in inflammation it’s completely abolished so this in theory would allow the fiin to to remain and to form those per
Adhesions and if you remember the pathway I just showed you it’s initiated by this enzyme plasminogen activator and if you look at the uh the bottom left you can see that the levels are quite similar between normal and inflamed tissue um however if you look at plasminogen activator
Inhibitor uh that’s not normally present uh but is massively increased in inflammation so it seems like it’s not the enzyme it’s the inhibitor that is increased and that leads to an abolishment of this fibrin clearing ability so that was the theory that was years of work in one slide obviously
I’ve left a bit of detail out of that but so just to summarize that first border one uh the lining of your abdomen has this fibrin clearing activ ity this is reduced in inflammation which occurs after surgery and infection and so that may explain why these adhesions form within your abdominal cavity the
Mechanism appears to be a large increase in the enzyme that initiates that process so one treatment option and we looked at this experimentally uh and others continued the work after I finished working in this area one treatment op would be to add some more of that activating enzyme that initiates the
Pathway and this is available as a clinical drug it’s used as a clock Buster um for some forms of stroke when uh restriction of blood flow to the brain is due to a cloth if you very quickly administer this enzyme uh you can relieve some of that um
Blockage so it is possible that you could inject that after surgery or infection and maybe prevent adhesions the difficulty uh is that you need blood clots to form initially when you’ve had abdominal surgery it’s the first stage in which your scar will heal if you’ve had bowel surgery joining two ends of
Bowel together that will initially join by this fibrin so one has to be careful what one does which is why I suspect this is not in um widescale use already but anyway we were very successful with publishing this material uh including as you can see at the top right in a medical
Journal called the lanet which if you’re not familiar with is a well respected medical journal um and the article has been quoted uh nearly 400 times by other researchers um but there is a danger if you do that with your PhD work uh that you may have peed too early is the
Only problem with that okay so then um I moved away uh from um the research on adhesions after one post-doctoral position investigating that and another in the area of vascular biology before I landed uh in the area of dental research and there’s the Eastman Dental Institute it’s no longer there unfortunately was
In a beautiful building um and my office was overlooking that very attractive Courtyard with a fountain in the middle um and uh that’s where I was between those dates uh before moving to the school of clinical dentistry in Sheffield which for those who know about their geography is on the border of
Yorkshire and darbishire uh and so the rest of the work I will describe um is from that time and and that Sheffield in particular as V they had said I became involved much more more with teaching during that time as well so the wonderful world of Dentistry Dentistry
Is full of borders we’re we’re always looking at Borders in dentistry uh the mouth is an entry Port isn’t it a Port of Entry um and there are layers and interfaces um at all aspects uh inside the mouth including the tooth and transgression of these borders uh by
Microorganisms in particular are are key processes that go on in some of the most common diseases that humans uh suffer from um if we try and uh cure some of these diseases by removing uh dental decay or carries and put a filling material we’re creating other surfaces which can also eventually degrade over
Time because our mouth is under constant attack from acid and bacteria so these are very important borders though because as I say carries and perodontal disease or gum disease are some of the most common um uh who report on cares published last year suggests that 30% of those above the age
Of five have carries active in their mouth and various Studies have suggested that up to 50% of the adult population suffer from some form of perodontal disease so these are hugely significant conditions uh they don’t get the attention that they deserve or the government funding um but they are
Significant burden on society for cost and lost working days Etc uh and children turning up at A&E to have all their teeth removed uh so it’s somewhat embarrassing that I’m here to say that but I think I have a role we have a role uh in trying to promote the importance
Of these um oral diseases because they are a huge burden but also mostly preventable as well and that’s obviously something we try to do here so the second border is one of these involved in perodontal or gum disease now what happens as you can see from the diagram on the right uh is
There’s a change in the Border uh between the gum and the tooth uh and in fact sticking metal things in this new border is a way of measuring the progress of this disease isn’t it Professor mcco he does that all the time um now this um degradation in this
Border between the gum and the tooth um provides a new environment and this new environment is populated by different bacteria that would normally not be present in the mouth um and then there is an overreaction of the immune system to the presence of these bacteria and that’s essentially how perodontal
Disease forms and progresses now one of the bacteria um that has been implicated in this process is a bacterium called ponus gingivalis known as PG for short rather helpfully uh and this is one of the bacteria we’ve been interested in studying it is only one um but even
Though it’s present in quite small amounts it’s thought that this bacteria shifts the population of other bacteria to a more disease promoting um microbiome now the thing that we were interested about this bacterium is like a number of bacteria it gets inside human cells and that’s what we think is
An important pathogenic process um because once it’s inside the cell it’s protected from the host immune system from your immune system but also from most therapeutic agents so most antibiotics for instance don’t cross the human cell membrane so these are hiding away these bacteria inside the cell
There’s some evidence they can grow they access new nutrient Source uh in this protected environment um and that process from this bacteria has been associated with disease progression in parodontal disease so it it may be one of the things that’s important in progression so these bacteria are literally stowing
Away on the border they’re hiding uh on that particular border now I have shown this slide to many colleagues before and I won’t apologize for it uh because it’s one of my favorite images and I have it as inspiration pinned to my notice board in my office so this is one of those
Experiments where you just needed to have a look and one of those experiments that creates more questions than answers so here we’ve got um a cell culture of human cells uh that should all be identical genetically they should be identical and then we’ve added two different types of
Bacteria here so the on the right you can see the brown staining is that ponis gingivalis gum bacteria I just told you about uh and on the left hand side um is an organism found on skin normally but is a key organism uh that infects skin wounds uh that’s storus these back IIA
Are quite different um but you can see that if you add them to this monol layer of cells that should be the same uh some cells are completely covered in bacteria they stick to the cell and then they get inside so these might be on or in um
Some cells are completely covered with bacteria whereas the cell next door has got absolutely none in at all and the same is true of this other bacteria the black dots are the bacteria in this case and the red areas are the cells some cells are completely covered
Whereas ones next door have little or none at all so there must be something different about these cells they must be pre presenting a different kind of border to these bacteria to explain this observation but it is a good example of how just sometimes looking down a
Microscope uh can initiate a whole area of new research now again for reasons of time I have to cut quite a long story short um but one potential reason why these cells might be different is there at different phases of their growth cycle or cell cycle um some of you will
Know uh that cells go through quite a complex process to prepare to divide into two to daughter cells and our cells are growing even in mature organisms like myself uh they are growing all the time so this is happening uh to a to a a
More or less degree all the time so this process is quite complex again as I mentioned with enzymes it’s so it provides lots of different places where this process can be tightly regulated cell growth is one of the most important things that our body can controlled um so you can see that the
Cell goes through various processes of growing and then it reaches this phase here called S phase where the DNA is copied so um briefly um the cell has twice the amount of DNA that it should have uh and to prepare it to um be split equally between the two daughter
Cells uh so lots of areas for tight regulation as again some of you will know the proteins that control this cell cycle are commonly mutated in cancer so cancer is disregulated growth and so a lot of proteins that control this process they go wrong in cancer and that
Leads to this uncontrollable growth now a clever little trick you can do in the laboratory is to remove growth factors from the cell culture and the cells can stop at different phases of this cell cycle so this allows us then to add bacteria when the cells are different
Phases of the growth cycle so then we can investigate whether that’s the reason uh why there is this difference in adhesion and invasion of bacteria with some cells and not others now I wouldn’t be telling you this of course if this didn’t turn out to be the case I
Did say I was cutting a long story short um and this is work from hopefully he’s joined online a very capable phg student of mine from Iraq called FAS Al toel I hope he’s here um because his work was fantastic uh and he showed this very
Well I used to call him donkey which he said was because I made him work so hard but then I reminded him about the Christian tradition where the donkey is sacred and it has a cross on the back because it carried Jesus into Beth so um there we are anyway that I digress
So donkey I hope you’re listening and I hope you’re well uh because this was his experiment and you can see on um the left hand side the blue dots are all of the cells under this particular kind of microscope and then on the right hand side the green cells are those that are
In S phase of the cell cycle this phase in which the DNA was is copied and in fact the green dye is a Dye that picks up the increased amount of DNA in those cells now we’ve stained our gun bacteria or fonus gingivalis red in these images
On the right and again you can see something similar to the image that I showed you before uh in that the bacteria are largely Associated uh not 100% but are more prevalent in the cells that are green as opposed to those uh that don’t show up uh would be black and
I think you can see that even more clearly in the image here so there’s something different about these cells in SAS uh which might explain why the bacteria are binding to them as with before all of my research is looking at mechanisms of disease uh and and we
Looked at the mechanism of this um the images in the middle show some of these um receptors that you find on the cell membrane of human cells and you can see some of those called integrin are involved in binding bacteria and we showed that particular type of this
Receptor is increased in S phase so that might explain why you get more bacteria inside those cells uh and the graph on the right hand side is not mine it’s from Jones who works at the dord research facility and he fairly recently showed that SAS cells have something
Else different about them uh they have uh complexes called focal adhesions on their cell surface the area of those is increased in S phase of the cell cycle and these complexes contain proteins including integrin receptors so we might have a mechanism to explain that observation two okay so to summarize border
Two um bacterial invasion of human cells we think I think is a key pathogenic process not only for gum bacteria um but for skin bacteria too understanding why some cells seem to be uh have bacteria attached to them and others don’t um reveal potential mechanisms by how the
Bacteria get inside human cell and obviously as before with our peronal adhesion if you know the mechanism then you could do something to block or prevent this happening and maybe that might um be helpful in treating persistent infections including those of of the per of the parodontium okay so the final border I’m
Going to talk about uh tonight is uh oral cancer Invasion and this comes from work um that I did with Professor States group so um the head of my department at the Eastman Dental Institute who I went on um to join at at Sheffield University
And I do hope he’s listening as well and as well um because we had a very successful group looking at Oral Cancer and he’s and orales now retired so head and neck cancer again uhlike many oral diseases doesn’t perhaps get uh the attention that it deserves it’s
The eighth most common cancer in the UK it’s more common in men um possibly because of the increased risk factors um but it has to be remembered that we sometimes get very UK Centric uh when we’re talking about disease and we shouldn’t do that because if you are a
Man in Papio New Guinea it’s the number one cancer uh in that particular population and this relates to to a social habit of chewing the the uh the nuts of the ARA tree Bal nut which is a stimulant um but is placed in the oral cavity and is carcinogenic uh and there’s nothing
Worse than putting something carcinogenic in your mouth for hours on end every day and that unfortunately is the result there’s been an increase in oral cancer uh quite dramatically since the 1990s possibly due to the increased prevalence of human papiloma virus uh is um a big risk factor for some of the
Cancers that you find in the head and neck oral fendal cancers in particular um if we look at oral cavity cancers in particular the 5ye survival from diagnosis is rather disappointing at around 50% and that’s because most oral cancers are detected when there are or already at an advanced stage and they invade
Tissues of the neck locally which are rather complex to say the least and of course there are issues uh with the general public not accessing dental care and going for checkups because this is when the dentist is trained to spot changes that might happen in your mouth that may be precancerous or cancerous
And some of you may have seen that one of our Dental students uh spotted this in a patient a couple of years ago uh who then went on to have treatment for oral cancer so we’re very proud of that and we will teach our students Dental students and hygiene and therapy
Students what might be suspicious in the oral cavity and what might need someone else to have a look at so uh my pathologist friends will look at images like this all the time so most people it’s pink and purple dots and ATS um but these are thin slices of
Tissue that are then stained with two different dyes and you get images like this which help you uh to determine uh the architecture of the tissue that you’re looking at under the microscope so you can see on the left hand side the sort of pattern you might
Get if you took a piece of the lining of your mouth the oral mucosa it has a protective covering a bit like skin that is keratin and then these two different uh layers of cells here and here uh these two different tissues which are an important part of the function of the
Oral mucosa on the right hand side you might see a specimen that would end up with one of my oral pathology colleagues to look under the microscope and this is oral scamell carcinoma a form of oral cavity cancer and I think even to the untrained I uh you can see that this
Normal pattern breaks down and these areas of tumor uh they invade the underlying tissue so this is a battlefield process that’s going on uh and the pathologist will look at the pattern and how this is happening which has Diagnostic and prognostic um uh benefits uh for the pathology and have
To tell you what’s going on so we also did some work uh On A protein that you find on the cell membrane I mentioned earlier some sit on it some go through it and these are ones that go through it uh these are border molecules uh and these molecules you can
See on the right top right hand side they are affected from signals both outside the cell and inside the cell so these integrin receptors they are truly border molecules they can see both ways literally um now one particular type of this integrin we found was not present in normal oral mucosal tissue but
Started to be expressed in oral cancer and more than that was expressed at an area shown here by the brown coloring at an area where the tumor uh is progressing into the normal tissue around it and so that suggests to us that this protein could be intimately involved in that invasive process we
Also did uh some experiments in the laboratory where we made cells genetically made them uh produce this protein and then they became more invasive they started um uh obtaining characteristics of more invasive cancer so again that was another sign that they might be involved in cancer progression
So it could be that this could be a diagnostic marker and there has been some work done on that probably not the best but uh the fact that it’s there in cancer and not in normal tissue is is a a good um sign um but other colleagues
At some Bartholomew cruk down in London um have done experiments to use that as a potential Target for therapy so if you could attach something poisonous cytotoxic uh and it found its way to where this integrin was being expressed it would find its way to the bit of the
Tumor that was invading normal tissue maybe also they’ve looked at targeting this um protein in imaging to make it clearer uh on various images as to where the tumor is in the body and therefore at the best treatment that can be made available um and I love it when a plan
Comes together and this is why this is one of my favorite molecules all researchers have a favorite molecule this one is mine because this integrin or the family they are also those ones I mentioned earlier that bind bacteria as well so they’re completely critical to everything um and have been an important
Part of my research career now I said that uh that protein is expressed on the border of the tumor and the normal tissue the tissue surrounding a tumor is is not normal I lied to you about that uh it’s a very busy border of lots of different cells
That are recruited to the area and in fact they’re recruited and co-opted to send messages that allow the tumor to spread uh more thoroughly and so this has been a focus of a lot of research recently uh where the attention is this stroma this tissue around the tumor
Plays uh at least as much if not more of a role in spread of the tumor uh than the features of the tumor itself and there are a number of different cells that could be playing a role here some of those I’m going to be investigating
With Andy Foy who sat here who’s an immunologist so immune cells form part of this busy border um but the experiment I’m going to show you in a minute concerns another cell called a fiberblast normally present in a number of connective tissues that’s the cell that makes
Collagen in your body largely and you find those in in the tissue around a tumor as well and they’re different kinds of fiber blasts around a tumor than they are elsewhere in the body so what we found a very useful tool to use is to model these different
Tissue borders in the laboratory you can do much more in that very controlled environment that you can put on a patient for example so this is technology that um colleagues in Sheffield uh helped me work with uh and Ved s has also used the same technology
Here in Plymouth um to grow cells on top of a collagen gel so it looks a bit like those images that I showed you earlier of the oral mucosa with the two different types of tissue layers that you can see and what we’ve got here is some oral
Cancer cells that we’ve put on top of a collagen gel and these cells have largely uh stayed where they are uh uh in that layer there which doesn’t look too different from normal but when we try to mimic that stroma that tissue around the tumor and we add those
Fiberblast cells to the collagen gel you can see the fiberblast cells here within the collagen gel the tumor starts to form these islands and invade into the deeper layers of the collagen gel just like that image I showed you where the tumor starts to go into the tissue so
There’s something these fiber blasts are producing or have been co-opted to produce which is encouraging forming a signal uh that the tumor cells can invade the tissue beneath them and obviously if you investigate what those signals might be again you could try and block that from happening so to summarize the final
Border border number three um some molecules cross the cell uh and these integrin cell receptors are particularly interesting in a number of aspects of the work that I’ve done uh they see both ways they can be good markers of what’s happening on the border and they can be
A good Target for therapy or Imaging as well uh the cells surrounding a tumor are certainly not normal and these cells send messages encouraging tumor cells to cross the border and we found modeling that border in the lab to be a very useful process because we can uh test things then to
Block that juner Invasion from happening okay so my overall conclusion is that biological borders to me anyway are interesting and complex uh borders break down in disease processes and they’re a key Battleground particularly in cancer that’s where the battle is going on between normal and tumor studying borders uh can be
Interesting but also reveal Diagnostic and therapeutic opportunities um borders strangely can be different on cells that should be the same and that was an interesting ing area uh of research we all need to raise awareness of oral disease would be one of the take-home messages and the next
Would be to remind you when you’re on the border to look both ways so just a few uh final comments about lessons that I’ve learned uh I spoke when I was uh interviewed by Alan Williams at the University recently and there was an article published online I mentioned the
Word lucky quite a lot I’ve been very lucky in my career um now I don’t think that I’ve made my own luck um but make the most of it once you’ve got it would be one of my messages um time right time right people to work with I’ve been
Extremely lucky with that some of them some of those people are uh joined online and in the room uh generally found as in most walks of life if you help somebody out they’ll generally do the same to you multidisciplinary teams that’s a really important message from my experience the
Surgeons have this problem so then you try and sort it out and you work with the cell biologists and the Pathologists and like most things it’s about teamwork isn’t it and and healthc Care is definitely a good example of that and so is health related research uh I would
Also say Multicultural teens as well um but certainly multidisciplinary um you’re unlikely to have the first idea about something unfortunately is what I found out I’ve thought about something walking to work and then I’ve looked it up and there are 48 papers on that very same subject Oh I
Thought that was a really good idea so be aware of the literature around you be inspired by the literature around you um people won’t necessarily be thinking in the exact same way as you so there’s a lot and my favorite image which I should have showed you again just look
Down a microscope sometimes or look at any set of data and ask why why is that like that that’s the most valuable thing as well um industry as I’ll show you in a minute has been a really key source of funding it’s not a dirty word anymore at
Univers ities I suspect it used to be um but it’s a key uh area of funding but also of translation of your science so these healthc care companies they want to make treatments they want to make drugs and so it can be a really useful collaboration uh I’ve got it on here but
I don’t do it uh if you’re a researcher that has teaching and administration commitments it seems like research can always be done another day but I’m just putting that down because I don’t do that um It’s a small world it’s a small world you see you come across colleagues
Years and years later so be careful how you treat your colleagues you never know one day they might be your boss you never know um but also I’m here because dreams come true uh and the previous head of the dental school rang me up and
Said do you want to come to pouth do you want to be made a professor it was literally my dream coming true uh and uh so if if you ever need any inspiration in that they do sometimes come true okay okay I’ve got lots of people to thank
And I’ve probably forgotten to thank some people um from St Mary’s Hospital in particular Jeremy Thompson who who wasn’t my PhD supervisor who but who took me under his wing and I owe him an awful lot uh Paul Spate I’ve mentioned uh in particular that team at the
Eastman that then we located to Sheffield uh Dan Lambert and Ian Douglas in particular at Sheffield Chris trewin made my dream un true I’m currently working with a number of other colleagues listed there um also I must thank my family as well that’s the most important thing isn’t it so they’ve not
Only supported me emotionally but at the be beginning of my career certainly financially um and so they are also the reason I’m here um I’ve got lots of students to think I the list would be quite long of students that I’ve supervised uh but particularly I’ve shown the work of
These students today but if there are any others of my students watching I’m honestly so grateful I’ve been lucky to work with some fantastic colleagues but also research students uh the British Society for All Dental research I owe a lot personally and professionally to that organization which I’m very proud
To be current president of uh I must thank uh Anusha alavi as well who worked for Colgate and then works for helion and she’s been really important in this industrial funding that I mentioned uh so the welcome trust uh funded my first post-doctoral position the British Heart Foundation my second
Vascular biology position so just remember when you see a charity cancer or heart disease or whatever and you might or might not not put some money uh in the pop they paid salaries of people like me and and we try to make a difference with what we do so do bear
That in mind uh so with that I have to thank you very much for your time and attention it’s been honestly an honor to talk to you this evening thank you very much Simon thank you very very much sh colle can pick us up on the microphones that was a really amazing
Insight and a a journey over 25 30 years of your research which has shown us some of the complexities you’ve had to deal with some of the marveling borders that you’ve have to deal with what sales can and can’t do and so now we can open up
The evening to some questions and I do have a only a couple of one comment and one question on slider at the moment but if I open up to the audience first I’m sure some of you are busting First Years to ask a question no pressure so can I
Are we oh two questions at the back well let’s let’s start with the first by my words I’ll see now get the microphone um I saw you mentioned about um when it came to oral cancer that the general public had a sort of reluctance to attend their General checkups which
Is why it was never really um noticed do you have any ideas to sort of of any ways to prevent that I’ve seen like things explored but they all had their sort of limitations and I want good question isn’t it I’m looking at Rob wit there um yes a multi-pronged approach
Really is all that we can try to do isn’t it so it’s about health promotion it’s about telling people this what could happen in your mouth it’s about encouraging people to go to the den that’s easier said than done uh I you know I think there’s a lot we could do
Uh more we can do obviously but it costs money doesn’t it and uh that’s difficult that is it is a real challenge it’s also struck me as quite surprising as well I mean people have significant disease and don’t go to see a healthc care professional don’t they so they pretend
It’s not happening which is common I think particularly in men um but it is amazing I’ve seen pictures of the inside of someone’s mouth with a significant growth within it and you’re wondering how these people can a not think something’s wrong B not swallow talk eat you know it’s
Incredible I I bite the inside of my cheek and I’m dancing around the room like somebody’s shot me uh and it’s staggering isn’t it it is quite surprising what some people just will leave they’re afraid they don’t know but as with most tumors the earlier you get it the
Better and yeah it’s a real challenge I don’t have the answer to that my public health colleagues might be able to help me out but would you like to uh um the part where you mentioned about the gum disase for the Border too one thing I found really fascinating was
The part where you me about how I believe PG bacteria invades human cells yes uh and you reveal that uh during the S phase of the cells during the eukariotic uh cell cycle that that might be a potential step where they invade do you have any uh current theories on how
You would deal with these bacteria uh these human cells infected with these bacteria yeah I’ve got a few theories none of them are very well Advanced so um there might be a way of targeting bacteria inside the human cell that’s tricky because obviously if you have something cytotoxic it’s going to
Kill the human cell anyway maybe that doesn’t matter we’ve done some work with um photosensitive D that cross the cell membrane and then if you shine a laser light on them uh they kill the bacteria now they might kill the host cells as well so we need to do some more on that
Um so you might be able to target cells which are heavily infected you might be able to do that you might also be able to block those integrin receptors to stop the bacteria getting in in the first place um those are all potential mechanisms which we haven’t had time to
Advance very much at the moment but we’ve done quite a bit on on getting some Therapeutics inside the cell But It’s Tricky they’re hiding away in a normal cell um but it it yeah it is a challenge I I’ll be um yes I just want
To follow up a tiny bit on what sering said in terms of like how the parodontal basically the disease basically caused by the bacteria and then invade the cells um and I was just wondering if I have any thoughts so basically I believe uh there is this um major his
Compatibility complex which is sort of like displayed on the cells and sort of help the natural killes to dis distinguish between the sort of like normal cells and the ones that can have something like inside of them that’s potentially dangerous or like pathogenic um do you think is is that
Something that would sort of like help the issue with the with the bacteria that causes this disease or is there anything else that that’s also like really important I I I think the first thing to say is that I’m not necessarily suggesting that this invasive ability is the whole story about perodontal disease
Is more complex than that um as for MHC expression uh that’s certainly a normal part of how immune cells would present and pick up um things like bacteria we’ve not looked at that specifically we’re looking at epithelial cells in particular but these areas are heavily in flamed um in chronic
Peridontitis so there will certainly be immune cells as well uh and they almost certainly contain the bacteria as well um but I think the epithelial cells will probably hang around for longer and maybe that’s a better Target but there could be a number of receptors that are
Involved with this we’ve just looked at integrin but there are other molecules that um Can can promote the invas invasion of bacteria yeah thank you can I can I just this point give you a couple of comments from the as we have people not here contributing fromi who you mentioned
Thank you for delivering such an inspiring talk thank you and we have a question from Dr tapy Robinson where do the Border integrin who is actually here he sliding where do the Border integrin in oral cancer originate from you talked about making cells Express them so do
The sales only make them during C yes good question so the interin family is a whole family of more than 30 different cell receptors and they have slightly different jobs so they are important cell cell adhesion molecules so they’re important in the formation of a normal epithelium as well it’s just some uh
This one in particular that we were interested in is not normally present but is present in cancer so they definitely have a role in normal physiology which is why you need to be careful if you’re targeting them a bit like the adhesion story uh different integrin different pattern through the
Epithelium and then some become expressed in cancer other ones go down to allow the cells to move so integrins that would normally stick cells together they’re downregulated the cells separate and then they spread so it’s quite a complex picture actually so it depends which integrin you’re looking at but good question
Layman from a general practitioner I don’t think so um I’m oh thank you very much I’m I was interested in the role of the human papilla virus yes and I couldn’t help but Wonder in cervical cancer yes we do regular smears and then do treatment to
Prevent has it got a significant role in mouth serious disease significant role in some of the head and neck can you can you do any tests to check whether people have got it and if so what kind of cure yes uh you can do that um that the
Also the hope is that the vaccination program of firstly women but now of boys uh may have an influence on the um uh significance of those particular anwers um but I think that uh yes so not necessarily the presence of the virus would mean you’ve got the cancer um but
Uh so I’m not sure whether testing of the virus itself is is useful enough as a um diagnostic tool if you know what I mean but it definitely with one particular type of henck cancer it causes most of them so yes it it does have a significant role um
And we’ll see what vaccination does but that’s one of the public health things that you really can make a big difference so so the incidence um of of the other cancer of of the cervix has gone down massively as a result of that vaccination program so that’s where you
Can really make a difference Yeah question gentl um having had a water my uula which of course is HPV myself Y and having a hell of a job to get rid of it yeah the the problem I found afterwards was is that they were happy to they
Definitely wanted to have a look at the thing under the microscope yeah but no one actually wanted to test which DNA type to find out exactly what type of water it is or mention it on any notes would it be more useful if people actually did did you know test of the
DNA of bits you’ve hacked off to find out what exactly which version of the virus is rather than my clinical colleagues there’s two different types aren’t there of HPV that cause these things and but it depends whether that’s a useful thing to know as far as your treatment or
Likely outcome or risk of developing something else it’s it’s only worth this molecular analysis if that tells you something you don’t already know uh so I suspect that’s what may have happened in your personal circumstance yeah no I to be fair I I don’t know completely the answer to that
Um but so the question would be whether if it was this type of virus or that type of virus does that affect your now if it did then obviously that is worth finding out but I suspect from what you were saying that maybe that doesn’t and so they haven’t done that test that’s
All I can suggest any I question any everyone’s having oh not Janet she asked really tricky questions I I I hope this one is not tricky okay um um you you’ve mentioned an enormous number of uh different Rogues and um threats and different Avenues of research uh and obviously uh
There’s only so much time in life to be able to uh address a small fraction of these things I was just wondering uh to what extent you can uh envisage that uh uh models can be built and experimented upon uh using artificial intelligence in order to reduce the huge demands on uh
You and all your colleagues very good question I think not only AI but other Technologies can help with um looking at fast arrays of genes or proteins all in one go now relatively cheaply and relatively quickly so diagnostically things have gone fully into the molecular age and the
Information is still coming out about this so big screens of saliva for instance in oral cancer you can instantly look at thousands and thousands of proteins or genes within saliva to help you with that and they’re using AI in pathology already uh so there was a study published recently
About breast cancer screening and they they they programmed an AI um application that was as good as X number of Pathologists in spotting early lesions in in uh images of of female breast suspicious lesions so AI could have a fantastic impact in a number of areas of medicine
Pathology being certainly one of them but it’s a panel of a number of Technologies um you you know developments of the biochemical side of things needs to happen alongside the computer power to to determine what suddenly all this data means so that’s where the develop ments have happened as
Well is with Computing to make sense of this so so Health informatics Health technology um but I think that there are tools now I mean the danger is getting too big rather than too small now I suspect so you’ve suddenly got vast arrays of information it’s how you
Process that um but we’re still seeing those big changes that you’ll hear about in the news on a fairly regular basis now about advances in medical Technologies long me last very much interest I think point we say huge thank you to you the audiences here and online as well to our
Colleagues and friends in the Wi-Fi Cloud hope you’ve enjoyed the evening and thank you so much thank you for your time and questions stent questions and for the members of the public and to the AC academic questions we have members from Year One only started five or six
Days ago to University the third age represent there we are there we are the full full range inur Professor thank you very much inde thank you