Scientists Develop a Hornless Cow Through Gene Editing
Dairy cows, which come from the Holstein breed, naturally grow horns. On farms, the horns are often physically removed because they can pose a threat to other cows, a well as to farm workers handling the cattle. But a group of researchers from the University of California, Davis has developed a method to remove the horns through gene-editing. The team inserted a gene from the naturally hornless Angus breed to create hornless Holsteins. Have the researchers developed a new type of cow, or are they just speeding up the breeding process?
Animal geneticist Alison Van Eenennaam, who led the research, and Jennifer Kuzma from the Genetic Engineering and Society Center talk, about the future of biotechnology in agriculture, what defines a “genetically modified organism,” and how these technologies might be regulated.
We want listeners to share what they think about Van Eenennaam’s research. To spark conversation, we sent a rough cut of our video to experts in the fields of animal biotechnology, animal welfare, and bioethics and asked them to send us their thoughts. Here are a couple responses, edited slightly for clarity:
Jeff Burkhardt, Ph.D.:
There is a segment of the population for whom almost anything we humans do to or with nonhuman animals is considered morally wrong. So-called “animal rights” proponents believe that animals are entitled to the protection of their lives, liberty, and pursuit of happiness, so that practices such as animal agriculture—growing animals for food—which necessarily involve confinement and eventual death, are by their very nature unacceptable.
A more common belief among people concerned with our treatment of animals is the “animal welfare” view, which holds that because animals can experience pain (and pleasure), it is our moral responsibility to minimize or eliminate that pain whenever possible. In this light, whatever we can do to reduce suffering in food animal production systems is a good thing. Animal welfarists recognize, of course, that the end-state of animal agriculture is the animal’s death, but that is permissible because of the overriding benefits to people from the nutrition that animal farming provides.
From the animal welfare perspective, Dr. Alison Van Eenennaam’s research is worthy of high praise: The prospect of reducing the pain associated with de-horning, which itself was introduced to eliminate risks of animals hurting themselves and others, is exactly the kind of thing that animal scientists should be doing. One potential ethical rub comes from the fact that Dr. Van Eenennaam and her colleagues are using “genetic engineering” to accomplish this otherwise laudable goal. As she rightly notes, the public and government agencies responsible for protecting the public have legitimate concerns about various aspects of bioengineering. For example, the practice of “transgenesis”—moving genes from one type or species of organism to an entirely different type or species—has already raised the issue of so-called “frankenfoods.” Some frankenfood issues stem from questions about health and environmental consequences of moving and mixing genes across species boundaries. Some concerns, however, simply have to do with the fact of genetic engineering, reflecting an unease people have with the very idea of humans creating new life forms, or as it is sometimes put, “playing God.”
As Dr. Van Eenennaam points out, what makes her hornless cattle research a poor target for the frankenfood-playing God objection is that there is no transgenesis involved; the engineered cattle are getting their new, horn-free genes from other cattle, just like they would have through conventional animal breeding techniques. Her method just makes that “crossing” activity more precise—only the horn-free genes are transferred—and faster. This “faster” aspect, however, alerts us to a different kind of ethical concern with this and other species of biotechnology-employing research. As she notes, public opinion and especially regulation typically slow her kind of science down. Regulators focus on assessing risks. It should be clear, for example, that Dr. Van Eenennaam’s same-species genetic transfer is low-risk, with obvious benefits (both to people and to the eventual hornless animal herd!).
Now, what’s interesting is that Dr. Van Eenennaam’s comment about regulators is the exact argument one hears from scientists engaged in more exotic kinds of trans-genetic engineering—the kinds involving, for example, inserting genes from a fish into a crop plant, or even more, inserting human genes into pigs or mice or plants. From an ethical perspective, the latter are the kinds of biotechnology research that we want somebody to assess in order to determine whether benefits do outweigh whatever risks there might be, even if (or precisely because) we slow the science down.
It is just interesting how hearing a researcher talking about such ethically positive research (from an animal welfare point of view) ends up reminding us how easily scientists seem automatically to default to a “regulation holds us back” mode of thinking. My experience is that the “my research is highly beneficial, low-risk, and oversight slows me down” attitude is a trait that almost seems genetically engineered into scientists from graduate school onwards. The process of transferring that trait is maybe something that should be subjected to more or better oversight. I might go so far as to say that it should be looked at, even when the belief that “my research is beneficial, low risk, and oversight slows me down” is actually true! But that would probably be another story.
Jeff Burkhardt, Ph.D.
Professor of Ethics and Public Policy
Institute of Food and Agricultural Sciences
University of Florida, Gainesville
Goetz Laible, Ph.D.:
The genetic dehorning by genome editing is a great example that demonstrates how much we could improve on current genomic selection strategies for livestock. By combining genomic selection and genome editing, we can add highly valuable mutations, even those that would be outside of the available breeding population, onto the best genetic backgrounds. Thus, genome editing is not the sole answer, but when combined with genomic selection and assisted reproductive technologies, could transform current livestock improvement strategies.
Naturally occurring mutations are the cause of the variation between individual animals, and our present genomic selection schemes identify animals with the best available combinations of mutations. With genome editing, we can now make sure that we can bring the most beneficial mutations together and eliminate detrimental mutations in individual animals.
Whilst some aspects could also be achieved by conventional breeding approaches, it would take many generations, making it prohibitively expensive. In contrast, genome editing can introgress beneficial mutations much more directly and within a single generation. Importantly, if we again take polled cattle as an example, the outcome of multi-generational breeding vs. genome editing would be essentially identical. It would not be possible to differentiate the two polled dairy animals based on the technology used to produce them. Thus, genome editing is a contemporary extension of current efforts to genetically improve livestock.
Adoption of new technologies such as genome editing will be important to realize greater efficiencies in animal and food production to sustainably feed an increasing global population.
Goetz Laible, Ph.D.
Senior Scientist, AgResearch
Honorary Associate Professor, University of Auckland
Alison Van Eenennaam is a geneticist and Cooperative Extension Specialist in Animal Biotechnology at the University of California, Davis in Davis, California.
Jennifer Kuzma is a Distinguished Professor in Social Sciences and is Co-director of the Genetic Engineering and Society Center at North Carolina State University in Raleigh, North Carolina.
IRA FLATOW: This is “Science Friday.” I’m Ira Flatow. If you’ve been to a dairy farm, you might have noticed something that all the cows have in common, and I’m not talking about the mooing or the cud chewing. Each cow hornless, but they weren’t born that way. The horns are often physically removed so they don’t hurt one another or the farm workers. In case you’re wondering, both female and male cows of this Holstein breed are born with horns. As you can imagine, horn removal is not a pleasant experience.
Well, researchers at the University of California, Davis, UC Davis, tackled this problem, came up with a novel way to remove the horns without actually cutting them off. Instead, they prevented them from growing in the first place by using gene editing. They swapped a gene from a naturally hornless breed, inserted it into the genome of dairy bulls.
Is this a new type of cow or a bull, or did the scientists speed up the breeding process that could have happened naturally? And how should these biotech methods be regulated when it comes to agriculture and food? Has this bull now become GMO, a genetically modified animal, with all the controversy that label carries with it?
My guests are about to talk about this. Alison Eenennaam is an animal geneticist, and one of those researchers from the University of California, Davis. And Jennifer Kuzma is a distinguished professor of social sciences and the coordinator of the Genetic Engineering and Society Center at North Carolina State University. That’s in Raleigh. Welcome both to “Science Friday.”
JENNIFER KUZMA: Thank you.
IRA FLATOW: You’re welcome. Alison, tell us what you did here. You used a technique called TALENs. Is that similar to CRISPR that we hear about?
ALISON VAN EENENNAAM: Yes. They’re both site-directed nucleases, which basically means they’re molecular scissors that cut at a specific location in the genome that you tell them to cut at. And so TALENs were a little bit before CRISPRs, but the concept is exactly the same.
And what happened with this project is actually a collaboration with a company called Recombinetics, is that they targeted the gene that grows horns and basically used the site-directed nucleases to swap out the allele that grows horns in Holstein, and replaces it with the allele that stops horns growing in Angus. So it’s basically a DNA sequence from a cow at the same location at the same gene. Except in this case, we’ve now got the Angus allele, and so the Hosteins no longer grow horns.
IRA FLATOW: Sometimes, there are often unanticipated consequences of doing genetics work. Did you detect any other differences in these, other than that they were hornless?
ALISON VAN EENENNAAM: Yes, they were hornless. We actually sequenced both of the animals, because of course, now we can look at all three billion base pairs that make up the bovine genome. And we didn’t see any unanticipated off-target effects or anything other than the fact that we had replaced the allele at that one particular location. And really to me, this is precision breeding as much as anything. So we’re able to introduce a desired genetic variant very precisely without affecting any of the other genetics that make them great milk-producing animals.
IRA FLATOW: Do these bulls pass on these traits with the next–
ALISON VAN EENENNAAM: Well actually, that’s our part. That’s UC Davis’ part of this experiment. So we would hypothesize they would. And of course, being good scientists, we have to actually do the experiment to show that. And so we’re collecting semen from the bulls. And it’s a dominant trait. And both of these bulls are homozygous, meaning they’re carrying two copies of the dominant trait that stops horns growing.
And we would anticipate that when we breed them to horned females, that their offspring would inherit the dominant polled allele, and that those offspring would not grow horns. But we’ll breed our cows in the fall, when it’s breeding time at UC Davis, and we’ll tell you in nine months’ time.
IRA FLATOW: Can you patent these cows, these bulls?
ALISON VAN EENENNAAM: Well, that’s an interesting question, because what is there to patent? It’s just a naturally occurring allele that occurs in base breeds like Angus. And so I think probably the question that you’re asking is, would the technology used to make the change in the bulls themselves be patented? And of course, that’s in the middle of a fairly public debate at the moment, that you know who owns rights to gene editing.
But really, I think if you look at how genetic improvement is done as it relates for a cattle, for example, you buy genetically improved semen from the artificial insemination companies currently. And those improved animals belong to you. They no longer have any reach into the animals. And so I would see this more as probably a value added trait that would come along with an artificial insemination sire. And so you’d pay a little bit extra for the semen perhaps, rather than having any kind of patenting associated with the animal itself.
IRA FLATOW: Jennifer Kuzma, what’s your take on this? What are your questions about this technique?
JENNIFER KUZMA: Well, I think the goals of the project are quite noble, to decrease both the animal’s suffering from the dehorning process, which I can understand would be painful to young cows or calves. Early on, they’re dehorned. So I think in that respect, animal welfare concerns are somewhat decreased.
On the other hand, we want to make sure that these products are safe for people who drink the milk or for if the dairy cows go to beef someday when they get older. We want to make certain that we have a good regulatory system in place in order to ensure the safety of the products coming from these cows.
IRA FLATOW: Our number 844-724-8255 is our number. You also you can tweet us at scifri if you have any questions. Alison, you did this with two bulls, right? Is that right?
ALISON VAN EENENNAAM: Correct.
IRA FLATOW: Isn’t that a small n equals 2?
ALISON VAN EENENNAAM: Well, these are really prototype animals that we developed. We hypothesized that the sequence that’s present in the Angus is what makes them polled, or not grow horns. But until you actually do that experiment, you really can’t tell. And so we have now done that. And so they’re actually clones in addition, which makes it not even an n of two. And so of course, we are working to do more animals, to look at that.
And in terms of the safety of these animals, there is no foreign DNA in them. So it’s a little bit different to traditional genetic engineering or the GMO debate, because really, it’s just the naturally occurring DNA that’s already present in bovine species. So there is no safety concerns associated with eating polled animals. That’s basically what an Angus burger is. And we’ve been eating that that particular allele for many years.
And I think one thing that’s kind of interesting is we’ve now sequenced a number of cattle. And we find that there’s literally millions of variations between the DNA sequence of two bulls from the same breed, for example. And so we’re frequently, or every meal we have, we’re eating all of this genetic variation that exists, just due to naturally occurring spontaneous evolution and mutations that have occurred over time in the breed.
IRA FLATOW: Yeah, you seem to be intimating– I’m just going to infer from this– that you’re trying to defend that these animals are not genetically modified in a sense of GMOs, which you have edited their genes, have you not?
ALISON VAN EENENNAAM: Well, I think GMO, unfortunately, is kind of an amorphous term that really doesn’t mean anything. And so I think specifically, perhaps your question is, are they genetically engineered? And that traditionally has been defined as carrying a recombinant DNA construct. So for example, the BT protein in insect-protected crops.
In this case, there is no recombinant DNA construct in the animals. It’s just basically bovine DNA. And its sequenced indistinguishable from the naturally occurring allele that occurs in Angus.
IRA FLATOW: I understand. Dr. Kuzma, what’s your reaction to this?
JENNIFER KUZMA: Well, there’s a couple points. I did read that some of the bulls had physiological differences. So during the cloning process, they may have introduced some very pronounced physiological differences. So I’d like to hear from Alison what they saw when they looked at the bulls, if there were any morphological changes.
And then the second thing is that you’re taking a gene from an Angus, which can [? eat ?] beef, typically. And you are swapping out the allele in a Holstein, which you drink milk. So I would want to see the milk tested just in case having the hornless allele, had anything changed in the milk coming from that hornless cattle.
So there are some safety concerns, especially the cloning process. There’s a lot of epigenitic effects. That’s my understanding, these bulls had reduced sperm levels, and some problems with the testicles and anemia, I think I read as well. So there have been some changes to the physiology, in which case, I would want to look at the physiology and the biochemistry of the milk.
So yeah it’s safety, but it’s also consumer confidence. I just think because this is the first gene-edited animal that’s going to be entering the food supply that it would be wise to go through a mandatory pre-market approval process, and to actually test that milk and to make sure it is substantially the same as milk from other Holstein cows that have their horns.
IRA FLATOW: Dr. Eenennaam?
ALISON VAN EENENNAAM: Well of course they’re bulls, so we’re going to have a bit of a hard time testing their milk. And so we will be producing–
JENNIFER KUZMA: I’m talking about futher down the road, as I understand that bulls don’t have milk. Thank you.
ALISON VAN EENENNAAM: So we have to differentiate the cloning process from the genome editing process. So in this particular case, these bulls were produced using cloning, which is not necessarily how I think you’d use the technology going forward. As I mentioned, there’s are prototype animals.
And what ideally I think breeders would like to do is edit the next generation. And so really, we’d be targeting the edits into the developing embryos of the next generation rather than going back in time and editing animals that already exist on the ground. And so I think there are known epigenetic issues with the cloning process. And that’s really not an ideal way that this would get commercialized. It’s really these, as I mentioned, are prototype animals.
And what we’d like to do is be able to tweak the DNA of the next generation such that they wouldn’t actually have to go through that cloning process. And that would remove the concerns related to epigenetics as it relates to this particular technology.
IRA FLATOW: I can see the dialogue we’re having right here, I know that our listeners are having the same thoughts about themselves about the pros and cons of this. So Dr. Kuzma, shouldn’t the public opinion be brought into this when bringing–
JENNIFER KUZMA: Yeah. I would think that we should consult the public on emerging technologies. And that’s not to say that everybody votes on whether or not we want this topic. But at least to hear the different concerns that people have about whether it’s gene-edited cattle, whether they’re bulls or cows, or whether it’s transgenic [? fix ?] or what have you, I think that the public should have a voice in decision making about this.
So to combine the science and the safety studies with people’s comfort level, given that they are the end users of the product, I think it is important in a society that’s somewhat democratic. So I do think that the public’s voice is important. Not to say that they should be just basing decisions on values, but it to be a combination of sound science, regulatory process and public values for wanting to have this milk from the future cows tested.
IRA FLATOW: The public is already tweeting us, letting us know what they– here’s an interesting– this is a typical question we get every time we talk about something with animals. Scott Hansen wants to know, could this genetic modification technique have use in humans, such as in cystic fibrosis?
JENNIFER KUZMA: Yeah, definitely. That’s a good candidate for gene editing is cystic fibrosis, which you can pinpoint an allele. And yes, so gene therapy, there has been work done in the lab looking at gene editing in humans.
There’s been a lot of public discussion about whether that should be done at the embryo level. And the National Academy of Sciences had a meeting about that last December. And so I think the consensus is to wait on it for embryo modification. But perhaps through gene therapy or targeting to certain tissues, it could be a very useful process in humans.
But there, you have the medical patient is bearing both the risk and the benefit. So it’s a more equitable and just kind of process. So that patient can make an informed decision about whether or not he or he wants to be edited through gene therapy or what have you.
With food, It’s a little bit different, because the consumer is sometimes removed from the benefit. And so however low the risk is, the consumer’s still going to see that risk as pretty high if there’s no benefit. I think that’s the difference between medical applications and food applications is there’s a different risk/benefit profile usually with these products.
IRA FLATOW: This is “Science Friday,” from PRI, Public Radio International. I’m Ira Flatow talking with Jennifer Kuzma and Alison Eenennaam. We’re talking about new research and creating a bull using some genetic engineering techniques, that doesn’t have horns, is hornless.
Are there other simple– I mean, I’m going to call it simple because there’s only one allele, one little piece of the genome we’re talking about– other simple modifications we could make we could look into for animals that might be improve–
ALISON VAN EENENNAAM: Yeah, actually. There are already a couple of examples out there. So for example, the University of Missouri has done an edit that basically inactivated the protein that is the target of a virus that causes a thing called PRRS, porcine reproductive and respiratory syndrome virus. That costs about 600 million annually for the pork industry in the United States.
And basically by inactivating that particular gene, by tweaking the DNA and turning it off, they’ve removed the target where the virus actually binds. And so those pigs are no longer susceptible to that virus. So I think for me, disease resistance is a really important trait where we could actually use this technology.
And so the risk/benefit evaluation, I think in this case, and perhaps the horned one as well, there’s a very obvious benefit to the animal in terms of not getting sick or not having horns. And therefore, it’s a bit of a different discussion. And that’s really, I think, something I want to have a discussion with the public around is understanding that thwarting the technology has consequences, too. And to have a robust discussion around both benefits and risks. Because I think that there are very clear benefits that could be associated with the use of this technology in agricultural breeding.
IRA FLATOW: Dr. Eenenaam, where do you take this now? What happens to it? How do you move this forward?
ALISON VAN EENENNAAM: Well, one of the big uncertainties– and I think Jennifer alluded to this– is the regulatory around this. So according to the current regulatory regime, the FDA is in charge of regulating genetically-engineered animals based on the fact that the recombinant DNA construct is a new animal drug. And that affects the form or function of an animal.
In this case, in the couple of examples I’ve given, there is no recombinant DNA present. And so it’s unclear whether the regulations cover these animals, or are just really precision-bred animals that don’t have any new novel DNA? And that’s basically the foundation of all our animal breeding programs working on spontaneous variation. So, unclear.
IRA FLATOW: I only have a minute left, but somebody was writing in saying, could you possibly create tuskless elephants or hornless rhinos so that people wouldn’t kill them for their ivory? And that’s where I’m going to leave it, because I see a lot of nodding of heads on the other end of the telephone.
ALISON VAN EENENNAAM: I’m not sure if it’s a single gene trait like it is in bovine, but conceptually, you could do that, and maybe remove that prize from the hunters and help that animal population.
IRA FLATOW: I think we’ve reached a little compromise here. I want to thank both my guests, Alison Van Eenennaam– sorry about pronunciation– animal geneticist at the UC Davis. Jennifer Kuzma, distinguished professor of social science and co-director of the Genetic Engineering and Society Center at NC State, North Carolina State University in Raleigh.