The Round Barn Podcast – Episode 39 “Gene Editing” Transcript

Dr. Jim Lowe

And we’re back. Again. More still. Long time.

Kaylee Hillinger

Yeah. We should really bring someone else on here for fun. I mean, not that I don’t have fun with you. We have a lot of experts around here. Well, I just. Our intro is weak because it’s just us.

Dr. Jim Lowe

I know, but now you’ve hurt my feelers.

Kaylee Hillinger

You’ll get over it.

Dr. Jim Lowe

I don’t know. I’m pretty fragile.

Kaylee Hillinger

It takes a lot to hurt your feelings I think. Welcome to The Round Barn. It’s. Yeah, it’s us.

Dr. Jim Lowe

It’s again. It’s us again. What are we talking about today?

Kaylee Hillinger

Oh I… So I think we’ve kind of touched on gene editing before. At different points, but it just keeps coming back.

Dr. Jim Lowe

It’s the thing.

Kaylee Hillinger

It’s in the news.

Dr. Jim Lowe

It’s the thing.

Kaylee Hillinger

Yeah. It’s not going to go away, which is great.

Dr. Jim Lowe

It’s gonna to get better.

Kaylee Hillinger

Yeah. There’s a lot of confusion out there. The animal livestock groups are pretty optimistic right now with some different resistant animals BVD, PRRS resistant pigs and some promises and optimism that the industries have about having specific disease resistant animals. But it’s tricky. We’re in a tricky spot. Science is advancing faster than human acceptance.

Dr. Jim Lowe

In many ways.

Kaylee Hillinger

Yeah.

Dr. Jim Lowe

Yeah. And gene editing is one of those things. Well, let’s, let’s talk just 2 seconds about gene editing. So it’s gotten co-mingled with the idea of genetically modified organisms. So GMOs are best on really only on the crops side at this point. And in GMO, we insert genes from another species into that organism.

Dr. Jim Lowe

So we take corn and we stick a bacillus thuringiensis, which is a bacteria gene into it. So it produces a toxin to kill corn rootworms. Or we stick a gene in that prevents… it induces tolerance to glycophosphate. Roundup or Liberty or or or. Right. You know, and so we’ve done all these things and it’s really done quite crudely.

Dr. Jim Lowe

So they literally just threw new genes into cell mixes and physically beat it into the genome. And it didn’t work. It wasn’t very efficient, but they could do it. So that was kind of gene modification 101. Or 1. And we’re kind of phase about ten now. We’ve moved fairly quickly. So it’s all based on this idea of CRISPR and a particular bit of CRISPR, which is Cas9.

Dr. Jim Lowe

So it’s an acronym.

Kaylee Hillinger

Now we move to the gene editing.

Dr. Jim Lowe

That’s gene editing. And so well you can gene insert with it as well, but.

Kaylee Hillinger

Okay.

Dr. Jim Lowe

So we’re at the CRISPR stage of life.

Kaylee Hillinger

And, and everyone has heard about CRISPR but may not know exactly what it is.

Dr. Jim Lowe

So CRISPR is a set of enzymes that we can mix with DNA and it will go along based upon where you target it at. And so you put a little tag on there and you say, hey, go find this spot in the genome. And it goes along and it makes a cut. And so you use a set of those tags to cut out pieces, and then there’s another bit you can actually use to insert stuff in.

Dr. Jim Lowe

That’s the same approach. So this is bog standard cellular biology today.

Kaylee Hillinger

So what are we cutting?

Dr. Jim Lowe

Cutting DNA. So we’re cutting nucleic acids and we can insert nucleic acids or we can just cut pieces out. And this happens like every day of the week at every university that does any biological research. And this is like even I can do it dumb. I’m terrible in a lab but I mean it’s just- I don’t want to say it’s a recipe.

Dr. Jim Lowe

Now designing what you’re doing is pretty challenging. Understanding why you’re doing it and what you’re targeting and all the bits. But the actual genetic surgery, for lack of a better word, sticking the knife in there is like cooking.

Kaylee Hillinger

Let’s clear up with the audience that you have a lab at the college, but you definitely don’t run your own lab.

Dr. Jim Lowe

For a thousand reasons.

Kaylee Hillinger

Yeah. Dr. Storms. She is the gatekeeper of your lab.

Dr. Jim Lowe

Yes, we have to- we have someone who knows. Yeah. We don’t want to offend anyone.

Kaylee Hillinger

Tape on the floor. Do not cross.

Dr. Jim Lowe

Yeah don’t go in there because I don’t know what I’m doing. But so what CRISPR lets us do is actually cut out bits of the genome. And that’s really been the way we’ve done a lot of this. And so it’s being used everywhere, including human medicine today. But we’ve now decided we’re going to stick it in animal medicine.

Dr. Jim Lowe

And we’re always late to the party, but- because of cost. But so I think we’ve talked about the PRRS genetic resistant pig before. So basically when we think about a virus, it has- So a virus has a bit of genetic material, RNA or DNA can’t replicate on its own. It has to get into a cell to replicate. To do that, it needs what we call a receptor on the surface.

Dr. Jim Lowe

So it has to have a little lock in it. It’s the key that sticks into that and it gets sucked inside the cell. And in the case of many of these viruses, they have to cross not just the cell membrane, but probably the nuclear membrane as well. They have to get into things to do replication. And so what they figured out with PRRS virus was there was one particular receptor that was really critical for replication in the virus and they just took it out, went in there and they didn’t take it all out.

Dr. Jim Lowe

It’s a quite big protein and they just went on. Right, so DNA makes proteins. So the receptor is actually protein, but it’s encoded by DNA. And the basis of all biology is DNA is transcribed a protein via messenger RNA.

Kaylee Hillinger

This is a lot of science for us.

Dr. Jim Lowe

I know, but it’s DNA. The record of what should be. The messenger to take it from DNA to protein is this stuff called messenger RNA. mRNA we’ve heard about that with COVID vaccine. Yeah, that’s the messenger. And then there’s some enzymes that take that code and make it into protein.

Kaylee Hillinger

Yeah.

Dr. Jim Lowe

So mRNA is a copy of the DNA, but one sided not two sided. And so they go in and actually just clip a little bit of the DNA, clip the library, and then when the mRNA comes along, it doesn’t work. Or it comes along and it makes a bit of protein that doesn’t have the right pieces. So it’s folded differently, it doesn’t work, etc..

Dr. Jim Lowe

So with very, very small amounts of removal, we can change the function of a protein. This is actually how all of biology works. When we talk about mutations or we talk about changes that occur over time, it’s the same mechanism you’re losing or adding little bits.

Kaylee Hillinger

You’re just not mechanically doing it in a lab setting.

Dr. Jim Lowe

You’re not targeting. So when we do natural selection in animals, we are selecting for specific changes in that DNA, specific different bits of DNA. And so we say oh, we like that one and not this one. And so we take that version. Take that we take this library, not that library. And so what we’re saying is, instead of waiting for the right library to occur, we’ll just go, well, let’s stick a knife in there and cut out-

Dr. Jim Lowe

the bit we don’t like. And those things occur naturally. We’re speeding up what would occur naturally. So we know, like in the case of PRRS, there are some pigs that already had this mutation that.

Kaylee Hillinger

Just naturally.

Dr. Jim Lowe

Naturally resistant. Unfortunately it is so rare that it’s not economically or population wise useful.

Kaylee Hillinger

And to be able to go find them.

Dr. Jim Lowe

To find them. And then. Right, it’s such a low frequency.

Kaylee Hillinger

That’s the same thing. Like some people just never get the chickenpox unvaccinated, exposed.

Dr. Jim Lowe

They just have a bit of a broken protein that doesn’t let that chickenpox get in there. So we just created the broken protein is really what we did. And so they’ve done that for PRRS and that’s getting closer, like Porcine Reproductive and Respiratory Syndrome. We’ve now done it for BVD or Bovine Viral Diarrhea virus in cattle. And so those are examples where we went in and just took a knife and cut it out.

Dr. Jim Lowe

And these things have like huge potential to improve animal welfare. Two of the biggest drags on animal welfare. We think the biggest drag on animal welfare is often disease and we can take away probably the most significant disease in pigs and probably the most significant disease in cattle.

Kaylee Hillinger

You just snapped. Why aren’t we doing it?

Dr. Jim Lowe

Well, we’re not-

Kaylee Hillinger

This is a loaded question.

Dr. Jim Lowe

For two reasons. One, we’re not as clever as we’d like to be. So I said, this is really easy and it’s really easy to do the bit, but to get it exactly right and clip exactly the right bit and know you’ve only got the right bit is actually not a minor problem. So doing it is hard. And then we got to convince people that that safe and this is where science runs into public policy and public perception.

Dr. Jim Lowe

Obviously, we’re all aware of the controversy surrounding COVID vaccine and the use of mRNA vaccines. And that one seems pretty straightforward to me. And so here we’re going to run into another one. And so it’s science public and the public accepting science becomes the hard bit. And to me, the interesting thing is we are doing this today using CRISPR in a couple of ways for human health that are really exciting.

Dr. Jim Lowe

That people haven’t asked a lot of questions yet or maybe they’re asking questions, but they’re like, it’s so bad, I should get on with it.

Kaylee Hillinger

Do you think that they know? Do you think people know that we are close to curing sickle cell?

Dr. Jim Lowe

No, I don’t think people know. I also think people- So we should not let that hang. So we can use CRISPR today to go in and do like a bone marrow transplant. I don’t understand all the details. I’ve just read a bit and this is obviously outside my wheelhouse, but we do bone marrow transplants all the time. So we go take a piece of bone marrow out of you, put it in the freezer.

Dr. Jim Lowe

If you have cancer, go wipe out the cancer cells, wipe out all of your bone marrow and put some fresh back in, put your own. An autogenous transplant of bone marrow, back into your body.

Kaylee Hillinger

And it happens all the time.

Dr. Jim Lowe

That’s a super successful like bing, bang, boom, down the road. They do that today and so in that bone marrow are the cells that produce all your red blood cells and all your white blood cells. The progenitor cells for those. So what they do now is actually go in and they can, if you have sickle cell, which is a known genetic, you’ve got an extra bit of DNA in there that makes a funny protein.

Dr. Jim Lowe

So your cells fold- your red cells fold instead of being flat and they don’t carry enough oxygen. So they can go in. “They” being scientists and doctors can go in and take the progenitor white blood cells and go use CRISPR to edit them, to take out the little bit of bad protein again. Just take it and nick, change it all of a sudden that gene doesn’t work anymore.

Dr. Jim Lowe

Their bone cells are normal. Put them back in.

Kaylee Hillinger

Cured.

Dr. Jim Lowe

Cured.

Kaylee Hillinger

Gene editing.

Dr. Jim Lowe

And it’s interesting, they believe that the reason that people have sickle cell is is that they’re actually resistant to malaria. We know they’re resistant malaria. So if you have sickle cell disease, you are resistant to malaria. So we had an evolution, a genetic defect, sickle cell, which actually conferred a competitive advantage in malaria endemic regions millennia ago. And now it doesn’t confer a competitive advantage because we have other ways to handle malaria.

Kaylee Hillinger

Right. Yeah. I was just thinking which one came…?

Dr. Jim Lowe

But malaria is ancient, malaria was around. There’s a lot of malaria selection pressure on people, right? So people were dying, particularly little kids were dying of malaria, which is where most of the death loss is. If you had sickle cell, you didn’t die from malaria. So they were selected for in the population. And so now that mutation, which conferred an advantage at one point, no longer. Does not confer a competitive advantage. In fact, it confers a competitive disadvantage.

Dr. Jim Lowe

And so they can fix it. And so instead of saying, “oh, we shouldn’t breed more people that make-” this sounds horrible, right? But that’s- in livestock actually think about right? Instead of saying we just have to wait for that gene to die out because those people are very reproductively successful, which is amoral and mean, we can actually go in and fix it.

Dr. Jim Lowe

We can say, sure, no problem, clip. And then the other spot in humans where it’s being used, I’ve got little visibility of this. We do a little bit of work with a company called Meccano and there are several groups that are actually in making kidneys and livers and hearts for people in pigs. And so they’re going to take- they’ve taken pigs and pig organs don’t exist in people because we, we have these thing called surface leukocyte antigens.

Dr. Jim Lowe

So we have these proteins on the surface of our cells that our immune system recognizes as us. And so pigs have a couple, three of certain antigens, swine leukocyte antigens that don’t match up with human leukocyte antigens. And so when you put a pig organ in, a person rejects, that’s a rejection. So it’s immediate rejection. It’s not like, Oh, I took Kaylee’s kidney and-

Kaylee Hillinger

Let me give her some antibiotics or there will be a rejection.

Dr. Jim Lowe

Took Kaylee’s kidney and I have a minor thing and I can manage that with anti-rejection drugs. It’s immediate rejection within hours. Immune system says huh-uh. It doesn’t know that it’s any different than anything else foreign in the body. And so there’s some, a lot of really smart people who went back and figured that out. They’re like, oh, pigs have these and humans have these and these are really bad for people.

Dr. Jim Lowe

So let’s go clip that. Let’s go remove them. And they figured out where they’re at. I mean, it’s a simple thing to say oh, these four swine or three swine leukocyte antigens are a problem. Then they had to figure out where they were at the genome and what’s the bit of DNA. Where are they at in the library?

Dr. Jim Lowe

There’s no… right?

Kaylee Hillinger

And then you get rid of them.

Dr. Jim Lowe

There’s no Dewey Decimal system to go find them. So then where do we find them and how do we clip them and which bit can we take and which bit can’t we take?

Kaylee Hillinger

Then what happens when we take it?

Dr. Jim Lowe

Yeah, and what other things do we get etc.. So they’ve done this. So there’s double and triple knockout pigs today. And there was one of the stories out of Mount Sinai, a company we had the good fortune to work with a bit. They’ve had them in monkeys for years. But monkeys are the right model to test these things in.

Dr. Jim Lowe

They reject things very quickly. And so it gives you a lot of- that’s the pre human studies. And so they’re moving to human studies now. And so we’re not tomorrow but in five years we’re going to have pig kidneys or pig hearts or pig livers. Specifically produced to solve the organ transplant problem.

Kaylee Hillinger

Awesome.

Dr. Jim Lowe

Now, do they- anybody think those kidneys are going to be good for 40 years? No. But most people die of kidney transplants because they’re on the waiting list and we don’t give them a kidney before they. So if I can bridge them four or five years. Okay, maybe. Maybe we get another technology, right?

Kaylee Hillinger

Absolutely.

Dr. Jim Lowe

So here’s another example of where CRISPR has been- So we’re tying genomics, understanding where the genome is, which is what this is all based on, with this enzyme process, with some really other clever people thinking about global problems and saying, hey, listen, we can solve that. So I think people haven’t gotten cranked up about editing pig kidneys to stick in humans, although there’s some pushback, which is interesting.

Dr. Jim Lowe

And they certainly, I don’t think, have been cranked up about curing sickle cell because like, oh, that person’s suffering, we should do it. And it doesn’t infect me. It’s a little NIMBY thing, right? Not in my backyard. Wait a minute. You’re editing my food? Yeah, I don’t like that.

Kaylee Hillinger

Yeah, and seeing it as your food instead of an animal that someone manages and cares for in order to become your food before that.

Dr. Jim Lowe

Yeah. And people don’t want to think about that. Most people don’t. Even if they know where their food comes from, they don’t want to think about Wilbur.

Kaylee Hillinger

I want Wilbur to live through PRRS so he can become a pork chop. Don’t want him to die a sad PRRS death.

Dr. Jim Lowe

Yeah. And so that’s his whole thing, right? Like our job is to be super stewards of our animals under our care and alleviate suffering. The hard bit, right? And veterinary students don’t understand. Like all of my patients are going to die. I just want to name the day. So what I don’t want is an unpredicted mortality.

Kaylee Hillinger

Exactly.

Dr. Jim Lowe

And it’s not just that that unpredicted mortality is bad economically. But it also is bad for the animal because it probably suffered before it died. Not nobody likes to be sick and then die.

Kaylee Hillinger

Yeah.

Dr. Jim Lowe

And so it’s to me, the CRISPR thing for disease prevention in animals is a huge welfare discussion. More so than- The economic value of PRRS elimination in the long term is zero.

Kaylee Hillinger

Explain that.

Dr. Jim Lowe

Commodity market.

Kaylee Hillinger

If everyone has it.

Dr. Jim Lowe

If everyone has it, it’s not a competitive advantage. So is the industry more efficient? Yes, the industry is more efficient. But because it’s a commodity market price will reserve, back to net zero profit. So there’s some short term economic-

Kaylee Hillinger

It’ll just be built into the genetics of the entire industry.

Dr. Jim Lowe

And it’ll be built into the pricing, the entire industry. So we have an advantage today economically and we have more disease because we have fewer supply, price goes up. Well, if we have a steady supply, right, if we produce more pigs, price is going to go down. So we’ll have to revert- blah blah blah. So if you just look at market theory over the long haul, it’s not a competitive advantage.

Dr. Jim Lowe

It might be for the consumer because theoretically you produce pork cheaper. Or beef or whatever. But it’s certainly a welfare thing. And then we’ve got this other bit in cows, which is- nobody’s talking about but it’s exciting. And that’s we can make any cow poll tomorrow.

Kaylee Hillinger

And so I know what polled is but just in case.

Dr. Jim Lowe

No horns.

Kaylee Hillinger

No horns.

Dr. Jim Lowe

And the interesting bit about poll, the poll trait is this dominant gene. So it’s not the absence of horns, it’s the presence of a gene that prevents horn growth. So with classic kind of mammalian Mendelian genetics. We always think about homozygous heterozygous and you can be homozygous poll or homozygous horn. But a heterozygous between those two is always polled. It’s the dominant gene.

Dr. Jim Lowe

So one copy of the gene is enough to suppress one growth. So unlike disease resistance where we’re clipping or removing a bit of the genome to make something, we’re going to stick a little bit in it. So the good news is, Angus cattle are as a breed 100% polled. So they have two copies of the poll gene.

Dr. Jim Lowe

And so we’ve bred black, Angus are black, we bred black cattle across all these other breeds, so we basically pulled up a whole bunch of breeds. So most of the beef breeds today, we can get a polled version of that. Partially because we either stuck black in or because there were some naturally occurring. So Herefords had naturally occurring polled animals. The two biggest groups of cattle, two biggest breeds of cattle that are not polled today are dairy cattle.

Dr. Jim Lowe

So Holsteins Friesians and Jerseys and that’s the two dominant dairy breeds. They are both naturally horned. There are a few animals that are polled in those breeds. Polling occurred, but they’re not very productive.

Kaylee Hillinger

So I can guess why you don’t want horns. And it’s an injury risk sort of thing with handling and with the animals towards each other when they’re aggressive. Getting them hung up on equipment and that kind of thing. So it’s an animal welfare choice that you would not want them to have horns.

Dr. Jim Lowe

And none of them have horns today because we dispose of them. We take them off. So, painful for the calf, no matter how we do it. And we do it in dairy cows very, very early. So the horn isn’t actually grown into the skull yet. I mean, the horn goes into the frontal sinus in the- like the right on your forehead.

Dr. Jim Lowe

So that big sinus is right above your eyeballs is where it is on a cow. And so it’s just a piece of skin when they’re born. So if we disbud them, we take the horn bud off. But it still is uncomfortable. It’s a process, surgical process. Right. And so now they breed it off. And so I can take an Angus gene now cow gene and stick it in the Holstein and tomorrow all of the offspring in that line are polled.

Dr. Jim Lowe

So the good news with Holsteins is because we use very, very few bulls it’s all artificial insemination. I can poll a few genetic animals and put a whole- change the herd over very, very quickly because the dominance of a few elite animals in that industry. So that’s really exciting to me. And it’s not a GMO, it’s a cow gene.

Dr. Jim Lowe

I’m just accelerating the selection of that by sticking it in instead of…

Kaylee Hillinger

And another interesting piece of this whole gene editing is it’s good for the animal, the welfare pieces, animal health improves, but you also get a decrease in antibiotics with a lot of these different disease resistant opportunities. Which none of us want to be using antibiotics, they cost money and there’s withdrawals and all those pieces. So there’s some positives there just better utilizing the resources that we have.

Dr. Jim Lowe

Yeah. And less mortality rate. So there’s two big problems with mortality. One is the animal suffered, which is the biggest one. But from a sustainability standpoint, that animal consumed a lot of carbon. And we didn’t eat it. It was unproductive carbon consumption. And so lowering mortality or even suffering poor growth, whatever, from disease, not only has a welfare effect, it has a carbon effect.

Dr. Jim Lowe

So it helps move our food chain down a path of using less carbon. None of us want to talk about that, but it’s fact. We’re going to have to figure that out. And so- because our customers are going to demand it. And so here’s a chance for us to do like- I don’t see any Ls.

Dr. Jim Lowe

There’s no Ls. There’s no losses. This is all W’s. If we can convince everybody we’re doing it for the right reasons. And I think that’s really the take home. We’re not doing this to make money, right? We’re doing this to actually make the system better, make our animals better, make it better on our people. Nobody likes to watch sick animals, right?

Dr. Jim Lowe

And at the end of the day, that makes a more sustainable food system.

Kaylee Hillinger

So what do you think is going to come first? Is it going to be a solution that humans have to face in human gene editing for acceptance in protein gene editing? Or are we going to be able to push through the message to the consumer that this is the right choice?

Dr. Jim Lowe

I think, trying to read the tea leaves, that we are going to get federal government, FDA, USDA approval for these products. There’s already some gene edited salmon in the market and there’s strong signals that these products are safe. We haven’t added anything in, science will win the day. And I think if accepted in a regulated format like, it needs to be regulated, we need to talk about it and we shouldn’t disclose it.

Dr. Jim Lowe

I think as long as food is cheap and safe and we don’t have any issues, I think the average consumer fairly quickly says, I really just want cheap and safe. I don’t want to stop and think about.

Kaylee Hillinger

They always go back to that. I think that they want the niche brand until it comes down to the ticket at the grocery store.

Dr. Jim Lowe

Yeah. And I just think people don’t I mean even us, I mean we obviously know where our food comes from. You know, like the pork chops I had last night. I know exactly where that pork pig came from. Right? I mean, like, I know where it was harvested. I picked it up and, you know, blah, blah, blah. And so I have an intimate knowledge that I don’t really care.

Dr. Jim Lowe

I was interested in dinner last night, not Wilbur’s story. Didn’t care about Wilbur, and so I was hungry and I wanted a nutritious meal and so I had a pork chop. And I think that’s really true. I think what we can’t have is any big flub ups. And I think everybody that’s working down that path… Kaylee Hillinger: Kerfuffle.

Dr. Jim Lowe

The flub up is different than a kerfuffle. Beautiful, yes. Yeah. But we can’t have any things that hey, we were not real transparent about this, so we were trying to pull the wool over somebody’s eyes. And I don’t think- You know, Geneious is walking down that path, Recombinetics is walking down that path, and they’re both pushing pretty hard that I think they are acutely aware of that.

Dr. Jim Lowe

And we could have had these products four years ago or two years ago or something. Well we had COVID, right? So it’s a drag, but they could have moved much, much faster than what they’ve moved, not because they’re not capable, but because they are dotting the I and crossing every T and making sure we don’t have any flub ups.

Dr. Jim Lowe

And I think once we get that, we’ll move much more quickly. But I think this initial one, I think they’re doing the right way. They’re just right foot, left foot. And it’s dot all the i’s and cross all the t’s.

Kaylee Hillinger

So we’ll have to overcome the consumer piece and then the actual productionization or commercialization of these technologies will be another incredible battle.

Dr. Jim Lowe

Yeah, I think-

Kaylee Hillinger

A challenge maybe not a battle.

Dr. Jim Lowe

Yeah maybe not a battle. Yeah. It’s not a minor thing to scale it up. That’s the issue. The scale up will be tough. Not impossible. Just tough.

Kaylee Hillinger

Just tough. But the need, the demand. I hope science prevails. So this was a long one today. We can wrap this up.

Dr. Jim Lowe

We should wrap it up.

Kaylee Hillinger

Some good stuff, though.

Dr. Jim Lowe

I know you didn’t talk enough, and that’s okay.

Kaylee Hillinger

Yeah, we should video this sometime. I was really into it and I just looked down. Almost a half an hour.

Dr. Jim Lowe

Well the world needs more Jim Lowe.

Kaylee Hillinger

I got nothing. Thanks for listening. Please subscribe and tell your friends about the Round Barn podcast available on any of the pod catchers of your choice. In addition to this podcast, we offer a wide range of learning opportunities, including a master’s of veterinary science degree. We’re accepting applications for spring of 2024 semester. To learn more about this program, please visit vetmed.Illinois.edu/MVS.

Kaylee Hillinger

Thanks for listening.