The revolutionary gene-editing tool known as CRISPR can alter, add, and remove genes from the human genome. The implications are immense: It could help eliminate illnesses like sickle cell disease and muscular dystrophy, and could even allow us to alter the genes of future generations of humans, leading to so-called designer babies. But will this ever really happen? Medical journalist and pediatrician Alok Patel investigates the current state of CRISPR—starting with a bull calf named Cosmo. Patel discovers how scientists edited Cosmo’s genome so he would produce more male offspring, and what that means for humans. In conversation with scientists, artists, and ethicists, Patel explores what kind of gene editing is actually possible right now—and what we should be thinking about when we consider manipulating human traits and, ultimately, the human experience. (Premiered September 9, 2020)
Gene-Editing Reality Check
PBS Airdate: September 9, 2020
Alok Patel: Cas9 plasmid. gRNA plasmid. The DNA template. This is so nuts!
The new gene-editing tool CRISPR has revolutionized our ability to edit nature. So, where exactly is this technology today and where is it headed next? It’s time for a Gene Editing Reality Check.
I can’t wait until kids are playing with this instead of LEGOs. And just CRISPRing bacteria in their bedrooms.
I literally ordered an at-home gene-editing CRISPR kit. You can get anything over the internet, and this shipped to me in about four days. Now, to be clear, this CRISPR kit only modifies bacteria, but still...
Do not inject yourself with any of this.
This is just what CRISPR looks like in the lab: test tubes, pipettes, and plates of cells. But, what can CRISPR do in the real world? I’m Dr. Alok Patel, a pediatrician, medical journalist, co-host of NOVA’s Parentalogic, and host of the podcast NOVA Now... which, yeah, I record from my closet.
You can’t tell, but I’m surrounded by clothes right now.
I want to find out how CRISPR is actually being used right now. And how far are we from being able to edit humans or create designer babies? Is this all science fiction? To my surprise, I found out that I could actually meet a designer baby— of a slightly different variety— about an hour outside of San Francisco.
So I’m, like, really excited to be on this farm right now.
Alison Van Eenennaam: Welcome to UC Davis.
Alok Patel: I did my absolute best to put on, like, an urban farm look.
Alison Van Eenennaam: Well you got the urban right. I don’t know about those white shoes. You know what cows do, right?
Alok Patel: Fair point. Can we go meet some cows?
Alison Van Eenennaam: Let’s go see Cosmo.
Alok Patel: I’m here to meet Cosmo, a calf that was gene-edited with CRISPR as an embryo to do something surprising: to load the reproductive dice in favor of making male offspring.
Alison Van Eenennaam: We will go in here. That’s looking for your shoes.
Alok Patel: That’s looking for my shoes.
Alison Van Eenennaam: That’s what she thinks of you.
Alok Patel: It’s an udder delight to meet you.
Alison Van Eenennaam: Oh god! Should we go down and see if we can speak to Cosmo?
Alok Patel: So we’re going to see the star of the show right now, right?
Alison Van Eenennaam: Yeah; hi, Cosmo!
Alok Patel: How’s it goin’, cutie pie?
Alison Van Eenennaam: Aw. Don’t run away. How you doing, dude? Sometimes if you just kind of kneel...
Alok Patel: Now, why would someone want to make more boy cattle? Sounds kinda random. But livestock geneticist Alison Van Eenennaam explains why this actually makes sense.
Alison Van Eenennaam: There are certain sexes that are suited for different purposes in agriculture. In the beef industry, the males are more fuel-efficient at converting hay into beef. And so it's basically trying to improve the efficiency of, of beef production.
Alok Patel: Today, cattle grown for beef contribute a lot of greenhouse gases to our atmosphere. If we could get the same amount of beef with fewer animals, that could lessen the carbon footprint of the whole industry.
Alison Van Eenennaam: If you're interested in lowering the environmental footprint of agriculture, geneticists are your friends.
Alok Patel: But how is it possible to make more males? In mammals, sex is determined by the sex chromosomes. XX usually means you’re female. XY almost always means you’re male. But, Alison told me something pretty cool:
Alison Van Eenennaam: There's actually just a single gene on the Y chromosome that triggers differentiation down the male pathway. And that's the Sry gene. So what we were interested in doing is seeing if we were able to move that gene onto another chromosome, if we could get male pathway triggered in an XX individual.
Alok Patel: Alison and her team used CRISPR to insert the Sry gene—the gene for male development—onto Cosmo’s 17th Chromosome, which is a non-sex chromosome. That means if he has calves that inherit this Sry gene on the 17th chromosome, they might develop male characteristics even if they don’t inherit the male Y chromosome.
Alison Van Eenennaam: And we bring it out here to a 1,500-pound cow, and then we put the egg into embryo transfer the same way that is used in human fertility clinics. Nine months later we get a calf.
Alok Patel: The trick is to be as small as I can. And I feel like that dude from Lord of the Rings. Hi, Cosmo. Hi.
Alok Patel: Now, sadly, Cosmo didn't want to be friends. So instead, Alison let me meet another, newly gene-edited calf.
Alok Patel: You have very pretty eyelashes.
Alok Patel: One that I could get very close to.
Dr. Bret McNabb: Here’s some lube. You’ll both appreciate this.
Alok Patel: Oh, but I left out one detail. This calf is still in utero.
Dr. Bret McNabb: You’re going to go in, and you’re going to just gently push. She might give you a little bit of resistance.
Alok Patel: Yeah.
Dr. Bret McNabb: You’ll feel the opening of her rectum as you go through.
Alok Patel: I’m going in. Ohh! There’s a little bit of resistance. She’s good! Oh! Yup. So there’s manure on my shoe.
Dr. Bret McNabb: I want you to gently push down and try to bounce or blot below you.
Alok Patel: It feels like there’s, like, a water balloon. But then there’s like a little rock in the water balloon. Is that your bébé? I feel it. This is crazy. And I’m moving around.
Alok Patel: I know what you’re thinking, and no, this is not a punishment for having scared the cattle.
Dr. Bret McNabb: So, next step is the ultrasound.
Alok Patel: This is actually how they perform ultrasounds to check on the calves.
Dr. Bret McNabb: I usually keep my middle finger on the top of that probe.
Alok Patel: Instead of looking through the belly, like on a human, they look through the intestinal wall—by sticking a probe up its butt.
Baby baby, where are you?
And while it might look uncomfortable to us, it doesn’t seem to bother the momma cow very much.
I’m sorry heifer. I have no idea where I am in you right now.
Alison and Bret should be able to determine if a calf is developing as male or female after about 70 days.
Dr. Bret McNabb: You can start to see the vertebral column, so the spine of the calf.
Alison Van Eenennaam: Yay! I saw a little face!
Dr. Bret McNabb: Right now it’s about the size of a fat cat.
Alok Patel: Look at that.
Dr. Bret McNabb: Oh, that will wash out.
Alok Patel: It’s all good. This is not all that bad...
Dr. Bret McNabb: That’s not that bad.
Alok Patel: In the grand scheme.
Dr. Bret McNabb: Not at all.
Alok Patel: Did you expect worse?
Dr. Bret McNabb: I did.
Alok Patel: The next step for Alison’s research? Cosmo needs to grow up and have some calves of his own. If about half of Cosmo’s would-be daughters—with two X-chromosomes —instead develop as sons, the experiment will have been a success.
Cosmo looks perfectly normal and healthy and happy to me. I mean, he doesn't like me, but I’m not offended by that. I don’t take it personally. But he looks great. Is there anything you worry about—an unintended consequence—with editing in cattle? Something that you may not be able to foresee in like two or three generations from now?
Alison Van Eenennaam: You're always worried: Did you alter the genome anywhere else or make a big deletion? In the case of Cosmo, he actually got several copies of the gene inserted, not just the one that we designed the construct for. So, I mean, this is a long way from ready for primetime and certainly a long way, in my opinion, from ready for doing work in humans.
Alok Patel: This raises an important question.
You gene-edited little marvel! Do you want to come be friends with me now?
When will CRISPR be ready for humans? To tackle that, we need to understand how it works today, and how fast it’s changing. So, let’s do a quick CRISPR overview.
Now yes, crisper is that drawer in your fridge. But when people talk about CRISPR, they are usually referring to CRISPR-Cas9. Now, this system was discovered in bacteria as a way for bacteria to defend themselves against viruses.
Here’s how it works: The DNA double helix is made out of the chemical bases T, G, C, and A, represented here by colored popsicle sticks. Cas9 is a protein that acts like scissors.
Just call me Cas9, the molecular scissors.
And, it can be programmed to cut the DNA exactly where we want, because it also carries with it guide RNA, a one-sided strand of the bases G, C, A, and U—in purple—instead of the yellow T in the DNA.
But where to cut? It’s a good thing I got my guide RNA.
Scientists can actually custom build this guide RNA in the lab to match a specific DNA sequence.
Oh, give me a match; I’m ready to cut. Give me a match.
When the RNA that the Cas9 is carrying lines up...
Oh snap! It’s go time.
...it knows to cut. Once the DNA is cut, it will try to repair itself. And scientists can hack this process by introducing template DNA that guides what bases are inserted in the gap. Mic drop—the ability to edit genes! So, how will this affect humanity’s future?
So think of it like a pair of scissors that can go into the DNA.
I talked to some young artists—designers in their own right—to hear what they think about the potential for designing life itself.
Various Teens: I can do something with a tree! Do a tree, dude. Have fun!
Brianna Sapienza: Like maybe people could have fins or something. Like, I really don't know.
Liana Novoa: I feel like our scientists are so, like, peak technology, peak advancements.
Ariana Pelaez: If they're changing your DNA, like, they could change completely how someone will look.
Xavier LaPlante: I do think that there will be designer babies in the future, most likely.
Various Teens: I’m gonna draw an eyeball right here. Yeah!
Alok Patel: But how likely is it? And how soon could we do it safely? Those questions are a lot harder to answer.
Scientists I talk to say there are still a lot of limitations about what it can and can’t do.
Karmella Haynes: CRISPR normally functions inside a little, teeny-tiny bacteria. But when you move it out of bacteria and into a human cell, now you got to get CRISPR in there— and the template DNA. All of that has to get into every single cell. It's very inefficient. And sometimes CRISPR will produce some changes in the DNA. In a lot of cases, it's something that you don't even want.
Alok Patel: Just because we can find the target doesn't necessarily mean we can make an accurate change. And making an inaccurate change—that could lead to disaster.
Karmella Haynes: Right.
Alok Patel: So scientists like David Liu have been tinkering with the CRISPR system to make it more precise.
David Liu: If you think of the original CRISPR as it occurs in nature as a pair of molecular scissors that cuts the DNA double helix, but instead of cutting the DNA, we precisely change, for example, one DNA base pair to a different base pair. That form of CRISPR editing is called “base editing.” If the original CRISPR is like molecular scissors, you can think of base editors like pencils.
Alok Patel: Even though the early scissors version of CRISPR is not perfect, it’s already being used in clinical trials to try and disrupt the genetic mutations that cause diseases like sickle cell disease or cancer. And even more precise base editors will be heading into clinical trials soon.
David Liu: So many people may not realize that the era of human genome editing—that is the era where we are purposefully making changes to the DNA sequence of human patients who are then better off as a result of those changes—that era is here. It's already happened. It's already now.
Alok Patel: Today, there are already clinical trials using CRISPR to change genes to treat diseases. This is incredible. Now all of these clinical trials are using gene edits that affect only your body. They don't get passed on to future offspring. That's germline editing. That's a completely different category. This is not designer babies.
Alok Patel: So, are there any human designer babies out there?
Françoise Baylis: Yes, there are designer babies. It's the work of a scientist who was looking to genetically modify the children so that they would have resistance to HIV.
Alok Patel: Françoise Baylis is a bioethicist who told me about Chinese scientist He Jiankui,
who in 2018 claimed twin babies were born that he had genetically edited with CRISPR.
He Jiankui: Two beautiful little Chinese girl came crying into the world as healthy as any other babies.
Alok Patel: Then, in 2019, a third was born.
Françoise Baylis: He was absolutely seeking to push the boundaries. Most of the comments that I have heard have been critical of the science, uh, and indicating that in large part, he didn't know what he was doing. And so he was roundly criticized for having done this.
Alok Patel: In December of 2019, the Chinese government found He Jiankui guilty of “illegal medical practice” and sentenced him to 3 years in prison.
Françoise Baylis: The science isn't ready at this point in time. We aren't yet the master of this technology.
Alok Patel: The technology for germline editing in humans isn’t there yet. The technology’s not precise enough. But pretend for a second it was. What exactly should we be editing? Whose decision is it? I spoke to someone who has a really unique perspective on all of this.
Teresa Blankmeyer Burke: In the disability community we have an expression: Nothing about us without us. Who is making the decisions? Who is being impacted? Who will have a voice—whether that be spoken or signed—at the table in those discussions? With the experience of being deaf, it's not merely about not hearing, not hearing noise. It's about how we connect to the world.
Alok Patel: In 2019, a Russian scientist made headlines when he announced that he had recruited five deaf couples to participate in a CRISPR experiment to, quote, “correct” a gene mutation that causes deafness.
Teresa Blankmeyer Burke: One of the big responses to this announcement of this research was why did they choose deafness? Let's suppose we have a person who is deaf and their family is hereditarily deaf, all deaf multi-generationally, Deaf and signing, who do not see that experience of being Deaf as a loss. I think many Deaf people are saying, "Hey, our way of life, our values, and what we experience, what we contribute is worthwhile. And to think about throwing that away without, including us in the discussion, is really unimaginable.”
Liana Novoa: I feel like it just depends—genetically modifying people—it depends on what hands it gets into to decide that factor: if it would turn for the better or the worst.
Françoise Baylis: It is really important now that we invite everyone to have the opportunity to participate in this conversation. There are different ways of knowing in the world and different kinds of knowledge that have to be respected.
Xavier LaPlante: I guess undesired traits makes you special in a way. And that's something I don't want my child to lose, I guess, by having all the desired traits.
Françoise Baylis: It's a two-way conversation. Yes, there are things the general public can learn from the scientific community, but the scientific community can learn things from the general public.
Alok Patel: Do you think that people should be able to have that ability to make those decisions, for their children?
Ariana Pelaez: So if it's changing life-threatening diseases, I like that idea, it’d be pretty helpful.
Alok Patel: While the ability to edit single-gene mutations is within our grasp, the ability to truly design humans is so complicated that we are nowhere close.
Alok Patel: Like I don’t know how much your artistic talent comes from you, as a person, versus...
Alok Patel: Scientists have barely scratched the surface of even understanding the genetic basis of complex traits like height, intelligence, or creativity. But, the technology is advancing quickly and its power is so profound that the time to talk about this is right now.
Françoise Baylis: The project we’re talking about is ultimately taking over the human evolutionary story. Well, we need to think about the human genome as something that belongs to all of us.
Niaz Uddin: Honestly, I feel like it's kind of scary. I feel like it would cause, like, a divide within, like, the people that haven't been genetically changed or anything.
Françoise Baylis: The conversation is really about the biggest most important question of all: What kind of world do we want to live in?
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- Françoise Baylis, Teresa Blankmeyer Burke, Karmella Haynes, Xavier LaPlante, David Liu, Bret McNabb, Liana Novoa, Alok Patel, Ariana Pelaez, Brianna Sapienza, Niaz Uddin, Alison Van Eenennaam