Today I speak with my good buddy Kevin Hackett. Kevin works in the world of genomics and has a biochemistry and genetics degree from Clemson University. In this episode we talk about gene editing and CRISPR. We start basic, with what genetics are and touch on topics including – how CRISPR works, what sorts of diseases it might be used for and what the future of gene editing looks like. If you’re interested at all in this topic but like me, have limited knowledge on it, this podcast should be right up your alley.
LINKS:
Chinese researcher goes to jail for editing CCR5 gene https://abcnews.go.com/International/chinese-scientist-reportedly-gene-edited-babies-sentenced-prison/story?id=67982103
What is the SMN1 gene? https://ghr.nlm.nih.gov/gene/SMN1
FDA-approved SMN1 gene therapy https://smanewstoday.com/2019/05/24/fda-approves-zolgensma-gene-therapy-newborns-toddlers-with-any-sma-type/
Recent use of CRISPR in the news https://www.cbsnews.com/news/crispr-used-inside-a-humans-body-for-the-first-time-scientists-say-today-2020-03-05/
Eric:
Thanks for joining me, Kevin.
Kevin:
Thanks for having me, Eric.
Eric:
So to preface this whole conversation, to start it off, I just want to kind of, express why I’m interested in what we’re going to talk about and we’re going to talk about gene editing and CRISPR and all that good stuff. So the reason I’m interested in it is because I just find disruptions to society very interesting. Like things like AI, the green movement in terms of climate change, like all of these things where we’re going to have massive shifts in the way people live really interest me and I think genome editing specifically interests me because it’s not just a technological advancement, it’s like a species advancement. You know, we’re changing our species, so I think that is just fascinating and that’s kind of why I’m interested.
Kevin:
Excellent. Yeah. I’m happy to provide as much context, background information as well as just kind of firsthand knowledge as it relates to genetics and specifically gene editing. I feel as though I have a, maybe a little extra knowledge in comparison to, kind of the normal landscape of people simply because of my background. I have my degree in genetics and biochemistry from Clemson University. I work for a local biotechnology company that is in the world of genomics and genetics, not necessarily specifically gene editing, but we do provide technology, that may be employed by people within the world of genomics, whether it’s for gene editing or, simply genetic mapping. And I am very interested and very passionate about this topic. I mean since, since essentially high school when I learned about the complexities of the genome and that really we were at and still are in my opinion at the very beginning stages of what will be a massive, kind of opening of knowledge and access to, genetic insights and overall scientific research that could benefit the human condition, benefit the human race, benefit a number of species across the world. You know, both in the realms of, therapeutics and clinical, clinical kind of application as well as agriculture. And essentially optimizing who we are as a species potentially, if done in the right way, as well as kind of what we get out of the place in which we live, planet earth.
Eric:
Nice. Thanks for sharing that. So to get us started, I have this icebreaker from, I was given a deck of icebreakers, and I found this one prepping for our conversation. I thought it was a good way to start – if given the choice would you live forever? Common question. But I think it sets us up nicely.
Kevin:
Hm… I don’t think I would. I mean, I think that that’s a, it’s a very big question and a lot of it comes with, I would say, maybe it depends. A lot of it depends, you know, what would be my physical condition throughout the course of forever. But imagining living forever… it’s kind of a difficult thing for me to swallow because I think that, I think the finiteness of life, empowers us to live it boldly and to get the most out of it. Maybe living forever… yeah, maybe there are certain things that you don’t want to see, you know, that it, it’s kind of your purpose to be on earth for a certain period of time to get the most out of it. And, maybe we’re, maybe our brains, where we’re at right now and what we’re able to comprehend, maybe it’s not meant to be forever, you know? Yeah, I think the finiteness of life as I mentioned, it should embolden you to get the most out of it, you know, and not just say, Oh, I got another couple thousand years. I don’t need to go for that. You know, I don’t need to go smell the flowers today or whatever, you know, stop and smell the flowers sort of thing. So, yeah, I don’t know if I’d go forever. I kind of like what we got going on right now. Maybe we can extend it, but if we extend life in some shape, form or fashion, then the quality of life also has to be there too. Right?
Eric:
Yeah. I, I agree with you there. I’m back and forth on it. It also depends on loved ones as well. Are they going to live forever? Is this a, a friendship wide thing or am I the only one doing it? That would definitely influence my decision, but I lean no, just because like you said, the finiteness of everything is important to actually enjoying it, I think into appreciating things. Right.
Kevin:
And who knows? I mean, what our condition will be or the condition of the earth for that matter, you know? I don’t want to say I’d live forever if something happens and I’m the only one here.
Eric
Yeah, for sure. Not a future I want to be a part of.
Kevin:
Yeah, yeah kind of scary.
Eric:
All right, so let’s just jump into it. So this can be kind of a dense topic. And I am a journalism major. I have no scientific background. I’m just, like I said, interested in the topic. So I want to make this just as easy as possible to understand. So let’s just kick this off with the basics here. What are, what’s genetics? What are genes? Let’s lay some groundwork.
Kevin:
Okay, great. So genes are, essentially encoded information into the nucleus of the human cell. We’ll use humans as kind of our case study, or our model organism of sorts. So genes are the information that is essentially, a lot of people use the term blueprint for life. Within the nucleus or the center of the cell, you’re going to find that deoxyribonucleic acid, or DNA, is encased across a number of chromosomes. So genes are essentially the singular take on a set of genetic information – meaning, A’s, T’s, C’s and G’s or base pairs are orchestrated and put in a certain order that when read or when accessed by different proteins, as well as RNA or ribonucleic acids, they can be translated into physical form essentially or something that, provides a function in the body. So, genes are, can be, you know, anywhere between let’s say a hundred base pairs A, Ts with Cs Gs, up to, you know, thousands. And sometimes it is the coordinated expression of multiple genes that then turn into a specific protein. It’s not just one, maybe one gene equals one, you know, result, you know, blue eyes. Sometimes it is a multitude of genes acting in kind of an orchestra together in order to create what is called a phenotype. A phenotype is a physical expression or, culmination of genes. A genotype is essentially the the characterization of the type of gene that you have. So, let’s contextualize this again in the, in the form of a human. So a human has 23 chromosomes.
Eric:
Every human has 23?
Kevin:
Every human has 23, and that’s what gave name to the 23andMe. You also have your, your X and Y are sex chromosomes. Males are X, Y while women are a Y, Y. I’m sorry, X, X. So in those 23 chromosomes, there are multiple loci or locations. That’s how what we refer to them. Essentially it’s like a map of the genes. Now within those loci are specific genes of interest. So you’re kind of, you start big, you got your chromosomes, you drill down, you’ve got your loci or locations, and then within those locations you have the specific genes. Now we have just started really mapping the human genome. It was successfully done a little over 10 years ago. I think it was to the tune of $13 million and now we’ve gotten it down to essentially $1,000 genome. That’s the rate of advancement as an acceleration of technology has allowed us to reduce the cost per genome, you know, dramatically, which has enabled so much more groundbreaking research. And it not only in the form of say gene editing, but just identifying what is where and what does it do. Once we understand that, then we can, you know, kind of move down the course of, of research or further, further down the course of research to say, if we do this to this gene, then what happens? And that it’s essentially the birth of gene editing. So, there are, like I said, 23 chromosomes, but there’s around 20 to 25,000 genes across those, across that genome…
Eric:
So does every, so every human, we have the same amount of genes in each chromosome?
Kevin:
Really really good question. We do, we have the same amount of genetic material. I would say the large majority of humans have the same amount of genetic material. The very, I would say the, the, the variability there is say with genetic mutations like trisomy 21, which is three of the 21st chromosome, that’s what gives way to say something like down syndrome. So there are mutations and conditions that can result in more or less genetic material, but that typically is associated with a disease or a manifestation, a phenotype of some sort that can be deleterious or you know, perhaps, have additive effect to, the condition of the organism. A good example of that, you know, some, so we as humans we have the same amount of genetic material, but then there are certain, other organisms like say the oyster, that can have a diploid genome. So that’s essentially you get two sets of parents come together. So haploid, haploid come together to form a diploid, meaning you get half of your genetic material from your mom, half your genetic material from your dad, you put it together, you’re a diploid organism. So there’s essentially two genomes are coming together to form your personal genome. Something like the oyster, they’ve found that can have a triploid genome. So, much more genetic material. But that said, I think what’s important to note is that genetic material or amount of genetic material doesn’t equate to sophistication or complexity necessarily. It is the expression of the genome that truly gives rise to highly complex organisms and really differentiates us from each other as well as us from say the ape. You know, we have, I think it’s, I forget what the actual figure is, but the similarity in genome between us and the chimpanzee is, is it’s astounding, but it isn’t necessarily that we have all of the, you know, such similar DNA. It’s that the parts of that genetic material are expressed at varying levels to differentiate Eric from Kevin, Kevin from Chimp.
Eric:
So it’s the combination of ATC and G which is giving us the differences. It’s not the quantity of genes, it’s how those letters are paired up within each gene.
Kevin:
Precisely. So like I said, we have 23, 23 chromosomes. You have your sex chromosomes. Now those are going to be expressed in varying patterns and varying times at varying, under varying conditions. Certain parts will be accessed and to say, create more, immune cells or to proliferate more growth within a specific area of the body or for that matter, when something goes wrong, like a cancer cell, maybe certain genes are being expressed in rapid succession. So much so that the body can’t suppress that or stop that. And that’s what gives way to cancer or tumor.
Eric:
So they’re not always on?
Kevin:
Certain genes are not always on. Certain genes are kind of constantly running. and certain genes are expressed in only certain conditions, certain points in our lives, or under certain duress and circumstance.
Eric:
So why, well, I guess let’s, let’s start with, let’s start with the why. Why would someone want to go in and change their genetics?
Kevin:
Yeah, yeah, that’s a good question. You know, they, I think that the most obvious is to improve, maybe something that they were born with that impairs their life or again, impairs their, the human condition, impairs their health. Good examples of this are going to be, you know, something like blindness or, some sort of heme, condition like a, like a, like a blood, like a blood disorder or blood disease. Or for that matter, cancer. We do want to possibly go in and specifically change the genetics of a tumor in your body so that it can be perhaps more accessible by the immune system to fight it off naturally. Now I, I know that a lot of people think of gene editing, again, where a lot of people quickly go with that is well, you know, selectivism and being able to say, I want, you know, like I want blue eyes over green eyes.
Eric:
Or tall or short.
Kevin:
Yeah, yeah, yeah. And, I think that that, you know, the kind of the designer baby, take on, gene editing often gets popularized in headlines because of what could clearly be considered kind of like a, you know, selective advancement of, of our species. And for, for almost, aesthetic purposes as opposed to, those that can, bring a lot of added value to people’s lives and, and allow them to enjoy their lives and like the finite time that we have here on earth. Unless we do you pull that card again and we decided to live forever. I think what may be helpful is perhaps an example of what gene editing would be. So, gene editing can come from essentially three different flavors of it. There’s going to be gene editing where you’re replacing a certain gene, or repairing, let’s say a gene that is off or your what we’re supposed to have an A, you have a G and because you have that, let’s say the retinal cells, the cells of the retina are not as sensitive as they need to be, causing blindness. Causing maybe mis-formation of the rods and cones in your eyes. And the idea here is maybe we can introduce the changing of just that one G to an A so that those rods and cones are actually, they’re essentially replaced or turned over by the body and we do have, you know, let’s say there’s 20 to 40,000 cells turning over in our body, in regular succession. You know, our body is constantly repairing itself. So if we can somehow teach the body how it should be repairing itself, then we can repair those rods and cones in your eye. Another consideration of gene editing is going to be a knockout, meaning go in, there is maybe an extra couple pairs of a certain gene, maybe, a gene has been, repeated. You’ve got two sets of it, which results in you producing twice the amount of, retinal cells. Let’s stick with that and now you’re hypersensitive to light so you can’t look at light because you’ve got too many of whatever cell in your eye. So perhaps, now, now the, approach is we need to remove one of those sets of genes so that you have the proper amount of retinal cells rather than too much.
Eric:
Is that taking away genetic material though? Is that, is that, so that was something I was getting hung up whenever I was looking into this. Was that the knocking out of genes, cause it, doesn’t that leave you with less genes then or is it being replaced by something else?
Kevin:
You know, you would, I mean at a very micro scale, be reducing, a gene. But think about it this way. You have 4.6 billion bases across your 23 chromosomes. One less base, or, or maybe a couple, in order to have the body work properly, technically, yes, you are going to have less genetic material because you’re telling the body, I don’t need this one adenine here, you know, so on a micro scale, I guess, yes, you’d say you’d have less genetic material, but in total mass, that one less base probably is going to have, it’s going to get you back to normal rather than it would, you know, being kind of feeling left empty handed.
Eric:
I’m just like imagining cells with less genes just like liquefying and disappearing, you know, not having enough internal structure.
Kevin:
Totally. I get what you’re saying. And the body’s incredible in the sense that the repair mechanisms, the, kind of, uh, the pre-programmed means of cellular death that we have. When something is wrong in a cell. It, the, body is so immensely incredible in terms of its capability to identify wrong cells and remove them, or for that matter to repair them internally. It also creates a good example of how gene editing happens naturally in the body through natural endonuclease and enzymes. T he research that we’ve done has taught us essentially what to go after in the future and, and how we can, for lack of a better term, hijack naturally occurring gene editing mechanisms in the body to do essentially what we’re asking doing our bidding. The CRISPR technology that is, you know, really getting a lot of buzz right now is an incredible technology that was actually hijacked from a naturally occurring virus where, an endonuclease or a, it’s essentially an enzyme that works within the nucleus. It is given a, essentially a target strand of DNA. We were able to say, okay, this one gene, it’s a, let’s say it’s a hundred base pairs and on the 54th base pair we noticed in your body that, or in your eye that, you have a C instead of an A. Well we’re going to give you that actually we’re going to attach a strand, of the accurate interpretation of that DNA strand of that a hundred base pairs. They’re able to essentially give a transcript to that endonuclease and endonuclease then has essentially, a map of what they’re looking for in the cell. And that’s why CRISPR so, groundbreakings cause it’s so specific, it can find that very specific hundred base pairs. Again, this is just a pure example and not being overly scientific here, but it can find that very specific or in your genome that it is intended to go in bind to, cut and repair. Essentially turn into the correct version of that transcript. So, now with that said, we have, like I said, this level of repair happening constantly throughout our body. With so many cells being constantly turned over and created it, we, we would, we would to your point, dissolve and vaporize, had we not have some sort of naturally occurring repair team at work within the nucleuses of our body and throughout the entirety of our body at all times. We’ve essentially just been able to say, Hey, this one works really well. What if we teach it where to go and give it the information necessary so that it can find the specific mutation that we feel as though is worthy of repair.
Eric:
It’s insane. It reminds me of like a, like a police dog or something who they, you give him the scent of what he’s looking for and then he just goes and gets it. Except the dog goes in and makes the arrest and everything. So you mentioned, the destroy was one and then there’s also the replacing…
Kevin:
And then there’s the new gene or essentially introducing a new gene that was not there. Now that may be because 99% of the population is born with that gene, but you were not. So what we want to do is essentially provide a, a means by which we can introduce that gene into your genome so that now you’re whole and you’re not less a gene. Those are the three, the three kinds of flavors you get, your replacing or repair, your knockout and then your introduction of new genes. You know, some applications of this, like I said can be in the cancer world. They can be in the blood disease world. I think there can be in the rare disease world. There was know, I think one of the most, noteworthy or headline worthy, uh, applications was the Chinese scientist who using embryonic cells when after the CCR5 gene. The CCR5 gene is actually, it is a gene that is naturally occurring within, a very small sliver of the human population that, provides essentially a natural defense from HIV. It is a, CCR5 is a, surface binding protein. Essentially it has this innate immunity to the HIV virus. So, what this doctor did was, essentially using, embryonic cells in a controlled environment, and went in to see if he could introduce this gene into an embryo that previously did not have that gene. So really wild stuff that they’re able to get to that point and now introduce into, an embryo, a genetic material that was accepted by the rest of the genome at such a nascent stage of the embryo essentially said it could, you’re, you’re, you’re affecting the, the, the essentially germline cells. These are the cells that, turn into everything else in your body, right? So every cell in your body now has that added gene.
Eric:
Would offspring of that person have those mutations as well?
Kevin:
Yeah, so really good question. There are two different kind of states of cell in the body. Well, there’s millions of states of cells, I take that back. But you have germline and you have somatic. So somatic cells are going to be the ones that are essentially only tissue. You can’t pass them on. It’s like me developing a therapy for let’s say skin cancer on your arm. You’re not going to pass that skin cancer down to your, down to your children. And if there is a therapy for that somatic cell in editing the genes of those somatic cells, that isn’t then going to be absorbed by the rest of your body and then into your sperm and then passed onto your child. But in contrast to that are your germline cells. These are the cells that essentially make everything up within you and that you pass on to your offspring. I believe, at such a kind of budding part of the, of a human, you know, like you know, essentially in you start with one cell. If you can edit that one cell, your, your very first cell, it’s then going to proliferate and divide into all of your cells. The, a lot of the therapies that they’ve developed right now are focusing on somatic. I think that somatic is a, is a, is a much safer place to start. Right? You know, you know, fixing, say esophageal cancer or you know, AIDS. And in order to, I would say progress through this technology, explore this technology and its application safely, we should start with something that is finite and not going to be passed on generation to generation. Let’s start slow and learn as we go. And then, you know, perhaps they will get to a point where they find a, let’s say if, if there is a gene that you, you know, that you are going to pass on to your offspring, and it would be, you know, it’s essentially going to, it’s going to ruin them, it’s not going to give them the life that you wish to provide them and, and it’s not going to… It’s going to slight them. Where the ethical kind of quandaries come to play is like, well, how bad does it have to be before we actually feel feel is that we have the level of confidence where we can go in and edit this thing and, and feel good about it and know that we haven’t crossed a boundary and, you know, played God to a certain extent. What I think I know about the, the, the Chinese researcher is that it was done in such an environment that the, the cells weren’t ever intended to be grown into an actual human fetus. It was in a very controlled embryonic stage, very early stage just to see if the uptake of the genetic material would actually stick.
Eric:
What was the reason for all the uproar around that? Was that because of his secrecy in which he did the experiment or was it because it was an embryonic change?
Kevin:
I think it wasn’t really in secret too much. And I think it was the fact that he was the first to actually go after a human embryo. What that you were, you were essentially, altering the cells and now this person will… you’re, you’re, you’re changing their deck of cards that they have to live with for the rest of their lives, as opposed to maybe changing the seat that they’re at at the poker table, you know, that is somatic versus germline, you know, how, and, and changing a part of you that, or a tissue, versus something that affects every tissue in your body.
Eric:
Does the, does CRISPR ever miss, does it ever edit the wrong part?
Kevin:
Really good question. I’m glad you brought that up. So yes, that is one of the longterm concerns is the, the fact that we haven’t seen the, the longterm data and the longterm effects associated with, gene editing or CRISPR. Again, it’s such a new technology that, we don’t really know what could happen, you know, with anyone who was given this, given this, therapy, over, not just in a short amount of time. You know, like, you know, Oh, you’re cured of your X, Y, Z disease. Well did that change actually propagate a new disease later in life? So one of the concerns is off target edits. And that can be for a number of reasons, but typically, that transcript that, or the kind of, the scent that you gave the endonuclease or CRISPR, the CRISPR enzyme, sometimes that can be extremely similar to other parts of the genome. Sometimes a version of that gene can be represented in multiple places throughout the genome. So off target edits are, are yes, a very, a very big area of concern and something that should be considered and explored quite a bit prior to launching therapy. And that’s what essentially why we’re in this kind of golden era of discovery and really understanding what this type of gene editing therapy, can do for us. And what we do there is typically we’ll, we’ll sequence a genome or sequence a specific gene, cause you can do genetic mapping or DNA analysis, genetic sequencing. You can do it on a large scale and you can, you know, sequence your entire genome, or you can pick a very specific area of the genome to target to sequence. So that’s obviously a lot more cost efficient right now, a hundred base pairs versus, you know, the 4.6 billion base pairs that you have. So what we can do is we can sequence it before we can essentially go in, okay, we know this is your condition. We’re going to confirm this by sequencing the, you know, 12th chromosome, you know, this area of the 12th chromosome and then provide the therapy, let’s say it’s for your eyes and then they can do a second followup sequencing run to essentially confirm the change in that base pair. And again, the, the rate of advancement within the world of genetic sequencing has, both in terms of the, the cost going down as well as the specificity of confirmation in genetic sequencing has allowed us to not just throw these technologies in the body like CRISPR, but to do it in a way where we can do it iteratively and you know, small bit by small bit and also to let, let’s say back to kind of the off targets, let’s say that a hundred base pairs that you intended to change. Well let’s confirm that, but let’s also sequence the rest of your genome to see what else changed as a result of the introduction of something say like CRISPR Cas9 is,
Eric:
Is it more helpful then to have more base pairs in the area you’re trying to change because it diminishes the opportunity for there to be some overlap? You know what I’m saying? So the RNA you give to the Cas9 protein maybe is a little bit longer… would that help?
Kevin:
Yeah. Yeah, it would, specificity and the ability to accurately target and lock onto an area of the genome is going to be enhanced by having more of a transcript or more of a scent to go after. Now with that said, longer RNA molecules are what would be connected to, the CRISPR Cas9, the longer they get, the more fragile, the more, the, the more, the more they are susceptible to, let’s say a naturally occurring, other enzymes in the body to say, okay, well what is this? You know, what does this endonuclease actually, I don’t recognize this as something that’s normally happening in the body. I’m going to now eat this thing or, get rid of it. But, yeah, longer, oligonucleotides, which are essentially a long chain of nucleotides, you’re sent, the longer they are, the more essentially area they have to be broken down, you know, or for that matter, you know, RNA itself can, can mis-form, you know, perhaps now we’ve introduced such a long strand of DNA or RNA to the CRISPR Cas9, you know, maybe, and we think it’s going to be so specific that it, because, because it has this very long strand, but you know, halfway through kind of targeting the area of the genome that we went to edit, maybe another enzyme finds it and cuts it in half. Now it’s half as specific. So I know that again, the, the rate of research is very impressive, but they’re trying to find what that exact amount is.
Eric:
So is there a limit to how little, how few base pairs can be used for a swap and replace?
Kevin:
You know, it’s a good question. Offhand, I don’t have it in my head, although you know, there are, you know, a hundred base pair genes, there are couple hundred base pair of genes. There are certain genes that work again kind of poly-genetically. So multiple places throughout the genome that come together. Multiple genes come together to form one phenotype. I, I also know that, you don’t want it to be too long so that it potentially could overlap with another gene or for that matter if it doesn’t, you want to find the just the right amount of fit and not requiring the potentially such perfect fit that it’s always going to miss if there is say another gene that overlaps or right next to it that does have a small mutation, but perhaps that mutation isn’t as deleterious or or can negatively impact, the body as much as the one that you’re actually going after. So increased specificity may actually lead to a decrease in overall attachment and correction.
Eric:
So just kinda in review to paint this whole picture using the dog metaphor. So you have, well, we’ll say the bad guy is your DNA that you want changed. So you’re giving the dog, your enzyme, your CRISPR Cas9 dog enzyme, a copy of the DNA, which needs to be replaced – the scent. Yeah. And so then the CRISPR Cas9 is put into the subjects’ body and it finds, it sniffs out, that sense within the, within the nucleus, the DNA. And it either changes it or knocks it out. Okay. And so from there, how long until the changes are seen in the body? How long does it take for that to be expressed?
Kevin:
From what I’ve heard, it’s pretty miraculous in terms of the turnaround. I don’t wanna say it’s like put it in and 10 minutes later you’re healed. But I did look up one example of the SMN1, it’s a motor neuron disease which leads to spinal muscular atrophy in children. It’s a fatal disease with this one gene, SMN1. It affects the muscular tissue of various organs and ultimately what leads to patient death is the lungs don’t have the muscular capability to contract and deflate so the child essentially suffocates to death. But what they’ve found in some of these patients – and as a caveat I think it’s important to mention, this technology is being implemented in very limited case studies but for the people who don’t have any other option. And that’s where we should start. But in that circumstance they’ve found that children are breathing and upright, weeks, months after this initial therapy. And it has just blown researchers and physicians away alike.
Eric:
So what is happening in that waiting period, is that just the cell dividing itself and creating… Once that new DNA has been in created in enough cells, then it becomes expressed, it becomes dominant?
Kevin:
Exactly. It becomes the one that is essentially the new norm.
Eric:
We’ve mentioned before, some of the diseases that are being thought of, you know, you’ve mentioned diseases heme diseases, things that affect the blood. Is there any in particular that’s being more talked about than others? Any application that has the community more gung-ho than the rest?
Kevin:
Sure, sure. You know, I, I think that, in the world of immuno-oncology, which is, is, using your body’s natural immune system to attack cancer cells rather than say bombarding with radiation or chemotherapy, is where a lot of people are excited and they’re seeing a lot of potential applications for CRISPR. So there is a, there’s, there is a protein on the surface of tumors, essentially PD-L1, PD-L1 gives way to this, this surface protein. And what it does is it’s actually, it’s a pretty mischievious little gene in a tumor cell in the sense of, it tells the immune system, no, don’t attack me. It enables the tumor to central be masked from the natural immune system. So the idea here is, well, can CRISPR be leveraged to knock out that gene so that now the body’s natural immune system recognizes this tumor that’s maybe been there and growing, but the entire time it’s telling the body, no, I’m natural. I should be here. I’m just growing at a rapid pace. And by knocking out that gene, we can actually give the body’s natural immune system the visibility and capability to now attack that tumor cell, naturally. Kind of unnatural that we’re introducing CRISPR, but natural in the sense of we’re tasking our own immune system to, to, to, to repair the body.
Eric:
Like you said before it something that’s already found in nature. The protein is a naturally occurring thing. So it’s all really natural, but it’s kind of just being, instigated by us.
Kevin:
Right, right. And I think that that’s really where I think a lot of innovation throughout all of the medical community, that’s all it is, is really over the past hundred years. It’s just identifying naturally occurring things that happen in the body, things that benefit us. And then being able to harness that capability for the, for the benefit of other humans who maybe don’t have that capability, that protein, that enzyme. You know, other areas of application are going to be around rare diseases, blindness, cystic fibrosis. And as you mentioned, HIV and AIDS. I think that those are kind of the, the biggest buckets of application that people are most excited about .
Eric:
Is act of changing traits, genetic traits. Is that something that’s, I mean, like physical characteristics – is that something that’s not even being kicked around in the scientific community? Is that more a scifi headline?
Kevin:
I kind of perceive it as a scifi headline, but at the same time, you know, physical traits can be manifested in any number of ways, you know, and, and, and I think physical traits on, at the level of, you know, like almost aesthetic interpretation, you know, eye color, hair color, muscular build, things of that nature. I think, yeah, at this stage, of course it’s in conversation because it’s like, well, this technology’s obviously going to lead to at some stage, the ability to be selective in terms of what we are or maybe what we aren’t. But, right now the biggest area of focus is the things that are hurting people the most. And, I think that where it’s also having the biggest impact is in patients who don’t have any other options. You know, this is something that they can do as a last resort or for that matter, maybe it’s going to be a first line therapy in the future. But how do we get there? We start with the people who do not have access to any other therapies and again, they are at their last resort. And we are validating technology and validating the, implementation of CRISPR Cas9, understanding what side effects are out there, understanding the efficacy, understanding the safety of it. And then once we’ve learned quite a bit through these kinds of very small clinical trials, small patient populations, then we will start to, I would imagine, start to introduce other considerations of CRISPR Cas9. And just gene editing as a whole.
Eric:
Is the main obstacle then just figuring out the safety of it. Is that kind of the main obstacle that CRISPR faces in becoming a public… or more widely used technology?
Kevin:
Yeah. You know, I think it’s, well, one, it’s, it’s safety, but then it’s, it’s two, it’s clinical validity, right? How much impact can it truly have? And based on an impact, what is the downside? What then are the safety concerns? Is it better than what is out, other options that are out there right now? That’s what the FDA goes through, that that’s kind of their process is, okay, we know it’s a new therapy, but does it do it better? Does it do it safer? Does it provide, patient benefit? Does it provide, some sort of unique, differentiating factor in comparison to what’s currently in the market right now? Or is it, you know, just so similar to another therapy that it’s not worth putting this through? Because the other therapy that is out there is proven and, and it’s, proven to be safe, proven to be effective. But yeah, I think right now it’s, it’s a balance of efficacy and safety.
Eric:
You mentioned before agriculture. This is something that’s been used in agriculture for a long time already, right? And
Speaker 2: (38:28)
yeah. Yeah. I mean gene editing, I mean, you can really consider it in the most basic form. I mean, think about Mendel. you know, he, the men Delian genetics, he was doing gene editing essentially by introducing the pollen of one pea plant onto the, you know, onto the steam and, you know, answered a stamen. and, and that was essentially in gene editing. He was selectively breeding plants to gain certain traits, in, in their offspring. It’s not as kind of sigh fi as, as, as one would believe. When you start to think about it from that perspective, you know, we crossbreed plants to get, let’s say, you know, increased survivability or greater, yield from crop or, so that they can endure different environments in different climates. or for that matter, if you want to go as far as, you know, say the big players in the world of, of, of crops like your Monsanto’s who are introducing genes so that they are resistance to herbicides and we can then spray herbicides all over plants, but they don’t affect the plants. They only affect the, the weeds. So I mean, that is essentially your editing, the, the, the genome of a plant, by introducing genetic material that gives it say resistance to, a material that other plants aren’t resistant to
Eric:
Is our genome close enough to something like a mouse for, animal models to be used in testing certain human applications?
Kevin:
Yeah, yeah. You know, I’m at the most basic level. Yes. We’re all As, Ts, Cs and Gs. You know, we’re all, carbon based life forms with a, you know, a double stranded DNA helix that, you know, comprises a number of, genes that turns into a number of chromosomes. But a mouse has a different number of chromosomes than us. Different sizes and even plant species have far bigger genomes than we do. But at its most basic level, yeah. The actual function of the technology is essentially going in and doing the same thing that it would do in a mouse as it would to us. But because of just, you know, the different functions of the body in, in, in a mouse and the human because they’re so vastly different. That’s why we do these controlled trials within say a model organism, like a mouse. Then you go to a smaller, you know, kind of cohort of patients and you know, kind of the first patient, or human patient trial and then you scale up from there. But it wouldn’t be as simple as saying the CRISPR Cas9 therapy that we provided a mouse to cure of diabetes is going to be the same one that we give to a human to cure their diabetes. It’s going to target a different part of the genome, but at the same time it’s targeting, measures and the, the actual mechanism by which it’s going about that change is essentially the same.
Eric:
So they can use some, some of that information in human models.
Kevin:
Absolutely. Absolutely. You gotta start somewhere and then you grow from there.
Eric:
How much longer do you think it’ll be before we see this being used more widespread?
Kevin:
Yeah, that’s a really good question. Um, I think in the next 10 to 15 years, I think it will be a, not a regularly accessible therapeutic option, but something that will be, available to a specific set of patients and based on essentially whatever their condition is. So I, I think it’s going to become more of a readily acceptable therapy and proven therapy, and prescribed therapy, in the next 10 years for sure. I mean, they, they actually just did, they’re the first FDA approved human trial with CRISPR, recently and that was, August of 2019 is when they did that. And that was that SMN1. The motor neuron disease, causing, spinal muscular atrophy. Yeah. so I think it’s gonna become more and more prevalent. Now the interesting thing is, you know, well, where, where will we see it? Where will we see the prevalence grow? Likely not in the US. There are regulatory bodies are such that, and, and for and for good reason are, they, they want to be a part of that process. They, they are, are going to, ensure that the research and the therapy are done in controlled environments so that, we can, safely understand, the true effect of this technology in other areas of the world. Like your China and even in Europe. The regulatory bodies are, I would say have, are not as conservative. They, they adopt, they’re early adopters of new technology much more so than, the US and, and this, this varies from country to country. It’s not, you know, the US is, you know, the hardest, you know, harshest, regular regulatory body like with the FDA and whatnot. Nut, I would say that there’s a lot more discovery happening, via earlier adoption and through more trials outside of the US than say in the US.
Eric:
To what extent is the global scientific community working together on this or is it a country v country type of situation
Kevin:
You know, that’s a good question. And I think, I think that there is a lot of information sharing or across the globe happening and there’s a lot of partnership on this, on this technology because of the promise that it holds. I’m unaware of say a, like a CRISPR team, a unified team across, across the globe. And a lot of researchers are obviously going to be, protective of their discoveries for so that they ensure that the data and the understanding and the discovery is, is used the right way. But also because of potential commercial application and being able to, gain the fruits of their labor. But I do see a, a number of, researchers around the world coming together for, you know, a number of other technologies or, or therapies or cures.Um, but this is like, really, we, we don’t even know… what people are trying to discover is… okay, how we know what we want to cure, but how will this potential therapy, improve our ability to cure that – again safely efficacy and safety. And the sharing of that information, I mean daily data is coming out. And you know, the, the more you publish, the more notoriety you get. And, and then the more funding you usually get. So it is in the scientific community’s best interest to publish your data as quickly as possible. Yeah.
Eric:
This just seems to me like something governments around the world would be so invested in and in, I don’t know, kind of a darker view of the world I guess makes me feel like it becomes like some sort of arms race or something. I know I had sent that in the notes. Is this like the next arms race where it’s like you’re trying to make your populations genetically superior, you know, you gotta kind of get into that eugenics field, which is a little scary. Is that something that frightens you or your coworkers or anyone you know at all is that like the worst case scenario?
Kevin:
Yeah, I mean, obviously we want to make sure that this technology is, it imparts positive value to the human race and to the world. I, in terms of widespread adoption to the point of eugenics, I would think that we as a human race and as, kind of watchers of the world, would be aware and kind of, and, and involved in, in discussions and actions at a, at a, at a global level to inhibit and to control that. But you, when you extrapolate examples like this, of course you’re going to end up at some, you know, potentially, you know, far out place. So I think it’s natural for the, for the imagination to go there. But I don’t see the technology moving so fast that we can’t keep up with it and be able to, to essentially control or throttle its application to the point where it would get there. We’d be able to hold it in a… and, and guide it in a, in a manner where it is not turning humans into a super race, you know? But there’s so much subjectivity to that, right? Like what is a super race? If, if I, if I’m able to give you the CCR5 gene CRISPR Cas9 editing and now you’re immune to HIV, we’re one step closer to a super race. So it, I, I can see it from both sides. It really is an interpretation of what someone feels as though you superhuman or optimize human is. Is it just being able to live your life in confidence knowing that you’re, you’re less likely to get a disease, or to be a superhuman – you know, I, I can say you have to have increased muscle mass and like you’d be beautiful and you know, you’re not susceptible to any diseases. So I can see far at the far ends of the spectrum, right? One simple change, you know, CCR5 – optimized super soldier, you know, and, and both of them are genetically edited, but both of them can be considered superhuman or at least better than the normal human condition. And I think the other kind of longterm implications to think about are not just, well, what if I do reduce the susceptibility of HIV globally? Awesome. Great. We did it, we knocked, we knocked it out. Now the human lifespan has gone from 72 years to 75. Do we now have the resources to be able to sustain that extra three years per person on the planet? So, or you know, do we have enough… Because now you’re going to live to 75. Now you’re going to increase the human population and just density and the number of humans by, you know, 2%. Because there’s people are living longer people having more kids, more kids, you know, and so now do we have enough kind of like I said, natural resources to sustain us or actually can we optimize to a point where we are putting ourselves out of the game? You know we’ve now gone so far in, in pursuit of good that we actually run the risk of, of, net negative impacts globally because of, you know, a space habitable space to live, water on earth, food to eat, air to breathe. you know, with these small changes, what does it do at a macro level? We’re talking very, very, very micro, you know, even at the genetic level. And then micro in terms of the single patient level, what about the global population? What is, what is, what is this small tweak in human survivability, susceptibility to disease, the ability to see light better, you know, if we change that, you know, what does that really do long term, not just for that single human but for humans at a greater scale.
Eric:
I guess we’ll find out.
Kevin:
I guess we will!
Eric:
Has working on this and coming to understand it changed your perspective on life and if so, in what ways?
Kevin:
It has changed my life in a way that has, has challenged me and forced me to think about not just as you mentioned a few seconds ago, singular impact, but really bigger impact. What can this do for the human race? What can this do – what will this do to, you know, planet earth? What will, what will the adoption of a technology like this, be it fast or slow, affect the way new technologies are adopted, both in a regulatory capacity and in a research capacity in the future. This technology has potentially groundbreaking status, right? But we have to do it… We have to, we have to adopt it in a manner that is, precautious and weighs risks, and not to be so, so wrapped up in it that we’re, we’re, we’re kind of blinded by the positive upswing and what it can bring. So it’s made me think about things a lot more longterm. It’s also made me realize that regulation will come and I think it’s important for us to not turn to our, our, our research community and say, “Whoa, Whoa, Whoa. Everyone stop. We need to talk about this. Like, everyone’s stopped what they’re doing right now. Put your pipettes down because we need to put some laws in place”. To halt research in, in order to, discuss every single situation, circumstance or scenario, and decide what’s right and what’s wrong, to halt all the research just to have that conversation… I think it’s pretty shortsighted. We need to empower the research community to continue to push on all fronts so that we can explore every scenario, but we don’t really know what scenarios are going to come down, you know, come down the pipes if we don’t continue to push research and consider the applications of the research and technology. Um, you know, for instance, we just, we spoke about HIV, but you know, of course as we begin to push and research, you know, there’s bioethical kind of considerations come into play where HIV, yeah, let’s great, let’s attack that. But when you extrapolate, you know, the potential applications, you will ultimately get to that blue eye. You know, I want to be taller, I want to be more muscular. I think if we give someone a deck of cards that is devoid of any life threatening condition and allows them to live a life worth living, that is where we need to go with this. And if we start to, if we start to, edit the deck so that someone can be, say smarter. Well again, what is the longterm risk of that? Not necessarily what are the, you know, what extra neurons or you know, neural networks do they get, but I mean, you can take it as far as, well, you know, let’s say they become a brilliant, you know… a brilliant scientist and they become so wrapped up in their research that, that they get some form of psychosis or something. Essentially – you don’t know, even if someone is able to be more intelligent, well what does that, where does that intelligence bring them? Maybe it brings them to the loony bin because they’re so smart they drive themselves crazy. I think it’s important to give our future generations, well, one – we should leave the earth better than we found it for them. Secondly, we should enable them to live a long, prosperous, within means long, prosperous, and, and an enjoyable life. But not do it in a manner where we are orchestrating their lives for them. We’re predestining them to be something or someone or for that matter, expecting them to be something. Because if we give them, give someone enhanced intelligence, well then doesn’t that also kind of set some high level or some very high expectations of that person? If they don’t live up to those, then, you know, what, what does, what does that do for kids? You know, just overall, you know, demeanor and a psychological state. We upped your intelligence, man. You should be killing it in this math quiz! You know, like, no, that, that’s nuts. No. And, and another thing too is there is our genome and then there’s our epegenome. So we really go all the way back to the beginning of our conversation. So the epigenetics are the, it’s essentially the over genetics. So we have, we have, you know, our entire genome let, let’s, let’s use the, let’s use a book as an analogy. So you have your entire genome from, you know, we said 4.6 billion base. So first letter, the book base one, last letter, 4.6. So throughout the course of your life, you are not, reading every single letter at every single moment. Certain chapters are accessed, certain parts are read. And the epigenome is the, essentially the over genome. It is the lens by which you look through to look at that book. And, it’s, it is the, variable expression of the genome and the why behind it. So why do we have all these genes? Why do we have, and not every part of the genome is essentially, a, an important coding region. Some are, we don’t even know what it is. It’s, we have this a thousand base pairs here. They do nothing at all and they’re kind of, they seem like nonsense. We don’t fully understand it, but we know that for very specific reasons, certain parts of the genome are accessed or hidden, at certain parts throughout the life. So it’s kind of this over genome that exists. Um, and it’s not just the book you’re, that you were given as a kid, you know, when you came out and you know, here, here’s your genome, here’s your book. It’s essentially the epigenome is how you read that book throughout the course of your life, how your body reads that book and accesses that book and expresses that book. So it’s, it’s not always as simple as one to one back to the intelligence gene consideration. If we give someone, let’s say five copies of the intelligence gene, maybe the body actually can’t interpret those five. It doesn’t have the other genes necessary to create the proteins to access and to express those other five intelligence genes. So it’s not always one to one. And that can also lead us down the conversation of nature and nurture. You know, you’re born with a certain set of genes and a certain biological blueprint, but through the course of your upbringing and through the environmental stresses, through, you know, what you take into your body, certain parts going to be accessed or for that matter not accessed. So, and it’s not always one to one. And right now we’re really helping define how close can we get one to one, especially with the inclusion or the consideration of therapies like CRISPR.