#FallingWalls #ScienceSummit23 #FallingWallsCircle
In cooperation with our partners, Falling Walls is hosting this unique format to connect researchers in the life sciences from all over the world. The symposium gathers the 2023 Winners in the Life Sciences category as well as experts and early-career researchers to discuss the most pressing issues and recent breakthroughs in this field, from the study of life and organisms, bioscience, and human health, to molecular and cellular life sciences. The event is supported by our partner Else Kröner-Fresenius-Stiftung.
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About the Falling Walls Science Summit Three days of intense scientific discussions, networking, and knowledge sharing in the incredible cosmopolitan city of Berlin! The Falling Walls Science Summit is a leading international, interdisciplinary and intersectoral forum for scientific breakthroughs and science dialogue between global science leaders and society. The event takes place every year from November 7–9 in Berlin, commemorating the fall of the Berlin Wall. With formats Falling Walls Pitches (7 November), Falling Walls Circle (8 November) and Falling Walls Science Breakthroughs of the Year (9 November), the Falling Walls Science Summit is the leading forum for global science leaders from academia, business, politics, the media, and civil society to debate the potential of scientific breakthroughs to solve grand challenges and shape a sustainable future.
The Falling Walls Science Summit is organized by the non-profit Falling Walls Foundation.
Falling Walls Foundation: https://falling-walls.com/
Newsletter: https://falling-walls.com/newsletter/
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Save the Date: FALLING WALLS SCIENCE SUMMIT 7 – 9 NOV 2024
Chapters:
00:00 – Introduction – Alexander Lehmann, Else Kröner-Fresenius Stiftung, DE & Alison Abott
06:37 – Session 1: Diseases of Worldwide Significance – Malaria Prevention with Monoclonal Antibodies : Peter Crompton, National Institutes of Health, US.
31:00 – Noninvasive Imaging of Coronary Artery Disease : Marc Dewey, Charite Universitätsmedizin Berlin, DE
46:40 – Q&A
1:01:00 – Session 2 : Diseases of Worldwide Significance
A New Concept of Cancer : Sophie Heuer, Frank Winkler Lab – University of Heidelberg, DE
1:26:33 – Placental, Immune Cells and Maternal HIV Infection : Doty Ojwach, University of Stellenbosch, ZA
1:59:00 – Session 3 : Breakthrough Technologies in Life Sciences
Cost-Effective, Minimally Invasive Regenerative Medicine : Karen Christman, University of California San Diego, US
2:22:48 – Visual Brain Prosthesis for Blind Users : Pieter Roelfsema, Netherlands Institute for Neuroscience, NL
So good morning everybody um on behalf of falling walls and the El of resting it’s my pleasure to welcome you to the Symposium for breakthroughs in life science the el el short ekfs funds medical research and scientific exchange and um this is why it supports today’s Symposium the Symposium brings together
The winners of the falling Life Falling walls life science call 2023 we are very happy and honored that we are not only funding the Symposium but that we are that we were also asked to give our input to the program design so the as you might have noticed
The range of today’s topics is impressive to know to name only a few of them um they range from enhancing crops to mimicking photos synthesis to the fight against malaria or tuberculosis and other diseases together with falling walls we came up with a common threat for all
These very diverse topics it’s all about breakthrough Technologies in life science diseases of worldwide significance and how they might influence each other just allow me to highlight uh two of the speakers first there is the falling walls break bre through of the year in the category Life Sciences um
Which is Tran ha from Chicago um who will give the keynote on breakthrough te Technologies in the afternoon he will talk on on RNA methylation and the regulation of gene expression the other keyn note on diseases will be given by Akiko iaki um Akiko iaki from real was was
Awarded with the El ofus prize for medical research 2023 for the those who don’t know this price um it comes with €2.5 million EUR and honors highly ranked researchers whose work might yield pathbreaking findings in the future so Akiko has received this prize for her work in the
Field of infection biology and long Co unfortunately Akiko could not travel to Falling walls she couldn’t come to Berlin due to a Corona infection together we decided that she will remotely give her talk in the afternoon so we would like to draw your attention to a change in the program the sessions
At 11:00 a.m. and 2 pm have swapped you find the updated program in the on your seats in the maps so sorry for this or sorry for any inconvenience and thank you very much for your understanding most importantly we send our best wishes for a full recovery to
Aiko so there are two more things that I have to say first let me introduce uh our moderator for the day Alison Abbott I guess many of you have at least already heard her name Ellison is a well-known freelance science journalist she worked at the journal Nature for
More than 20 years almost 30 years as I yesterday learned and among other distinctions she has been named the European science journalist of the Year 2019 we are very happy to have such a proven expert and great person is our moderator today thank you so second this
Is uh the perfect time to S say thank you not only to Allison as moderator but say thank you to all the speakers who followed our invitation and who will make this a really great event we are looking forward to um and a very big
Thank you to all the people at radial Sy te and falling walls who are working literally Behind the Walls as I see here and are running this event and making all this possible with this regard special thanks go to so sh Nathan haidak and mati Bowman who perfectly organized
The Symposium so with this I hand over to Ellison and just say have fun and an exciting day thank you very [Applause] much um thank you Alex and good morning to everybody it’s a great privilege for me to be able to to moderate this session which I think is going to be extremely
Interesting and I think in one way this whole three day event is about how science cons serve Society but I think that particularly this particularly noticeable in this Symposium which is talking about globally significant diseases and what we can do about it and I think um there’s the only point that I
Would make that’s relevant I think is the think to to note in advance the distribution of these diseases so in the high income countries only one of the top 10 the top 10 leading deaths is by a communicable disease and in low-income countries the figure is six out of the 10 leading um
Diseases and this shows that science really isn’t serving Society in an equitable way um but anyway as Alex said this session is bringing together the the falling walls science winners in the life science categories and we’re going to hear about in the morning we’re going to hear about
The breakthroughs in the um the handling or the understanding of these globally significant diseases and with the exception of Akiko whose session has been changed uh in the afternoon we’re going to hear about breakthroughs in biological techn Technologies and at the end of the day we’re going to have a
Podium discussion which thinks about how these uh new technologies could actually help with developing medical interventions for the diseases that uh that we’re concerned with and again this is the point where we’ll be able to talk perhaps a little bit about the equity and ethics involved so we we’re on a very short
Time limit I see I’m down to 10 seconds so let me just call the next two speakers the first two speakers onto stage please and this is Peter Crompton and Mark JY can I invite you thanks so our first speaker is Peter Peter Crompton from the NIH who’s been
Involved in tropical diseases since he was born I think he told me or since his training at least and he he has been involved in partnering in developing cohorts in marlei that are collecting data on molecular and immunological uh responses to parasitic infections and of more recent years he’s
Been involved in developing clinical trials using you partly in Marley taking advantage of his epidem epidemiological knowled the new thing that he is talking about is monoclonal antibodies for malaria so please Peter okay thank you Allison guten Morgan uh it’s a pleasure to uh kick off this wonderful Symposium I look forward
To learning about the exciting breakthroughs in life science from my colleagues today um my colleague Robert Cedar and I uh would like to thank the falling walls Organization for this honor um and for for the opportunity to present our work on monoclonal antibodies uh for malaria prevention um
So I’ll just uh remind you that malaria remains a formidable Global Public Health threat uh each year there over 200 million cases of malaria resulting in over 600,000 deaths uh the vast majority of which occur among uh young children in subsaharan Africa uh in addition approximately 13 million
Pregnant women are exposed to malaria each year resulting in substantial Maternal Fetal um and infant morbidity and mortality now among the five uh plasmodium species that infect humans falum is the most common and the most uh lethal uh and the most prevalent in Africa um unfortunately the progress we had been
Seeing since the turn of the century uh that coincided with the scale up of malaria control interventions in reduc reducing the number of cases and deaths that progress has stalled uh in recent years and so there’s a broad consensus that new tools are needed if we are to
Succeed in combating uh this devastating um ancient disease um so I’ll just remind you that the infection begins when anaphes mosquitoes uh inject anywhere from 10 to 100 uh sporozoites uh into the skin and blood uh within minutes to hours these find their way to the liver where they
Invade hepatocytes they replicate and they differentiate into the blood stage that then exits the liver to begin a 48h hour cycle of arthrite invasion replication rupture and reinvasion leading to a very rapid exponential expansion in the number of parasites in the blood which as you can imagine uh causes disease and potentially
Death over the course of days um a small percentage of these bloodstage parasites differ differentiate into the sexual stage gyes which are then taken up by the mosquito uh to continue the the life cycle um so what are our current tools to control malaria um they include insecticide based Mosquito Control in
The form of bed nets and spraying insecticides on the walls of homes the major issue here is the emergence and spread of drug resistant uh I’m sorry insecticide resistant mosquitoes um an exciting Milestone recent ly was the uh the endorsement by The Who of two malaria vaccines the rtss and r21
Vaccines uh an exciting uh advance but broad recognition that these are first generation vaccines that are limited in their efficacy the duration of their efficacy and the age dependency of of their efficacy um a main state of malaria control is early diagnosis and treatment of the blood stage with rapid
Diagnostic tests and EMES and incombination therapy therapies um the the major concern here again is the emergence and spread of drug resistant parasites across Africa uh and finally The Who recommends chemo prevention for high-risk populations such as pregnant women uh and infants the problem here again being drug resistant parasites and the
Difficulty of implementing frequent uh up to monthly dosing regimens uh and so new drugs including monoclonal antibodies um that prevent malaria for up to six months after a single dose could improve malaria prevention coverage in these vulnerable populations uh and so monoclonal antibodies uh that are engineered to
Have an extended halflife um that Target the sporo stage are a potential new tool for malaria prevention in these high-risk populations among the advantages of targeting sporozoites is their small number so this represents a a bottleneck in the parasite life cycle importantly they also don’t replicate
And so we don’t expect Escape mutants to arise under the pressure of a monoclonal antib body uh in Vivo unlike a virus uh infection for example and of course blocking infection at this early stage prevents not only the disease uh but also the onward transmission to mosquitoes and and other
People and so the antibodies I’ll be discussing today Target the circumsporozoite protein this is the most abundant protein on the surface of the sporozoite uh and it’s required for sporozoite motility and invasion of uh hepatocytes this is a schematic of the protein uh showing the N Terminal C
Terminal region and a central repeat region and and it’s worth pointing out that the the two vaccines that I mentioned earlier are a truncated form of of this protein and you’ll see in a moment why uh the the omission of this n terminal region might be
Important um so CIS 43 LS is a first generation monoclonal antibody for malaria prevention in humans it was isolated from a volunteer who had been immunized with an irradiated sporozoite vaccine by my colleague Bob Cedar uh at the NIH um this antibody binds uh to this so-called junctional region uh in
Between the repeat region and the M terminal region this is a highly conserved epitope uh that is critical for the sporozoites ability to invade uh liver cells um the antibody was modified in its FC region uh with two amino acid substitutions to extend its Half-Life um and a phase one
Study uh showed that nine of nine uh individuals who received this antibody were protected from infection in a controlled uh clinical setting in the US and so the key question of course is whether a monoclonal antibody could could prevent uh infection in an endemic area and so to address that question uh
We collaborated with our uh long-standing uh uh colleagues or or colleagues with whom we’ve been collaborating for quite some time in mly at the University of Pomo uh to conduct this trial um and we’re just going to zoom in here on the um the study site where this
Trial was conducted Khalifa Buu uh Mali um we’ve been uh as Allison said we’ve been conducting observational studies here of malaria epidemiology and Immunology and parasitology for many years uh in collaboration with our colleagues at the University of mamico we have a research Clinic uh staffed 247 to diagnose and treat
Malaria and for those uh soccer fans this is a soccer pitch right here where I’ve embarrassed myself on many occasion playing soccer with the kids in the village um but it seems to make them laugh for some reason um so what what does malaria look like in Khalifa Buu
Mali um and this is really representative of what malaria looks like across the Sahel region of subsaharan Africa where transmission is very seasonal so this histogram shows the number of febal malaria cases um per month since 2011 in a cohort of over 1100 individuals and the obvious pattern
Here is this very predictable and sharply demarcated six-month malaria season that coincides with the rainy season so if we zoom in on just one of these seasons and look at the risk of infection um shown here if we start with an uninfected uh cohort before the
Season and every two we two weeks we look for the appearance of blood stage parasites by PCR in the blood uh in an AG stratified fashion you can see that over the six-month malaria season nearly everyone becomes infected so very intense transmission and these infections occur uh independent of age
And so all ages are at risk of becoming infected adults uh have acquired some immunity that prevents severe illness but they are susceptible to infection and so the simple question we had with this trial was could we take the risk of infection in adults from here by giving
Them a monoclonal antibody before the season uh to something lower uh and so 330 healthy adults were enrolled during the dry season uh they were given an antimalarial drug at enrollment to clear any Baseline infection they were then randomized to receive uh a single dose of normal
Saline Placebo 10 migs per kig of CIS 43 LS or 40 migs per kig um and then every two weeks for 6 months we looked for the appearance of blood stage parasites through a finger prick uh blood drop um remarkably over 93% of uh participants completed the six-month follow-up Baseline characteristics were
Similar across study arms the antibody was very well tolerated and there were no uh evident safety concerns uh so this is the efficacy result and as predicted uh over the course of the six-month malaria season 78.2% of participants who received Placebo became infected and we found that the efficacy of the Low Dose
10 Mig per kilog compared to Placebo was 75% and efficacy of the high dose um 88.2% um so uh this figure shows the serum concentration of the antibody in individuals who received the high dose and red the low dose and blue over the six-month malaria season uh this is a very characteristic pharmacokinetic
Profile um showing of after an intravenous infusion of a monoclonal antibod showing the immediate U maximum concentration an early distributive phase as the antibody equilibrates between the circulation and the interstitial space and then a more protracted elimination phase um we observed dose linearity and the half-life of this antibody with the uh
With the um engineered uh extension in the FC region was 60 days uh so we then estimated the daily concentration of c43 Ls over the study uh period to develop a pharmacodynamic model to understand the relationship between the level of the antibody and infection risk and the
Result of that analysis shown here on the y- axis is the probability of infection on the x-axis the uh serum concentration of the antibody and you can see that the risk of infection remains below 5% over a broad range of antibod concentrations from 600 micrograms per ml
Down to less than 100 micrograms per M where the inflection uh occurs uh and you can see that a a concentration of about 20 micrograms per Mel corresponds to a probability of infection of less less than 10% uh and remarkably this is uh very similar to what we observed in
The phase one trial in the US under a controlled infection setting where 22.5 micrograms per Mel corresponded to a probability of infection of less than 10% um like any study this trial had limitations it only included adults so clearly we need trials in the Target population of children and pregnant
Women across diverse transmission settings and the antibodies uh was administered intravenously which is not a practical approach in subsaharan Africa so more potent monoclonals are needed to enable lowd subcutaneous uh Administration to children and also to reduce cost so to that end uh L9 LS is a second generation antibody that was also
Isolated from a volunteer immunized with radiated sporozoites it binds to a similar junctional epitope on the CSP protein it was also modified to increase its Half-Life but importantly it was three times more potent than the first antibody in preclinical models and a phase one study showed that 15 of 17 individuals were
Protected from controlled infection in the US four of five who received a low dose subcutaneously of 5 milligram per kilog so on the basis of that uh last year we started uh two new Phase 2 trials um one in Mali targeting uh children 6 to 10 years of age who are
Exposed to seasonal transmission and the question here is whether a single subcutaneous dose will protect these children over the six-month malaria season and then in Kenya um a trial targeting younger uh children uh infants 5 months up to 5 years of age were exposed to year- round Transmission in
Western Kenya the question here being whether uh one or two doses given at month Zer and month six will protect these children over 12 months and so um just to wrap up the key features of monoclonals that could complement our existing tools uh high level protection against infection as I
Said would prevent both uh clinical malaria and onward transmission a single dose provides rapid protection for predictable time period we expect efficacy against all parasite strains as this antibody is targeting a conserved region uh and we expect efficacy to be independent of age and prior malaria exposure which has been a challenge for
Malaria vaccines and finally we expect uh safety across all ages and in particular in pregnant women uh given the the uh General uh excellent safety profile of monoclonals U for other diseases and so we’re considering using mon clonal first and foremost for the prevention of malarian infants and
Children either with a single dose before seasonal transmission once or twice yearly dosing uh during perennial transmission malaria prevention and pregnancy uh and the other use cases shown here um so in conclusion uh CIS 43 LS was safe and efficacious against falum infection in adults and Mali uh
Providing for the first time proof of principle that an antibody can prevent infection results of the phase 2 trials that I mentioned of L9 LS in children will be available in 2024 we’re planning a phase three trial on children for 2026 a phase one trial in pregnancy next year and of course
Work is ongoing uh in in my lab in Bob Cedar’s lab um and colleagues around the world to find more potent monoclonal antibodies which would further uh reduce the dose required and and therefore the cost so I will end there and and just quickly thank first and foremost the
Study Volunteers in Mali and Kenya who uh generously participate in these studies the wonderful team in Molly uh that I’ve worked with now for over 15 years led by my friend and colleague kassum kenau uh the hardworking folks in my laboratory as I said uh my colleague and close collaborator on this project
Robert Cedar and his team at the NIH uh and our colleagues at the CDC kemry uh in Kenya and and other colleu at Harvard University of Washington uh the study uh was funded by the NIH in malan Kenya and the Kenya trial in part by the bill and
Milled Gates Foundation so thank you for your attention thanks so much thanks so much Peter that’s a really really interesting new approach and the one thing that struck me immediately and I’m I’m not an expert in this but wouldn’t these Spyro zoites be a suitable Target for a vaccine
Um yes and in fact the two vaccines uh that I mentioned the rtss and r21 vaccines that were recently endorsed by The Who Um Target the same protein on the sporo but but they’re not as effective um they they are not as effective as we would like them to be um
I they’re considered first generation vaccines and and I think may maybe to your point Allison what what um in addition to using monoclonal antibodies directly they teach us something about what might be the important targets and so as I mentioned the rtss and r21 vaccines um are a truncated form of this fulllength
CSP protein and it turns out these antibodies are targeting an epitope that’s not included in the vaccine so second generation vaccines are now including uh this this epitope that um monoclonal antibodies Target yeah interesting so let me open the floor to questions there’s a roaming microscope somewhere um can we go over
Here I have two questions number one you didn’t say anything about the nature of the antibod I assume it’s an IGG is it is it complement binding or is it not complement binding y good question so it’s an igg1 it’s a fully human igg1
That was isolated from B cells of a of a vaccine um the the preclinical data suggests that it that the vast majority of the activity is direct neutralization uh without much of a contribution from FC affector function whether it be complement or ADCC or other affector functions experience
Shows that is very difficult to raise antibodies against conserved regions for whatever reason so the vaccine story what you say fits into that yeah but now since you know the conserved region what about an mRNA approach yeah it’s a great Point um as I said um Next Generation
Vaccines are including this region and mRNA is is one of the approaches that’s being taken so it’s a great great question thanks um Stefan cman may I also ask on the implications for the future um so first do you expect this like a drug that is reinfection which is frequent in children would
Occur and the second do you financially this looks like a traveler treatment approach rather than a approach for the people living in malaria emic areas because of the cost do you have any ideas did you think about that for the future application so this were two questions yeah no two very important
Questions so the first question this this would be prophylaxis not treatment so the idea would be to give it to healthy individuals to prevent infection um and yeah our um the the target population here are are infants and children um in subsaharan Africa um and so to make this a
Viable uh solution or product it will have to be cost effective um and the modeling suggests that at scale uh if we uh succeed in optimizing the uction of the antibody let’s just say at about $50 per us uh $50 US per gram we’re we’re getting into the range if if we need
About 150 milligrams for young children so this is weight based um we’re getting into the realm of the of the cost of the current uh prevention measures for seasonal malarian children for example the chemo prevention is is about $5 per child uh per year um so this this really
Is going to be the major challenge is to um produce this at scale in an affordable way um but the optimistic prediction is that this will be possible Travelers are important uh as well but our our Interest really is in in where the greatest burden of disease is so it’s a great
Question just for curiosity do you find such antibodies also in people living in these areas and and exactly the same kind of of antibodies targeting the constant region uh it’s a great question so as Allison said we’ve been doing imuno epidemiology in this population
For 15 years and uh this is not a very immunogenic epitope uh that these antibodies Target uh which may explain in part its conserved um nature and we really don’t if you when we actually measure uh concentration of the antibody in in the population uh in mly and the placebo
Group there is no antibody so we don’t see these particular monoclonals um coming through natural exposure um which is kind of it’s striking it’s interesting it’s maybe another whole discussion as to why that doesn’t happen but as I said were were these antibodies were derived from uh us volunteers immunized with radiated
Sporo we’re continuing to to mine for more potent monoclonal antibodies in endemic from B cells from individuals in endemic areas and we think um that after 30 40 50 years of intense exposure to sporozoites that we will find rare but very potent monoclonals that are highly mutated um that Target these
Neutralizing epitopes so yeah really good question do we have one last question if not can I ask you just a general question yeah what would make things go faster is it just amount a question of many well you may have heard that there have been malaria cases in the US
Recently a handful of cases I think if malaria became a problem in wealthy countries this would have been solved 20 years ago so yeah it really is a question of uh resources I think Equity as you said earlier um if if we were to bring to bear our capacity and our
Technology that we’ve brought to bear on covid-19 for example I’m sure this would go much faster so we’re doing our best with what we have but good question so I see no more questions so thank you Peter thank you thank you for the questions so now we’re moving on now we’re moving
On to a non-communicable disease and I’d like to welcome Mark jwy to the platform Mark is a physician at the charate here in Berlin and he’s also where he also studied medicine with a short stay at the John John’s Hopkins but he’s dedicated the best part of his career so far to developing
Better testing for coronary artery disease which is the worldwide the biggest killer um and it’s only um exceeded in the very lwi income countries by it’s put into third place by neonatal diseases and lower respiratory infection diseases so what we’re talking about now is biggest killer and important not only in the
West um but also in the South and other areas of the globe thank you Mark thanks very much Ellison it’s great pleasure being here and as you alluded to uh coronary otter disease is not only the most common cause of death worldwide it just became thanks to efforts you’ve been alluding
To the last minutes the most common cause of the death in the global South as well and what you do see here on the next slide depicted by probably the most influential German uh newspaper The Daily Mirror is coronary CT in Germany one has to say that that’s just the
Translation of tagish what you do see here is a CT volumetric image that encompasses 100 million voxels acquired within 200 milliseconds in an individual and this provides to you a radiomics feature of the individual risk a patient will have for coronary arer disease and the article that you do see here is
Specifically about the question whether CT will replace other more invasive tests such as cardiac catheterization which at least in this country where we are world leaders not in socer anymore but in cardiac catherization we do 1% of the population cardiac cathon every year this 1% calculation includes neonates so
It’s probably in the above 65% 65 years population it’s a heavily overused test which doesn’t show you as you see here the complete picture of how coronary AO disease actually does evolve we’ve been working on this the last uh two decades with technology Partners industry Partners to make this
Something that can be translated into clinical practice so this is what a setup looks like you do an EKG in patients you trade trigger it the image acquisition and you can identify stenosis and coronary arteries now non-invasively and accurately by computed tomography not only that CT can also reveal coronary artery plaques the
Thing that forms in the arteries and actually leads to myocardial INF function and is the risk component which cannot be seen by cardio catherization itself interestingly as you see in this three dimensional display we also see the entire chest so if people come with chest pain it’s not only all about the
Heart it’s commonly An Origin outside of the heart and with CT we now have the ability to discover these extra cardiac Origins as well so stenosis can now be visualized non-invasively excluded or confirmed leading to further therapy this is what is set up on the CT scanner
Looks like patients get a little bit of an intravenous pharmaceutical to display the coronary arteries and the test is rather quick this sounds simple but it’s been a long story to make this test being able to do so the last two decades as I said we’ve been very fortunate that the
Discharge trial was selected by the European commission for funding we did the discharge trial together with Partners in 18 European countries that has been an enormous cultural learning experience for me personally of course because I witnessed all of these sites I learned the differences and approaching science in these countries and centers
And I also learned that the economics differences within our continent are probably two to three times larger than the actually very discrepant situation we even see in the United States so together with these Partners we randomly assigned and that’s the important methodological aspect to do this for a diagnostic test randomly assigned more
Than 3,500 patients who showed up with suspected coronary arter disease and stable chest pain not acute stable chest pain we randomly assigned them to either undergo CT as you see on the left or cardiac catherization which they were clinically indicated so it wasn’t something we made up for them they
Actually had the clinical indication according to European guidelines after we had randomly assigned patients we then looked at patient relevant outcomes after 3.5 years of followup and the primary end point was something that is truly relevant to patients it is whether you die from cardiovascular disease it’s whether you get a myocardial infarction
Or a stroke so something that’s really disabling you to have high quality of life we did not include aspects such as whether you needed another testing or you needed you know another hospitalization as it’s often done by industry driven trials this is very rigorous we only looked at events that
Matter primarily to patients importantly these events were looked at by independent blinded assessors who did not know from which randomization groups this report was from because of course we cannot blind patients right you can’t tell them oh imagine this would be cardiac catherization while you’re getting a CT this is really hard to
Assess anyhow we also looked at patient reported outcomes such as quality of life engineer and importantly as a safety event major procedure related complications not from the testing but from anything that followed so not only from the CT itself but if CT detected this patient would need cardiac surgery
Then we included also any complications from cardiac surgery in this randomization group randomization was stratified not only for Center remember the economics differences we see on the continent but also importantly for gender so we have an equal distribution of women and men in the two randomization groups at all of the
Centers when we started this journey hell sucks who I owe a lot to said in this interview with the film crew we did a video that was translated into all the 16 languages and was displayed at the centers to patients to help recuit he said Mark this is a very
Challenging study to do but one that I think is really important to try to do friends in the United States tried to do they didn’t succeed this has political backgrounds I would prefer not to comment on now I have the pleasure to show you the main trial results the main trial results were
Published in njm so another thing we have in common it was published as a lead article in the journal with an editorial and importantly it was published by the disart trial group so that makes me emotional now this this is not authors first author this is really
A family which made it possible that after 3.5 years so really long time we had in 99% of patients outcomes data about the primary Endo so we knew whether they died and what was the reason we knew whether they had an infarction or stroke in 99% of the
Patients the journal also has a two minutes video which I could have shown you and then left stage to explain the results to patient but I want to guide you briefly through what the results were so this is an inverted traffic light system and for those from Germany nothing from politics
Um and this shows you coronary artery disease was depicted equally well by CT compared to cardiac catherization nonobstructive coronary arter disease so you know whether you have plaques or not was actually missed in cardiac catherization if you do the subtraction it was missed in 14% of the patients who were in The cardiio
Catherization group and leads probably to undertreatment in some of these patients and that’s the main outcome of the study looking at cardiovascular death Mi or stroke and the hazard ratio kind of suggests that if at all there is an advantage of CT the result not being significant and we’re currently working
With the discharge trial family on an extended follow-up which goes till eight years in patients because the curves actually separate quite convincingly but not significantly most important for the HTA organizations in this country and Beyond worldwide is the safety outcome and remember the major procedure related complications included what happened
During the subsequent treatment and they were reduced in the CT Group by a factor of four so CT actually makes your treatment SA safer because patients were treated almost equally as aggressively in the CT group but the treatment is individualized and reaches those who actually need it so going now back from
The NM publication remember we did a gender stratified randomization and that was probably the reason why our women results the women in man comparison was accepted by bmj same year as the njm publication and most important is disch charge the yellowish curve here is the cardio catherization women and the
Yellowish curve down here is the CT curve for complications in the two randomization groups The Violet groups are the males there isn’t so much a difference in complications there isn’t that much of a reduction complications in males remember all these devices they were tested developed for treatment of
Corn disease in man and you see here they made for women NCT makes them safer there’s a reduction in complications in women by a factor of seven while in the overall population it’s a all four and it wasn’t significant in man there is many subsequent Publications in leading Cardiology and
Radiology journals that I’m not allowed to talk about but which are in second revision already now but I can show you and this is really really important because that’s one of the highrisk groups I can show you if it lets me the results in patients living with diabetes
A very important risk group if you relate to people with Corner disease and this is the main result this is outcomes in people living with diabetes versus those without and I will show you now what it is this is people with diabetes in cardiac catherization you see a lot
Of events 10% events over the followup this is people living with diabetes in the CT group and interestingly the outcomes are similar to people without diabetes who get cardiac catherization so this is really a tremendous change in people living with diabetes what has been the impact of the
Discharge trial so far it’s been selected by several journals as the paper of the year it led to several additional articles there’s even articles saying now what is the consideration post discharge that makes you all very very happy and it’s really really fun from an academic perspective
But the translation is only there if it’s used in the clinic and this is what the taret sper reported about how we use this in the clinic and this is the patient who was reported on also in videos by taret spegel this is where you
Can see how she was examined and what we found in her and CT will really soon replace other approaches to coronary Ary disease and let me briefly conclude um CT is probably a very good alternative to cardi catherization in certain patients we don’t know much about those
With very high risk of coronary AR disease this needs another trial to convince CT is great there CT reduces events CT reduces procedure related complications women benefit from less complications patients with diabetes benefit from less event if you do CT instead it will certainly be used in the
Clinic and the most important thing for me to see was that in the final HTA report of the organization that is advising GB in this country so the most important decision-making organization we have here uh has cited discharge 100 times in its report and this where it
Gets emotional again because this is a teams effort of my team majority they saw this and they kind of said all right now we understand why we did this right and we’ll soon see that GB in this country and other HDA organizations worldwide will adopt this and in this
Country it’s the first Imaging related new reimbursement since four decades and that was really an important reason to work on this the last years I do thank uh my team at Char we work a lot as this Char high tower also tells you on AI you see the A and the I
As marked in White on our Tower uh which is really great fun to bring radiomics um to the community the medical imaging Community it’s it’s really with whole heart to say thanks to our major funders the European commission uh the German Research Foundation at the Berlin Institute of Health at charite and a
Final personal uh comment in the last uh seconds that I have as an East German it needs people to tear down walls they don’t fall naturally thank you very [Applause] much yeah great uh great talk Mark thanks um I’m not a cardiologist but I I
I do do still see patients and I’m just wondering if there’s a role for uh CT Imaging in in patients with sus um a suspected nonest non-st elevation Mi so I mean you you enrolled patients with stable coronary disease coronary artery disease I think if someone has an st
Elevation Mi they clearly go to the cath lab immediately but for for patients presenting where it’s not entirely clear it could be um you know an onest elevation in I do you see a role for Imaging there that’s a great question so it helps me advocating the third trial
We are currently trying to Pro opposed to funders and we’re collecting uh with our little box uh money um in addition to those who are asymptomatic remember 50% of the mardial inunctions are people who never had symptoms right I mean this is heartbreaking we’re addressing those with symptoms we’re missing out on those
With you know no symptoms before they just die and especially in the global South people in Bangladesh uh they die in in their third or second decade right and uh we’re not addressing that um we don’t address people with high risk risk and we don’t address people right now
With acute chest pain this is because there has been trials and there are several methodological reasons why they failed there have been trials in people with acute chest pain and non-st elevation mardial inunction who didn’t show an advantage of CT I think it needs and they weren’t multinational as we did
In this charge so I think it needs multinational efforts and it needs um a different design in the trial setting to to prove the added value of looking with radiomic at the whole coronary artery at the coronary plaque to better predict individually What patients with acute presentation actually need uh but for
This right now there is no indication upcoming but it’s probably one of the most important questions we have right now in imaging thanks yeah thanks is there questions from the floor please one here one here just for the money how do the costs for both procedures compare that’s a
Great question we recently showed the cost Effectiveness comparison of at the European shared decision-making Congress so if you’ve been there you were lucky cuz you you had a glimpse and it’s currently under conservation by journal and um of course CT is not as costly as invas of coronary angiography by card
Catherization it can’t be but the question of course is you need a true cost Effectiveness maybe you have more you know testing in the CT group in the years to come which adds on cost um I can’t tell you the details because it’s under consideration right now but I
Think in general the future for CT looks bright um and it’s it’s an it’s the second most important point you know following of course patients rights patients access and patients outcomes was there yeah there’s a question at the back there yeah thank you that was great um
Talk I was curious when you’re doing the Imaging since you have a contrast to see the vessels are you also collecting in data on like LV geometry and function at the same time yes it’s all in the game and and this relates to an important Point why
Do we do AI in our group right everybody may have said yeah but this is obvious you can read it as a radiologist right you are trained well you can and we train a lot of people we have now 100 a thousand trained Radiologists in the
Country who can do that but on average it takes 30 minutes to read a case it takes 200 milliseconds to acquire one of these volumes but it it takes 30 minutes on average and especially looking at things that you mentioned which are as important as the other aspects in the
Coronary arteries and AI is going to help us in quantitatively assessing this and bringing this to clinical practice um one of the one of the dramatic findings I thought was that in the case of catheterization you overlook 15% of plages how come how how is this possible
Well this is not in order to blame the the Physicians reading these tests uh remember you’re looking at a Lumin right you’re looking at a display which only shows you um the inner vestel part it doesn’t show you the plag and the surrounding unless you do additional invasive measurements based on cardiac
Catherization which you don’t do in every patient where it looks baby clean coronary arteries so the test itself does not give you a three-dimensional picture of the coronary arteries the formations of atherosclerosis and of course also not the things uh that the lady asked in the previous question of
Course cardiologists will look at that with the view of reimbursement I mean Clinics of Cardiology uh they use this methodology because it’s very the the catheter becomes very well ured how how about CT well it’s not as as I said next year we will start having this as a first new
Imaging reimbursement code in this country since four decades and and then will take off and that’s an important part because we have to avoid overusing this technology um as we’ve done with other tests in the past and it’s very important that the indication is jointly done into disciplinary uh which a great
Advantage we have in this country is independent Physicians from Radio radiologist so as as a radiologist I’m not allowed to pick you up from the street and say want to get Imaging with me uh come join me it has to be different Physicians being involved in the clinical indications and those
Performing the testing uh and that’s a very very important aspect to consider in that overall and that uh relates to your question there is calculations that probably half a billion can be saved annually only in this country by replacing in those people where we have the evidence not in all cardiio catherization by
CT do we have further questions his one question thank you very much so what is the difference concerning the radiation of post procedures that that’s a perfect question I I think in in table five of the 80 page appendix of the NGM publication uh there’s the information
That it’s both roughly five Ms um which is okay because it’s kind of equal um but we’re still working on further reducing this uh for CT which is important if we look at people who are asymptomatic but come with high clinical risk factors because then you want to do
It with even less radiation dose but I do think it’s far less of an issue when we started that we often had exposures of 15 to 20 merss um I would also like a question myself if I may interrupt that this is the the results on women versus men is
Quite extraordinary and I wondered what makes women so vulnerable to damage during this seene so so we haven’t looked yet and it’s about to be analyzed and submitted at the details of patient management differences that have may have led to this um an important aspect
Which is in table 11 of the appendix I still remember that because I I get this question a lot uh it shows you that the testing with CT makes your Interventional procedures safer so we had 10 non-fatal myocardial and Fons induced by cardiio catherization treatment procedures in the cardiio
Catherization group and only one in the CT group and those procedure related complications that were associated with the treatment and cardiio catherization in the catherization group were almost all in women and my theory there is as I said during my talk these devices were developed and tested in man and we have
To change our approach there it needs a culture change I mean half of the population is women and we still continue testing mainly in male studies and this may have been the reason remember that in women similar size and height as men the cornery arteries are
Smaller so the devices that I used are probably not gender sensitive yeah that’s um a lesson to us all it happens a lot I think in clinical trials that uh the gender differences are not taken into account so this is fantastically on time unless there’s another question which will make it run
Over time was there no good so it remains just for me to thank very much the speakers it’s been both of them fantastic interesting talks and very um encouraging for the future and and um I’m going to close the session with a reminder that in 10 minutes the next session starts so
Please do try to be punctual thank [Applause] you for e e just to make sure yeah um welcome back to the next session after the shortest two minute 10minute break that I incorrectly announced so now we’re going to do something a little bit different we’re not talking anymore
With the winners themselves with our next two speakers are young scientists um and again as in the first session we’ve got one communicable disease and one non-communicable disease and we’re starting with the non-communicable and it’s going to be presented by Sophie Hoyer sitting here who’s a physician scientist and
Neurologist at the University Hospital in hyberg and she’s standing in for her colleague Frank Winkler vinkler who is actually the falling walls science winner in the Life Sciences this year and Frank’s work straddles the worlds of cancer and Neuroscience and it’s really transformed the way um brain tumors are treated
These days and Frank is unable to be with us because of a clashing appointment um but Sophie is going to tell us about an interesting new approach to understanding why Goma which is the most common form of malignant brain tumor is so resistant to therapy thank you Sophie
Thank you very much I’m very honored to be here and um speak on behalf of um the head of our research group Frank Winkler um first I would like to start by um introducing incurable gomas high grade gomas um a bit um they are primary brain tumors which means they originate from
Brain cells in patients um they consist of glioblastoma which is the most aggressive form but also other sub forms arroyas grade 2 to four midline gomas um which have a specific mutation k27m and other other um subtypes of the disease the treatment consists of surgery radiotherapy chemotherapy but um we sadly experience
A high high rate of recurrence um which makes these diseases incur able and especially Goma um very aggressive with a very dismal um prognosis um this is due to a diffus brain colonization we have of the tumor cells in the brain as you can see here
From an autopsy um sample the black dots represent single tumor cells that invade all throughout the brain even to the contralateral so the other side of the um brain we can find single diffused tumor cells so a challenge is how can we effectively Target these tumor cells in
Such an organ um that is also so vulnerable to treatments and side effects and is the brain itself involved in the malignancy how does it does it and how um does it contribute to tumor growth how does it communicate with the tumor and um how do tumor cells um use neuron
Mechanisms how can we um t therapeutically Target them and this is how the new um research um um area cancer Neuroscience um developed so when we use our um Mouse model where we implant human derived um G blastoma cells that’s called a xenograph into a mouse brain that we can observe
Longitudinally over time the mouse brain we can see how single single tumor cells depicted here in green really invade into the brain and um and colonize the brain until it really builds a dense tumor cell network that is also um representative of the human disease where we see these very
Long and thin um membran protusions interconnecting tumor cells to this very dense Network also in the human disease we called them M tumor microt tubes and um they as you as you saw are really scanning the brain connecting the um tumor to a dense Network and they have similarities to neurod development so
When neurons grow they form neurites that really um scan the brain and invade the brain and we see similar proteins involved here in these um malignant um cells that colonize the brain furthermore once the network is established we can see that it is also a functional Network um as you can see on
The lower right side there’s also calcium activity between the tumor cells um um ongoing in really these these um wav likee activities bursting out so why is the network important for the tumor um we can see that the tumor um inte tumor cells integrate to a network which makes it resistance to
Resistant to treatments so if we have tumor cells that are non-connected these will disappear under treatment under radiotherapy chemotherapy under the therapeutic pressure but um the connected tumor cells will um survive the treatment and they will connect even more densely um this is also shown here
From our Mouse model where we can see the connected tumor cells build even more TMS and integrate even more densely into the network while the single cells disappear over time and are not resisting the radiotherapy treatment this can be overcome when we target the before mentioned neurodevelopmental proteins that are
Reactivated in these these nurd like tumor micu processes um we can expand the um effects of our treatment so we inhibit the possibility of the tumor to build the network and then we give radiotherapy and we see there’s a bigger response to the treatment as you can see here we have
The resistance I just showed you why when we have a knockdown so a lower expression of these proteins we have a bigger effect of the of the radiotherapy treatment as also shown here in an MRI study of the mice and here shown the lower expression of the two of of the
Tumor marker of the tumor micr tube protein we have a smaller tumor um after radiotherapy treatment so it causes vulnerability to the treatment and with this we can we can establish a whole new concept of this um of this disease we have the tumor microt tubes that extend um and scan the brain
Very um mly and and cause um Invasion proliferation dissemination of new tumor cells building of a network until it fully integrates to an entire tumor cell network that is connected between two cells with gap Junctions um allowing the passing of um small molecules um and also um communication factors such as
Calcium um between these cells and causes the resistance and I said before we also have this um communication in the network with calcium signals so we were looking more into this and this is um work that was led by our um very talented MD student David hman who used
Our two Photon in Vivo Mouse model where he looked at calcium activity so you can see the bright spikes here and showed that these connected tumor cells are not only um sitting there in a in a connected manner but they are communicating in a very structured way
And this could be also reproduced in an vitro essay so where we culture the cells in a dish and we could show that even without the normal brain around we could reproduce um these calcium activities between the tumor cells so it is also a tumor autonomous mechanism
That is sufficient to to be um built by the tumor cells themselves even without the input of the brain cells and when we further look into single cells and really diving into what is going on between the cells we can show that between from one cell a signal
Can be sent to other cells Downstream over time and really have the cell um let’s say cell a first followed by cell b followed by cell C and so on and this is also rhythmic it’s the same in in vitro um um in the inv vitro setting this rhythmic activity um was um
Um caused by these single cells as we can see here one single cell that is really triggering the activity Downstream in the further in in the further Network so we have a pacemaker like situations coming from these very connected Hub cells and these Concepts follow other Concepts of cth theory of
Networks that are scale-free and small word properties which means they are very effective in communicating and they’re very resistant to random damage pretty similar to um how the internet is structured or other networks are functioning so we have this very low number of um these pacemaker-like cells that are triggering the calcium activity
Downstream what we also found that the a specific channel is triggering the calcium activity is the KCA 3.1 channel that is enriched specifically in these very few percent of the of the um pacemaking cells Upstream in this whole communication Cascade and there’s an inhibitor to the specific Channel which
Is called senap poo that was a um that is a um drug that was tested already in a phase three study for a different disease human patient patients ensured a very good tolerability a very good safety and um permeability of the blood brain barrier to this drug and if we
Give this drug now in this new context of inhib inhibiting these pacemaker like cells inhibiting this driving of the tumor um Invasion we can see that these mice develop smaller tumors over time in MRI shown here and um also experience a longer survival um after being after treatment with this drug over time
So so with this we have a New Concept also not only of this network but also of the function of the network we have um these pacemaker like cells that are um driving the communication into the network they also show similarities to neurodevelopmental um um programs that
Have um with the um invasion of neural cells um some um calcium communication too they contribute to the resistance of the disease resistance of random damage um they are activ the networks are activated by these very connected pacemaker cells and downstream in this whole network they trigger Pro
Protogenic cancer Pathways in the entire tumor um so these Drive the progression even in the entire network but also Al offer new therapeutic vulnerabilities that specifically Target these pacemaker like cells in these very highly connected Hub areas of the tumor with this inhibitor senap po so this offers new targeted therapy
Therapies so now we discussed many mechanisms of tumor intrinsic communication that works also by the tumor cells themselves but furthermore we also studied the this was led by vun venat ramani um in our group the interaction of neurons and cancer cells and what he could find and others did as
Well in this very nice backtack um study that neurons of the non-malignant of the healthy brain connect via synapses to Goma cells to tumor cells and these tumor cells receive the input from the healthy neurons and this stimulates the tumor cells to proliferate to invate to build their Network once
More this communication is triggered with the ampire receptors which are post synaptic receptors sitting on the Goma cell mostly on these tumor microt tubes these cell processes connecting tumor cells and triggering the calcium activity within the tumor cell network again and driving malignancy luckily also in clinical settings already used is a ampire
Receptor inhibitor so the receptor that sits on Goma cells and receives the imput from neurons driving the malignancy and this re this inhibitor is called Parana it is already used in clinics in the setting of epilepsy and when used in the context of Goma cells seen again here in green we
Can see that after peral treatment for 14 days we have less proliferation of the tumor than with the control treat treatment um and show a a a lower cells a lower cell density of these two tumor models shown here and also in this back-to-back publication um in pediatric Goma model so a similar
Setting um so these many mechanisms can be integrated into several functions of the tumors we we also um looked at the invasion of the tumor cells that are um replicating invad mechanisms of neurons while they are um building the brain it’s called neurogenesis so in the time where
Neurons travel throughout the brain to build a cortex and to build your um specific brain regions this is reproduced by tumor cells with branching migration Locomotion translocation how the tumor cells invade and this is once more also in the invasive part stimulated by neuron Goma synapses that drive The
Invasion and with this we have several new approaches how to potentially Target this disease and really focus on the network activity on the communication of the tumor cells we are happy to um start with a first um study funded by the German Ministry for Education and Research which is called per search
Where we will give the perampanel the inhibitor of the synapses and in a clinical setting to really measure the effectivity on um the inhibition of t cell growth another study that has already found its way to clinical translation is the mcmeth trial also performed in Germany where MFA is given to Patient
Which is an inhibitor of Gap Junctions also the connection point between tumor microt tubes on um cells furthermore the senica Pok who’s which is inhibiting the specific channel on the pacemaker cells is a very promising new um agent and we have several other agents um that are um investigated currently
For TM formation specific inhibition of proteins structures and bringing something into this network um in a more basic research setting with this I would like to summarize so we have these incurable gomas that are highly aggressive highly resistance that hijack multiple neural neurodevelopmental mechanisms driving tumor growth into a
Tumor organism that colonizes the entire brain we have this very resistance resistant Network that is driven by endogenous activation periodic cells and exogenous activation with the synapsis which cause intracellular C calcium waves and causes tumor progression we could find new therapies here that are inhibiting the network
Architecture but we will have to make sure to preserve the brain function um in this um organ with that I would like to thank you for your attention thank everyone one who’s involved in these very um um breaking wall um studies and I’m happy to answer [Applause]
Questions thank you Sophie that was a fantastic and sort of terrifying talk and it’s good to see so many different approaches coming in um going to open it up for questions now and I’ll ask the first question which was what’s what do you think the selectivity is going to
Look like for these Network drugs the seal the seel activity so will they be safe will they be um selective to just the the brain tumor or could they have problems in the brain or other parts of the body yes um as pointed out this is always the question um with any drugs
That we try to develop for clinics but especially also for neurology and um for for tumors so perampanel for an example the um synapse inhibitor I would call it um is is already approved in clinics so it does show a good safety and tolerability profile um um for epilepsy
Um but yes the question will be how will it work in um gasta um settings we are giving it in a um um manner that is identical to how you would give it to epilepsy patients so we also expect a good safety here um for example the
Senap pook the inhibitor of the pemer like cells um has been tested in a phase three study for Cle anemia and showed a good safety a good tolerability but wasn’t tested in this Con context which of course um um eases our translation now it has been tested already in
Patients so we will um look at it from a different angle but we are hopeful well the these are very um um easy to translate um um drugs anything else of course that you develop from basic science to translation um are more challenging to make sure to not um um
Interfere with normal brain function yeah thank you so we have a question here at the front thank you great talk and great work I have two questions the first is the clinical trials are there going to be monotherapy or I actually quod treating um so the pur uh trial is a a
Window of opportunity trial that will be given to patients with recurrent gasta for which we currently do not have a standard treatment anymore so patients are went with diagnosis are treated with surgery radiotherapy chemotherapy and upon um recurrence there’s no um validated standard anymore so this is if
Receptable where this trial starts and the treatment will be um started with a phase of increasing dosing and after 30 days we will have a reection of the tumor which also helps us for um more informed research on on the question of how how effective the treatments is we
Can look at the tumor tissue for accumulation of the drug and so on and then um we have a 30 days after surgery um treatment phase so in in total 60 days with per search it’s a phase two trial so it’s the first to establish effectivity
In this context um the surgery is not part of the trial but is part of the treatment for the patient so yes this is a monotherapy although further treatment can be performed Downstream of course and um the the mcmeth trial um with the meclofenamate the inhibitor of the
Communication points of the tumor cell networks the Gap Junctions is a co- treatment of um meclofenamate and um temozolomide which is a chemother therapy also um used in recurrent tumors and the rational behind it is also what I pointed out in the beginning that you
That that we saw um and others too um the group in Bon that the disconnection of the tumor cells leads to higher vulnerability of um cytotoxic treatments so chemotherapy and I think um in in many cancers and especially here we are not expecting to have one perfect drug
Um treating it all but rather um several drugs combining um um from different angles that are helping us treat the tumor that’s what I would expect that you actually here have the increased vulnerability which is really giving you a chance the second question is if I correct recall it correctly in there are
Other tumors outside the brain where metastisis is uh driven by neurons so so they they met testid the cells along neurons can you elaborate a bit on that so this is the rising field of cancer Neuroscience um how how neurons or the the the central nervous system the peripheral nervous system interact with
Tumors and we have we have metastasis to the brain from let’s say um um breast cancer to the brain we are also looking how these cells then adapt to the brain and and really infiltrate brain functions but we of course also have tumors in in different sides of the body
That are not in the brain so in the um peripheral nervous system um involvement is is the new question we are also looking at um and um more and more evidence now that this becomes more of of a topic to be studied shows that tumor uh tumor cells and um nerves
Really interact and tumor cells um um let’s say um exploit um trophic factors from nerves at least or really um also connect to nerves but this is um now the new field that we’re studying more we have a question at the back uh how does the age of the patients
Impact on the management and outcomes of the treatment um it it does in in general um for the first treatment there are um recommendations to um let’s say um for example um for radiotherapy you use for younger patients below 65 you have longer treatment course for elderly
Patients you um prefer to do a shorter treatment course with higher radiation doses per day um this has shown to be um more toal for these patients um sometimes the decision making is depending on molecular um statuses of the tumor um um if you give these elderly patients chemotherapy or not um
Weighing potential benefit with potential side effects so this is something that is um always wait for the studies we’re doing their there’s no formal age limit if you’re above 18 years of age so we we have actually run out of time now I’m sorry I can see there’s
Still more questions but just before we wind up can you just say one sentence about the epidemiology of these brain tumors how do they manifest in according to risk group and according to geographical location so in Germany and the same numbers reported from the US um in the
Incidence of let’s of of for example the gasta which is the most common primary brain tumor most common Goma um is 4 to six out of 100 th a thousand so this is the incident so 4 to six people out of 100,000 people become sick with this
Disease per year it’s more of a um less it’s it’s more of a rare or less common disease um overall but um people are are affected every year we don’t know why the tumor um um grows at this point yet and um similar numbers are reported from several countries um um the numbers
Are um similar yeah also in the global South well I’m I’m not sure if there’s um the same um numbers acquired but I haven’t heard that there are less tumors there or less incidents um as far as you can report and measure okay well thanks very much that’s been very
Interesting and um now i’ would like to move on to welcome Doty oat who’s going to be speaking us today um as a falling walls young science Talent person this is this is an an initiative from falling walls to award award 20 winners of a competition to create a sort of network
Which um promotes mentoring and helps them with their careers Etc um Doty is a winner um she’s going to she’s got a history of um HIV studies she got her PhD in medical virology from the University of quulo natal in South Africa where she studied HIV and immun
Escape and then she moved recently to stenor University as a postdoc where she’s studying maternal HIV and CMV co- infection and its impact on fetal immunity and today she’s going to talk to us about her work on how HIV infection may increase risk of pre-term child birth so thank you Doty thank you
So much uh good morning everyone so uh I’m do J from stellin bos University and I’ll be giving a talk on the placental immune cells and the impact of maternal HIV infection so the HIV prevalence specifically in South Africa is uh potentially in the childbearing females
And in this uh plot I’m showing you there so we have the red are the females and the age range is between 20 to 39 and these are the CH uh the childbearing females and they have a higher prevalence of HIV compared to the men however the good news is that
There’s a immense uh anti-retroviral treatment coverage in this population and we can see that about 90% are virally suppressed and the art coverage has really improved in South Africa however this also makes it complicated for these women because you have high prevalence of HIV yes you have you’re
Properly uh suppressed or treated but these treatments come with adverse birth outcom so there are reports that have shown previously that these women will experience high risk of small for gestational age babies still birth delivery pre-time delivery and this incident is very very high in this population then this their infants are
Not infected by HIV but they are exposed to HIV in utero and they’re also exposed to the art treatment and these children are often not um healthy and they report various uh clinical symptoms when they come to the hospital like within the first year of life it’s not only
Specific to South Africa it’s also been reported in in other African countries but it’s really a subsaharan HIV endemic uh setting infection so what are the mechanisms that lead to these adverse birth outcomes that lad me to the interest of looking at the placenta so here I just show a schematic of a
Pregnant woman who’s uh living with HIV and is taking anti retroviral therapy what happens within the placenta that makes this child who is HIV exposed to have poor infant immunity compared to uh uh the uninfected infant or rather the an exposed infant and this has also been
Shown that they are more at risk of increased mortality and Studies have been shown in subsaharan settings including Uganda Zimbabwe Botswana and South Africa so what can we learn from characterizing the placental immune cells within the placenta so here I’m showing a schematic of a of placenta and my
My focus for today will be on the on the placental mcroof fages which are the h b cells so in this schematic I’m showing on the outer layer which is the maternal side of the placenta we have the decidual mcroof fages and from the fetal
Side of the placenta we have the half B cells there are various markers that have been used to describe these of B cells and specifically we have the cd163 the CD 206 the CD 209 and for me this morning I ear to claim that factor 13 A1
Is a key marker and is a specific marker for h b Sals and how did I come to come about this Factor 13 A1 uh it’s been described long time ago within the food industry and what does it do in the D so this is a puff pastry with transglutaminase and without
Transglutaminase you can see that it’s puffed up like the croan is puffed up when it has transglutaminase and this is with control and the factor 13 belongs to this transglutaminases family however in the body they have different uh functions that including hemostasis coagulation and embryo implantation so I having known that that
That is the function of the transglutaminases I looked into the Single Cell RNA sequencing data sets of FAL maternal interface and identify that factor 13 cor localized with uh csf1r cd163 and cd68 these are markers that are specifically highlighting the myoid cells within this fetal maternal
Interface and in this uh graph I’m not able to delate whether it’s from the mother or it’s from the fet so I took the next step forward to verify this expression from the insilico data on placental tissue and for this I utilized uh the pims cohort which is the
Prematurity Immunology in mothers living with HIV and their infant studies and in this cohort we are able to recruit pregnant women who are both living with HIV and those without HIV and who had different adverse birth outcomes so when I tested for the factor 13 in this
Placental tissue I uh found out that the factor 13 cooll localized with csf1r cd16 3 and cd68 and this is the merged image of it and clearly it shows that this Factor 13 A1 is a good marker of the H B cell and this uh the imuno reactivity was highly present within the
Vas tissue so to also delate the different placental membranes and specifically highlight which section of the plenter is really predominant of these cells so here I’m showing the different placental membranes we have the deal Paralis which is very close to the mother deid basalis which is a rid
Between the mother and the fetus and the VAS tissue is the fetal side of the placenta and the factor 13 A1 positive cells were highly expressed within the fetal side and this was consistent irrespective of disease status so in the vas tissue there’s High expression or the higher density of these cells
Compared to the deal Paralis which is the maternal side however when I looked at overall in my whole cohort of um uninfected and infected placenta there was decreased cell density of these Factor 13 positive cells so how was this translating to uh adverse birth outcome so I still looked at different uh birath
Outcomes within this Co within this uh cohort and in blue here I’m showing the placenta that were collected from negative HIV negative mothers who had ter delivery and in red is placenta collected from pregnant women living with HIV those who experienced at appropriate or gestational age these are
Just normal babies with appropriate age at Birth then those who had small for gestational age births and those who experienc pre-time birth so for the pre-time delivery this Factor 13 uh cell density was lower compared to the HIV negative population and what was striking and rather interesting was that
In this population those women who initiated treatment prior to conception had a lower density of these cells so there’s a significant reduction of this uh Factor 13 positive cells in the HIV positive and it’s even further reduced in women who initiated treatment prior to conception what can we learn from the
Morphology of these cells within the Hof B so I looked at the various parameters of the cells these include the area the perimeter and the circularity and looking at the area of uh all the Hof power cells that were collected from pre-m delivery they had a lower area
Compared to those who had a t delivery and this is I’m just showing a depiction of how it looks within the pretam placent so you can see that the areas are smaller compared to the those who exp who had uh ter Del or rather the HIV negative placent then the in terms of
Circularity for the half B cells are more circular within the placenta that experien pre-m delivery compared to those who had ter delivery and looking at the relationship between circularity and area we see that in pre-time delivery these cells occupy less area and are more cirular compared to the t
Uh time pregnancy placenta or t pregnancy of B cells which occupy a larger area and are less circular however there’s a different mechanism for those uh uh placenta that had experienced um small for gestational age they have a higher area as well as high circularity and at the extreme end I’m showing what
I mean by circularity so you can see that the Hof B cells here they are more spindled they occupy a large area and they like they spread across the V tissue however for pre-time delivery they very very circular and static so could Factor 13 A1 be a possible predictor of pretam birth yes
We observed a good prediction for adverse birth outcome when I compared this with HIV positive and HIV negative however there was no prediction for small for gestational age and great prediction for pre-time delivery and to summarize fact 13 A1 is a Noel marker for the Hof B cells and it’s
Exclusively expressed within the vas tissue because we compared the maternal side and the fetal side of the placenta and there’s reduced uh density of these cells in HIV infected placenta and we have some significance in terms of the cell morphology in in of the h b cells
And this could help us to alienate what really pred makes the cells is it that the factor 13 is produced as a paracrine effect extrated from these cells and does it affect the function of the Hof B cell my hypothesis is that the low expression of these Factor 13 on
Placental macras may be uh leading to poor implantation or angiogenesis and arterial formation of the placenta I would like to thank thank my uh collaborators as well as our fers and everybody who’s been involved in this walk thank [Applause] you thank you Doty that was a real tour
To force a lot of data there and a very important area of research have you got any idea of um the mechanism whereby this could be induced in I mean it’s so you’ve got this strong Association but have you got a a mechanism that you’re putting forward to how it all
Happens yeah so uh I’ve um I’ve looked at setting up functional assay Downstream to just look at what really Factor 13 does in terms of functionality of these cells but Factor 13 is has also been described like in uh pripo sites and there it shows that it really s acts like a
Switch for differentiation and proliferation of cells so probably it does this it has a similar mechanism in placenta such that it makes the h b cells either to proliferate or differentiate and this is hampered in pretam uh scenarios where maybe the hofb cell has not proliferated enough and therefore the functionality is hampered
And the placenta is just not functional it gives in before the 9 months of time yeah so questions from the floor thank you very very nice talk can you just remind me about the incidence let’s say of HIV positive neonates let’s say in a rural area quu natal North or
Um or somewhere Cape Town stush okay so in the current situation the most recent yeah with HIV preventive treatment in the current situation actually I think South Africa has the best uh vertical transmission prevention models at as we speak and it’s maybe 0.1% or so it’s completely completely
Eradicated yeah so the infants are not HIV infected as I said earlier the only problem is that they are not immunologically as stable as the yeah a question at the back there please very nice talk so I was wondering since the transaminases are involved in like extracellular Matrix crosslinking have
You looked at how in your different cohorts like how the changes how there might be changes in extracellular Matrix across the the different placentas yeah I’ve only stained the imuno imuno histochemically but have not tested the cross linking all the trans glutamines activity or the factor 13
Cellular activity but I’ll do that and I’m also looking forward to testing the peripheral blood for any other proxies that could highlight or that could be easily tested to predict or to give us an idea of what’s Happening while during gestation I wonder if there may be changes in like
Mechanical properties from The Matrix thank you okay thank you sorry um do we have some more questions from the floor so I would like to ask you um is there any sort of um difficulties or blocks in your work that you think if you had more money to do the work things
Could be done more quickly or anything else that is standing in the way of um of moving forward quickly yeah uh of course the the the the the establishing of these cohorts and just going around and participant recruitment there’s a lot of work and science communication or rather science
Uptake or research uptake that is needed over and beyond that there’s also the resource uh limits in terms of do uh establishing placental um functional assets because to just collect one placenta process it and isolate sales from it is about 48 hours and it’s it’s intense so we need a lot
Of like expertise Personnel finances and yeah but we do with what we have yeah yeah very good so I mentioned that you were part of this network the falling walls initiative the science talents could you tell us a little bit about how that um how people like yourself can
Profit from this sort of activity what they do and and how much you’ve enjoyed it yeah so I’m I’m I’m truly grateful for the falling walls it’s an establishment that offers uh rather the soft skills like how to how to carry on with an academic career particularly if
You’re an early career and a PO other avenues or other options beyond the PHD if you’re really not uh keen on taking the academic career but however all in either way that you decide to choose your career path on how to flourish how to communicate how to write grants and
Compete for them as well how to manage them how to present and yeah I’m truly grateful fantastic so let’s um close this session and thank both of the speakers Sophie and doe for very inspiring talks and wish them well in the future because they’re both got the
Future ahead of them and this time I’m going to tell you what time you have to be back which is at 11:00 rather than risk giving you the wrong break time so please be prompt thank [Applause] you for welcome back to the next session and in
This session we’re going to move on to the next area of business which is the Breakthrough Technologies in life sciences and our first two speakers are going to talk about Technologies applicable to regenerative medicine and to blindness and so I’d like to welcome onto the stage Karen Chrisman and Peter
Roer thank you and um our first speaker is Karen and Karen Chrisman is a bioengineer from UCSD and as the terminology goes she has broken the wall to cost effective minimally invasive regenerative medicine a regenerative medicine is usually uh a very expensive Enterprise it involves cells and living things and
Karen’s approach has been to use biomaterials which are both cheaper to make and to store and to move around and she’s developed an injectable gel which Finds Its Own Way to the site of injury and reduces tissue permeability and inflammation it’s a very interesting and novel approach and she’s going to talk
To us about her research in applying this biomaterial in myocardial infarction so thanks Karen thank you very much for the invitation and um yeah it’s a pleasure to be here uh so first just quickly my required disclosures I am a co-founder of two companies and I will talk about
Some of the work related to ventrix bio today so as was mentioned um my focus is on myocardial inunction and heart failure and been working on this for um about two decades ago now and so um as you heard in the first session this morning you know obviously
Cardiovascular disease is a huge problem uh across the world and so my lab has been very interested in uh designing uh regenerative Med medicine strategies to treat the heart and so I’m going to tell you today um briefly about kind of our translational story in designing um one
Of the early Technologies in my lab to treat kind of the Subacute to Chronic uh myocardial inunction patients and how that led us kind of down a road to actually even less invasive regenerative medicine strategies and now trying to treat more acute myocardial infection patients so uh when when I started my
Lab we were very interested in designing um as was mentioned biomaterial based strategies to regenerative medicine and so there are a few reasons for this so one kind of the the standard regenerative medicine therapy when you I think when most people hear regenerative medicine they think Cell Therapy um and
That has been explored extensively in the heart both in preclinical models and clinical trials um but it’s extremely expensive so um in US Dollars and approximately equivalent for Euro is you know tens or hundred thousand dollar per patient um depending on the type of sell therapy but with biom materials you can
Do this um with an order or two magnitude L and so that’s something we’ve been very interested in um and also down another downside of cell therapy is you get very poor cell survival so if you think about um which you don’t have to worry about with an
Acellular biom material so if you think about what you’re injecting into the heart um if you’re treating patients kind of in that Subacute window weeks or months after their heart attack or out to years in chronic heart failure patients what you’re injecting into is something that looks like this a very
Dense collagen scar so acutely after a heart attack you get up break ation of Matrix metalloproteinases an inflammation that degrades the natural cardiac extracellular Matrix and then it’s replaced by this collagen scar so when you’re injecting cells into the heart this is what you’re injecting them to um a diseased micro environment that
Displays both abnormal biophysical cues but also abnormal biochemical cues and so I think it’s not so surprising um that cells or say other growth or growth factor therapies that are including the body’s own cells this is what those cells are seeing and so I think it’s not
Too surprising that you know it hasn’t worked as well as originally intended so our approach um initially was to instead of delivering a cell inject a biomaterial scaffold that could recreate a more healthy micro environment of the heart to encourage the body’s own cells see a more healthy extracellular Matrix
And promote healing uh in uh that wound which is uh a heart attack or myocardial infection and so the one of the first Technologies we developed in the lab was what we call our myocardial Matrix hydrogel so we my lab actually works with synthetic polymers as well but we
Decided to take a more natural approach here because it’s really it’s basically impossible to recreate the cardiac extracellular Matrix synthetically because it’s hundreds of components both proteins as well as parley saccharides so we took what nature gave us which is a lot of pig hearts um it’s you know
Easily accessible byproduct of the food industry uh and so what we decided to do was design an injectable cardiac extracellular Matrix scaffold so for those of you who might not be aware there’s a lot of work going on um in tissue engineering and also clinical products with decellularized meaning
Strip out all the cells leaving behind the extracell Matrix as a patch and they’re used clinically both in Europe and the US um for surgeries and they stimulate a pro remodeling immune response as long as you desize appropriately strip out the cells leaving behind the extracell Matrix so
We wanted that to take that general idea but have it cardiac specific and also be injectable so it could be delivered minimally invasively and so what we do is we take pig hearts we chop up them into small pieces stir it around in a detergent to desize it and strip out all
Those cells and you can see it leaves this kind of ghost white extracellular Matrix we dry it and Mill it into a fine powder and then we use an enzyme pepsin to partially enzymatic digested to gain injectability since we wanted a minimally invasive therapy uh so when
You uh as long as you neutralize it or adjust to physiological salt and pH when you inject this material back in um the body into tissue it reassembles back into a poris and fibrous scaffold that’s very reminiscent of the original cardiac extracellular matric which you can see
This inset here is this stage here before we’ve done this processing and if you look at the the biomaterial or the hydrogel with a scanning electron microscope you can see it forms this nice nanofibrous architecture again reminiscent of the original extracellular Matrix and so we optimized this basically digestion processing and
Concentration to enable catheter delivery and so in the heart uh if you want to inject a biomaterial directly but via catheter you can use a transendocardial approach where you’re accessing through the femoral artery snaking up through the aorta and then you have the end of the catheter inside
The left ventricle with a needle at the end that can be deployed and retracted and you can inject multiple times so that seems simple but actually with the delivering a material is challenging because you can’t have it gel inside the catheter you know you have to per perform multiple injections without
Clogging in so we kind of optimize this process to enable that delivery and then we’ve done over um actually more than a decade now my lab has done a number of studies looking at what happens when you inject this material in in pre-clinical models of myocardial infarction both small and
Large animal and I’ll just give you a brief summary of that but essentially You by creating this new micro environment you really do create a template for healing so endogenous cells will migrate in degrade the material and replace it with host tissue so what we find kind of the end result of
Stimulating that healing process is we get increased cardiac muscle through at least two mechanisms one is decreases in cardiomyo apoptosis and so we found that the material is actually a reactive oxygen species snc which we think um via the free thile content which we think is
Help to promote survival but we also saw in the um rodent models that we got significant increases in multiple cardiac transcription factors as well as small but significant increases in cardiomyocytic muscle both in the rodent and pig models um and we think it’s through these two kind of pro- survival
As well as slight but small proliferation uh we also see changes in card uh cardiac metabolism increases in blood vessels so which helps with the esic environment as well as decreases in scar tissue or fibrosis so because of these studies as well as um functional studies and the
Preclinical models and a lot of safety studies uh ventrix bio um completed a phase one clinical trial right before the the pandemic started um and this is what it looks like commercially it’s called Venture gel it comes as a lyophilized cake you add sterile water
And then you can inject it into in the cath lab so this was a phase one trial in 15 patients um starting between about 60 days patients were enrolled between 60 days after their heart attack out to 3 years and were they were all treated and then looked at it Baseline and three
And six months so overall um demonstrated safety and feasibility which just the safety of results alone were exciting because nobody had while I mentioned the desized extracell Matrix patches that have been used in our commercial products no nobody had delivered this kind of digested ECM hydrogel form of desel extracellular
Matrix in any tissue in the body so showing initial safety in the heart was great because obviously the heart is a high risk Oran organ uh but we also showed significant increases in uh exercise tests decreases in heart failure classification uh and then using MRI showed that 80% of patients either
Maintained or decreased their left ventricular volume so as the heart is going into heart failure the left ventricle will dilate so you want smaller uh volume so overall uh very promising and we’re actually about to start a new trial in U bypass grafting patients who can’t have a region that
Can’t be bypassed to stimulate neovascularization and our collaborators at emry um in the US are uh just received approval from FDA to also test this material in hypoplastic left heart syndrome patients who um are basically single um ventricle patients who eventually undergo our right ventricular heart failure
But what I’ll share with you for the the rest of my talk today is how we’re moving even less invasive which also means actually also more cost effective so um that catheter approach I showed you is great in terms of compared to sayfe surgery but it can’t be delivered
To acute patients because of the risk of arhythmia nothing to do with the material but just poking the heart with a needle um and so we knew the material could be Pro survival Pro vascularization that would also be great and ideally you treat a patient as soon
As possible after the heart attack to really prevent further damage so a way you can deliver a material to the heart acutely is through uh intracoronary infusion using the same uh catheter that’s used for anoplasty procedures so after an angioplasty with the balloon you can actually blow that balloon back
Up for few seconds you know 15 30 seconds at a time and through the same catheter Infuse a material so the way it get gets into the heart is uh normally endothelial cells have these tight junctions but in injury and inflammation they become leaky and so the idea
Initially was to design a material that could go through leaky blood vessels concentrate in the infar and then perform similarly to what I what I showed you with our original hydrel and so we re kind of designed the formulation this a through D is exactly what I showed you before but in this
Case we took this uh liquid and uh did High speed centri ucation to remove the submicron particulate that would be too large to go through the Leaky blood vessels which you need about if you look at nanoparticle literature about 200 nanometers or less uh and then you can
Still actually sterile filter it now which is great relaize it and still be ready for easy um rehydration injection if you look at what that supernon is which in form which forms the infusible ECM the yellow arrows here are pointing to this Nano fibular archit ecture the
The white AAS are just ice so basically in that supern are kind of nanofibers of extracellular Matrix so we delivered this first in a rat model of Mi using a simulated intracoronary infusion procedure you can see here this is one heart doing short AIS cross-sections uh and where the labeled
Material is is exactly where the infar is so we thought great the material works exactly how we thought it does it goes through the Leaky vasculature however uh when this was mostly done by my former PhD student Marty Spang when he finally got around to doing confocal Imaging on it we found
It didn’t actually work how we thought it originally did so red is the material green is are the endothelial cells and just blue is nuclei so what we found is that instead of going through the Leaky vasculature it actually bound to the gaps of the Leaky vas vasculature which
I’ll show you at the very end was actually even better than what we had originally intended so we thought because you know if you imagine you know here’s a blood vessel these are you know cartoon version of our extracell our infusible extracellular Matrix if it’s binding into those gaps it should reduce
Vascular permeability which is known to um basically cause greater cell death and also um allow for immune cells or inflammation to come in so what we looked at to see if it was affecting vascular permeability we did the uh infusion of our material and then we infused this time a fluorescently tagged
BSA uh and then scan the hearts so here and if you look at a sailing control you see that the BSA is allowed to basically can extravasate through that leaky vasculature and this is reduced with the um infusible extracell Matrix so almost immediately at 30 minutes after um BSA
Infusion uh which was performed basically almost immediately after the infusible or the iecm infusion you get decreases so that’s a physical blockage that’s not a biological effect but at three days you still see that decrease and by then the material has largely degraded so we think first it’s
Physically blocking and then after that it’s basically accelerating vascular healing earlier than what would typically occur which is about seven days the body would naturally uh heal the vasculature so we then performed uh another study in the again the rat model of myocardial infarction using MRI to assess cardiac function and within 24
Hours after infusing the material again via simulated intracoronary infusion you got significant decreases in in diastolic and in systolic volume remember decreased volumes are better uh trending increases in injection fraction and that was uh significant still five weeks later so what we found when we looked at
Histology by I think kind of blocking part of those gaps between endothelial cells we were able to reduce um macras infiltration so reduce inflammation we I think secondarily then saw decreases in cardium iate apoptosis and then uh increases in uh neovascularization or the arterial density in the infar we’ve
Also recently done a lot of single nucleus RNA seek um post treatment and I think you can hopefully appreciate the differences between the material and saling groups on these umat plots but just to give you a summary is that similar to other decel extracellular Matrix materials we find that the um
Immune cells that are present are pro remodeling so kind of M2 type th2 type M2 type macrophases and th2 type te- cells um we get angiogenic phenotypes for endothelial cells as well as the increased progenitors and then cardiomyocytes have a pro- survival phenotype so we’ve also done the more
Translational Pig model where we can actually use the catheter that would be used in patients and we similarly saw decreases in uh in diastolic and ins systolic volume you know suggesting this has potential um to go into uh patients and we recently got uh a couple grants
One to my lab and one to um ventrix to uh perform indd enabling studies to hopefully start a trial within the next couple years uh so now we have a new type of infusible extracellular Matrix material I showed you can now deliver it intravascularly I showed you intracoronary delivery reduces vascular
Leakage accelerates vascular healing it’s immunomodulatory and it’s Pro survival but as I said that kind of accidental finding of blocking or attaching to the Leaky vasculature you know there’s leaky vasculature in basically in all areas where there’s inflammation and this can affect many other diseases so we think this can
Actually be done well beyond be used for things well beyond U myocardial infarction and actually we’ve also discovered that you can even deliver it uh via intravenous infusion uh and and still will Target the heart but we’ve also shown uh that you can Target traumatic brain injury pulmonary arterial hypertension and even systemic
Inflammation um and it goes to all the organs with inflammation significantly dampens inflammation and particularly in this model we were about to submit a paper we’ve shown um quite drastic improvements in animal survival when you have severe inflammation so we think it has really the potential to um you know break the
Wall to you know costeffective um truly minimally invasive regener medicine and with that I like to thank all the great members of my group Uh current and former clinical collaborators as well as funding sources so thank [Applause] you thank you Karen lovely talk um just a small point is this something that
Would be regulated as a medical technology or great question so the original hydrogel um is regulated as a biologic in the US but Barm has given it a device designation the because all the ECM patches are devices the newer therapeutic we’re expecting a biologic in the US and I’m not sure how Europe
Will handle it it is a little bit different the fact um but it does create this physical blockage which is you know a physical mechanism of action so to be determined how Europe will handle that one and what would you prefer I mean device has advantages in terms of you
Know more rapid translation into or actually you know acceptance for a product since you have to do um smaller trials so you know we would it would be easier if it was a a device but there are some silver linings for biologics as well like you get exclusivity upon approval at least in
The US for um I think I forgot how many years about a decade or so so um but it’s definitely more expensive to develop a biologic right right so let’s open this up to questions you wanted to say something Peter yes uh that was very
Exciting um new for me so but you showed a lot of functional improvements but did you look also whether uh heart cells muscle cells grow back to into the legion so in this case we’re delivering them acutely you know basically at the time that they’re dying so what we see
With a single nucleus RNA seek we’re looking at that time point also acutely what we see is more of a pro survival so we don’t think that this therapeutic is necessarily going to grow new muscle but the hope is that we can prevent more of those myocytes from
Dying in the original hydrol we did see evidence of new myoides uh thanks really interesting um so I maybe I missed it but I is is there evidence of increased contractility so you mentioned that the ejection fraction didn’t change and I’m I guess related to that I’m wondering if in the phase one
Trial where you mentioned decreased left ventricular volumes was there a change in ejection fraction so for the original hydrogel we saw the main differences were in volumes um versus say changes in ejection fraction although we did see improvements in Regional contractility we didn’t look at that patients but in
The pig study we did see evidence of regional contractility in the infusible elra cellular matrix I think we were underpowered there so we did you know on average ejection fraction was greater compared to say the previous hydrogel I think we’re just slightly underpowered for an ejection fraction uh and there
And also in the pig study we we saw increases uh or improvements in Regional contractility as well looking at Echo so I think particularly with the infusible that we that we do anticipate and getting improvements in contractility by preventing myoides from dying thank you have you started to combine this
Treatment with others you mentioned the the Ross syn function so you could think of phosis Inhibitors which are out there or maybe even a cellular therapy so not yet we are very interested with the infusible to see if we can use it as a delivery vehicle as well so it clear
Clearly has inherent biological properties but we are now looking to see if we can conjugate I don’t think we’ll conjugate anything large with it or include cells we can definitely include cells with the hydrogel versions and we’ve seen improvements in survival but we are interested to see if we can uh
Conjugate small molecules and and more peptide Therapeutics um but stay tuned so you mentioned that this could be used in a number of other disorders what do you think would be top of the list what’s what is the lwh hanging fruit here uh so right now um as I
Mentioned we the model for a multiorgan dysfunction syndrome which you know basically it goes along with things like sepsis or you know even severe covid um and so that’s something we’re very interested because the data there is like we see you know I think it was either 100 or thousand full decreases in
Is 6 for example in the blood we see decreases in the tissues but really drastic decreases in inflammatory cyto kindes in the blood so I think for these really sick patients in the ICU that you know have hyperinflammation cyto kind storm um the data so far in a mouse
Model you know looks really promising so I think that would be the probably the next Target after my cardial inection well that’s really fantastic so thanks very much Karen and we’re going to move on now to Peter Ro Seer who is is a neuroscientist who also deals in devices but
Um um more of the prosthetic variety he’s a neuroscientist at the Netherlands Institute of Neuroscience in Amsterdam and the wall that he’s breaking down is Blindness right yes um so we go from the heart to the brain and I’m very proud to be here as part of the
Falling walls experience so I’d like to uh to to learn about what we’re doing in terms of uh trying to create a visual prosthesis for blind people and in the world there are about 40 million people who are blind um their numbers are increasing especially in Europe because of the Aging
Population and this shows you how information reaches the brain so it’s first projected onto the retina of the eye then there’s this small nucleus that you you seen a center in green that’s called the lgn lateral gen nucleus which is relay station that then projects the information onwards to the primary
Visual cortex which is actually at at the back of our brain and um if the IML functions then it’s usually the eye bulb so there are many diseases it’s a very fragile organ organ in some sense so in previous work we have now targeted the primary visual cortex as a
Place to interface with these nerve cells that are deprived of their visual input how does this work so we place electrodes sounds fancy it’s just wires we place wires in the brain and if you place a wire close to a nerve cell as you see in this picture and you
Stimulate and you are in primary visual cortex but you see here is an array of electrodes 100 electrodes on on the plate if you punch that into the brain and you stimulate those brain brain cells artificially even in people who are blind so these cells are waiting for
Input which is not coming if you then artifici artificially activate them then the person and can be a person who has been blind for several years sees a DOT of light and we call that a phosphine now the visual field as we see it is mapped in a very systematic ma
Manner onto the primary visual cortex which basically has a map of space so if you place your in one position the dot of light is going to appear at one particular location in the visual field if you shift your stimulation location the dot of light will also shift so it’s
A very systematic mapping and that you can exploit so if you place say 1,000 electrodes or preferably even more then you can create 1,000 phosphines each which its own unique position and the idea and it’s not our idea that exists for in the field for many years is then to stimulate a
Pattern of electrodes and you can work with it like a like a matrix board or a scoreboard that you know from the highway or from the stadium right by switching on some light bulbs you can just create pattern vision and of course it’s clear that the more electrod you have the better
Because you’re going to increase the resolution of artificial vision and a system and and there have been systems alike would look like as follows so the the patient or the user is is wearing a camera that can be embedded in glasses something that you can just buy
Nowadays and look at the street scene now if you have 1,000 electrodes this is too much information you’re not going to squeeze it into your prosthesis so you have to simplify that well for that you can use artificial intelligence so they are now very sophisticated algorithms
That allow you to kind of concentrate on the really relevant information so here it’s about Vehicles if you’re navig ating a city and then you’re going to have a wireless communication something maybe on the back of the head that communicates wirelessly to a brain chip that is then uh connected to a
Stimulator and these um electrodes so high density electrodes that are really placed in between the nerve cells so that requires surgery and hopefully then it works and the patient will see what is out there so we tested the roof of concept A few years back and what we did is we placed
16 of these so-called UTA electrode arrays We Had Each array had 64 of these electrodes and we plac them in the brain of a monkey and this is the work of s Chen who started our own lab in Pittsburgh and what you see there in the
Right every black square is one of these electrode arrays you’re looking now from the back so the nonp pointy side and they were still on a connector that was uh screwed onto the skull of the monkey and um of course in future versions We would like to make this thing fully
Wireless but we are not yet there although the technology exists okay so this is how we placed these electrode arrays so every square that you see here is one of these arrays so they were placed in primary visual cortex and then these animals were not blind they could just see so then you
Can see which part of the visual field you have to place stimulus to activate the neurons and this is shown in the upper left so every color dot corresponds to one of these electrodes and you see for instance that these these red dots they’re in central vision
So in the Bull’s Eye the center of the bull’s eye is central vision and you see that these bluish uh dots they belong to the electrodes that are kind of more to the center of of the brain that they are more in the periphery okay so you see
Again this very nice mapping of visual space onto onto the cortex we replicated that in a second monkey and now I hope the movie will work so what you see here are all these green circles these are the locations where we can create create these phosphines these rudimentary
Perceptions and so if somebody can start up the movie for me okay so you see that the monkey is um making eye movements so the magenta dot is where he directs his gaze he starts a trial by looking in the center of the screen where the cross is then we
Stimulate one of these electrodes so the monkey is seeing a DOT of light and he he’s trying to make an eye movement there so that works and also confirms that these perceptions are taking place at the at the locations where you expect them so this has been shown before maybe
We’re the first to be able to do this for hundreds of electrodes okay now the big question for us was if you stimulate more than one electrode can this scoreboard analogy work so can we create patterns that are recognizable to find that out we trained
To monkeys on a task in which they had to recognize letters so here we present the letter D to them and then there is a choice menu and the monkey reports what he saw by making an ime mov into the corresponding letter okay these animals were seeing so they were not blind so
They trained on this for many months and then the exciting part of the experiment we’re not showing the sample letter we’re just replacing it by trying to paint a letter onto their visual brain so here we try to paint the letter a and hope that the monkey will go to the corresponding
Letter and if you can start a movie again so what you see here is painting a letter so here we paint the letter o and yes the monkey chooses the O from the choice menu he repainting the letter L and it worked so we were so happy when
This came out we made a small dance in the lab so this is proof of principle this this this can really work and in patient that had not been shown before okay so we think that that it’s time to test this also in humans because in
Humans you can just ask you know what do you see which is very informative so we work together with Professor Eduardo fernandz in Spain who has a clinical trial and placing these same electrod arays I was talking about in the visual brain of people who are
Blind and this is Berna Bernarda Gomez I can name her because she’s quite famous in Spain now she was the first patient to to participate in this first inhuman trial um and what you see here in the a lower right is one of these uh one one
Of these implants so it was had only a single AR AR with only 100 electrodes and also the connector that was screwed onto hor skull this shows you where this electrode was implanted so it’s a 4×4 mm electrode and that’s actually quite small you have to realize that the size
Of the map I was talking about is 25 square cm on the right and another 25 square cm on the left so you’re covering only a very small region of the primary visual cortex but the first results were quite encouraging so now they stimulated a set
Of electrodes in in the shape of a larger square and vereta reported I see a large o and then when they only stimulated for adjacent electrodes he reported seeing a small o so that looks good but it was not always as easy to understand so here she reported seeing
The letter I and here she reported seeing the letter L now I don’t see an L there so we think what’s going on there is because in her case all the electrodes are on this small 4×4 Square million meter area and you get some interference patterns so if you
Stimulate two Electro nearby you might still also influence some of the neurons that that are in the middle which is not the case in our monkeys because there the electrodes were distributed across a larger region of visual space can you start this movie as well so this is bernardetta Reporting foree Speee For so thank you so for for me she’s she’s a hero right because she is not expecting to get Vision back she just participates in this experiment where she is undergoing brain surgery and her goal is not to regain Vision but actually to help science and also help
Future patients who might in the end also receive a prosthesis that is really functional and and has more capabilities and so these are also the the limitations we are now kind of trying to solve so what you see here on the lower left is the degree of visual field
Coverage as I said we are only covering 4×4 millimeters of of a brain region that is 25 square cm so covering less than 1% and um what you see on the right is the extent of a visual field so it’s 90° left and right and then 70° up and down
And the red ellipse is what we’re covering here so she’s not g regaining Vision except in this 1% of our visual field so that is something that we actually working towards solving and another problem and here are the the fibrotic cells they’re back so they also
Of course are present in the brain and if you have an implant that have stiff stiff electrodes then glea cells will build up and they will push away the neurons so these electroid arrays are presumably only functional for a year maybe two years and then typically you you get into trouble unfortunately there
Are new materials so these very soft and flexible electrodes that you can make so we work together with a lab at rise University where they make these electrodes hyper thin and super flexible and that seems to result in a much better longevity of the implant and hardly any fibrosis so there are ways
Now to solve those problems now in the last movie if you can start at Nathan I would like to also give you some realism so if we can get this to work it’s not going to be as good as normal vision and we can test this actually in in normally seeing
Humans in virtual reality so try to imagine what you see here do you see it the person who is waving right so it’s it’s not going to be comparable to normal vision we don’t give color back we don’t give dep depth Vision back so there there are many
Limitations but if you ask people who are blind at least a large percentage of them it would definitely be better than being in the in the Eternal dark so to say with that I would like to thank my team so sing genen and fun W were really involved in in the monkey study
Demonstrating that you can recreate form Vision with electrical stimulation and the other people were uh yeah involved in many other aspects and Eduardo is the person reallying the the first in human trials thank you for your [Applause] attention yeah thanks so much Peter that’s so impressive iive I think we’re
All quite moved by that you mentioned that 40,000 40,000 40 million 40 million 40 million people suffer blindness What proportion of those would be suitable for this type of approach yeah we we have looked into that so we think that these types of treatments are quite involved and require some Neurosurgical
Precision so I think we probably are will focus on on those countries with a Better Health System then you have to think of people whe have a sufficient health status to undergo surgery we’re actually now thinking of a form in which we can do an implantation through what is called Keyhole surgery that’s
Comparable to what they do for de brain stimulation of course that increases the number of people that you could treat now you don’t want to treat people who are blind from birth because they don’t have a fully developed visual system so there’s not an information processing
Stream that you could hook up up to so so of all the people are we thinking now first about maybe 1 million who are eligible and then we we can see if if this turns out to be a treatment of course how well it works and I can
Imagine that then uh it’s the same with C implants right so they were first very restrictive in in applying C implants and then as the the cular implant field matured and many more people kind of got experience with what it can and cannot do then of course of course the
Indications can be more inclusive right so questions I think Karen has a question yeah very impressive you answer I was going to ask about the fibrotic capsul encapsulation so you you answered that question already I was wondering if you could talk more about kind of I guess what techn technological advances
Do you think you need to be able to cover more of the field of vision in a in a patient so we were we’re working towards that um so one that is between the ey and the primary visual cortex is this lgn I briefly mentioned it when I
Introduced the visual system there you have the entire visual field or actually Hemy field because there’s one for for the left Hemy field and one from the right Hemy field um with in a volume of about 120 cubic millimet so it’s about 6X 6
Millim or 6 by 6 x 6 mm and um that is comparable to another structure that neurosurgeons are quite familiar in targeting the so-called sdn which is the target for Parkinson’s Disease so I think there you have a good chance in with a single implant on the
Left and a single implant on the right to cover the entire visual field and we’re not the first to propose that there is another researcher Don bazares who already kind of proposed this and demonstrated that you also get very nice and well behaved phosphines if you stimulate the
Lgn we have a question at the front it reminds me a bit on on science fiction I’m sure you know this character from from Star Trek Jordi la Forge with this thing called the the Visa or whatever that was called but if I remember correctly he was able to not
Only get Vision but also others other signals and stimuli were trans transmitted into his brain I are there any thoughts that in future you could also whatever temperature information whatever comes from from from the sensor going to different parts of bra is that kind of a vision as well
Yeah so of course we have all kind of very powerful uh tools so you can just use your vision look at your phone and if you have a temperature sensor maybe hook it onto your phone rather than onto your brain that’s would be would be my advice yeah but may
Listening yeah so these these Technologies are applied for people who are deaf so you have the coill implant that they put it in the inner ear and um these these work remarkably well for specific tasks like speech recognition people have a cocar implant they cannot re appreciate music because
The number of channels on the Coan plant is functional channels is in the order of 8 to 10 and the normal human ear has I think 16,000 hair cells so there’s a huge reduction of your coating space and that’s what we are going to experience also in the in visual prosthesis of
Course we have our human I is one mega pixel 1 million fibers in the optic nerve that bring the information to the brain we replacing this now with 1,000 so it’s just never going to be as good as as real so um talking of C implants one understands where the sensory
Information is coming in where is the sensory information going to come in when you’re not actually tracing it yourself onto the um electrodes there because there’s no information coming through the eyes is there no no there the patient has a camera and glasses oh it’s the camera right yeah yeah and and
The camera and glasses that that was the picture of of the city I showed with the vehicles and that that camera image you cannot just simply transfer that to the brain so you have to usually simplify it but it’s really and that also what you
Saw in the in the movie with the person we wearing a VR right he’s just looking around the camera is pointing to different scenes now another interesting aspect that that may not be completely intuitive is that you might have to consider eye movements so our eye is
Always pointed at the part of the visual field that we’re interested in and uh um so you could actually have a camera image but the camera image will of course not move with the eyes right so then you can take maybe a wide field image and take the snapshot where the
Subject’s eyes is looking at and then magnify that and place then the part of the of of the image that that is the one that the patient will be looking at with his or her eyes so that’s one all other kind of way to to take into
Consideration well the nor the the eye movements that we we normally make and they are of course very important because we don’t always realize it but only central vision has this super resolution and the periphery of the visal field has actually quite a poor resolution this always two dimensional
Or also hopes to develop into a threedimensional vision so if these patients move they can Orient themselves yes yeah so there are many cues to depth one of them is stereopsis that is one eye sees a slightly different image than the other eye and there are neurons in primary
Visual cortex and also other brain areas that are exquisitly sensitive to these small disparities between the two eye images that’s going to be very difficult uh because our resolution is simply not good enough to to resolve those those small differences in positions when seeing to do dwise but there are other
Cues so if you if you walk around things olude each other dynamically right so a person who sits in front starts to include somebody for me when I move like this and if you have sufficient number of phosphines you will definitely be able to take advantage of these other depth
Cues um so there’s another question here this will have to be the last question thank you very much really fascinating um I was wondering what is the intraindividual differences between human beings on that part of the cortex on the spatial map so is it comparable for many people or is it are big
Differences yeah so I mentioned two structures I mentioned primary visual cortex and there is a huge variability so it has differences in size maybe even double or triple one person could have three times larger visual primary AR Vis C than another person and then um the place of primary visual cortex is also
Not ideal so it’s in the back of the brain but it’s largely between the two hemispheres and in a circus so it’s it’s super difficult to put these electrode arrays I was talking about there because you would have to open up a circus it’s your brain groove right and there are
Vessels there so the neurosurgeon is typically not very uh happy if he would have to open up a circus now so that is that also is one of the reasons that we think that the lgn is a better Target because the lgn is very uh reproducible and very comparable across
Individuals and it’s a nice sort of volumetric structure um maybe you can think of it as a as a coffee bean something like that and that that is always the same across individuals so that is from that perspective also a better Target yes fascinating thanks very much Peter that’s quite
Extraordinary and it just remains to say thank you for listening and come back again at 1:00 after lunch or after attending the plenary session which I think is just starting in the main lecture hall so thanks and see you [Applause] later it’s