Biotech Story Time With Tal Zaks, M.D. (Part 1)

Alas , I did not bring any popcorn to my chagrin I'm sorry next time bad planning a lot of people know him as the guy who was chief medical officer at Moderna before , during and after the company became a household name thanks to its mRNA-based answer to COVID .

But even without that gold star next to his name , dr Tal Zaks has built a fascinating career as a physician , scientist , an investor , a board member and a biotech builder .

Today he's CEO and chair of the board of directors at Exsilio Therapeutics , a non-executive director at five companies , I think , including Teva Pharmaceuticals , a private equity partner at OrbiMed , and probably holds a few more titles that I'm missing .

So we're really looking forward to the conversation today . We have a ton to get through . I don't know if we'll do it all in one one episode . We might have to revisit with a part two . But before we get into the Exilio story , I want to get to know you a little bit and intro you to the audience . And I'm going to go way back .

We're going to rewind the clock quite a ways . You immigrated to the US from Israel to do your postdoc at the National Cancer Institute and presumably at the time practiced medicine . I mean , you know you practiced medicine back then when you made that move . Was that your sole intention , career-wise , to come over here and practice ?

It wasn't the thing that it has become since , but I was super curious and I had a wonderful opportunity to come to the lab of Dr Steve Rosenberg at the National Cancer Institute . And you know , as an immigrant coming from across to the Mecca of the NIH , you don't really think what's going to happen next .

You just say , boy , I'm at a place that has really redefined our understanding of immuno-oncology benefits for patients with cancer and the sky's the limit . And I have to tell you , cancer and the sky's the limit .

And I have to tell you I am to this day a very proud immigrant to this country and really , if anything , have been fortunate to take advantage of an ecosystem where truly , the sky's the limit in terms of what we can achieve for patients , for ourselves , for mankind .

So I , in all honesty , I knew I was a physician , I had some interest in science and I just wanted to explore it .

I tried to understand immunology . We had a theory as to what could be what are today called checkpoints . We actually debunked it and it wasn't that . And after kind of three years I said , oh , you know , I better go back and finish my clinical training . Yeah , and it taught me the value of scientific depth .

But I can tell you , years later , when I came upon a saying by the late Nelson Mandela it's become my favorite quote of all time and he said in life I've either succeeded or I've learned to be fair . In those early days I had a lot of learnings still do to this day .

You've got a little bit of research budget . And I came home really proud . My son , who was 12 , looks up at me and says Dad , what's , what's all the commotion about ? I came home really proud . My son , who was 12 , looks up at me and says Dad , what's all the commotion about ?

I was clearly excited and I look at him and said well , you know , I just won this Young Investigator Award . And the kid looks up at me and says Dad , what do you mean ? Young Investigator Award ? Like , how old are you ?

And while I train myself , thinking I was going to be an academic physician , I started my life actually as a pediatric intensive care unit nurse .

I worked as a nurse on that side of the patient's bed , if you will , as I was training to be a physician , and I always appreciated teamwork and the academic world is driven by the axiom that there can only be one first author .

A few years before that , I interviewed at a very prestigious institution for fellowship and they said great , yeah , we'll have you as a fellow . And with a little bit of chutzpah , I asked them well , you know , if I come here as a fellow , how quickly can I be faculty ? And they said , oh , okay , let's think about that .

And they took it up the flagpole and down came the answer . It said look , we , we've looked at your resume . Yeah , you did a postdoc at the NIH . You had some papers , great , but you actually had more second authorships than first authorship . So we're not really sure about you .

And I have to tell you I like I really took that to heart because I was actually more proud of the second authorship , because when you're a second authorship , it means you got to be part of something . Somebody else did the work . You got to play a role in enjoying it , leading and thinking through it while you were doing other stuff as well .

And so when the time came to sort of make the career move , the the notion that I could actually go do it in a more team-based environment where really the purpose was getting better drugs , I just found that appealing .

And if you take a medicine and you open it up whether it's tabs or a vial you'll see there's a piece of paper rolled up in that that most people throw away . Well , if you open up that paper , it's actually the label . It's what the FDA says you should use it .

And if you look at where you know who signed off on that label , where do these drugs come from ? Well , they don't come from the university and they don't come from the National Institutes of Health . They actually come from drug companies .

And so if you , as your mission in life , want to actually do better , especially in oncology , with the state of affair of drugs while we have very good drugs we should and could do better , and you want to be part of that doing better . Then you go to where the action is .

You go to where these medicines are made to have an impact , and that's sort of what propelled me to despite having trained for so long to be an academic physician to actually shift gears and try it out in industry .

The innovation at the heart of the ecosystem is protected by intellectual property and that is the engine that's allowed us to be so productive in the US in the last 50 years as the leaders of the world of therapeutic benefit . But the beauty is that that contract with society actually plays out in the long run once the intellectual property expires .

And you now have generic medicines and you know the statin pill I take every morning and the fact that my late father managed to live for 40 years with chronic heart disease and taking , you know , taking five , six , seven different meds .

Those were all generics , or most of them were , and by now all of them are right , and so the benefit of the previous era is now available to society at a fraction of the cost .

Thanks to that , and in the discussion that we have about , you know , cost of drugs and intellectual property and all the other stuff , we often forget that there's a very long tail of benefit , that we just keep raising the bar , and then the price goes down years later for everybody to enjoy , and that's worldwide .

And so I take tremendous pride in Teva's contribution , both on the innovative side we are an innovative company , we do develop innovative medicines but also on the generic underpinning of that that provides drugs for hundreds of millions of people every day it frees up right .

So he could spend I don't want to do this , I don't want to do this , I want to get , I want to give this its fair share , but we could spend a couple episodes talking about stories from those Moderna days .

As you mentioned , I started GSK , ended up running Santa Fe's global oncology team and at that point I had sort of the opportunity to kind of look around at the biotech system and figure out well , what's new that's coming and what are some interesting ways to fill our pipeline . And up until that point I was a medical oncologist through and through .

I cared about better medicines for cancer patients . I didn't care about where they were coming from . The proof point I actually spent a couple of years at Cefalon . Cefalon had developed two of the oldest poisons known to man as a very effective cancer chemotherapies . One is arsenic trioxide , which cures a subset of leukemia . So fine by me .

The clinical benefit is what speaks to me .

But as you're a scientist and you get sort of curious about where's innovation coming from , I had the opportunity to look within the Boston ecosystem at a whole bunch of stuff and I came upon Moderna and the idea of mRNA and it made me stop and sort of think differently about translating science into medicine , differently about translating science into medicine .

So by then I sort of realized that my happy place , if you will , is between the science and the medicine not pure science for the sake of science , not just pure medical practice , even though I did that a number of years as a volunteer at the Philadelphia VA .

But it's actually that in between that in between , and Moderna had an emerging interesting idea and platform that was very orthogonal to my thinking . It was not hey , we have a cancer patient and cancer here as a need can you make a medicine ?

It was we have this innovative idea of a new platform and if we can translate it into medicine , what would those medicines be ? And that's a very different way of asking the question Now , in full transparency . In 2015 , all the data we had were just an animal model and mice and most people thought this thing was never going to work .

I have been fortunate in life that my wife , who's the smart one in the equation , actually has a PhD in biochemistry . She looks at me and says , well , you know , it's all mRNA , it's high risk , but hey , if this speaks to you , go for it . And I was in a place in life where it was time to take risks . You know , and the way to think about it .

I had a big birthday that year and one of the things that happens when you reach a certain age is that you stop looking at the next career thing you're going to do . You start looking at time in reverse . You said , ok , and the time that left to me in this world ? What do I want to get done ? What do I want to accomplish ?

And then you realize you'd rather fail or learn , trying to address a big question , than just do something small and incremental . This was a big question . This was a question that most people thought was not going to work .

I mean , I can show you nature papers back in the day , referencing Moderna and Theranos in the same sentence for crying out loud , referencing Moderna and Theranos in the same sentence for crying out loud , and it was a very different way to kind of challenge yourself to go make medicine .

So I signed on because I thought that if this would work , we should be able to go from an idea on a whiteboard to a medicine being studied in man at a fraction of the time and the cost of what traditional drug development takes , and it had such potential in terms of a platform that could lend itself to .

Once you do the first one , the other ones should actually work that repeatability . That is unheard of in traditional pharma and in fact , we'd actually proven it . One of the things the public is not aware of is that you know the COVID vaccine was not Moderna's first vaccine .

It was actually the ninth virus against which we tried to raise neutralizing antibodies in humans , and our success rate for the prior eight had been eight out of eight . So COVID , for us inside , was not a surprise actually that it worked . There were a lot of other things surprising about it , but we knew this platform could actually get there .

In fact , for years we have been working with an urgency to get there in time .

But I'm really I'm curious to learn more about you know your priorities as a CMO . Stepping into a company at this time when mRNA was again , as you said , compared to Theranos right , like it wasn't a household name , a lot of people were hesitant to believe that it would work . It was high risk .

You know what were your priorities as a CMO when you stepped into this company and in these early days ? What did that look like and entail ?

And then the very thoughtful risk mitigation approach to try and take several shots on goal in different dimensions , to try to work yourself across different things that could work , but you don't know that they could . And in those days they spanned infectious disease vaccines . They spanned oncology efforts . They spanned rare disease oncology efforts .

They spanned rare disease . One of the things that I personally started shortly after joining was the personalized cancer vaccine , and you know we can come back to that . You know , if you want to cliffhanger into this episode , we can talk about cancer vaccines because it's a fascinating story . In fact , it's much more fascinating to me scientifically than even COVID .

But when I joined and this is where your popcorn will find a place when I joined in March of 2015 , stefan Bonsal , the CEO , asked me to give an all employee town hall three months into my tenure , so in June of 2015 , and he wanted me to explain to the employees there were about 300 people at Moderna at the time .

Why was it that a unicorn on paper company in Boston , so secretive , is actually the first clinical trial is going to be a vaccine against the pandemic flu threat out of China ? That was our first phase one . We started at the end of 2015 . And so what we did back in those days is we used to rent the auditorium next door .

It was actually a movie theater , the Kendall Square Theater . We used to rent it out for random Thursday afternoon . We'd give all the employees free popcorn . They'd sit when the executives would get on stage and tell the story of what the company was up to in the last couple of months . And so it's my turn , june of 2015 .

And I told Stefan great , we're in a movie theater . I'm going to take some license with my presentation . I'm not going to use your usual slide template . I'm going to make believe we're in a movie . And so I get up Everybody's with popcorn . I'm the new CMO . I said guys , pretend this is a movie .

The theater goes dark and on the screen comes a slide and the title of the movie is how Moderna Will Save the World June of 2015 . The next slide is a PG-13 green rated thing , right to get everybody .

And then the rest of the presentation started with the Spanish flu in 1918 goes through the fact that still back then , in 2015 , we don't have a good vaccine response . We don't have good antivirals . All we have is these masks , these pictures of people walking around in masks , and I flashed those pictures up in June of 2015 .

And basically the gist of the talk was our platform . It's clear the low-hanging fruit is going to be vaccines , for a whole host of technical reasons , and we owe it to ourselves , to the company , to society , to make sure that we're advancing these vaccines , both those that are of perceived commercial value and those that could be of public benefit .

And in fact , that's what we proceeded to do . We had advanced a few candidates that have commercial background . I mean CMV right now is already in phase three there . But in parallel we worked on flu , we worked on Zika in 2017 .

That's when part of the US government got to go and we built this track record of the ability of this platform to actually execute towards a pandemic need . And I'll tell you it came full circle in September of 2019 . Stefan and I went down for our sort of annual meeting with the NHFO .

Don't know how , she was there at the time and they came to know us through the Zika pandemic in 2017 , and we started to collaborate and by then , we had shown that the mRNA vaccine could actually work to protect an animal model of a cousin of COVID called MERS , and we were telling the team there about the most recent data we had , and I remember at some

point , dr Fauci kind of stops me and says so are you telling me ? This is the best vaccine platform I've ever seen me ? This is the best vaccine platform I've ever seen , and you know me being me . I basically looked at them , dr Fauci . Yes , and let me explain why .

And so the upshot of that meeting was actually that Moderna and the NIH were going to form a collaboration to pick a virus , something nobody ever heard of . We'll just send you the sequence , you guys can start the clock , see how fast you can make a first batch and we'll run the phase one clinical trial .

And in November the NIH November of 2019 , dr Fauci actually published a paper talking about pandemic preparedness of various platforms and mentions mRNA there as the leading platform ready to serve in a pandemic , whether it's influenza or a related respiratory virus . And as we were talking to the NIH trying to figure out what would be that test case .

Somebody started coughing into Wuhan and the rest is history .

If , if , if we do everything we do in translating science into medicine but the public doesn't trust it , then it will have been for naught , and I spent a lot of energy as the chief medical officer back in those days and I still believe it's part of each and every one of our ethical obligation to be out there to tell the story , to explain to people where

does this stuff come from . This is not black voodoo . This is not some magic mystery . This is people hard at work trying to understand the science and trying to translate that science . And we did . We did a couple of things that were I'm really proud of back in that era . The first was in in as the phase three trial was going on .

I remember being on a , on a on a webinar with the National Academy of Sciences of New York State and they asked me OK , at the end of it there was a Q&A and they said , dr Zaks , what are you worried about ? And they expected me to say , oh , I don't know if it's going to work . This , that and the other .

I said , look , I'm not worried about safety , I'm not worried about efficacy . The one thing that keeps me up at night is that our trial enrolls people of diverse enough representation of the great country of ours so that when the data comes out , people can relate to the veracity of those data and can see themselves in the trial .

And I think Moderna went on to really pioneer enrollment of diverse populations in phase three and in all subsequent trials , partnering with both national and regional in phase three and in all subsequent trials , partnering with both national and regional sort of experts and leaders of the community to make sure that clinical research is both accessible to everybody and

representative of everybody . And the other interesting thing was , again as I was thinking , how do we relay this message to the public ? I actually convened a small ethics panel for the executive team at Moderna . You're not going to find this on any website . This was not done for external consumption .

This was really to get external advice of people like Art Kaplan and other experts in ethics on how should we be thinking about our protocol . And one of the experts there , a friend of mine , ann Beal . Ann is a wonderful black pediatrician from New York City . She was the first chief patient safety or chief patient officer at Stanofeu .

She's today on the board of GSK and I brought Ann in and Ann looks at me and says Tal , I've been in your shoes . The only way you can do this is to be transparent to the point of discomfort . And I listened and I said that's going to be the motto of our medical affairs organization . And in the ensuing weeks we had a lot of internal conversation .

I was pushing to have the phase three protocol of the COVID vaccine actually published , and companies don't usually publish protocols on the web certainly not unredacted and certainly not as the trial is still ongoing and we finally prevailed and in September we went out and we put the entire protocol on the web and I'm very happy to say that all the pharma followed

suit , some of them within hours . We got one of the most favorable articles ever written on pharma on the New York Times in September of 2020 . But , more importantly , journalists who used to call me up in those days and say , hey , you know what are you not telling me ? How many patients are you going to see , et cetera .

Suddenly the conversation was tall on page 87 , paragraph two of your protocol . Can you explain to me how the power of the statistics work ?

Right , so you could actually take now the conversation with the public and I you know I have tremendous respect for two journalists because at the end of the day you're the ones who translate this to do what the public actually gets to listen and figure out .

And so it changed the dialogue that we had with with the public on what that protocol was actually trying to do .

The the big priority for you as the pandemic started to hit and in the the big priority for you as the pandemic started to hit and in the year after right as you released your vaccine , was really making sure that you were telling the full story and that everyone who needed to and wanted to see that data as a CMO in an mRNA company , once it kind of became

a public good right , a publicly known household name , or how did you see your priorities sort of shifting as mRNA suddenly became an actual medicine that was commercialized and you had to continue moving forward and being a CMO of this company .

a completely novel manner . That was all consuming .

I mean , if you would have told me in 2019 that I'd be developing a vaccine in 2020 , and I'd be doing it with a team of dozens of people , all of whom I had hired through Zoom and never met , and I would be doing it with three government agencies who had to align on protocols and endpoints none of whom got in the room together with each other , let alone

me , and I'd do it in record time , such that we went from an idea and a whiteboard to an authorized vaccine in 11 months , I would have thought , yeah , that's , that's , that's impossible , and yet , and yet , we did it .

And so that's where you kind of there's learnings from that success in terms of how we work across individuals and what can work with remote working and Zoom and what actually takes people to get in the room together to align on things , and I think we as a society are still learning that lesson , but it's clearly .

I think for us the development of the vaccine was probably a unique edge case that everybody else experienced in terms of what can you get done remotely and how to go about building an effective remote working environment .

The second half of the year , I think once the phase three was sort of rolling on its tracks , and then I had to pay attention to two things . I think one of them is , as you said , being the public face , making sure that I can tell the story , that I can represent Moderna .

We had very critical FDA meetings , advisory committee meetings , cdc meetings , et cetera .

The other one that is a story that's not often told actually has to do with safety , and what people sort of don't realize is and probably this is a good explanation for some of the conspiracy theorists out there the mRNA vaccines are the most intensively studied from a safety perspective , medical intervention in the history of humanity .

We have dosed I don't know one , two billion people with these medicines . We've done it with the most modern tools for data collection ever available to mankind . We've done it with reporting through all forms of modern communication technology . We've done it using the best tools available today of big data analyses for any kind of signal .

And the proof is that when you had very rare adverse events that happened at a rate of 1 to 150 or 1 to 200,000 cases , those were picked up within months . And that's what happened to the AstraZeneca vaccine , the J&J vaccine , if you recall back , and even Moderna had this very low signal of the myocarditis that had been picked up and then validated .

So I don't think there's anything significant about the safety of these vaccines that we don't know . It just doesn't make any sense , given the way we collected and I can tell you the amount of man , hours , hundreds of millions that it actually cost to collect the safety data . That is the iceberg under the water .

And to the degree that I was sort of steering the ship in those days , that was the thing that I had to pay careful attention to , to make sure that we are actually collecting the data as required by regulations .

And , by the way , global regulators around the world would have weekly teleconferences without me FDA , the Europeans , et cetera , et cetera and they would be talking about the safety of our vaccines and what it is , that they get direct reporting and when you think about it just to give you a numbers on it , when we started down this path , we took a look at

the previous vaccines launched and we thought that we would get about three to four times the reporting of adverse events that any other vaccine would happen . That's what we geared up to .

When it actually got rolled out , we got about 15-fold I mean , I don't remember the exact numbers , but it was over 10-fold what we had expected because of this heightened sense of vigilance , because of the public scrutiny , and all rightly so and it was our job to react to that , collect the data , sift through it and make sure that we report it accurately .

And so that's a story that's not often told but for me was critical , so that I can be out there and say yep , if you want to know what the side effects are , you remember that FDA label , go back and pull it up , because if there's anything we saw by law , it's on there .

like you know . Hey , the contributionsch .

But , um , I want to , I want to kind of shift back to like what , what makes Dr Talzak's Talzak's who he is today and and kind of keeps him moving forward .

So , taking sort of sort of that specific experience off the table , what other inflection points during your you know CXO , you know VP , even research experiences with your previous companies have , in a similar but maybe more muted to the public way , influenced your confidence in your career trajectory .

You know your decisions to go on and be a board guy , be a founder , be a you know the leader of Exilio , for instance .

That was in phase one , just the first phase of clinical research , and it targets something called CD38 for patients with a type of blood cancer called multiple myeloma . And this phase one had been going on for very long because we started at very low doses . We were going very , very slowly and it wasn't clear that it was going to work .

So people weren't excited to enroll . And one day the team comes back and tells me you know , you remember that 70-year-old patient that we had and he'd just gotten a couple of doses . Well , he decided to go off protocol . He's no longer participating . And I'm like why ? You know we just lost the data point . This is hard enough as it is .

And they say well , you know , here's what happened . We gave him two doses or three doses of the drug . He went into a complete response . He's 70 year old . He's been feeling like crap for the last decade of his life . He finally got the opportunity to go to Europe and take the summer off and do that trip he's been dreaming of .

So he decided he's not coming for his next dose . He's going off to Europe to live Right , and you go OK .

So so those stories , that that you sort of that you live for on the , you know , I think I've been fortunate to have mentors and colleagues to be able to talk to and have sort of steered me right , whether it's people like Steve Rosenberg , who is still there at the NCI now , 50 years as the towering modern giant , father of immunooncology I mean a lot of

therapies we see today , the T-cell therapies all started in his lab back in the day . I've been fortunate to have a supportive wife who understands what I do and , more than that , will actually tell me to my face when I'm talking nonsense and telling me the stuff I don't want to hear . And I've been blessed with having colleagues .

You know , one of the privileges that we have in the world and this ecosystem is that the end game is something tangible that is easy to be passionate about . We're not making widgets , we're making people feel better , live longer . We're trying to cure diseases , we're trying to prevent horrible illnesses . It is easy to get that as a rallying cry .

What's hard is then to figure out . Okay , with all the unknowns in biology along the way , how do you do that ? Now I think in this phase of my career , one of the things I learned at Moderna through doing is the importance of aligning return on investment with innovation and doing good for patients .

And it sounds trite but it's actually not obvious and it's not trivial to get right . It's actually not obvious and it's not trivial to get right . Our ecosystem has been so productive .

But you have to understand the drivers of this ecosystem Because if you look at other economic models of trying to translate innovation into healthcare benefits , they have not worked nearly as well . Benefits they have not worked nearly as well .

And so I judge it by the results and I am deeply respectful of the underlying economic ecosystem that rewards innovation and rewards investment in high-risk areas with a return on that investment .

You know I was kindly invited to a recent summit that one of the National Academy of Sciences in Medicine and Engineering had about how to better align investing in innovation and therapeutics with unmet need , and one of my points to them was I'm not ashamed of saying return on investment when we talk about drug pricing , you know we often talk about kind of

reimbursement , and reimbursement is a term that is fit for when I go out and have a meal and I need somebody to pay for the meal . We don't work for reimbursement , let's be fair . We work for a return on the investment . My shareholders , my limited partners right now in venture a lot of them are pension funds they give me a pot of money .

Seven years later I need to give them a bigger pot of money back because they got to go pay those pensions . That's what propels our system . That is commercial investment .

And for me , since I was fortunate to never actually do anything strictly for money , I became super curious to understand and immerse myself in an ecosystem where that part of the value is actually a very objective and legitimate yardstick . The value is actually a very objective and legitimate yardstick .

You know , sweat equity and capital equity tend to be rewarded differently . I've sort of lived now through both and when investors at Moderna used to ask me well , you know what's the stock price ? Should I invest ? Is it too high ? Is it too low ? What's it going to ? I used to look at them and say , look , you can do what you want with your money .

I'm actually investing something much more valuable than money at Moderna and that's my time on Earth , so you be the judge of your money . I think sweat equity and capital equity are different and these days . I'm curious to immerse myself in this side of the business of biotech , if I may , to understand what that return on investment looks like .

To understand what that return on investment looks like and how do I best align it with the things that I still inherently care about , which is translating science into medicine .

Builders thus go about their business searching for solutions to unmet medical needs why not ? It potentially wins the favor of markets and agencies , but you , on the other hand , have shared a somewhat you know , at face value perhaps contrarian opinion that unmet medical need is not really what drives innovation in this industry .

So I guess I'd ask you for some explanation of that philosophy .

Unmet need hasn't changed , and so we've had cancer for eons , and so it's not unmet need per se that's driven all the new medicines we have . So it's actually new understandings in science and technology that are driven primarily by curiosity .

You know , when Caitlin Carrico , whom I have a ton of respect for , started fiddling around with the structure of RNA to understand why in some cases was it killing cells and what could she do to the chemistry to stop it from killing cells and get progeny expressed , she came upon a really interesting discovery , but nobody knew what to do with it .

In fact , the IP lay fallow for years . They kind of licensed it to somebody else , and it wasn't until people who actually said , huh , there's something that maybe we can get translated . And even then the first folks who picked that up , their idea of what to do with it was just following their curiosity .

Oh , can I reprogram the stem cell to go be something else , which is super interesting scientifically , but we still don't know how to make a medicine out of it . And so for me , that bit of translation in the middle , pure innovation , opens up the potential . That's the curiosity driven , that's basic science , that's basic technology .

When Bob Langer discovered that he could make lipid nanoparticles and Bob is a legendary MIT professor who's the father of the modern lipid nanoparticle and , frankly , one of the fathers of the current ecosystem as we know it , of Boston Biotech and that's because of his deep understanding that when he discovered he could do something and that something was , everybody

else thought he couldn't do it and shouldn't be possible that opened up a wonderful world of intellectual property . And his understanding of the value of intellectual property and the ability then to showcase what you could do with it to attract investment , that's what started the ball rolling .

And , frankly , moderna is sort of the culmination of the curiosity of people like Bob Langer , like Caitlin Carrico , but actually putting it together in something that now is useful . And in fact , even in the early days of Moderna , we were exploring a whole bunch of different things and trying to make different types of therapies with it .

Moderna still is exploring the next frontier , whether cystic fibrosis or rare disease . Now we know vaccines work and what happens is unmet need becomes the prism by which you focus the light .

It's not the source of the light , the source of the energy is actually that scientific and technical innovation and that's brilliant people who just are just super curious to go to go do something or investigate something . But the ability to then focus that potential through the prism of unmet need is what gets us medicine .

So you know there's still so much unknowns right around the science of mRNA and how it works and the delivery of it , and how it's going to perform in different cell types and how we get it to express longer .

There are so many different scientific questions and we also tend to , I think , celebrate mRNA at face value for the ability to manufacture more efficiently , right . You've talked about this in comparison to other cell-based medicines , right ? So you know I'd be curious to get your sense on the trajectory of innovation in this space .

What you really think are some of the pieces here that are really driving further innovation in that space , right , and that we are starting to funnel into unmet need to some extent , to make these into therapies . But what are those ? You know , what's stoking the innovation in the mRNA space today that has you the most excited and what's at the root of that ?

Vaccines were the low-hanging fruit , because all you need is a needle in the arm and it goes to the local lymph nodes and all you need is a smidgen of protein produced and you mimic a viral infection and off you go . The next place where you can put it is likely intravenous , and I think that's also been proven .

We've demonstrated we at Moderna back in the day , shown that we can inject mRNA encoding just for an antibody intravenously and it goes to the liver and it will make you antibody and you get therapeutic doses of antibody . So can you get it to the lungs ? Can you get it to the bone marrow ? Can you get lupinano particles into immune cells ?

Can you get that into the brain ? I think that's some of the . Those are some of the frontier areas where people are trying to push the boundaries , tier areas where people are trying to push the boundaries .

The next , the other dimension , is well , what actually can you encode in the mRNA and initially , the place you start is the stuff that's best understood , because you want to minimize risk , and nothing is better understood than an antigen for a virus .

And you know , it's no mistake , that all the COVID vaccines all use the exact same spike protein , that everybody , now , you know , knows what a spike protein is . And you know , it's no mistake , that all the COVID vaccines all use the exact same spike protein , that everybody , now , you know , knows what a spike protein is .

Okay , that was easy , but you could actually make proteins that are much more complicated . You can make proteins that require several subunits to come together and you can make proteins that have not been seen in nature . You can invent new proteins that have novel functions or improve on functions in very creative ways . I am curious about that frontier personally .

That's where Xilio comes in , because for me , xilio , this gene therapy company that I've now taken on , is actually at the forefront . It can combine innovation that comes from two different sources . One of them is mRNA and a lipid nanoparticle . As a drug format we can give it .

It can go to cells where we understand it can already go to , whether it's the liver or immune cells , and it can translate protein and you can actually give it repeatedly . You can give it once , twice , three times . In fact . You know Moderna and their lead indications have gone now for about a year in their first two diseases .

Giving it every two to three weeks , no problem . But the second thing is gene therapy . Can I actually integrate a novel piece of genetic material in a safe way into the human genome to produce a therapeutic protein , and then I don't have to keep treating that patient ?

Well , that's as close to a cure as I know , and so what this company that I'm now running is trying to do is basically take a page of evolution as a starting point of some elements that can actually do this in nature , but use modern tools of protein engineering to improve upon their utility so that we can actually use mRNA and a lipid nanoparticle as a way

to bring gene therapy to the forefront , and do it not just by doing one or two small alterations of a genome , but actually to insert an entire piece of missing genetic material and cure a kid with a genetic disease , for example .

This has been a fascinating conversation , um , and I appreciate your time . Stay tuned .

There you'll find this and hundreds of other videos of our interviews with biotech builders . While you're there , subscribe to the Business of Biotech newsletter at bioprocessonlinecom backslash B-O-B . In the meantime , we'll see you next week , hopefully for part two of Storytime with Tal , and thanks for listening you .