#43: Tilmann Buerckstuemmer and Thomas Moser - Gene-Editing - The Next Game-Changing Technology?

Thomas Moser and Tilmann Buerckstuemmer lead the Austrian Life Science Company Aelian Biotechnology.

Episode Links:
Article to the Episode: https://lsg2g.substack.com/p/gene-editing-the-next-game-changing-d3f
Video to the Episode: https://youtu.be/3bf7ChYUHLE
Aelian Biotechnology: https://aelian.bio/
Thomas Moser: https://www.linkedin.com/in/thomas-moser-79819a5/
Tilmann Buerckstuemmer: https://www.linkedin.com/in/tilmann-burckstummer-19b65949/

Podcast Links:
Podcast Website: https://www.lifescienceget2gether.com/
Community Partner: https://linktr.ee/lsg2g
Christian Soschner: https://linktr.ee/soschner
LSG2G Twitter: https://twitter.com/LGet2gether
LSG2G Linkedin: https://www.linkedin.com/company/life-science-get2gether
Podcast Episodes: https://pod.link/1493847125
Episodes on YouTube:  https://www.youtube.com/playlist?list=PLlZfrwd6iXrQ3LIANISUpP22seS2CsCEV

Timestamps:
For those who want to listen to specific parts of the episode, here are the timestamps:

(00:00) Introduction
(02:23) Introduction Thomas Moser
(05:45) Introduction Tilmann Bürckstümmer
(08:40) Aelian Biotechnology
(10:20) The Science Behind Aelian
(17:50) Life Science Business Model
(27:00) How to Setup Business Relationships in Life Science
(34:35) Gene Editing - Why Did it Create Such a Hype?
(41:00) History of Gene Editing with Insights Into CRISPR/Cas9
(45:30) Vienna - Part of The CRISPR Community
(47:50) IP of CRISPR
(50:00) CRISPR - Real Life Use Cases
(55:05) CRISPR in Cancer Research
(59:20) Are Genetically Altered Human Beings Possible?
(01:04:20) Genetically Enhanced Human Beings - Reality or SciFi?
(01:08:00) Gene Editing and its Role in Agriculture
(01:12:00) SARS-CoV-2 - What Role Did CRISPR Play in Fighting the Pandemic?
(01:12:20) CRISPR Screen for SARS-CoV-2 - Technology of Aelian Biotechnology
(01:15:00) Drug Discovery for SARS-CoV-2 with CRISPR
(01:18:00) Fundraising for Life Science Companies
(01:27:00) Comparison of the Investment Culture in Europe and the United States
(01:31:00) Major Players in the CRISPR Field
(01:32:00) CRISPR - IP Landscape
(01:44:00) Final Question: Advice for First Time Entrepreneurs

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Transcript

Introduction

Christian Soschner 0:00

Welcome to a new episode of the Life Science Get Together podcast. Today with a very special topic. A couple of years ago, I it came to my awareness that in the United States a fund exists. It's called the ARC Fund, founded by Kathy Wood in 2014. And she has an investment approach that I very much appreciate. It's investing in high-tech and deep tech companies. And she has put together a research team that is on the lookout for game-changing technology since 2014. And the nice thing with her fund and her team is that every year she issues a report, which she calls Big Ideas Report, in which she dissects with her team the five platforms of innovation she has identified and of which she believes that they will shape our society in the coming one or two decades. And amongst these platforms of innovation, there is one life science application. She calls it the genomics revolution, and everything around gene editing, gene sequencing, the therapies connected to what she calls genomics revolutions and also diagnostics. Welcome to the show.

Thomas Moser 2:10

Thanks, Christian, for having us. Great to be here.

Christian Soschner 2:13

Good to see you. Let me ask you uh one initial question first. Um, what is your background?

Introduction Thomas Moser

Thomas Moser 2:23

Yeah, if I may start. So my background background is in genetics. So I studied in Salzburg, then yeah, did my PhD in developmental biology, then uh went into industry for a few years, and then yeah, moved to Vienna to work uh as a technology licensing office for officer for Austrian universities, which was a quite interesting uh task these days. This was late 90s because this was also the time when the Austrian biotech scene really uh evolved. And I also got drawn into this uh this uh field of of uh seed financing and by my colleagues because we also had a fund that invested into this area. And yeah, one of the first uh business plans I got on my table was from Intercel, which uh back in these days made the first financing round. So it was really super exciting times. And yeah, in the in the coming years I have grown into this role, and and yeah, in the end, we we managed our own uh venture capital fund and invested into early stage uh companies. Uh but after some time I I went back into the the operational area again, early 20 uh 15. I 2014, I yeah, I went into the biotech scene again as a operational manager, and and together with Tilman we managed a spin-off of another biotech uh company called Aplogen Genomics in the area of gene-edited uh cell lines. And this startup was reasonably successful. Yeah, within a short time period, we we could sell this to Horizon Discovery, UK-based company, which was back in the days really considered one of the main tech companies being active in this area of gene editing and having a very strong also IP base in this area. Yeah, and then it was quite an exciting time where we uh worked for three years for this UK company. But uh after some time, as you know, yeah, it's it's uh interesting to work with this medium-sized to big companies, but after some times as an entrepreneur, you want to take your uh own fate again and and decide uh and make it make the decisions on your on your own, and that's uh why we we then founded our own company again, yeah, which we probably will discuss later on, which was called beginning uh 2018. We started alien biotechnology, which has uh developed since then quite quite well.

Christian Soschner 5:23

Thank you very much for the introduction. Um, I completely agree with your statement that uh working with big corporations is uh a completely different world than uh evolving a new idea from the ideation phase into the pre-seed and seed stage and uh first financing rounds, and uh it's a different world. Absolutely. Tilman,

Introduction Tilmann Bürckstümmer

Christian Soschner 5:45

where are you coming from?

Tilmann Buerckstuemmer 5:48

Yeah, I'm a I'm a biochemist by training, um, did a PhD in Berlin on virology, um, host virus interaction, and then came to Vienna as a postdoc where I joined uh Julius Operti Furga's lab. Um, and after some time there, um Giulio asked me whether I want to join Haplogen as the first scientist, and that was sort of a very exciting prospect to join um a newly founded company that back in the days um was really sort of being built. Um and so then I spent um essentially um three, four years at Haplogen. Um, and that is was around the time then uh when when CRISPR um came to the scene and we and we very quickly realized that this was going to be a game-changing technology and and started using it early in 2013. So the the that was really around the time the first papers suggested that this could be used in mammalian cells and very quickly built what back in the days was the largest collection of knockout cell lines um available sort of to date. And uh that was then the basis for the acquisition by uh Horizon Discovery, and then at Horizon I had um various roles in in RD essentially, um driving um technology development. I had sort of teams in Cambridge, teams in Vienna, and um in the end was in charge of um innovation across the entire company, um, which was sort of had a US site, a UK site, and a site in Vienna. And then sort of recently, as as Thomas um pointed out, we butted off and we we founded our own company early 2018, and really the main driver there was to get um back into the driver's seat. I mean, that was really the the thing that um that in a in a bigger organization is, you know, if you've once you've had the privilege, let's say, to work in a small, um, efficient organization where um decision making works and and and and and you're sort of used to that, it it's not easy to find um yourself uh in a in a in a bigger organization where everything needs a committee and and and sort of different people weigh in. People point out caveats and then you know nothing happens. Um so um we're very much enjoying, I think, that um um flexibility and agility that we now have um back.

Christian Soschner 9:59

Amazing points. We are trading safety and security uh for the excitement of the startup world. So let's let's put it that way. Uh you explained uh that you founded in 2018, your current company. Uh it's named Alien Biotechnology. Where is the name coming from?

Thomas Moser 10:21

Uh sorry, this was an interesting process to find the name for the company. Basically, it can be tracked back to a Greek scholar called Elianos,

Aelian Biotechnology

Thomas Moser 10:31

who was a famous natural scientist that back in the days, and who had yeah, did some landmark kind of books in of uh characterizing the fauna and flora of the of the ancient Greek. And and we felt that this is a a good a good characterization what we do with our our technology base. So it's really about going into the mechanisms of life and of cells, and then that's what we can essentially do with our technology base and and platform. Therefore, we felt this this was quite a suitable name for our company.

Christian Soschner 11:12

I like I like all names that begin with A. I think it's uh a tremendous amount advantage uh for companies that need to attend conferences because when I get the company names listed alphabetically, uh and I want to reach out to it, doesn't matter if it's investor or farmer companies, you always start every conference with A. And when there are 2,000 companies uh at uh this event, then I end up somewhere at C or something. Yeah, so I always comes to my mind names beginning with A uh have an advantage in our world. That's why the companies now start with numbers.

Thomas Moser 11:49

This is even more difficult.

Christian Soschner 11:52

Let's take it up and outshow with a point or with uh bracket marks. What is the core focus of alien pair technology? What what what what is your business?

Thomas Moser 12:02

Yeah, so the core focus is really to bring together these two landmark technologies. One on the is is obviously

The Science Behind Aelian

Thomas Moser 12:11

the gene scissors, CRISPR technology. I think we will go into detail later on on that. But the other very important part is this uh part is this single cell component that uh forms an important part of our technology portfolio. When we bring this together, what this means, what does this uh single cell resolution and revolution mean? So if you think of a tumor biopsy, uh then as a biologist, you or or or medical doctor, you are probably aware that the biopsy uh that you take from uh from a tumor creates many different cell types. So you have some cells that are kind of necrotic that are uh that have died, you have some fibrotic uh tissue, you have different blood cells maybe, and and you have the the tumor cells. So if you analyze this whole tumor sample, you always look at the average between all these different cell types. So the analysis in the end is is somehow average, the signal may be weaker. What you can do with single cell technologies is that you really look at each single cell, and uh this provides superior resolution. And therefore, if you are able to only look at the tumor tissue, uh you can learn learn a lot from that because the signal is not blurred by by some other cell types that you're not interested in. And what we take this approach one step further in that we perturb genes in uh single cells and and look at the consequences this genetic perturbation has on the phenotype of the cell. And what we can do with that is is really to look for new targets for new therapeutic therapeutics with really unprecedented resolution. And that's obviously of very big interest uh for many international for uh international corporation partners like uh big pharma companies, biotech companies. I mean, it's a super specialized business. I think we have built a very uh significant know-how in this area. It's very specialized, and therefore, yeah, we feel we are on a good good track. I think the kind of uh secret in in these days is really to have a kind of special topic that you work on and and really focus on that. And and we have built of a team of we are more than 30 people now that really exclusive exclusively focus on this this very special topic, and and I feel we really uh uh could create uh very interesting partnerships through this technology base.

Christian Soschner 15:20

Tillman, do you want to to add to this great explanation?

Tilmann Buerckstuemmer 15:25

No, I think um Thomas Thomas summarized it very well. It's really the um the single cell topic, which which which is sort of which is married, if you like, with um CRISPR. And I think what's interesting for for a startup initially, as they say, you know, it's important that you work in a in a in a relatively small niche because you have very few people. So you need to focus on on something, and ideally, ideally, that something is quite narrow. And then, you know, in our case, we we sort of started in this space when this when the field was much less developed, and uh, and we were sort of betting on this field um uh on on the expansion of this field, and this is what we're really seeing after um sort of being in this business for two, three years. There's a lot um of excitement in single cell technologies, and people really appreciate that um we cannot just grind up tissues or grind up cells and sort of average above them, but we really need to learn um sort of from the individual cell what's what's going on because these cells differ very much. It's like looking at a group of people, right? You can now say, oh, we look at uh all the faces uh individually, or we create sort of an average phase. The average phase will maybe tell you uh a little bit, right? Are we in Western Europe or in Africa? So it's not that there's still information in that, but looking at the individual faces will will sort of give you a lot more flavor and will reveal um a lot more information. And then the other bit is really the the CRISPR allows us to um provide causative data, and that's very important and very powerful because a lot of the other um uh techniques that are out there, you know, for instance, single cell sequencing on its own is essentially a descriptive technology. It's a technology that that looks at you know cellular properties, reports the cellular properties, but they really are there there is no sort of way to say why a cell developed in this way or developed in another way. What CRISPR allows us to do is change gene expression, change one gene in a cell very specifically, and look at the functional consequences of that. So that um you know establishes then a causative relationship between that gene and the change we observe. And and such data are still very scarce, right? A lot of people out there, even in the target um discovery and target validation space, they will look at large epidemiological studies, they will look at population genetics, they will look at you know often very biased starting points like, oh, let's look at the papers that people have published in the past five years. But to have an unbiased start provide a data set that provides causative relationships, that I think is very strong. And um and that's why we're seeing sort of growing interest in our um technology from sort of pharma and biotech companies.

Christian Soschner 18:34

That's that's amazing. Um let's you mentioned a little bit um the business side of life uh in in your opening speech. And let's before we dive deeper into CRISPR and uh gene editing and gene sequencing, uh let's dive a little bit also into the business model of uh life science companies. Um I'm coming from business background and uh started to learn more about this B2B value chain in 2006 when I joined Nobriva and Novati's Binot. Um, and the first few years in life science were scary because it's a very, very unique value chain and a very, very unique um let's say, uh, sort of business models that I uh learned to appreciate. But unfortunately, they are not very well documented. So it would be really great uh to get more insights into how you have set up the business side of alien uh biotechnology.

Thomas Moser 19:33

Yeah, obviously, this is uh one of the most important points in when we formed our company and we we gave

Life Science Business Model

Thomas Moser 19:41

this significant uh consideration. Yeah, so as you already pointed out, in biotech, there are many in many different business models. And yeah, also in my life as an investor, I saw many, many companies and many different business models. So obviously, yeah, if you do it on your own, you you want to make it better than others. So we have set up alien as it is. And then this basically, at least where we stand for now, is is uh a status where we perform these uh functional genomic screens as we we call it uh for uh big farm and biotech companies. And uh we we get a certain chunk of the of the value chain of these results of these screens. And uh these screens are as as we said before, these are typically used for target discoveries, so you can find new uh points and and proteins within the cell where therapeutics can be uh developed. And you learn also a lot about uh mechanisms uh of disease. So on the one side, we can generate these data and results out of the screens, and on the other side, obviously, we are a very specialized technology platform company. We develop sustainable intellectual property out of these uh screens because yeah, this whole field obviously, as you can imagine, is uh high is developing at uh a very high speed. So the best organizations on the East and West Coast are active in the in this area and and have a focus on this. So the the pressure on on staying ahead is is really uh significant. But uh as we have a very focused team in this this area, we we can afford uh doing that and really yeah, staying staying on top of the technology development. Yeah, so that's basically our our business model. We obviously are generate uh cash flows and revenues in in the project with our international customers. It's a very international business, so I think we only have one uh one customer in co in in continental Europe. It's really the main markets in US, UK, Japan, where our cooperation partners are located. And and yeah, with these we we typically work on a project basis of let's say yeah, typical projects uh have a duration of let's say nine to eighteen months. And within such uh such projects we we develop uh develop these this technology further and and generate the results that we described before.

Tilmann Buerckstuemmer 22:33

Yeah, and maybe to add to this, I think we um there always there are always different ways to to uh sort of um make a business out of technology. And um one other one other um sort of recent development that we're very excited about is that we that we founded a spin-off a daughter company um together with a Cambridge UK-based biotech named um BitBio. And in this Delta company, we sort of carved out a particular area in this uh in this specific case. Um it's stem cell biology. There's a lot of um and growing interest in human stem cells um for various applications, um certainly for gene and cell therapy, but also as um research models and and tools. And and we said, you know, the technology that we have developed at Alien um has sort of very interesting applications in this space, and and this application has gotten so big that together with a partner, we're actually setting up um a separate. Vehicle, a separate company, and within that company, where we're both managing directors as well, we're really um driving the development of novel um stem cell types that that can, well, not stem cell types, novel cell types as they can be obtained from stem cells. And and that vehicle, because if it was such of such great interest to us and to our partners in in Cambridge, um, sort of was then was then co-funded um by the partner in Cambridge. Um so we think that's that that's that's another interesting way of sort of getting technology funded. It can be sort of projects that run for a certain duration and then they end, but it can be that these projects become big and important enough so that you can actually set up a separate company with a dedicated team that will grow um this additional application of the technology and that secures separate funding in this entity.

Christian Soschner 24:44

That's great to hear. Congratulations. Uh, so you did it twice. Uh won the first foundation in 2018, uh, back into the startup world. And then the second one, which year was it?

Thomas Moser 24:56

Yeah, the second one in September, yeah. September last year only. Yeah. But it's somehow, it's somehow linked.

Christian Soschner 25:05

So kind of so it's not a real foundation.

Thomas Moser 25:09

No, I mean, although it's it's a separate company, it's a separate entity, and not because we have to yeah, recruit the team there, and and uh but we felt in this very special case that that this really makes sense uh to form an own entity, really, for the work to be done in in stem cells and and cell types derived from the stem cells. Because maybe this should be mentioned as well, that kind of the bracket that keeps all the work at Alien together as well is really this focus on cellular models that are highly physiologically relevant. What we mean by that is that the cellular models we work with we feel are much better suited than the typically used immortalized cancer line, the cancer lines that are used in uh in pharma and biotech uh research and development. So the goal really is to have something a model that can be uh well translated into human uh into human trials in the end with a much higher probability than these uh typically used cancer cell lines, which in many uh cases have very weird uh genomes, have lots of mutations. Even the fact that they grow uh unlimited is is not natural. Every cell that you take out of the human body is typically quite limited in lifespan. So this is an important focus of our work as well. I mean, which means that's super challenging because on the one side, in alien we work in in primary T cells. So you take blood from the patient, extract these uh these cells and cultivate them. So you can easily imagine that it's very challenging, but uh we have managed these uh these uh these uh very uh tough points, and and our team yeah has established the systems, and therefore, yeah, we can perform our kind of other technologies now in these advanced LM modes.

Christian Soschner 27:19

That's great. So basically, you instead of um say founding a second division in your company, you decided to spin it out, uh get it financed separately, yeah, and keep with both entities your particular core focus on the market so that the storytelling is not diluted with uh with an approach that might, when we look at it in one company, uh might a little bit uh raise questions why it is uh in in one part. Yeah. Um when I understand your approach, uh it's a B2B business model in which you are uh uh let's say accumulating expertise in the company, in the field, around these two topics of your companies, and then you approach the pharma industry and enter into research collaborations with them, which I assume is not uh let's say a week or so. Uh am I right with my assumption that these are multi-year collaborations down the road that uh uh consist of several projects and are not uh let's say like buying a used car so that you uh approached once. So they really want to understand get your expertise in the fields that they don't have, right? Um do you and I also assume that they take over the expenses and the cost. Uh, do you also participate in the upside? I mean, um, if something evolves into a product later on.

Thomas Moser 28:45

Yeah, and the existing partnerships, we don't have this yet, but you're making a very good point. Obviously, this is the goal

How to Setup Business Relationships in Life Science

Thomas Moser 28:51

for the future that we participate in the downstream value creation in terms of yeah, percentages of milestones and and also maybe royalties. Uh, but this is a bit dependent on the face of the company. Obviously, in the beginning it was important uh for us to get the alien off the ground and really establish ourselves as a major technology player in this very special field, and and we have gained significant traction in the meantime. I mean, yeah, recently we could uh uh we could communicate that yeah, we are doing uh three large projects with GSK. Congratulations. Yeah, this was really a major, major step forward uh for alien. And this also probably gives us a lot of uh credibility. Uh but as you rightly pointed out, this these are long projects that take take many months uh and and also involve a lot a lot on our side. And yeah, in in the next projects that we will get on board, definitely this participation on the downstream side is important for us. In addition, the the improvement of the technology base is a value on its own. So we obviously apply for patents uh in this this space. Certain patents on on parts of the workflow uh have been uh have been applied for and they contribute to to this building of a sustainable value position for alien besides this other uh lag that Tillman already mentioned, forming forming joint ventures with specialized partners for specific topics which has already been exemplified for the stem sets, but that could also be true for certain therapeutic areas.

Christian Soschner 30:51

Yeah, IP protection should not be underestimated, so it can create a really nice mode around the business and drive the value when the IP strategy is set up very well, especially if it's a new field, which uh I consider CRISPR and gene editing still is uh um uh still is rather new and uh mostly unprotected. Um, when I when I think about the typical startup that I meet at incubation or acceleration programs these days, uh first they present a business plan, and the second their will to reach out to investors for investment. And what I find interesting in your story, it sounds to me that you did it the other way around. So, I mean you established your expertise, your business plan, and then went right to the customer, or did they overhear that you also uh were in talks with investors and got investment money in? What was your strategy in funding the the initial days?

Thomas Moser 31:44

We were in a kind of very privileged position on the on the one side, this was not our first company, so we have seen lots of companies before before and and have gained significant experience before. And also, as I said before, our three years at working for this uh UK-based horizon discovery company was really kind of very important times for us because we could really uh expand our international networks to to customers, to distribution partners. And obviously, this uh this has helped us in in setting up uh uh alien later on then. So in terms of financing, we did not uh really make big financing runs. We have a bit of business uh money, business angel money on board, which which comes from a yeah, I would say a friend. Uh and besides that, we don't have uh institutional institutional capital on board uh because we were in this kind of uh privileged position that we really could fund us right from the beginning with significant uh project money coming from our corporation partners. But yeah, obviously this would not rule out that in one of the maybe JVs that we plan for the future, then that we bring in, uh we see money there for yeah, for certain uh therapeutic developments that could be done in such a Toto company.

Tilmann Buerckstuemmer 33:19

I mean, for the time being, I I would add we're really enjoying the fact that we have independence there. We we we we don't have um a board or an you know investors that we that we need to meet on a monthly basis, provide reports, you know, answer questions, right? We can really decide um what we think is right for the company. Um on the other hand, it means that we are focusing on the clients. This is, I think this is um this is also a good point because it's um it allowed us sort of from the first day to get real-world feedback, right? We were not in a position to develop something for two, three years only to learn that nobody really needs this, right? We were we were because we were dependent on money flowing in from people that want to work with us, we had to be sure that what we're developing is is sort of in a very short period of time going to be um um, well, maybe not monetized, but it's going to be needed, right? So so a lot of our developments are guided um by customer needs. And because we have that direct interaction from day one, um, we're really not falling into the trap of developing something that we think is incredibly cool, um, and then it maybe isn't.

Christian Soschner 34:43

Um testing the market is always a good idea. I got my training in the 90s, and the typical business model um back then was um develop a prototype, find a customer. So once you have the first customer, it's validation enough, and then look for growth capital. When I look at uh the investment world today, especially in the early days, I think it's a little bit the upside down. It's uh develop a pitch tech, find an investor, and then hopefully you come to a prototype, and later on you find a customer or other investors. So it's an interesting direction. Um however, what I what I saw when I entered the life science industry, I mean, of course, scientists were excited about new technologies, it uh helped to improve their processes, their product development processes. Uh that's that's that's cool. But in 2014, 15, 16, and especially in 18 and 19, this um CRISPR and gene editing uh did something amazing um compared to other technologies. I mean, other technologies mostly stay hidden, and uh the usual uh retail investor from the streets or the usual investment fund is not very interested in that. Not so with CRISPR, and not so with gene editing and gene sequencing, as I said in the uh initial uh in the in the opening of the podcast episode. Uh the ARC funds, uh huge fan of uh the genomics revolution. Uh, can you explain to the average investor a little bit what this excitement is all about, why gene editing is so different uh to other technologies in our industry?

Tilmann Buerckstuemmer 36:23

Yeah, I can I can try that. So essentially,

Gene Editing - Why Did it Create Such a Hype?

Tilmann Buerckstuemmer 36:26

the you know, we know sort of since the completion of the human genome project, which was first sort of completed um in 2001, I believe. Um what we know since the completion of the human genome is we know the the building blocks of the of the cell and of the human body, the so-called genes, right? And we have 20,000 of them. And we essentially know that drugs act on gene products. So they they um take a product, a protein in a cell that is encoded by a gene and they modulate it. And as a consequence of that, we can treat disease. But you know, until the advent of CRISPR, we really had no way of manipulating genes, let's say, in a faithful way. There were there were sort of other technologies out there that could try to do this, you know, for the aficionados, this was RNA interference. It sort of worked a little bit, but not really. And and what's exciting about CRISPR is that we're now able to do this. And this gives us sort of two, I think, angles that are that are that, or two opportunities that we couldn't tap into. One is, you know, for the researchers in the lab, we can now ask, what does that gene do in a cell? Right? It's a very fundamental question. And and if I have a hypothesis as to whether this gene is a target of a drug, I can I can ask, does it just sort of targeting this gene or targeting this gene product, does that make a good drug? Right? And that's super important because the drug discovery process is a very long one. It takes sort of, you know, if it's not the COVID vaccine, it usually takes sort of something like 10 years to go from nominating a target to having a drug on the market, if not longer. And so the nomination at the beginning is sort of the critical starting point. And if you don't get it right at that point, you will do 10 years of you know, medicinal chemistry and toxicology and you name it, but but the drug will not do what it's supposed to do. So, sort of, that is the first angle that I think is super exciting. That we now have a tool that at least conceptually or potentially allows us to nail the most important drug targets and thereby increase the chance of a drug to be successful. The second is if you want to, if you want to take that thought a little further, you know, in basic biology or in basic science, it's very similar. We we're, you know, people are looking at a process. Let's say you're a researcher studying uh diabetes, right? You suddenly have a way of finding out whether a gene has a role in diabetes or not. That's what the basic science uses uses CRISPR for. And then sort of the future of CRISPR is really sort of not only as a tool to discover new drugs, but is you know, CRISPR could become the drug itself. So we could face a situation where you have a you, you know, the probably the simplest model is you have a gene defect, right? You might you might have um sickle cell anemia, that's that's a common one that people are interested in these days. It's a blood disorder. So your your your blood cells, sort of in this case, your red blood cells are dysfunctional. And they're dysfunctional because you have an error in your genome at in a particular gene. And this error, you know, people know for decades, but there's nothing you can do about it. That's the that's the sad thing. It's and it's very similar about many other heritary disorders, right? You find out your kid has Duchenne muscular dystrophy. You you can precisely map it to the mutation, but there's nothing you can do about it. And the exciting prospect about CRISPR is you might be able to correct this mistake, if you like, or this error in the genome and thereby cure disease. Of course, there's a lot of technical hurdles in the way, so it will not be something that will happen tomorrow, but at least conceptually, that's why it's so exciting. Any disease that's caused by a defect in a gene, and there are many of those, many of those that we know and that that a lot of people have heard of, you know, cystic fibrosis. I mean, it's it's a it's a long list, it's hundreds, if not thousands, of disorders. Um, those we can potentially treat and potentially cure um with CRISPR. And that is just unheard of. Um, there was no sort of similar development, I would say, in a long period of time that opened up such a vast field as gene editing did.

Thomas Moser 41:06

I mean, maybe to add to this, also from a mechanistic point of view, the system is very elegant and relatively easy to use. I mean, there were systems around that could be used for similar purposes for editing the genome very specifically, but these were complicated and very specific. And with CRISPR, you basically have a protein that is kind of programmed by a short stretch of a nucleic acid, which can be easily synthesized in any lab. And you bring this together if if you tell it uh very simply, and you can uh you can make a genome edit. And and this ease of access also contributed to this hype hype around this uh CRISPR editing that only can be compared to uh polymerized chain reaction, uh this this uh gene amplification that yeah also was was maybe the latest landmark uh invention in in biology before CRISPR.

Christian Soschner 42:09

So when I put it bluntly, on one hand, uh there is excitement uh about the diagnostics and understanding the development of diseases better, uh especially those that are rooted in genetics and have their causes so that you really can trace back uh which gene plays which role in what disease at what point of the development of the disease. And the second is that you correct it so that you uh go into the therapeutics field and uh say, okay, when we identify the problem, why not solve it? Um when was all this developed? What is the history of gene editing? I don't I don't think it comes out of nowhere that uh in 2013 suddenly uh someone woke up and said, let's do

History of Gene Editing with Insights Into CRISPR/Cas9

Christian Soschner 42:51

gene editing. Uh, can you give a little bit more information on the history of uh this technology?

Tilmann Buerckstuemmer 42:57

Yeah, so so the history, you know, very briefly is that already quite some time ago, people noticed that in in bacteria there are certain regions that contain repeats. And you know, people found these these repeats and they were not quite sure what they were and what they were for. But already quite early on, people suspected that these might have to do with immunity. And and and sort of one key insight was then that so repeat is essentially a 20-base pair sequence in the genome that is sort of duplicated, but between those repeats, there were sequences, and and when people first um sequenced those, they realized that the sequences between those repeats came from bacteriophages. Now, bacteriophages are essentially the viruses that infect bacteria. So that sort of meant um or or that sort of strongly pointed to these repeats being involved in in immunity, right? Because these are sequences found in a bacterium, but they're not from the bacterium, they're from the phage that infects the bacterium. So it sort of reminds us of immunity that that you know, much like we know it um um sort of um in humans. And then um the key insight came um really that that sort of got this entire field um um to sort of heat up and and become very exciting, um, came from the discovery that there was an enzyme. This is the enzyme called CAS9, and what this enzyme could do is it could take these sequences that you know in the bacterium come from the bacteriophage, and they could essentially trigger a DNA double strand break in a sequence that's complementary to the sequence inserted between the repeats. So, what that meant is if the phage comes in, you know, the bacterium has seen that phage before, remembers it because that sequence is integrated between those repeats, it can take those sequences, mash them to the phage DNA, and the phage gets destroyed, it gets cut and cleaved by this enzyme Cas9. That was sort of the key, the key piece of the puzzle. And and sort of people had figured parts of the puzzle out um before. Um, obviously, it was sort of an entire field with a lot of people contributing. But the key insight for which then Emmanuel Charpentier and Jennifer Dardner were awarded the Nobel Prize last year was they were able to take all the components that were needed in the system and make them in vitro. So make the Cas9 endonuclease in bacteria, make a so called guide RNA. This is this this RNA. RNA molecule with the repeat sequences, put that together in a petri dish or in a in that case in an Eppendorf tube and show that this could trigger programmed targeted cleavage of the reaction that is of the of the DNA that's complementary to the to the guide RNA that you put in. So they'd sort of identified the minimal components of the system and said this is this is what we need to make it work. And then obviously people could take this very quickly and make it work in human cells, in plant cells, in animal cells, and so on and so forth. But that key insight that was really um what got the field started. This is a paper they published late in 2012. It's actually work initiated um here in Vienna by Chris Krinsky, PhD student in Emanuel Charpentier's lab when she was still in Vienna, but then the work sort of was completed when she was in Sweden. Um and there was sort of a partner effort at uh at Berkeley, where um Jennifer Daudner um was based together with her PhD student Martin Jinneck, who is today a professor in Zurich.

Christian Soschner 46:57

That's that's amazing. So Vienna um seems to play a key role in that field. Um when I look at uh the community you are here, then you mentioned um Haplogen, the company that uh was also I think 2013 uh established. And then the company CRISPR Therapeutics is also uh run by uh Rodkonovac, and I think

Vienna - Part of The CRISPR Community

Christian Soschner 47:21

Emmanuel Charpentier is also still on the board of the company. Um why is Vienna so attractive? Uh is this uh just pure luck or uh coincidence, or is there um a special reason why why CRISPR is uh is leaving such a heavy impact on the industry here?

Tilmann Buerckstuemmer 47:39

Yeah, I mean first I would not like, I mean, as much as I like alien and haplogen, I think to name them in in the same um sort of um row as as CRISPR therapeutics or Emmanuel Charpontier is a bit of a big pair of shoes to wear.

Christian Soschner 47:51

Um no, I think it's essentially the reason it's just coincidence that you're all in the same city.

Tilmann Buerckstuemmer 47:56

No, I I think it is to some extent it is coincidence. Obviously, the fact that um Rodger Novak was involved in and and Emmanuel when when Arin is involved in in CRISPR therapeutics is because Emmanuel had such an important role in discovering that. I think you could say that uh it was important for Vienna to have um this this sort of this group at the at the university, not only Emanuel's group, but also sort of Pavel Kovarik, um Thomas Decker, people that were focusing on bacterial genetics, right? That was that was sort of the key subject. These people didn't didn't start to discover a novel gene editing tool, right? Um particularly Emmanuel, she was a bacterial geneticist, trying to understand what these repeats do in the bacterium, trying to understand bacterial immunity, if you like. Um, so I think in in that sense, um that is probably Vienna's contribution, right? That they had this focus on bacterial genetics, and that then whatever we learned um from bacterial genetics could be translated and became uh a tool that that now we're using um for a different purpose. Um so yeah, I think that is um um it's that that was quite important, and and the University of Vienna obviously is still involved because um the intellectual property, which is the foundational IP, let's say, around the world, is still partly owned by the University of Vienna, together with Berkeley and Immanuel on her own, which is is another interesting detail because she moved to Sweden. In Sweden, academic researchers retain full rights on their on the IP they discovered, which is different from the situation here, right? If you're a professor at the university

IP of CRISPR

Tilmann Buerckstuemmer 49:41

and you make an important discovery, that is typically owned by the university. You get a share of that, typically, but you don't own it, right? Whereas in in Sweden it's it's it's the other way around. So because she had moved to Sweden, which is probably the only place that has such an IP uh right, she actually personally owns that IP um you know up to this day. And um and and obviously that had a significant um financial impact, positive financial impact for um Emanuel, I assume.

Christian Soschner 50:17

I think it's uh very interesting to learn more about uh IP protection, different IP protection strategies, especially uh in the area of basic research. Um and it's really interesting. Um what I really like uh is to see how such ideas evolve. So first you have a small group to start working on it, and if it works, then uh the industry just gets bigger and bigger, and more companies evolve, and more researchers are drawn in, and uh everything grows naturally and and effortlessly. Uh, it's also interesting to hear Vienna in the same sentence with uh Berkeley, for example, University of Vienna. It's um there's a lot going on here in the city and uh in the heart of Europe, which is uh not so obviously marketed like digital advancements or app development. So I really like that. When I think about gene editing, um I think um when we're uh looking at the yellow press, there's also a lot of uh fear and uh discussions around that, if this is really good, uh, if it's risky or dangerous. Uh, can we talk a little bit about real life applications? So, what this uh just to give people more insight, what can we really do with gene editing and what is more on the superstitious side or on the fear press side and not really realistic? Um, what are some applications that you think about that this technology can uh really grow into?

Tilmann Buerckstuemmer 51:39

Yeah, I mean, apart from the functional genomics, which is what we are doing, sort of trying to understand the functions of genes, I think the biggest um hope is that we should one day we will be able

CRISPR - Real Life Use Cases

Tilmann Buerckstuemmer 51:51

to cure disease. You know, it's obvious as you as you just pointed out, um, that this pertains to genetic disorders. We've we've talked about that a little bit, but it's also true that we might potentially treat cancer. And that is, you know, cancer also has certain dependencies on certain genes more than others, um, and we might be able to use CRISPR to switch off these genes that are either driving or supporting a cancer cell and thereby eliminate um cancer. Um, there's a lot of interest in in an area called immuno oncology, where um what we can do is we can essentially take the blood from a patient or take immune cells as they reside in a tumor, and we can we can change them with CRISPR to sort of reawaken them, right? That they're typically not very active against the tumor. That's part of the strategy, if you like, of the tumor to make them sort of not recognize the tumor, because the tumor in principle is something that's that that in an ideal world would be considered foreign so that the body gets rid of the tumor. But of course, the tumor has sort of, if you think of it in evolutionary terms, the tumor has an interest to stay hidden so that it can grow and it does not get attacked by immune cells. But these immune cells can be reawakened, and there and there are ways to do this with antibodies. Um they're they're very famous uh examples of antibodies, and that was sort of the the basis for the Nobel Prize given in 2018 for antibodies that if you give them to people that reawaken these immune cells, but there is also a potential because blood cells are readily available, right? You can take them out of the body, you could CRISPR engineer them and put them back into the body. There is a there is excitement about this opportunity, and that is, I think, one of the things that is on the on the near-term horizon that we might actually get sort of our customized tumor treatment where people take the cells out, reprogram them with CRISPR, put them back in. Um, the thing that people are obviously afraid of is manipulation of the germline. So that means um changing the sperm cells or oversights so that we give rise to genetically engineered human beings. Um this has apparently been done in China, and there was a lot of there was a there was an outcry for good reasons um uh about this. I don't think neither first I don't think this was a particularly good example because the researchers eliminated a receptor that um um typically allows um HIV to enter cells. So it's there there are many different ways to treat HIV these days, so it's not needed to manipulate the genome of these babies so that they cannot get HIV anymore. Um so I think for the time being there is a moratorium. Nobody nobody is advocating the use of CRISPR in the germline. Um I think that that is that is the state of the of the affairs. Um and I think it's good like that, right? We need to understand better the risks um associated. Um and with risks, I mean, you know, this is a is a you know, CRISPR is sometimes described as a genome scissor. So you can imagine that the scissor comes in and it cuts somewhere, but then you know, if the scissor is not so precise, it might cut somewhere else in the genome, which would potentially cause harm. Um and so that needs to be looked at very carefully before people consider something like um germline treatment. So it's I think it's um it's not on the horizon really, and is nothing to be afraid of at this point because the entire scientific community is acting very responsibly about it. There are clear bands, um, and and you know, that is is not a risk at this point.

Christian Soschner 55:50

I think it's uh very interesting this this idea that you pointed out, um, of let's say reprogramming antibodies, um, to which can help just put it bluntly, reprogramming anybody. So take it out of the body and uh uh let's say uh give them a clear order how they should act in the body, and which could evolve into the potential of making cancer a manageable disease. So it must not be uh that patients then die from cancer, but simply can live and can manage the disease and stop it from growing, or also maybe also reverting the process so that it really uh it's driven. Let's say it's driven out of the body, uh, in in simple words. Is that really a feasible goal? Do you see do you see this uh this direction that it really evolves into um therapeutics that really have an impact, or is it just uh more like a combination therapy that you still have to use the toxins?

Tilmann Buerckstuemmer 56:47

I think there, I think it's a really realistic opportunity. Obviously, we've seen the admission of the first so-called CAR therapies. These are T cells which are

CRISPR in Cancer Research

Tilmann Buerckstuemmer 56:56

reprogrammed with an antibody on the surface so that they recognize a tumor cell that they could previously not recognize. And so these therapies are given to patients and for particular types of cancer, particularly cancers of the B cell lineage, so that that arise from antibody-producing cells, um, these types of therapies are, you know, I would say quite good. Um however, I don't think realistically now with the therapies that that are being developed, there will not be an easy route into sort of um a cure for cancer as a whole, right? Cancer is is is a very heterogeneous disease depending on where it arises. But even then, if you look at all the breast cancers, there are some that are quite manageable these days with drugs, and others are really poorly manageable. And um to to think that there will be one treatment that sort of one for all, I mean, that's that I don't think is realistic. But to um I think the sort of since the discovery of CRISPR, the field of um cell therapy, so to think of a cell as a therapeutic agent, right? That is sort of, I think, a concept that with the advent of CRISPR is becoming a reality. And and you know, we're seeing more and more examples of, I would say, clinical trials where um where people explore the feasibility of that. And and my my anticipation is that in five years' time we'll have a bunch of these, and in 10 years' time we'll have more. So it's it's a growing field, and um the prospect is very exciting. So the prospect is that we might actually be able to um treat diseases because because there are clearly cases um where we've not made a lot of progress. I mean, there are cancer types, there are particular cancers where you know we've we've developed targeted therapies, you know, chronic myeloid leukemia, for instance, was a disease that was very difficult. The entire, let's say, blood cancers. Um, we've really seen a lot of um improvement over the past sort of 10, 20 years in in median survival. So we're a lot better at managing those diseases. And then there are other areas where we're really, really not doing well. Uh, you know, many of the brain cancers, glioblastoma, for instance, is is is really still as bad as we were 30 years ago. We've seen very little progress, um, to my understanding. And um, and the hope is that uh in in some of these areas at least, CRISPR-based um therapies might um provide novel opportunities.

Christian Soschner 59:35

Yeah, I find the point interesting that you mentioned uh the drug that cures everything or all cancer types. So it always reminds me of J.R. Tolkien's Lord of the Rings, the one ring that pints them all. Um I don't I don't think that this will ever evolve. So that's one therapy can be used for everything. I see it more like uh adding uh additional tools to the toolbox of physicians so that they can treat their patients better on a more personalized way, uh, rather than hoping that uh the cure everything drug that also makes pretty and rich uh comes to the market. I don't see that coming. Um let's go a little bit uh further down the superstitious road. Uh I really liked it. So, for example, the Marvel Universe with all the superheroes that can uh that can fly and uh have super powers and super strengths, and uh this I think is one fear on the market or one hope on the market, so that you can go to uh to your physician and say, Um, today I would like to fly. Can you uh edit my uh genome a little bit so that uh I can ignore gravity and the laws of physics? Uh, is something really possible that uh the Marvel universe is coming to life with gene editing, or is this just um just just just a fear that isn't that should not be taken so seriously?

Tilmann Buerckstuemmer 1:01:00

I I would say yes and no. Um I think the the the problem with CRISPR, as with any cell and gene therapy, is always delivery, meaning, you know, if if if you

Are Genetically Altered Human Beings Possible?

Tilmann Buerckstuemmer 1:01:11

could do something, if you could get access to certain cells, then you could potentially manipulate them and you could potentially improve them, right? So I give you an example of that. There is at least suspicion in the in the in sports that you know, people instead of taking erythropoietin, which is one of the drugs that people take to improve their fitness, they might actually take sort of deliver, they might actually deliver erythropoietin through molecular biology, right? And that's totally plausible for a molecular biologist to see that. You don't even need CRISPR for that. You might take a virus that makes erythropoietin and you put that into the blood cells of an athlete, that will have a very similar effect as taking um as taking that drug, right? So it's it I think it's possible, but here, you know, in the case of the athlete, you know, you do this in a blood cell. So in a blood cell, I think it's feasible because you can access the blood. There is also a sort of potentially a safety, a safety net, if you like, um, because because you could potentially take the blood out, do the treatment, and only when it's safe you put it back. Now, I'm not advocating that we do this with um with erythropoietin for for sportsmen, but I'm trying to illustrate that you can manipulate the blood potentially, and you could potentially create superhumans if you wanted to stay in that in that uh picture. Um, with a lot of other things, it's it's very difficult. With a lot of other traits, it's very difficult to envisage that, right? If you think you could make someone more intelligent, right? If you believe that intelligence resides in the brain, which we possibly all believe, then then you would need to get something into the brain and you would potentially need to affect a lot of cells and a complicated varying. So to believe that a simple change in a cell, you know, would change your ability to be um you know to think, let's say that is that I find that very unrealistic. Um, so I think that the main limitation will be on the one hand, our understanding of of the process. And if you stay in the example of intelligence, that's probably a very complicated thing to understand. It's regulated by a lot of different genes, it's regulated by the environment, their genetic changes, epigenetic changes. To believe that there you could make one change and suddenly become super intelligent is is close to impossible or at least very unlikely. But a simple change coupled like you know, presence or absence of erythropoietin, coupled with an accessible tissue like the blood, I think that's a that's a possibility. And and and obviously that's why then organizations like um NADA, which are looking at drug abuse in sports, have started to look at that because it's it's a possibility. And they're they might be a few years behind the in the athletes in that in that sense, but they will look at that and uh uh they will hopefully sort of find these cases and and make sure they don't happen.

Christian Soschner 1:04:16

Um, I mean, there are a lot of uh interesting ideas on the market these days. So one idea is from Elon Musk, and I think also Jeff Bezos is buying into that uh flying to the moon or flying to the Mars and uh putting a colony on Mars. And it reminds me of a book I've read uh when I was a teenager. It was a science fiction book about uh written for teens, um about uh a family who traveled to uh to a distant planet and uh with a little bit, let's say, different environments than the earth, and it was um hardly survivable for adults because they didn't have uh proper genetics for that. But uh the kid was uh genetically engineered uh to live in a hostile environment like normal human beings on the planet, um, which when I listened to Elon Musk where he says, okay, the future of the human race is uh in the stars, and we have to leave the planet at some point in time uh to ensure the survival of our race. Would that be possible in future? Will you think so that you can uh create genetically enhanced human beings uh that can also survive uh conditions on other planets that are currently um let's say a little bit hostile? Let's not think uh too scientifically uh to uh science fictionally. Uh, for example, also on Earth. I mean, um, we have this climate, uh, climate change that everybody's talking about. Would it be possible to also over generations um develop the genome in a way that uh we don't have to fear uh our race to go extinct? Is that a possible application, or is this uh still science fiction?

Tilmann Buerckstuemmer 1:05:58

Well, I think first, you know, personally, I'm more worried about technology killing the human race than technology is uh saving us, but but maybe that's my pessimism. But then I think what's what's possible is for instance, you know, genetics

Genetically Enhanced Human Beings - Reality or SciFi?

Tilmann Buerckstuemmer 1:06:12

determines your tolerance to heat, right? It's clear that there is a genetic component to that. I I haven't looked into that, but I suspect it's not just one gene that has a very strong effect, but it's sort of or one SNP, um, one sort of small change, but it's multiple. So I think if that were known, it's it's not it's not unthinkable that we create humans that can tolerate cold much more. If you think of you know going to Mars, maybe we want someone that can tolerate heat uh better or so. So it's I think that if you if you really think in the future, I think it's it's uh it's a possibility. Um again at this point, I would I would question uh if if if you sort of want to make very few changes to the genome, and that would sort of be dictated by uh caution, right? You just want to, I think if you if you make too many changes, you're worried about messing something up fundamentally. But if you wanted to make very few changes in the genome, then you would um you would need to understand what those changes are that you need to make. And those few changes, let's say if you allow five, those five changes would have to have a significant impact, which you know, if you stay in the example of heat and cold, I would suspect it's a lot more SNPs that give rise to that. But I think at least conceptually, it is possible that we get to a point where we have, you know, with more and more genomics data coming in, where we have a good understanding of the small changes. That make you know the Inuit more cold resistant than us, let's say, and that we can engineer such a property um back into our genomes to sort of potentially save us from uh uh from climate change. Um right, that's I think it's potentially possible.

Christian Soschner 1:08:00

Um I think I think I mean the the ideas you have are great. Uh on one hand, understanding disease better. Um so when not genetic, but um the entire genomics field to understand where it's coming from, what happens with diseases to go into therapeutics and also uh curing diseases or enhancing human beings, why not? I would not be worried about it. Uh when I look at the growth rate of uh the human race, I think uh don't don't correct correct me if I'm wrong, but I think it's doubled in the last 40 years or something, and it's still growing. Um so we run into when I look at agriculture, for example, I think uh it's it's obvious that at some point in time we run into a shortage of uh of nutrition. Uh, could gene editing play a role in this area?

Tilmann Buerckstuemmer 1:08:47

Yeah, I think potentially, I would say yes. Again, my my personal feeling is that there is a lot more we could do without gene editing to feed the world. But um, if you wanted to look at that angle, I think you know, in agriculture, we're sort of facing this weird situation that if we're making crops with ionizing radiation, like x-rays, right? We're shooting x-rays at plants to sort of create superior variants, um, then then this is sort of not considered genetic engineering. Whereas if we apply CRISPR or sort of other means to make a plant, then this is considered genetic engineering. So um I think that I think particularly in Europe, people are quite resistant to the use of um genetic engineering and um and I think rightfully demand that that this is declared. I would totally subscribe to that, that the consumer can decide whether or not they would like to eat a genetically modified tomato. At the same

Gene Editing and its Role in Agriculture

Tilmann Buerckstuemmer 1:09:51

time, you would like to educate people that if the other tomato that they eat is uh is engineered with x-rays, that that is probably not much better. Um but anyway, I think um to come back to that question, we can um definitely enhance um plants to become, for instance, resistant to um certain um pathogens, to become resistant to heat, um, right? That's another you know, with or or become more resistant to extreme weather conditions. Those are um things we could potentially build in, and and we could we could always build them in, right, with the use of x-rays, as I just said. So people have done that for the past 50 years, but it's very costly and laborious and time-consuming process. So the hope would be that if we have an understanding of where these favorable traits are encoded, that we can make these changes much faster, and we can then get um to the plants that um that we like and that you have superior attributes. Um so I think gene editing um can help there. And and and I would I would even say that I would prefer eating a gene edited tomato that was made with CRISPR over an X-ray tomato, possibly. Um but um but yeah, I think that's uh that's another um interesting and exciting um area of of the technology that um that um I'm yeah again, I'm not sure how to to what extent this will this will allow um us to feed the world because of course all of these crops, particularly genetically engineered crops, they will be accessible to us, right? You and me, they will not be accessible necessarily to in the places where people are starving.

Christian Soschner 1:11:42

So um one problem at a time, I think. One is the one is the development of uh technology, and the other one is the distribution or the fair distribution of technology.

Tilmann Buerckstuemmer 1:11:51

Yeah, that's true, and that's disconnected.

Christian Soschner 1:11:53

Yeah, I mean when I think about SARS-CoV-2, um what what I really like is uh the development speed that we saw with the vaccines. Um I grew up in a world where you mentioned it also in the podcast, it took five a minimum of five to ten years uh from the lab bench with uh let's say lead candidate up to the market. And uh what we really saw in the last year is when everybody works together globally and wants to solve a problem uh in a year can be achieved a lot. If this is morally or ethically acceptable, it's a different question, but only to see that uh the whole industry can unite and focus on solving one single goal in in only 12 months and bring a novel vaccine to the patients. This is this is amazing. And I hope that uh it remains in our industry and also politicians and and companies uh continue supporting this collaboration because with that spirit, we can practically, in my opinion, solve a lot of diseases and a lot of problems. Um, the second part, of course, immunity vaccines are on the market, and now we see the distribution problematic. So that some countries can afford to uh to get more vaccines and they start uh vaccinating kids with a question if the risk-benefit profile really justifies that. Whereas the WHO points out that in uh poorer countries or uh not so rich countries, uh healthcare workers don't have access to vaccines. And uh this is the population that is highest at risk, and uh they would need that. So these are more political questions that we can also solve with a lot of debate and discussion. Uh, speaking about SARS-CoV-2, uh, let me just ask a blunt question. Is gene editing playing a role in vaccine development?

Tilmann Buerckstuemmer 1:13:40

Is this uh well, I would say not to a great extent. I mean, first it it did play a role relatively early on, more for the um discovery of targets. So

SARS-CoV-2 - What Role Did CRISPR Play in Fighting the Pandemic?

Tilmann Buerckstuemmer 1:13:51

when when the virus first came out and nobody knew anything about the virus, um, something like a CRISPA screen, this is the technology that we use at Alien, can provide you very quickly with an understanding of the critical host proteins, so the critical human proteins that the virus needs to make a living, right? So you you

CRISPR Screen for SARS-CoV-2 - Technology of Aelian Biotechnology

Tilmann Buerckstuemmer 1:14:11

and that is what people did, you know, I would say within within two or three months. We had we had almost like a map um of the virus as it as it sort of travels um through cells and and sort of uses cells and and abuses cells um to its own benefit. And that is important because it potentially highlights intervention points. It highlights points where we could start making a drug. Now, of course, then making a drug is again a laborious process. We've been very fast with the vaccine, essentially because the entire platform had been set up by BioNTech, right? That was we were sort of in a particularly fortunate situation in that they had been building this mRNA platform, which was very scalable, easy to make very large amounts. Um, and they had prepared this for some time. But the truth is they didn't really have a very good example where they could apply this, right? And then they're now saying, oh, we want to be an immuno oncology company. But the truth is that they were sort of waiting for a first example to be sort of the first test case that would show that that the advantages of the platform. And I think, you know, then sort of SARS-CoV-2 came and they were immediately uh sort of spot on and said that this is the sort of the use case we've been waiting for, and we'll now show the world that we can do this. And then, of course, it was amazing execution and um it was it was very well done. With the vaccine development, I would I'm not fully sure there is a lot um that that um CRISPR could have contributed. Um again, you know, you could you sort of vaccine development is always has to do with with the immune response that the vaccine elicits. So again, one could one could take CRISPR screening technology to understand the the immune response as it as it um is elicited by the vaccine um a bit better to sort of um give an expectation of what's going to happen in the human body. Um but um yeah, I I would say at least in sort of when this virus first came out and nobody knew about it, that's where you know CRISPR was really powerful.

Christian Soschner 1:16:22

I mean, as far as I remember, um we have every three to five years such an event that new viruses um appear somewhere in the world. And uh what I understand from from your explanation is that in such events, uh your technology that you have at Alien Biotechnology uh can help to uh let's say uh unlock the secrets or discover the secrets or uncover the secrets of the virus. What is the virus doing in the body, which route does it take? Um

Drug Discovery for SARS-CoV-2 with CRISPR

Christian Soschner 1:16:51

where can you uh find access points for therapies, and that you can uh shorten the length of the time um until uh this process is uh is finished. So, this would be one point. And also later on, when vaccines are developed, uh, as far as I understand your explanation, uh, it also can help uh your technology to understand what's the vaccine doing in the body and uh is it really going down this uh the right route and uh can help uh the scientists to make the vaccines more effective in in later generations. Is that uh picture correct that I got?

Tilmann Buerckstuemmer 1:17:27

Yeah, no, I agree. Um with the only caveat being that sort of the the drug target nomination, I think for SARS-CoV-2 was something that's relatively quick. And of course, then the delivery of a of a full drug discovery program is something that we're still sort of awaiting, right? Even you know, we've been very quick with the vaccine, but it will probably take you know at least one, if not three more years, until we have a first drug that is a targeted treatment for the virus entering the clinic, right? That is usually a very laborious process, and that really cannot be short-circuited. There is really a lot of tests that just need to be done, and even with all the excitement and all the concern that we have of this virus causing the pandemic, nobody would be willing to take shortcuts there, right? With the vaccine, it was a slightly different thing. We knew that the platform was relatively safe. You know, mRNA is a molecule that's quickly degraded, it does not integrate anywhere in the human body. So, so there, you know, people were let's say willing to um, I wouldn't call it shortcuts because they have done all the clinical testing properly, but it's but it's um right there, people were willing to accelerate things with um sort of more conventional drug discovery and more conventional drugs. This is just not possible.

Christian Soschner 1:18:49

Yeah, shortcuts is such a nasty word, it uh uh could could uh create the impression that work was not done properly. Um when I look at the duration of uh drug development, um, my opinion, it's uh one one part that uh takes a lot of time is fundraising. So when you look at the traditional model, I mean uh all the the early stage development work usually happens in in small biotech companies like yours, uh, not so much in the pharma industry anymore. Uh, and even if it happens in the pharma industry, you have this long decision-making processes. Um I think what I saw last year um with my fundraising experience for vaccine companies from six, seven years ago, uh, that there was much more willingness to pay into high-risk projects uh in the vaccine space. Which, of course, I mean, if I got a billion uh dollar um cash in my bank account, I can develop a vaccine also in no time because I can hire all the right

Fundraising for Life Science Companies

Christian Soschner 1:19:51

people. Looking back at the traditional fundraising process, um, it just comes in in chunks. So you get 10 million, 20 million, then another 50 million, then you have all always a year in between uh where you have to talk with experts and uh go through due diligences. And this, of course, uh takes away resources for development. So this also adds time, and this was completely gone in the last year. Uh, the only thing that I saw is that all the money and all the political power was rooted into vaccine development, and nothing happened on the therapeutic side. So it's uh only recently that uh Biden announced that uh I think it was two weeks ago or one week ago, that the United States allocates three billion dollars into development of therapeutics. And I also hope that Europe is going down the same route because when we also would invest 3 billion, uh it's basically 6 billion is the money that uh we have to base a minimum to bring two therapies to the market. Uh, and if these 6 billion are really available and uh easily available to scientists, uh then I think also we can speed up the therapeutics development process. So this would just take one component out uh that costs a lot of time.

Tilmann Buerckstuemmer 1:21:05

Yeah, no, I I I agree. I mean, the truth is that a lot of the therapeutic development happens in pharma companies. And and my feeling is if they're convinced about the indication and they're convinced that they want to go down that route, they they often have enough money. If it's if it happens outside a pharma company, then you're right. Money is is always short, right? It's also that you can hardly raise the amount of money that is needed for drug development. Hence, sort of any startup um typically has a has a handover point in mind, right? They they they might say we have a therapeutic ambition in rheumatoid arthritis, but you know, typically we would only go until phase one that is completed, and then we need to find someone because if we if we then need to fund a phase two or even a phase three study out of our own pocket, it gets so incredibly expensive that very few people are willing to take that risk. So that you know, you could um potentially alleviate by making public money available um um to sponsor this.

Christian Soschner 1:22:12

I mean, I agree with what you say when I look at phase three studies or market access or phase four studies. Um, pharma has enough money in that area, and I think this is also the part of the industry that works very well. Uh, what, in my opinion, also works very well, especially in Europe, is uh basic research. Uh, everything that happens in research organizations, we have Horizon programs, we have uh FWF in Austria, we have FFG in Austria and other grant programs that help basic uh researchers and scientists to move their science forward. Of course, I know uh applying for grants is a nasty process, and uh I never met a scientist who was really happy about the process, but uh of course when the money comes in, it's great. And the good thing is in basic research, uh scientists don't need billions, so they can do a lot with a few millions or a few hundred thousand euros, and this is also solved. What's really tricky and difficult, in my opinion, and there I still see a shortage, uh shortage of uh capital, are the stages between. So, what happens between basic research and let's say the proof of concept in human studies uh is a really complex value chain with a lot of players in it, um, and most of them lack capital because, on one hand, farmer doesn't really want to tap into uncertain technologies. Uh, of course, I mean, when you have uh like CRISPR, yeah, when you have this uh game-changing technology um that is obvious, farmers very willing to invest very early. But uh a lot of inventions that are needed don't evolve out of game-changing technology. So sometimes there is this uninteresting technology, then you have uh by pure chance a finding and it makes it hot. So, and in this area, also VCs don't really want to invest, they don't want to pick up technology, form a team, and have to go through this uh company formation process. Um, on the other hand, uh business angels, what what I see in the digital uh world um expect usually a return within one or two years. So, drug development is not really an attractive model for business angels. And uh also the public side doesn't really want to invest there. And I believe if from this uh three billion from Biden, and also if we take uh money from the European Union, if they would really start focusing uh in this complex, let's uh call it uh tech transfer processes or valley of death, like it's called in finance, um, if they would allocate more money there, I think also a lot uh companies would be enabled to move far uh faster and quicker. How do you see that?

Thomas Moser 1:24:50

I mean, it's it's not only a function of money, I would, I would add here. I mean, as you rightfully pointed out, there are different programs and that are available, but it's it's really if you are thinking big and drug development always has to be thought of as a really very big and international game, then you have to think very international. They shouldn't be thought as a local local play. I mean, you know all the numbers as a uh as an investor. I mean, typically these East Coast companies are uh started with 50 million plus, and and that's the kind of uh play you have to compete with as a also as an Austrian startup. So you have to think very carefully where you want to get your funds uh funds from. And and this is the kind of competition and and uh play you're you're into. So I'm not 100% sure whether kind of these public programs really can uh can replace uh private funding. It's it's a fact that Europe is uh somehow different than the US here. The capital markets are not not as evolved as in the US. That's the reason why the Austrian drug developers, if they really become big, uh look for a second or or first listing at the US capital market because simply there is much more more liquidity there and and and more and and more but maybe also more educated uh investor base. I mean when I worked in this uh financing scheme scene, uh many cases I saw that the uh the kind of investors that really could judge what is a good investment in the life science area is a kind of a scarce uh resource. I mean it has been uh it's much better now in in the IT space, but in biotech, it's still at least compared to the US, it's a kind of uh limited, limited number of people that really are able to understand deeply what what the drug drug discovery company is about and and really to give a clear opinion whether it's worth to to be listed on a capital market, on market or not.

Christian Soschner 1:27:10

Yeah, my friends asked me in 2006 if I'm nuts. Uh you're going into the life science industry, they pretty much uh said the same what you are telling me now. Um, I think Europe is a great place to start a company, even in drug development, drug discovery, thanks to some uh public funding programs, and they make it really possible for scientists that don't have deep buckets. I mean, let's face it, they are not millions of billionaires on the market uh in the world. So you can also do a lot with 100 to 200,000 euros, uh, given the fact that uh public money flows into that area. When you look at the venture scene, I think it's a it's a directional decision by the founders that they have to make. Do they want to play the European single technology player of venture capitalists? Um, there is not enough money in Europe, especially in uh in pre-clinical development and clinical development. So the reaction of the VCs in Europe that I mostly saw was that they want to have a single asset in a single company, develop it to clinics and then sell it as quickly as possible to the farm industry. It's a just approach. It's uh I don't want to complain about it. But uh when I look on the United States, especially on uh key players also in gene editing, um, they have more a visionary approach, uh like CRISPO therapeutics, for example. I mean, it was founded in Switzerland, but basically financed in the United States, in my opinion. And uh it's listed on the Nasdaq and uh also gets a lot of uh US money. Uh when founders uh want to follow a visionary approach with a let's say a portfolio approach in the company with running a pipeline of 10-20 programs. I don't I don't see the right environment in Europe. I see the United States as uh

Comparison of the Investment Culture in Europe and the United States

Christian Soschner 1:28:51

the right uh cultural environment for such ambitions.

Thomas Moser 1:28:55

I agree, but uh I mean I wouldn't see it that negative. I mean, if we look at biotech and other very prominent uh German examples, I mean I mean there are people with deep pockets like like Mr. Hoppe and the Strömmmann Strögmann guys. They they are around and they they significantly helped uh these these German German unicorn companies to really develop very well. And also in Austria, we have in the meantime we have good examples of of companies developing very well, like uh Hookeeper and others. I mean, yeah, one can always discuss whether yeah uh they were not hooke, but others were sold too early. Yeah, that's that's uh and and did not get the full. uh value of the of of what what they would be able to to to develop but yeah that's that's as it is but uh and and in addition yeah uh even if you are kind of company that started in austria you have the chance of getting listed in another market be it uk be it us that has more liquidity and raise raise more funds there i mean we have several examples now where Vienna is kind of the R D and top of of certain companies even US companies come to to Austria and and create the the RT uh department RT kind of yeah part here in in Austria because we have so good a base is of of doing doing RT here and maybe do the commercial functions elsewhere that could also be be a model in the end it's always and this was also mentioned last time a function of of experience of people that are around and available in in our country and and in in Europe on a bigger scale no that's true and I see it's also the upside that uh especially our business can can be easily run globally you mentioned Okeeper Pharma I think O'Keeper Farmer started in Switzerland then relocated to Vienna and uh got listed on the Nasdaq and has now uh subsidiaries in the United States so I think the headquarter in the United States and still the the research is done here in Austria.

Christian Soschner 1:31:12

Also I think Nabriva is an example um started in Vienna and then got listed on the Nasdaq uh BioNTech I think financed by by Mick and uh their investors who helped to evolve the company with significant investments partnered up with uh Bill and Belinda Gates Foundation who also brought money in and I think BioNTech is also listed on the Nasdaq um so it just must be clear that uh at one point in time when we're looking for 500 million I still think that there are only very very few investors here in Europe who uh have the capabilities of supporting that and I always wonder if when the European life science industry evolves especially with uh the successes of BioNTech or who keeper pharma that hopefully also we will get more and more investors that are located in uh in Europe and fuel the talent no I definitely agree I mean all this corona corona phase definitely improved the case for good life science and biotech companies I think this has increased the investor confidence a lot and and made a very good case for for investors that biotech and life science companies uh are uh are uh that are uh well deserved uh good good investments and I mean we as we as a as biotech scene in Austria also yeah have some room for improvement but yeah with the now with the creation of the biotech Austria association I really think that's a a great step forward to also receive better public uh uh

Major Players in the CRISPR Field

Christian Soschner 1:32:51

knowledge in the in the in and the record kind of yeah what what the biotech uh companies can do for the for the society as a whole now hopefully we have room for improvement otherwise life would get boring easily so if there's nothing to do anymore um talking about investments and and pharmaceutical companies what are the major players in your industry what are the major players uh in gene editing these days i mean obviously we have you it was already mentioned several times CRISPR therapeutics definitely is one of the the large players and no and all the other companies that are yeah mainly in the US for now like Intelia but there are also some some companies in in Asia but uh yeah and and I mean many also big pharma companies I have now taken licenses for for CRISPR technology from the different licensing consortia and and probably follow

CRISPR - IP Landscape and Commercialisation

Christian Soschner 1:33:51

their own approaches.

Thomas Moser 1:33:53

So I think CRISPR technology in the meantime is so broad a technology that that it cannot be can be centered around uh single companies that's definitely too big a topic I mean we haven't discussed the IP landscape yet which is still stands in the way a bit of a even better development and more more efficient development of the whole CRISPR technology and CRISPR drug development scene because as we all know this is still somehow unclear how this whole IP battle will will be resolved in the end.

Tilmann Buerckstuemmer 1:34:29

Yeah that was that was that that was my comment as well that initially there were sort of two three big companies that were founded around the main patent estates and the two competing ones here are the Charpentier Downer patent that go back to the this sort of initial discovery that I described earlier and then the reduction to practice in human cells which was Fang Zang from the from the Broad Institute and and sort of companies were found around those main patent estates initially you know Editas was founded around the Fang Zhang portfolio and then CRISPR therapeutics and um Intelia around the around the Downer Charpentier portfolio. But it it seems in the meantime, you know a lot of other companies have come up and this question of who owns CRISPR and and you need to have access to the foundational IP because the technology is so groundbreaking and so important has become almost a I wouldn't say a mute point but you know in the early days of CRISPR people were like okay you know you need to be either this or that company because those are the two main pattern estates and if you don't have access you don't even need to play in that market.

Christian Soschner 1:35:37

But in the meantime, you know there are 15 other companies is my impression and um eventually the the whole IP situation will be sorted out because it's so big and so broad and there's so many applications that that it just cannot be in the way that um two universities are battling over that foundational IP I mean I think as long as long as uh the companies are developing or doing research the IP should not be the problem uh until market entry. And I really wonder what happens when the first company has uh developed a therapy that works um and it cannot brought to patients because of IP protection. So because uh there is an unwillingness of uh giving handing out licenses it would be an interesting case uh to see how that will be resolved.

Tilmann Buerckstuemmer 1:36:31

Yeah I cannot I cannot really see that happen. First the question is always sort of what exactly was claimed in these patents that is right initially for instance um yeah I mean let's not go into detail there but but there you know the the the precise formulation around the claims matters whether you're whether you're inside or outside so um I think that there can potentially be workarounds we've seen different nucleases other than CAS9 that up that could potentially be used. So I think there will be several technical solutions to the to the um to the to solve um um the problems that you're trying to solve so I I would be really surprised if that ultimately was in the way also I wonder if then you know University of uh Vienna or Berkeley or or anyone would really like to see their name in the news stating that you know a new therapy for cystic fibrosis becomes available but you're blocking it because you because people don't have access to CRISPR. I mean that is very negative PR and I'm really hoping that it doesn't go down that path because it would be um it would be sort of very tragic if that was the outcome right I can sort of see how you want to have certain stakes in the ground I can also see how you want to have a share in the program if CRISPR used to to to sort of make make um uh or break the therapy but um but it it we hopefully we're not seeing or we're not facing a situation where a therapy gets shot down essentially because people don't have the proper licenses in place.

Christian Soschner 1:38:10

I don't I mean maybe I'm too positive but uh as long as it's research um the IP is never a problem in my opinion. If there is really a groundbreaking uh breakthrough that also coming from from the investment side also when I look at the companies that uh have not secured the license uh once you have the results of course I mean out of courtesy you should talk with the university who holds the IP and uh agree on licensing terms that are also beneficial for the basic researchers to move that forward. But I think the the licensing terms are quite standard these days and there are a lot of examples in the world so that uh also when a licensing agreement cannot be found, I think with with outside pressure from regulatory authorities uh that might also be resolved beneficial for both parties. It might not be uh the lottery win but uh I think it can be resolved and I don't see a reason why universities should not um give a license on commercial terms uh but they should uh even it would make the money MA2 positive yeah yeah I I think in this getting a therapeutic license for CRISP is is a very complicated process.

Thomas Moser 1:39:21

So it's on the one side the universities and and the people involved have given this to certain specialized companies that commercialize this this IP on the other side I think you mentioned somehow mandatory licenses which are in certain patent laws but we have this discussion with corona uh vaccinations as well and and we have seen the discussions there. I mean mandatory licenses that's really this goes deep into the heart of our uh kind of uh commercial system and the biotech system so and and I don't think there will be an an easy solution to that because this really would significantly impact the whole business model of biotech companies uh in a in a sense that yeah they cannot rely on the proper patent protection they absolutely need for commercializing their products they have have discovered I mean the main problem we have these days is that it's not even clear to whom the the knowledge belongs because we have this interference process going on we have several uh several uh rulings going on at the EPO uh European patent office uh so this will unless there is a kind of uh solution and uh via negotiation if it's decided by court this I would assume this will take several years and this this is really resolved. And this will also lead to a situation where investors when companies will shy away from this unclear situation and will not develop uh certain therapeutics where the the licensing situation is unclear because if I am an investor I wouldn't invest in a case where where it's unsure whether I can commercialize that technology.

Christian Soschner 1:41:15

I think that's a question worth debating um when I think uh about the origins of patent laws um they all evolved in a time where the internet did not exist where traveling was really difficult and challenging um and also multinational collaborations were not uh in the day-to-day business it was just I think 1800 1700 1600 so they have a very very long history and now we live in a connected world where it's really possible also with with more and more people on the planet where it's really possible to to connect huge teams uh on one top over one topic and let them work to solve the same problem so and still we have this negotiation processes that just take a lot of time and uh coming basically are coming from a different society from a different background and when I think um also from the investment side when I think uh just just just start working to just move the therapy forward I mean nine out of 10 or 99 out of 100 uh approaches won't work anyways so uh should people start uh negotiating a license for a patent that probably is off patent uh before they can bring even bring something on the market uh early on or should they just postpone the process and say okay let's find out first if it works and if it works then let's initiate the process and sometimes get also hopefully help in future that maybe there is an arbitrage authority that can help uh just shorten the timeline for the negotiation not in um let's say uh denying um uh commercial benefits to one party but just to streamline the process and make it move quicker I think this would be very helpful.

Thomas Moser 1:42:58

I mean I'm I'm not talking about the kind of relatively cheap processes up to going into clinical phases. I was really talking about clinical studies that that cost several hundred millions and and more and I think taking this huge commercial risk of entering such studies without having a clear situation on on the whether an approval would be possible in the end with a proper license situation. Yeah I doubt that this risk can be taken easily because I think also of the the licensing partner if he knows that you absolutely need his license he will have a very strong leverage of of uh of setting the bar for a proper license very high.

Christian Soschner 1:43:47

I mean it it it's not in our industry but I think uh the developer of Fortnite is battling uh over the access on on on on uh Apple's App Store which is basically a monopoly and patents create monopolies um I'm not aware of a case that really pushed it so far that it just developed something up to the end of phase three invested uh billions of dollars without sorting out the licensing issues beforehand but the question would really be what would happen then I mean you have a therapy in the pipeline that works um and then the owner of the patent just blocks it and says no no I don't allow it would be really interesting to to to have a debate over that uh I mean Fasco to put it up there's a huge debate in the US anyway going on about this these patents uh in the in the CRISPR space whether they belong to a bigger extent to the public because obviously a lot of the research that led to this breakthrough uh discoveries was financed by public funds and and in the end by the public and and whether the the huge profits then should remain with the with the large university funds is definitely uh a big question and and should be should be considered carefully yeah because this is is somehow unequal distribution of profits yeah Thomas Tillman I'm I really like having conversations so we can go on uh also for another three hours and I think I will never run out of ideas don't don't threaten anyone here but uh but I think uh you have two companies to run and uh so I would suggest to wrap up our discussion and I would like to ask uh you two one final question you both have experience in the industry you founded several companies and uh there are so many people out there these days who think about uh going down the same routes that you did um but it's their first time so let's just assume somewhere at the conference hopefully in future again in person uh you pump into

Final Question: Advice for First Time Entrepreneurs

Christian Soschner 1:45:51

a bunch of entrepreneurs um from different age groups in their 20s 30s forties and 50s who come up with the idea and um tell you look I'm so impressed by what you achieved I want to do something similar I have an idea uh can you please give me one advice what would that most important advice to those people be from you that's a tough one Thomas I leave you the first yeah yeah for me for me it's it's relatively clear I think the the best advice would be to to really form a proper team to team up with people whom you can trust and who bring in different competencies different networks and if you have built a great team of two or three people then then that's already one of the best basis you can have for forming a a successful and and sustainable sustainable company yeah I don't I I think it's a very tough question.

Tilmann Buerckstuemmer 1:46:58

Put me a bit on the spot but I don't know I would I would probably advise to really you know first try to try to be very specific about what you want to do and try to really focus on a very small thing but then with this very small thing try to try to develop an idea that you really think has an impact.

Christian Soschner 1:47:19

So this whole this whole concept of focus I think is one that we always try to emphasize that we're trying to do one thing really really well as opposed to working at a lot of uh disconnected or loosely connected um things but I'm not sure I find that a very good piece of advice so I'm it would have to be a longer conversation for it to be meaningful I think we can make another podcast on that but um but uh uh you you nailed it very very well focus is the most important thing for um success of any company and later on when you succeed in one field you can then of course diversify and uh grow bigger like Amazon but Amazon initially uh I think it's a company everybody knows they did just one thing selling books over the internet that's it and both advice is uh form a team and uh focus initially on one idea become the best in that field uh is what made Jeff Bezos the richest person in the world ultimately after 27 years. So sound advice from you too thank you very much for your time and these nice conversations. I think it helped a lot for non-scientists to understand better what gene editing is, what the power of CRISPR is, what uh the risks and opportunities are and also hopefully we contributed a bit uh to the awareness of the life science industry and hopefully also one of the other politicians uh listening to that and helps uh moving forward the regulations around patent laws and help um also with bringing the right laws in place that our community here in Europe can evolve better. Thank you very much for your time and have a great day. Thank you Christian thanks a lot for organizing that have a nice day thank you for the great thanks for listening please please share the podcast and make sure you've subscribed have a great day