Richard Jacobs: Hello! This is Richard Jacobs with the Future Tech and FutureTech health podcast and I have Stephen Ekker, Dr. Ekker is the dean of Graduate School of Biomedical Sciences, Director of the Office of Entrepreneurship and a professor of biochemistry and molecular biology at the Mayo Clinic, an adjunct professor in genetics cell biology and development at the University of Minnesota that he’s been there conducting genome engineering for 30 years. Oh, lots of other accolades Dr. Ekker thanks for coming on the line I appreciate it.

Stephen Ekker: Thanks for the opportunity.

Richard Jacobs: Yeah! So I mean, we could talk about many things you’ve done over the years, but what’s the latest and greatest that you’re working on and researching?

Stephen Ekker: Well most of the work we’re doing is really using genome engineering to actually touch the world. So I was an Undergrad, had the privilege of working with Carl Lowe’s, the University of Illinois where I was learning modern molecular biology. Well, I was intended to become a semiconductor physics design making chips and Carl convinced me that instead of figuring out what how to make the next generation computer chips, why don’t I figure out how the code of life work? It was a pretty compelling story and I would argue that what I’m doing today is really that vision 30 years later. We can now change the DNA that quickly, but we can change the DNA with the precision that you do edit a Microsoft word document or are you a program computer code? Yeah. So that’s the reality is here and so now the question is you can think of the code of life as a programmable system, what are you going to do with it? That’s what the excitement is.

Richard Jacobs: Yeah! Well, that’s what I was gonna ask you is what are your plans? What do you want to do with it? You know there are certain diseases that do you want to tackle what kind of modifications are you hoping to make and to what effect?

Stephen Ekker: Right? So a couple of broad thoughts is that you know, this technology which has really been cooking for 30 years is now active as I said, touching the world so there are products that are getting built and you’re the first commercial food products for gene with gene editing, have been USDA approved by the United States and the first products using gene editing for therapies for health are in the pipeline. So I just wanted to get it from a broader perspective. What does that mean? so we assembled the genome writers skilled which are a genome engineering society to really build and communicate the high-end value of this technology in general. What does it mean to conduct this kind of research changing the code of life in a meaningful way? Molecular surgery in some is a useful term. What are you doing in that space and how do you do it responsibly? That means also educating people, it means understanding what you’re doing, educating it. But it also means looking for where the real opportunities are to help the world and we like to think of that it’s going to come into one of two categories. You’re either going to make a current product better in some way. An example would be the banana, the ubiquitous banana and 99% of the bananas in the world are made with the exact same genotype that clones but once you’ve got as we currently have some sort of a disease all of those bananas, 99% of them are now subject to risk so tools like CRISPR and talens and the other technologies before them allow you to think strategically about building in such resistance with absolute minimum amount of changes. The banana was famous there was an earlier generation of the banana that underwent this blight kind of a scenario and you had to replace it with the current banana that’s resistant to that blight, but now it has its own blight. You actually had to do a whole new completely different banana to get into the current state. With tools like CRISPR, you can in principle make a very small change, and still, have the core product be the same. So there are going to be products like the banana coffee, cocoa these food crops, oranges, anything that’s a monogenic has the opportunity to have a gene-editing provide some sort of basically genetic diversity for these kinds of resistances while you keep the main trait intact. The main thing the main reason that you liked the navel oranges, right? Cause it’s kind of flavor and it doesn’t have seeds and grows well.

Richard Jacobs: hey! Quick question here. There’ll be interesting why not from a competitive standpoint deliberately engineer diversity into bananas, for instance, again, for competitive reasons, for waiting for blights for making the product more robust, you can make a series of similar Blevins again, but deliberately diverse even for flavors for various uses, etc.

Stephen Ekker: That’s for sure this is going to happen, one of the major concerns is actually regulatory you know so if you’re going to bring something to touch the world you have to think of the whole ecosystem. It’s not just the science behind it, but how do you make sure that this new technology is being developed and used responsibly? What does that mean? That means all the stakeholders need to have input.  Everything from the consumers to the regulatory agencies needs to be aware of the updated science you’ve got the public they’re a major push back against why you wouldn’t want bananas in the world. But then you have the history which is unfortunate of the GMO space where the value proposition was largely to the companies and only indirectly to the consumer through price. In this case, you’re talking about a difference. It’s a fundamental, you either do have the bananas at scale or you don’t have the product so I think it’s going to be easier to communicate to a lot of people why you would want to do this so I agree. There’s also the opportunity to have different bananas at different flavors because I mean the curved bananas all really tastes the same so it is the opportunity with this new technology allows you to think about these kinds of things that are very powerful.

Richard Jacobs: Yeah! It’s interesting if you think about wine I mean it’s true in this diversity in apples and then certain things, there’s no diversity. The name is like you said etc. Does that tell you anything, does that teach you anything about how diversity’s on a least the offended typically like small scale, like you jab apples don’t seem that different, but yet they are. Does it show you anything about attached to doing this in a good way for a crop like bananas or a pass to even looking at a population of animals or people or whatever it is for making changes that are sustainable versus not?

Stephen Ekker: I think it’s actually a wonderful way to celebrate human ingenuity. We’ve been growing, especially we’ve been moved domesticating plants and animals for more than 10,000 years. And it takes a long time to grow and combine and put the traits that have rapid growth, they’re hardy reliable products that we want. I mean if you look at corn versus the original a plant that led to the maze, you wouldn’t even recognize it. A human ingenuity, it’s just with the liquid. The CRISPR system allows you to do is instead of what takes a thousand years, in some cases you can do in one lifetime or faster and it is our responsibility as a culture is to use it wisely and I think we need to be thinking carefully about it but I think that in many cases what you’re doing is using the exact same approach that can be done with traditional breeding but you can do it much more rapidly. I’m using the CRISPR and it’s much more precise. There are far fewer different anticipated changes and you can literally sequence down to making sure that the change is just the one you’re looking for so it is actually one of those scenarios where it is and it is better and it is more precise. I think it really is one of those scenarios where in many cases there’s no known scientific major negative.

Richard Jacobs: Well I mean fundamentally legend has it that it’s not a one to one ratio a sequence, a particular sequence in our genome for instance, and one function seems like what a lot of overlaps. It might be tricky to do this without causing who knows.

Stephen Ekker: The concept of understanding and interpreting the genome and as a resulting phenotype that’s complicated. In fact, that’s my day job, my lab’s job is I’m trying to understand the genome and using these kinds of genome engineering tools to be able to do so, but you the technologies you’re replacing have all of those same concerns and they’re far, even less precise and controllable. So it’s not that we are eliminating those concerns but we’re still within those concerns. We’re actually being far more precise on what we can and can’t do.

Richard Jacobs: Okay! How do you do such a thing? You know you can cut out a gene sequence but something else in its place or just cut it out. How do you evaluate, how do you evaluate what it’s going to do to the organism besides growing one and seeing what happens to it?

Stephen Ekker: Right? So intellectually what’s happening in a number of the fields is you’re taking already existing illegals. So the experiments have already been naturally run and what you’re doing is you’re combining the genotypes much more quickly. The most obvious one, easy to communicate is the hornless dairy cows. So cows and various cow breeds have been bred for milk production or Angus beef for steaks and you don’t want an Angus beef to be your milk-producing cow and you don’t want the milk-producing cow would necessarily be your state a source and there are naturally occurring cows that are hornless but the primary dairy-producing cows that we use have horns and what we currently do is share them off and it’s not very humane and it takes time and effort and a company common etix has done, has figured out and how to use gene editing to just put the hornless trait in the standard  dairy cow background. So you’re literally taking the already existing experiments and you’re just doing it much more quickly. You could do that by breeding or pry for Yellen is six or seven or eight different generations of cows to be able to do it and still maintain the milk production. This allows you to do it in one step. So those opportunities exist. There are many opportunities like that existing or the resistance, right to various pathogens or blights in various animal and food crops and plant crops. Those are far more straightforward than when a lot of people throw up as complexity. We’ll just start with those. We just have natural experiments that are out there. We’re just using them, moving them around and putting those in place. We can start with those and get a feel for whether there’s anything that’s anticipated happening and it gets US products that are making our lives better.

Richard Jacobs: Okay

Stephen Ekker: So making new things that never been done before.

Richard Jacobs: We’ll go onto the making the new thing. It makes sense that something just nature and it seems to be okay. An animal with certain traits that seems a lot, same for them, they’re trying to make new things, but we’ll go ahead with the research there.

Stephen Ekker: Right! So new things are cool, right? New things are great. I’m very excited by that I think you can still do these in parallel. They are being able to improve current products like ice. I think the banana or the hornet’s dairy cow that’s good. That’s a good thing that’s a direct impact on the world in a meaningful way. It will also get us some critical understanding of anything in our background in terms of science while we explore in the labs, especially critical areas for new things and there are opportunities. I will give one example I would call living therapies. So the FDA approved a series of therapies that are either gene therapies, cell therapies, the most famous are these car T-cells. These t-cells, you turn them into Nanorobots to go out and target cancer and the patients for leukemia. And you do that by adding this artificial gene, a Comerica antigen receptor and it goes after those t cells can live five years or longer in the patient directly going out and killing all of the tumors and in some patients, many patients you’re talking about a curative. It’s an amazing story. It’s the checkpoint inhibitors really has brought cancer immunotherapy to the forefront. The problem with those products is that they are made with a viral factory to be able to put those cells in. The cost of those viral factories, I think roughly set up to something, I don’t know, $40 million. It’s many, many millions of dollars, tens of millions of dollars and so if you want to be able to make these new products go you’re either having to go after a large market size so that it makes sense to build that factory or you need to be innovative in the technology. The car T-cell built trying to figure out, but I think most of the technology was from like the 1970s or maybe early eighties. So I think that we have the opportunity to take the technology of the last 30 years and bring it to market too. Instead of it being $1 million a patient to touch them for car T cells to dramatically lower the cost at least of the technology. The healthcare parts, obviously that’s a cost. It’s going to be, a variable that you won’t touch, but you can make them cheaper and better and faster and I think that there’s at least a 10 x cost difference that’s available if you want to use especially non-viral approaches rather than the viral approaches and using technologies like car Ts or like gene editing, you can use it in such a way. I think that you can be much more precise on the products, which should make the regulatory costs lower.

Richard Jacobs: Quick question. Why would viral factors be so expensive? And then CRISPR cas9 is just from bacteria and not be as expensive, for instance.

Stephen Ekker: Well so the right now, the way we deliver the Chi Amharic Antigen receptor is a virus and it gets, and then it integrates into the cells. So you actually have to make that factory that makes the virus. So if you can probably, you can do non-viral approaches that are also going to be cheaper. That doesn’t use CRISPR. You’re going to do another gene-editing like transposons and there are a number of businesses, companies, and researchers that do that. The challenge that transposons are you’re still, every cell is a different product because the transposons reading integrates randomly. The advantage of, of gene editing such as CRISPR or talens or even zinc fingers, all of those gene editing approaches is the possibility that the product, each cell that comes out of the cellular factory can be very similar, much more similar because they can have an integration site innovation with a single copy of the same spot in the genome each time. And you can do that in principle non virally. So you can do this at a scale where you don’t have to have that big capital cost of the viral factory using a physical delivery system or maybe a chemical delivery system that doesn’t require such extensive capital costs.

Richard Jacobs: Okay. So these systems are much more precise, therefore, um, cheaper.

Stephen Ekker: The cheaper cost comes from the regulatory cost actually not from the production costs,

Richard Jacobs: Why is that?

Stephen Ekker: Every cell that comes out of a viral factory is different. And so you actually have to worry about all the potential manifestations of what’s going to happen to those cells. Okay. Including differential expression levels of the gene editing, the genome engineering product that you’re adding if differential expression. So you don’t really know which level of expression or even if the level of expression of whatever you’re adding the car vector that the camera antigen receptor or if you’re doing this for gene therapy, the gene therapy product, you know, you get this, you get this sort of place on distribution of differential expression. So when you’re doing the regulatory part, you actually have to account for the whole spectrum of outcomes, right? So that means it’s not just more expensive because you have the initial cost of the virus, but you then have to actually go undergo and really and really carefully characterized all of the products. The potential out that downstream outcome is for the non-viral systems in the potential, right. The potential end game is that every cell that comes out of it may sound quality control, could essentially be the same genetic change. So I mean does every cell could have a very similar expression in terms of what the gene you’re adding could actually have far fewer, worrying about, integrating it oncogenes and causing potential cancers and other side effects. Right. You really can and should be able to make it and once you’ve got that initial platform built, many groups are doing this strategy, then the subsequent platforms and subsequent platforms get cheaper and cheaper. It gives you the opportunity to have sort of Moore’s law kind of effect in biology.

Richard Jacobs: Yeah. I’ve learned a little bit about endogenous retroviruses and how they integrate themselves into our genes and then they can actually be re-expressed a little or reactivated by other viruses. So maybe viral vectors that the danger as well. I don’t know.

Stephen Ekker: I don’t think so. I don’t think so. You can, you can make them so that they can’t replicate. That’s pretty standard practice at this point. But you do have to make the viral factory initially and then the product itself cannot replicate. That’s part of the strategy for the factory.

Richard Jacobs: Okay. So what are some of the front runners for these methods, what do you think that is going to be common? You know, clinically for people? What kind of therapies?

Stephen Ekker: So I think the obvious one that everybody is, there’s a lot of people betting on is just a next-generation car t cells. So you’re looking at a car t cells that are going to go after leukemia’s that are resistant to car 19, which are the initial products. You’ve got many other, liquid tumors that are getting built and the sort of the next Nobel Prize sort of afterward is Kenny get car t cells to work in solid tumors. So all of those, all of that excitement is going to involve gene editing and genome engineering. It’s just a co add at its core. In all of those cases. I think those are excitement. I think there’s if you think about any of the cells that you can remove from the body and add back. So that would be pretty much anything in the, you know, anything you can give from blood donors is opportunities. Natural killer cells, B cells, other, you mean logical cells? Those are all very exciting platforms for these kinds of changes to become a novel living therapies down the road. And I was at the FDA meeting, I think they said there’s 700 between those straight gene therapies, uh, both the Cleevio and some in Vivo gene therapies. So like 700 imds have been filed. So were we had three that were FDA approved in 2018 and now we’re looking at this sort of pipeline to coming out. What I’m looking for is where the innovation goes from $800,000 a patient to $80,000 a patient to $8,000 a patient in terms of cost of goods. I’m looking for where those opportunities lie because these technologies have the potential to be hugely powerful and hugely value. But if you want to, you can use whatever lens you want from access, a social justice point of view, actually from a wealth generation point of view, you want to be able to have the cost of goods much lower than what we’re currently doing. I, and you know, almost all technologies go through this scenario where, you know, the cost was very, very high and I’m just trying to think the, you know, the first Mac I bought the Mac 2ci was wow. I think I paid $6,000 for it in the early, you know in the 80s. And that would be, what, $20,000 today, right? It really a very expensive computer. You know, hose things are hundreds of dollars today. So we need to get to the point where we’ve got this ecosystem going where the products that we’re currently doing are successfully solving problems in a cost-beneficial way, so cheaper, better and faster. And then we set ourselves up for this flywheel where the next generation where that feeds the profits from that and the ecosystem leads us to the next generation that’s going to be cheaper. So go from a, a single transistor. I developed it, you know, invented in the forties to your iPhone, but in the area of therapies. And the reason I’m excited by that is it opens up the door to really making custom therapies for patients where the goal is potentially n equals one patient where the patient shows up at the door for the center. And you actually design a custom therapy just for that patient and, and I don’t think that science fiction anymore, I think it is possible that for at least some classes of diseases where such a therapy is going to be possible.

Richard Jacobs: Yeah. Why wouldn’t it cost, you know, 500,000 or $800,000 for a single person to get car t therapy?

Stephen Ekker: Well, so I said it’s, so only some subset of the B cell lymphoma patients are eligible for car t cells in the market small and you have to go through, you have to pay for the cost of that factories. You have to amortize the factory over all of the patients that you can do. So it’s expensive. Its expensive costs to make the virus for each patient because it’s a personalized therapy for each patient. It’s their own t cells that are modified and it’s got that big cost to overcome the 40 plus million dollar factory that then has to be amortized over every single patient that gets a therapy out of it.

Richard Jacobs: Hmm. That makes sense. When we talk about the horizon, what’s the horizon one year, five years? At what point do you think that a lower cost regime will be available?

Stephen Ekker: Well that’s a great question. I was a march of dimes pre-doctoral fellow, so I have a march of dimes, was supported my graduate training. And I was told that gene therapy, you know, was going to be something I would see in five years, for patients with rare diseases, with birth defects. So obviously that didn’t happen, right? So I believe that in the next five years we are going to define the next wave. So where are the areas of car t cells for four liquid tumors like leukemia, how many of leukemia’s that are gonna be viable with car t cells? And then we’re going to find out whether other dispersed tumors like Glioblastoma and the brain or certain forms of skin cancer are amenable to car t cells. So I think the next five years you’re going to define sort of the boundaries and then those particular areas that are going to get significant investment in bringing the cost down and raising the access. So I look at that as sort of the next five-year horizon and you know, there’ll be five years and then another five years and various new tons of new products. In parallel you’ve got in Vivo gene therapy happening where you really do have these viral vectors and the viral factories and people are going to get very excited and maybe the curt factor that cost $40 million becomes $20 million, maybe it comes $10 million and maybe these costs go from $800,000 a patient to $400,000 per patient to $200,000 a patient. Those are all be very good opportunities because many of these patients, in $200,000 for especially if it’s curative would be a bargain for based on the overall cost of treating their condition from a financial point of view and from a human and social point of view, being able to cure them and or have substantive lifeline is hugely valuable for the quality of life. So both qualities of life and financial, those are boundaries are also going to be a lot of it defined the next five years.

Richard Jacobs: I mean, how many individual therapies have been created it aggregated over the past few years and it must’ve been, I would think substantial learnings to bring down the cost tremendously. Each therapy can be the that different candidate or is it just because of the regulatory costs that it’s just unbelievably expensive.

Stephen Ekker: Okay. Yeah, so that’s really a great question. If we have 700 of these imds coming out the pipeline, right, we can’t, they can’t all be these massive regulatory costs. I really actually think that the potential for, if let’s say, let’s say these therapies where we’re in abundance, luck and everything works, the healthcare, they would bring the healthcare system down because you can’t afford those costs. So it’s going to be interesting about this Bolus of 700 plus imds. How many of them get boiled down into defined areas may be based on the different vectors their systems that are using. Yeah. Maybe that’ll get us even a twofold cost efficiency is probably worth on thinking carefully about right now. I think the 5 to 10-year horizon, I was giving you the zero to five. I think the five to the 10-year horizon is can you really do it at a 10 x cost? Can you really be the next, the truly the next generation? So that in such a way that all aspects of it is cheaper, including not just costs in terms of financial, but can you much more rapidly iterate on, can you do so with fewer patients because you’re more likely to know what you’re doing? Can you iterate and do the whole cycle, the whole therapeutic development cycle substantially, quicker than what we’re currently doing. I don’t know the answer to that, but I, that’s where I look at for the five to 10 years because I think that’s the enormous opportunity.

Richard Jacobs: I mean, we have been able to bring down the cost exponentially if so many things, once it’s understood, I can’t see that this couldn’t happen with this, I can’t see them different from everything else. Computer chips in it just seem like it’s going to get there really cheap level.

Stephen Ekker: What about insulin, right?

Richard Jacobs: That’s been rising the cost.

Stephen Ekker: Yeah. Yeah.

Richard Jacobs: Is that because of price manipulation or is that really because it’s all of a sudden harder to make?

Stephen Ekker: No, it’s an economic ecosystem issue. It is not a scientific issue. So, you know, I’m more than willing to have those conversations and I think those are the conversations we need to have. Right. What from a society good value point of view. I mean insulin was patented but the patent was sold for $1 for the humanity. We haven’t taken that gift and really made it as effective and as open as we should for whatever political, capitalistic reasons you want to give. I think we need to think carefully about this. The genome writer’s guild for example. I just put it out there. We are, our discussion is not just scientific. Okay. It is about access. It’s about who should, who and how should we set up the system to properly function when a traditional capitalistic society is going to, you know, should strongly encourage the cost of an antibiotic, should cost you $50,000 a treatment. Why? Because it’s lifesaving, you know.

Richard Jacobs: You said in some cases it’s, well not as easy as, but as a direct, as editing a Microsoft word document, any chances that this technology can be used by, I don’t know, people not in the lab that are just experiments again, caused all kinds of problems or by bad actors. Is there any talk of that or is that really remote?

Stephen Ekker: No, of course. I mean, the China experiment with people is inexcusable. But it was a technology that wasn’t the, there was full of predictable complications and different complications. But it was also, you know, as far as I can tell, I mean, I don’t know all the data firsthand, but a lot of the documents were forged. So you’ve got a bad actor that’s taking a technology that’s very accessible and using it. Right. And then there’s this Russian scientist, I’m not using their names intentionally because I don’t want to give them the celebrity, but you have a Russian scientist who’s interested, who’s basically saying are you gonna do the same thing? Right. And the technology is out, the Horse is out of the barn. What is remarkable about it is, it is a thousand times cheaper than it was in 2011 or more. I’d even be less than 10, maybe more than a thousand full cheaper. And that was done over, you know, an eight-year period or less. Something that’s a thousand times cheaper. Right. We have the axiom to something that’s 10 times cheaper is a new thing. Even though it does the exact same thing. We’re talking about something that’s a thousand times cheaper. We haven’t caught up. We haven’t really, in certain areas like a germline gene editing germ, I would say germline, a discussion. We don’t even have IVF regulated in most parts of the world and you know, preimplantation diagnosis with simple DNA sequencing, freezing down the embryos, doing sequencing to figure out what you’ve got and then selecting the embryos that go, you know, for the surrogate mom. There’s tons of potential for bad actors to innovate. And then if you add the CRISPR system to that ecosystem, which only costs, I still asked him, it was only maybe $400 with what was done in China to an experiment, really modest cost to do these other things. It lends ourselves to high peril and high concern. I’m worried that this is going to disrupt the scientists that are really trying to do this with responsibly and prevent the good because of a few bad actors.

Richard Jacobs: Well, very good. What’s the best way for people to learn more about the work that you’re engaged in, the discussions, the pros, and cons of the issues? Where can they go?

Stephen Ekker: Yeah, so the genomewritersguild.org is our website. It’s a nonprofit for sharing and communicating. We have an annual meeting that includes as many constituents as you can from there’s material on the site itself. As a scientist, I encourage you to follow the CRISPR field, although it is almost impossible to follow it all. But I think there are meaningful discussions that are happening in a few groups. There is the Haresh group in Europe that’s also very much active in these kinds of public communications. I’m one of the external, one of the American board members with collaborating. There’s a Japanese gene editing society. They are very interested in public communication and engagement, really engaging and trying to focus on educating the public on the good of this high potential value system. But also sitting back and saying, okay, where are the lines, where are the things that we shouldn’t be doing right now? In a meaningful way. But that engagement is important, but it’s difficult. I’m just going to say it right now. We’re dealing with the human germline is very difficult because we’ve avoided having that engagement essentially since IVF was developed. IVF has largely non-regulated or in globally. Okay.

Richard Jacobs: It’s not regular? What do you mean it’s not a regular house?

Stephen Ekker: In most places in the United States, there’s no regulation. You could set up your own IVF clinic tomorrow.

Richard Jacobs: Well that’s pretty bad. Okay. I didn’t realize that.

Stephen Ekker: Yeah, this is where we’re at. Right. So, you know, it’s difficult. I’d like to have a much deeper conversation, a reality the details for how you want to do gene editing and the germline. What would be reasonable when you can’t even start to have that conversation because the IVF clinics are not even being regulated?

Richard Jacobs: Okay. Well very good. I appreciate your time and your frank discussion. What’s the best way for folks to, again, I don’t know if there’s any follow-up with you or it’s better to go to the foundation that you’re working with and what’s the best way for people to learn more? Where is it already been discussed? And we’re kind of leaving with that.

Stephen Ekker: I strongly encourage you to go to the genome writer’s guild website that’s designed for public communication engagement. Ask questions there. And there are a rich group of international scientists excited to have the conversation and end to answer anybody’s questions.

Richard Jacobs: Very good. Steve. Thank you for coming.