Disclaimer: This transcript is auto-generated and has not been thoroughly reviewed for completeness or accuracy.
[00:00:00] Gus Herwitz: This is Tech Refactored. I'm your host, Gus Herwitz, the Menard Director of the Nebraska Governance and Technology Center at the University of Nebraska. Today I'm co-hosting the podcast with Crystal Shepard. In addition to being a distinguished fellow at this center and having taught patent law here at Nebraska since 2011, she was the inaugural director of the Midwest Regional Office of the United States Patent and Trademark Office, and has a PhD in cellular and molecular biology.
All of that makes her the perfect co-host for today's show because we'll be discussing the gene editing technology called CRISPR.
[00:00:39] Christal Sheppard: Thank you, Gus. I'm really loving being here today. Thank you for inviting me because, um, my molecular biology background makes me a total nerd about these things. I could not wait for this.
[00:00:49] Gus Herwitz: Yeah. We're, we're going to, uh, definitely nerd out on this one, or at least, uh, you all are. And I'm going to, uh, uh, sit back and watch.[00:01:00]
On today's episode we're discussing crisp. Which is a gene editing tool that acts like a pair of molecular scissors, which are capable of cutting strands of DNA and stitching them together. CRISPR technology is a simple ish, but extremely powerful tool for editing genomes. It allows researchers to easily alter DNA sequences and modify gene functions.
It should go without saying that this is equal parts. Very cool, and potentially very scary. So here joining me and Crystal, uh, we have two experts in the. Jacob Sheko is a professor of law at the University of Illinois, where he is also an affiliate with the Carl r Woes Institute for Genomic Biology. His research focuses on the legal and ethical implications of advanced bio technologies, especially is relating [00:02:00] to intellectual property.
He is a leading expert on IP protection for genome editing technologies, including crisp. Dr. Samantha Zions or Sam Zions is a fellow at the Center for Law on the Biosciences and a research fellow of intellectual property at Stanford Law School. Her research focuses on emerging technologies, intellectual property strategy, and the influence of institutions on innovation.
Her projects and publications have empirically analyzed a range of topics, including the adoption and diffusion of CRISPR.
[00:02:30] Jacob S. Sherkow: Thanks for having me, Gus.
[00:02:33] Samantha Zyontz: Thank you very much. We're excited to be here.
[00:02:34] Gus Herwitz: Yeah. Okay. So, uh, let's just jump right in. Sam, a lot of people have heard about CRISPR and DNA editing systems.
Perhaps, uh, we talk a lot about gene editing, at least casually in the news, uh, nowadays, but don't necessarily understand what this technology is or how it works so that we're all on the same page. Can you give us a brief explanation of what the heck we're talking about today?
[00:02:58] Samantha Zyontz: Sure, Although I'll [00:03:00] defer to, to Crystal for any of the super technical, uh, biological details straight up front.
I'm an economist, but the way I, I, but I study innovation and so I have to explain these kinds of concepts to business people. So I'm gonna do it that way here. So first, CRISPR stands for clustered regularly, interspersed short pmic repeats. It's actually, we use the same term for two different but related concepts.
And I think it's important to kind of like think about these two different things in terms of our conversation today. So CRISPR itself is actually a naturally occurring system that bacteria uses to protect themselves from viruses. And the reason CRISPR got its name, Is how a bacteria actually encode viral DNA in their own DNA in order to protect themselves.
So basically what happens is after surviving a viral attack, bacteria will store a piece of the virus in their own [00:04:00] DNA between these short sequences that read the same forwards and backwards, hence thero. All of these sit in the same piece of DNA in the bacteria. And basically what happens is it has these short little pieces, and then there's a piece of viral dna, and then there's the short, another short piece, which is identical to the first one, so repeat.
And then there's another piece of viral dna, maybe from a different virus, then another repeat, et cetera, et cetera, et cetera. And it's basically the way that bacteria learn and. So that when it's attacked again by the same virus, the bacteria can use that storied viral DNA to identify the intruder, and they use an enzyme called CAS nine, which is usually one we talk about to cut the virus in pieces.
So hence these molecular scissors concepts that you've heard about, and it just destroys it. The important insight though, that we're gonna talk about today, that scientists like Nobel Prize winners, uh, Jennifer Dow and Emmanuel Sharpen D had, was that the CRISPR [00:05:00] system that bacteria had been developing for like billions of years isn't limited to just finding a virus.
So, uh, so usually the way I ask people to think about it, and it's not a hundred percent like technically correct scientifically, but I think it's a, it's a good mechanism for people to think about is think about your word processor. So in your word processor, there's a target document. Strings of letters, you know, that tell us a story about certain things.
And in that program you can indicate a string of letters to find a particular word. So say I wanna find abstract in, in, in the first page of my document. Um, well then I can just type in abstract, tell the program, you know, to go find that word and then cut it at the location it's found. If I wanna remove it.
The very basics of crispr kind of work the same it. We need a set of target DNA in a particular cell or a test tube. So that's analogous to our Word document. Um, and then you can indicate sort of a string of letters that match [00:06:00] a gene within that target dna. You wanna find, we call it a guide RNA or a, or a single guide rna.
Sometimes you'll see it. And basically we just program that guide rna, which is a sequence of, you know, letter. To find that sequence in the target dna, we package it together with the molecular scissors or an enzyme CAS nine, and basically we package that system together. We throw it into a cell and the guide RNA will go look for that very particular G.
And once it finds it, the DNA or, or the, sorry, the guide rda, uh, will stop there. The enzyme will surround the area, cut it straight out. So at its core, I often say, Look, really it's two pieces. A little more than that, but it's really two pieces. It's a guide sequence that tells you where to go and an enzyme that cuts or, you know, modifies the, the DNA in some way.
[00:06:52] Gus Herwitz: So I have to, uh, ask, just because this is so much in the news right now, you've been saying DNA and rna, [00:07:00] and obviously we've got discussions of mRNA, uh, vaccines. I'm sure lots. The obvious question a lot of people are going to have is, is this related to the mRNA vaccine? In the same ballpark or at least completely unrelated concepts.
[00:07:14] Samantha Zyontz: I actually don't actually know a ton about the mRNA. So Crystal, if you wanna jump in and help me here in general, not exactly right, like this is about editing dna and certainly if we wanna talk about how CRISPR's associated to C, it has to do with the fact that CRISPR itself is actually many, many different types of tools, depending on the enzyme that you use.
So we actually have screening enzymes, not just cutting enzymes. And so what we're using. CRISPR for now in terms of Covid is trying to figure out, can we scan somebody's, you know, DNA segment, say, can we find, you know, is, you know, and basically ask, is there, you know, can we find the, uh, c. Virus here. Right.
And if we can, [00:08:00] then basically the screener enzyme will say, Hey, it's here, you know, and, and throw up basically a flare. Um, and now we have our diagnostic test. These are still being worked on. Obviously they're, they're not approved just yet, but like, that's how it's, that's how it's working. Although, like I said, in terms of the mRNA stuff, I'll have to, I'll have to defer
[00:08:20] Christal Sheppard: Sam, I totally agree with you what you said about the crispr. Yeah. You had it perfectly correct, but what I like to tell people sometimes is there are a lot of naturally occurring things that happen in ourselves every single day, and all this is doing is scientists have figured out what those things are.
And they've used it, you know, used it for their own purposes, one of which is to go in and edit dna. And this already happens naturally by viruses, by bacteria. It happens without you knowing about it. But now we can direct. And say, Okay, we wanna change from blue eyes to brown eyes. We can change all these different things.
And it's not just that CRISPR is [00:09:00] some, you know, some revolutionary technology that didn't exist before. We had PCR before. So a lot of times people are talking about these technologies, like they didn't exist. It's just that CRISPR is faster and more economic.
[00:09:13] Samantha Zyontz: Exactly. I, I, I completely agree with that.
[00:09:18] Gus Herwitz: So Jake, let's, uh, try and bring you into, uh, this conversation and just to demonstrate how over the, my head I am in this conversation, I'm going to ask the real fancy, pretty question of, Why does this matter?
Can you, uh, explain, uh, why this is, uh, so important,
[00:09:34] Jacob S. Sherkow: uh, uh, a tool? Yeah, sure. So, I, I think it's important to kind of go back to the literal dawn of dna, right? This is DNA Day, April 25th, 1953. This is when Watson Andrick and unfortunately left out, Rosalind Franklin discovered the molecular structure. Dna, the kind of a C's, T's and G's that we've all come to know and love.
Well, you know, just like the weather, right? Um, [00:10:00] everyone then knows about dna, but no one can do anything about it. And so there's a long period in molecular biology afterwards in which the capacity to edit dna. Is pretty poor. This starts to ramp up in the, you know, seventies, eighties, the lesser extent in the nineties.
And so we start getting some methods to be able to edit DNA in some senses, right? These methods though, they're pretty cumbersome. So if you wanna think of it like a computer for a second, rather than, you know, typing in whatever you would type in in your IDE to reprogram your computer, it's like you have to build a brand new computer every time you wanna edit a specific gene.
That's obviously a problem. And so what CRISPR's principle advantage is as it comes along is that the only thing you need to do to program the crispr, like Sam was saying before, to program the enzyme that effectuates the either seeking or the cutting, depending upon what function you [00:11:00] want is, is not the enzyme itself, but a short piece of RNA.
Roughly somewhere between 20 bases. Again, these are like the acs, T's, and G's. Somewhere between 20 to 30 bases long. That's really, really easy. There are companies, you just go online, you type in a string of letters that you want the, you know, you want your. CRISPR to find within the genome or some sequence within a test tube, and then we'll mail you a test tube of millions and millions of pieces of just that purified RNA sequence.
Actually, we were talking about this a little bit earlier about like, you know, what's the difference between DNA and RNA? So I used to be a lab technician in a former life, and so we got a bunch of like lab tech swag. And there's this company called Amon, not to be confused with the drug that used to make RNA like you would go on the computer, you'd type in the sequence that you want.
And so to encourage lab technicians to push their principal investigators to [00:12:00] purchase their RNA from ambi beyond. I got a T-shirt once and you know that old ad that says pork, the other white meat? Well, I got a T-shirt that said rna, the other nucleic acid . And I wear it around proudly. It's like the absolute nerdiest piece of clothing that I possibly own, but that's another way of thinking about it, right?
This relationship between DNA and RNA. RNA and there's a lot of different types of RNA. It's just DNA's molecular. That's it. So this is what the importance of it is, right? It's programmable, it's cheap. You don't need a whole new machine to do it, and you can really do anything that you want. It's been demonstrated to work, at least this type of CRISPR that we're talking about.
Type two, CRISPR Caine system, right? Works in any cell system where it's in any organism that it's been tried before. And so maybe a way of thinking about the importance. Is that the possibilities for CRISPR lie almost entirely in the imagination of scientists and the limits, if there are any, are biological, like things that [00:13:00] genes can or cannot do.
Not technical things that we have difficulty doing in the lab. Right?
[00:13:07] Christal Sheppard: So thank you for that explanation. It was wonderful. I wanna, I'd like to riff off of your mRNA thing, but I'll do that later cuz that'll, it'll just start making this way too nerdy. But I do have a question about how is the scientific and legal, legal community responding to some of the concerns that are coming up?
Have you heard any concerns? Are there laws, are there scientific standard? Has anyone gotten into trouble? And, you know, I'm asking this question knowing that this is not new. Um, and some of these conversations have happened before, but what, what are your thoughts, Jake or Sam?
[00:13:38] Samantha Zyontz: Well, I'll, I'll, I'll drop in, Jump in real quick, just riffing off of, of the conversation we were, were having about it's importance.
Like some of it is not only is important, but it's very fast. . Right. And so, you know, my recent, one of my recent papers, I've actually shown that, you know, in less than 10 years, there's, you know, 11,000 academic [00:14:00] articles. Over 4,000 worldwide patent families involving crispr, 50 clinical trials of therapies, uh, and hundreds upon hundreds of companies developing or selling CRISPR and CRISPR related tools.
So like even to get our hands around sort of the. Ethical, uh, portion of this, like we might have kind of missed the boat cuz it's, it's just, it's just flying, you know? And we really went from not really knowing what we had in 2012 when it was first introduced to editing viable human embryos in 2018. And that's been the big conversation lately.
Um, I often like to say, you know, anytime we talk about g uh, you know, gene editing, we, we, we go to Gatica real fast. uh, you know, I've been studying the social science of this since 2014 and, and Gatica and, you know, the island,
[00:14:50] Gus Herwitz: Dr. You're the one who brought Gatica up and, uh, oh. Island of Dr. Murrow was my next question for you.
[00:14:58] Samantha Zyontz: So comes up really fast. I think we, we. [00:15:00] Uh, like all things science fiction, right? We, we, that become real world, we, we like the creativity and sort of the thrill it gives us as, as a culture for, ooh, like what can we do versus what can go wrong? And so before we, before I ever start the ethical conversations, which are super important, I always like to say, Look, we gotta remember sort of like what the reality behind some of this really is.
You know? You know, yes, in theory we can do. But at the moment there are still some limitations, right? We don't know everything that CRISPR can do. And then some of my earlier research, I actually found that like doing mammalian research actually isn't as easy as you think. You can't just pick up crispr, use it and make it work.
So there are still some barriers that are happening right now, but very quickly we're losing them. So now is really the time to start. Thinking about some of this. And so two of the areas I've heard lately is, is that most people are most concerned about is one. Of course, you know, bio weapons folks are extraordinarily concerned about that.
But the biggest conversation right now has been [00:16:00] about germ line, human germ line editing, and that started in about 2015 or so originally and really heated up after Adhesion Cow announced to the world at the end of 2018. Hey, There are live humans that have been CRISPR edited and they can pass this on to their kids.
[00:16:18] Gus Herwitz: Can, can you, uh, tell us, uh, that that's probably one of the most famous incidents, but can you give us a bit of just a brief capsule, what happened in that incident and what was, uh, the response to it?
[00:16:32] Samantha Zyontz: Well response to it was, everybody freaked out, rightfully so. Um, and, and Jake, please jump in here. Uh, if I, if I get some of the history, uh, incorrect, the history sort of, this has been certainly.
People realized very quickly that CRISPR was flexible enough to use on human embryos. And originally in 2015 it was non-viable. So we were actually editing, you know, human, you know, human, human, human embryos to see, you know, can you [00:17:00] actually, you know, make the chromosome different. Uh, the answer was yes, and so Jennifer Doudna, and actually Jake and my colleague, uh, uh, Hank Grilly and a bunch of of. Very important. Bio bioengineers and bioethicists got together at Napa in, uh, 2015 in, in sort of echoes of aciar, uh, to say, Okay, like this is gonna be an issue. How do we as a community get together and put together some, some standards and thoughts in the general sense was, yeah, we should, we can't like throw the baby out with the bath water, but like, time out on.
On the whole, you know, human germline editing thing, until we actually have any sense of like what CRISPR might be doing, what our cuts are, what mutations we might get, and what does this mean ethically and socially. And most countries are like, Yeah, fine. Not a problem. Right? The US is, you know, the FDA does not allow anybody to do human germline editing that they will support in any way, shape or form China and Russia, however, [00:18:00] Little more lax.
And so my understanding is that the scientist in, in China actually studied in the US for a while, was a, was a fertility doctor, was interested in being able to edit the genes of, of basically embryos so that they would not be susceptible to getting hiv. And it's actually a, I'll put it in quotes, simple, uh, use of crispr.
Uh, we know what this gene does. It's been studied pretty, pretty standard, uh, or it's been studied a lot before. You know, obviously we've never tried, you know, editing a human like this before, cuz we couldn't. And so nobody knew what was gonna happen, but he decided to do this. He said, ah, you know, it's, it'll be, you know, it'll be great.
It'll help the kids. Unclear whether the parents knew what they were signing up. Um, and so two children were implanted into a Chinese woman in her, you know, uh, uh, in vitro, uh, [00:19:00] fertilization. Uh, they're twin girls. They were born, um, in, uh, November, 2018. And they technically have this particular gene edited out of them.
Uh, it was announced and he came in and he announced this at a big meet, big meeting in 2018, uh, right after it happened. And everybody. Oh my God. What? ,
[00:19:23] Jacob S. Sherkow: I mean, I think, I think one of the most amazing parts of history was that it wasn't just like some random scientific conference, right? This was the second international annual human Genome editing summit that was co-sponsored by the National Academies here in the United States, the Royal Society and the National Academy.
Um, in Hong, in Hong Kong. Right. Um, and part of the summit was specifically to discuss issues like these. So having someone just walk on the stage and be like, I did it is like pretty astonishing. So if you want a good analogy, right, like imagine for a second. Like someone just came up with the [00:20:00] principle for atomic energy and you're gonna have a summit to make sure that nobody ever made a nuclear bomb.
And at the second one someone just gets on the stage and be like done. Right? It's kind of nuts if, if you want a really amazing, concise and colorful history of just like the play by play, about what it was like to be there. Kevin Davies, who used to be the editor for Nature. Medicine has a book, I think the title of it is Editing Humanity.
And it's a great read. It's like really well paced. There's a, there. One of the cool things about CRISPR is that it's developed a cottage industry of CRISPR history books. So, uh, I think Kevin Davies is the first. Walter Isaacson's is about to come out. Hank really is coming out this month, I think so.
[00:20:53] Gus Herwitz: The example of the Gina baby, that's obviously an important and pretty scary example.
Um, what other [00:21:00] examples are there? I assume I, I know I've heard there's a well known NPR story about, uh, sickle cell anemia, I believe, and, uh, CRISPR being used to address that. Um, what, what are some of the, the good stories and good examples of what this, uh, uh, technology. .
[00:21:14] Samantha Zyontz: Well, I'm really glad you asked that, Gus cuz cuz this is my point about, you know, we get to Gatica very quickly, but, but actually there's so much good that comes out of this technology.
So there are, as I mentioned, there are about at least 50 clinical trials going on worldwide right now using CRISPR as a gene therapy. Um, and it's really opened that world back up. So we are trying to create new therapies for. As you mentioned, trying to cure sickle cell anemia in individuals. So they won't pass it on, but we can cure it.
You know it in people. Muscular dystrophy is another one that they've been working on, um, certain, uh, eye diseases that they're trying to solve. And these are all ones that are actually in clinical trials. Uh, What CRISPR's actually done also is just sort [00:22:00] of expand the world of things we can actually even look at carefully.
So, you know, we understand Huntington's to some degree, but CRISPR's actually really allowed us to understand what all the interactions are and build models so we can understand the diseases better. The hope is that maybe we can get to complex diseases like Alzheimer's, um, and it's not just. Right. Uh, one of the most important areas that I think CRISPR is going to start showing up in, and I believe Jennifer Dowd has said the same as in agriculture, right?
As, as you know, we can edit plants really well, and technically in some jurisdictions, they're not GMOs because we're not introducing anything, you know, not part of the system. So you can get. Drought resistant crops as the world gets warmer or we can get blight resistant, uh, rice so that, you know, we get higher crop yields, um, you know, uh, tomatoes, that, that ripen later.
Various things like that where we're really gonna be able to see that. And those will be actually be some of the first products we see on the [00:23:00] market, uh, using crispr well before we'll see any actual usable, uh, medical applications. I kinda wanna go
[00:23:06] Christal Sheppard: back to, um, something you said earlier. I feel like Gatica, So Gatica is a great movie with the world's worst name , but it has for for good reason.
The Atgc, um, situation, that's, that's all they had to work with. And talking about history and writing about the history of these, of these events. Unfortunately, like I'm kind of old and I remember having these exact same conversations back when p PCR first started, when, when restriction enzymes first started and having how the, the Berkeley and other universities said, Oh, you're not gonna be cutting up jeans here.
Go away. And that's how Silicon Valley started. So as a, as a professor, I'm always saying to my students, Okay, how does the law react to advances in science and technology? And people always think it's something brand new and you know, you've gotta make new rules. And when, when actually. We have seen this bef, you know, seen this [00:24:00] before.
Um, any comments about that? I know you were saying earlier, Sam, that it's this happening so quickly. It's more, it's happening so much more quickly than it happened like in the 1980s. Um, and I do also wanna get to the Nobel Prize, which they won Nobel Prize in 1980 for the exact same type of thing, but this is more precise.
[00:24:19] Jacob S. Sherkow: So there were these other technologies. Before. Right. Um, and so just kind of list to rattle off a couple of them. I, I realize this is like a podcast that's been shockful of acronyms so far, but I mean, hey, you know what's several dozen Molecular biology acronyms? Among friends, right? So, um, you had a technology for a while ago, and this is not an acronym called Mega Nucleases.
There's actually a big patent fight about this with the Duke University and this French company called Selectus for a while. Mega NUS are exactly as they sound, they're nucleases and they're mega. Those were like really dead. This was essentially. You having to recreate the computer for every [00:25:00] gene sequence you wanted to find within the genome that has its ups and its downs.
It's really, really hard. Technology never really took off immediately prior to crispr. You get these two other pieces of technology coming out. One's called ZFRNs. These are zinc, finger nucleases, and you get another one called als, TAENS, with his transcriptor activator, like effector, nucleases, right?
Um, and these are essentially modular components that can recognize different two or three letter, depending if you're in the ZN or the talons world. Two or three letter stretches. Of, uh, genomic sequence to do the editing there, but they have some hangups and limitations too, right? Um, and so these were technologies that were lauded when they first came out, but they did not have like the uptake that CRISPR had when it came out.
So if you want a good example of this, right? I don't know if we've still broken the [00:26:00] 5,000 Journal article barrier for either XFN or Talons. You can, I don't know, go on Google Scholar and try to figure it out. In the one year after CRISPR comes out, we get over 4,000 scientific papers that cite just crispr, right?
So you have all these molecular biology research labs out there that were doing a bunch of typical recombinant DNA technology stuff, you know, a little bit. Nle, a little bit of restriction enzyme here. A little bit of li gaze there. We'll make a bacterial clone, right? Um, and they all pivot on a dime. Um, uh, I mean, honestly, like we're talking about different tech.
I mean, I think the only really analogous technology is like pcr, which, you know, has its own like wig history too, right? If you wanna wig history of it, let me recommend Paul Rao's book, um, Making pcr, Um, anyway. Yeah. I mean, so like they, they like all have their own kind of stuff behind it. I mean, it's a, it's a interesting, [00:27:00] So on one hand, yes, it's a, it's a continuation of restriction enzyme research, which we've been doing now for, good god, I don't know, 60 years, right?
60, Yeah. 60 years. Yeah. Sixties. We've been doing this for 60 years. On the other hand, like, I think we've finally broken the. You know, spectrum between differences in kind versus degree, right? You know, like Marconi Telegraph, wireless telegraph. Okay. That's like kind of different from the internet, you know, like, I like get, it's like signals through the air.
I, I get that. But like, I think we've like finally like kind of gotten over the, this is a different thing, hump. That's just my, that's just my opinion. So,
[00:27:45] Christal Sheppard: So Jake, the analogy I have in my head is, is you know, so you're talking about, um, Beta Max versus bcr. Yeah. totally right. And I'm sorry, you had the, we had the ethical questions.
Um, and I don't know if you wanted to talk [00:28:00] more about that or we could talk about the intellectual property and the fights between one school versus versus the other and who got the Nobel Prize and who's still mad.
[00:28:11] Jacob S. Sherkow: Uh, Christal with you on the podcast, Like how, how do we not talk about patent stuff?
Right? I mean, this is like crazy, right? So, so let's talk about the patent stuff. There used to be, A medium. Clean version of this story. And by clean I mean like relatively simple, not like there's an explicit version and there's a clean version. Like it's just like there's a relatively simple version, um, and it has now just metastasized.
So, so let's start with the really basic simple version, right? The like basic, simple version is Jennifer Doudna, now Nobel Prize winner, and Manuel Sharpier, also now Nobel Prize winner. Are at a conference in Puerto Rico. One of them is [00:29:00] studying, uh, CRISPR as a bacterial immune system. One of them is a storied, even then rna, uh, biologist.
This would be Jennifer Dow. Um, And they essentially realize that they're working on, you know, I don't know, two opposite sides of the spectrum. And if they come together, they can do really something great. Um, so they end up building what seems to be the first engineered, and I think it is important to add that word here, the first engineered crispr ca nine system, right?
As Sam was mentioning earlier. Crispr, it didn't get invented in 20, in 2012. It has been on earth for, I don't know, you know, maybe 3 billion years. I don't think we could actually run the molecular clock back that far. , right? So, I mean, um, uh, so eventually they create the first. Engineered and engineerable.
CRISPR Cas nine Type two. CRISPR Cas nine system, Roughly speaking in 2012 and there is this open, outstanding question about whether or not it's going to work in the cells [00:30:00] of higher organisms, i e not bacteria, right? Um, Uh, uh, as the story goes, uh, our Broad Institute of MIT and Harvard vda Kin Fang, um, is at a conference.
He reads about this, um, and decides that he's gonna try to get it to work, uh, in a u carry system. Flies back home from Florida. And, you know, uh, a couple of lab experiments later, um, is able to demonstrate two things, is able to demonstrate that with only slight modifications, it can work in the cells of higher organisms like human cells.
Um, and then also, you know, because it's programmable, you can feed it a bunch of different RNAs at the same time and it'll make a bunch of different cuts. Uh, molecular biologists these days like to, Plexing, Right. Um, so these are the two contributions. Well, lo and behold, right, like everyone's going off and filing a bunch of patent applications based on their iterations of the technology.
Jennifer Dow [00:31:00] and Emmanuel Sharpier and a bunch of other casted characters first and fun jean's second, um, for a bunch of reasons, which I'm more than happy to go into detail about, but, uh, maybe please don't, a bit nerd even for. This podcast, which is like truly breaking the barrier. Um, Fong's patents get issued first, and Jennifer Daniela and Emmanuel Sharp's patent application Languishes, um, they file for a petition for interference.
Um, a or a suggestion, I should say, this is the appropriate term with all these funny, archaic, uh, patent office terms, right? They petition for a suggestion of interference, um, which eventually is granted, and we, uh, uh, eventually have a trial before the patent trial and appeal board as to whether or not fun Young's patents.
Are interfering with the issuance of DA intra PTA's patent application. [00:32:00] To answer that question, the first question you gotta answer is what the, What is right? Like, do they have the same invention or not? And our patent trial and appeal board, who I'll just say, has a presiding judge that has a PhD in molecular biology, she knows very well, like the underlying science about what's going on, decides that these are in fact, Patentable distinct inventions, right?
Doing this technology in the cells of higher organisms versus doing this technology in the cells of only bacteria. That would seem to kind of end it right there, right? Like that would like kind of seem to end the dispute. And so here is where things just get totally bonkers afterwards, right? Go back to the patent office for reasons that still mystify.
Most patent attorneys, their application turns into a real patent. It gets issued. Right. Then they have a bunch of other patents that claim priority to that patent. [00:33:00] Those get issued and then the patent trial and appeal board on its own volition says, Wait, wait, wait. Slow down. I, I don't think we really telegraphed what we wanted to say last time.
they issue a second interference ante, which is essentially. Almost the entire story about where we are now. In the intervening time, another company called Tool Gen from South Korea had unbeknownst to anybody, patents covering the same technology, and they petitioned for an interference, which the Patent Crown Appeal Board just granted a couple of months ago setting.
What I mean, I don't know how you, what you described this as setting up like the second double triple interference, right? You got two junior senior parties and one interference. You got a three-way interference on the other side. This is the second or the first one, um, that's now essentially winding its way through the patent trial and appeal board.
Who's gonna win? I have [00:34:00] absolutely no idea, but I will tell you this. Uh, if you're a patent attorney representing any of. Uh, parties, uh, it's a good line of work to be in. It's a full
[00:34:09] Christal Sheppard: employment for patent attorneys. Um, lawsuit. Absolutely. There's a couple things here, and we don't wanna go down this patent route, but you, you're using the word interference and I think most people don't understand what that means.
Basically, it's to say who's first and everybody else loses. So that's why it's so important to say. I was first, and the rest of you, you're too late. You know, Second place is just First Loser, right? So , these two are going at it, right? And then a third person comes in and even though it's a different country, it still could be that maybe no American has it.
So the other added fun part about that is that the Supreme Court is being doing a lot of fun things when it comes to naturally occurring. Natural occurring items, um, naturally occurring products, including dna. So [00:35:00] we all have no idea what's gonna happen here, although, as Jake said, is engineered. But most of these things existed and did these things prior to the human beings being, being, um, what we know of, know them to be on this.
[00:35:15] Gus Herwitz: There's this massive story, uh, of all these fights, um, and I, I'm learning things about it that, uh, I, uh, uh, didn't know, uh, as someone who, uh, uh, has some interest in the area. But the, the background meta question and, uh, Crystal, I'll, I'll ask you this question. Is this sort of fighting normal in the patent system?
Is it good for the patent system? Is it healthy? Is this how we want our innovation system to be managed? Does this sort fighting actually produce and promote innovation? Question.
[00:35:47] Christal Sheppard: Well, you know, there's, people have different ideas about, about what the patent system is supposed to be for and you know, I'm not gonna get into that.
Does it help the patent system? Well, the first thing I'm gonna say is when people hear about these cases where there's, [00:36:00] you know, multiple parties fighting over something, that's probably 0.001% of the patents that are ever issued. So people have to remember that there are hundreds of thousands of patents being issued every year, and only the ones.
Are extremely important and just say big money makers are the ones that are gonna gonna be litigated. So is it good or bad for our system? You know, I don't want to talk about that too much. Or is this under the old system or the new system? Jake and Sam. Old system. Oh. Cause it's all the, It's, that's what I thought.
[00:36:34] Jacob S. Sherkow: Every patent claims a provisional 2012 or earlier.
[00:36:39] Samantha Zyontz: Yeah, that's what, that's what I thought. Right. So like days, it's, it's completely stupid. We're never gonna see this again.
[00:36:46] Jacob S. Sherkow: Now's non-pro provisional has a March 15th, 2013 date. Yep. Why?
[00:36:53] Christal Sheppard: Okay, I'm asking.
[00:36:54] Samantha Zyontz: This will never happen again. Like, it's so stupid.
[00:36:58] Christal Sheppard: That's why I wanna talk about the new [00:37:00] law. So, back to August's question. So, so is it bad, bad or good for the system? I, you know, I don't wanna answer that, but Gus it's a great question. We fixed, wait. We Congress fixed the system so that this specific type of clash will never happen again. As of March 16th, 2013, we no longer go through this.
[00:37:26] Jacob S. Sherkow: Yeah, and, and. Let me just add that like there's a bunch of interferences historically for big pieces of technology that you're probably familiar with. So the first iteration of the laser, which was actually called the Maser. I don't really know why, but anyway, um, there was a big interference fight about that too.
And there is also a book about it with a great title laser that talks about just that. Let me add one thing, one oddity I'd say about the CRISPR interference with respect to [00:38:00] generating new technologies. Specifically, remember how we were talking about enzymes and stuff like that before we keep saying like, Type two, CRISPR Cas nine, blah, blah, blah.
Well, you know, cast nines the enzyme, as Sam mentioned, right? But lo and behold, there are other enzymes that do the exact same thing. So we've got CPF one, we've got CA12 A, We've got CA13. If you're looking in aa, Jennifer Banfield and Jennifer Dow found a Ca X in a Ca Y. And lo and behold, all of the patent claims that are subject to the interference are all cast nine specific.
And so in some weird sense, Right. And, you know, I, I don't, wouldn't draw cause and effect too stringently between these two things, but like the interference has encouraged other people to invent around the configurable subject matter. Um, and so we kind of have this market now where we've got like a menu of nucleases to use for CRISPR and then we have one, which obviously is like the preferred mode, but like [00:39:00] there's a big fight about it.
No one knows like how much the license is gonna cost. And stuff like that. So like, it, it hasn't been, I think as, you know, quote unquote bad as I think some people will make it out to be. Uh, we'll, we'll find out when, you know, we have our first like, I don't know, crisper, injectable products or something like that.
Sooner rather than later, but, yeah.
[00:39:24] Samantha Zyontz: Well, and if I can jump in on that, Jake, Uh, I've actually been. Doing work on this. My, my most recent paper is taking a look at, at sort of what's happening to the underlying innovation, given the fact that it, all of this is undercut by this interference case, basically since the beginning.
Um, and like I said, I mean, despite what you thought think might be chilling, We have over 4,000 patent families in less than, you know, eight years, uh, that deal in different versions of crispr. And, and what I'm seeing so far is exactly what Jake is saying, which is, uh, [00:40:00] people are like, You know what? Not gonna touch the CAS nine thing.
There are all these other, uh, other enzymes we can possibly use, or there's gonna be these other applications that if I get at least one license, then I can move on. And so to borrow a little from Jura. Park, you know, life finds a way, uh, if it's important enough, right? Um, and so this may be one of those cases where, where, although as we point out, the technology itself is not exactly new, it is, uh, structured in such a way that.
People are going to find a way to use it and they're going to find, you know, and either they're gonna, what I'm testing is are they just gonna worry about getting sued later and we're just gonna move forward anyway? Or are we designing around faster than, uh, perhaps we would've if we didn't have these fights in the first place.
So, so there, there are two, a couple ways to go on that.
[00:40:55] Gus Herwitz: Well, one of the things I'm taking away from this discussion is, does any of this really matter? Does [00:41:00] anything really matter? And in a sense, the answer is yes, it matters so much, which is why none of it matters, because that creates the incentive for inventing around, which opens up, uh, such a great realm of possibilities, uh, which, uh, I, I think is what this conversation has done for me.
Uh, Sam and Jake, uh, thank you for joining us and, uh, Crystal, thank you, uh, uh, for co-hosting. Um, I, this discussion has, I hope, opened up to a range of co, uh, possibilities for having you all, uh, as future guests because this has been a great conversation. Um, and I'm looking forward, uh, to, uh, thinking more and talking more about these ideas.
[00:41:36] Christal Sheppard: I was just say thank you. Thank you for inviting me to cohost. This was a lot of fun. I don't normally get to talk to about molecular biology, uh, and patents with people who know. It's so awesome. .
[00:41:45] Gus Herwitz: Well, I, I think we've only scratched the surface.
[00:41:48] Samantha Zyontz: Oh, well thank you so much for, for, for having us. This was so much fun.
[00:41:53] Jacob S. Sherkow: Yeah, thanks for, thanks for having me, Gus.
[00:41:55] Gus Herwitz: I've been your host, Gus Herwitz. Thank you for joining us on this episode of Tech Re. [00:42:00] If you want to learn more about what we're doing here at tc, you can go to our website at ngtc.unl.edu, or you can follow us on Twitter at UNL_NGTC. You can listen to or download our podcast on our website or find us on the Apple Podcasts, Pocket Casts and Stitcher websites.
This podcast is part of the Menard Governance and Technology Programming Series hosted by the Nebraska Governance and Technology. The Nebraska Governance and Technology Center is a partnership led by the Nebraska College of Law in collaboration with the Colleges of Engineering Business and Journalism and Mass Communications at the University of Nebraska.
Colin McCarthy produced and recorded our theme music. Casey Richter provided technical assistance and advice. Elsbeth Magilton is our executive producer, and Lysandra Marquez is our associate producer. Until Next Time, splice you later.