Recombinetics plans to market milk from the gene-edited cattle that went wrong

In Australia, ABC has broadcast a program on Recombinetics' gene-edited hornless dairy cattle, which were unexpectedly found by US FDA scientists to contain bacterial DNA which in turn contains intact antibiotic resistance genes, a fact that had been completely missed by the developer company.
 
The project appears to have ground to an ignominious halt, except in Australia, where some of Recombinetics' edited cattle have ended up. See the transcript of the program below – there's also an audio recording at the URL given.
 
Recombinetics told ABC that these cattle don't contain any of the rogue bacterial DNA, but we need to view that claim with skepticism, since the company's scientists previously claimed “our animals are free of off-target events” but were proven wrong.
 
The ABC program contains some interesting revelations. For example, the reason why Recombinetics targeted Australia appears to be due to their lax regulation of genetic engineering technology, including gene editing.
 
In another example, the edited cattle have a double row of eyelashes. At first glance this may not seem alarming, since the POLLED gene that confers the hornlessness was taken from the Aberdeen Angus breed, which naturally has this double eyelash feature. But the problem is that the POLLED gene was only supposed to confer hornlessness. The fact that it has also conferred the double eyelash trait – an unintended side-effect – begs the question of what other unintended effects were produced by this supposedly "precise" gene-editing event.
 
Given the issues that have already arisen with these cattle and the unforeseen issues that will no doubt surface further down the line, as well as the availability of high quality non-GMO hornless cattle with good milk yield in the US and Europe, why are Recombinetics and Australia going down this route of the gene-edited hornless cow?
 
There can only be one answer: money and patented ownership of the food supply.
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Mutants or miracles? Australia's GM cows

By Michael Slezak, on Background Briefing
ABC, 15 Mar 2020
https://www.abc.net.au/radionational/programs/backgroundbriefing/mutants-or-miracles-australias-gm-cows/12050786

Removing the piercing horns of cattle has long been an unfortunate consequence of the world's great demand for dairy products.

So when American scientists made a gene-editing breakthrough, with the promise that farmers could soon safely breed hornless dairy cows, it generated great fanfare across the globe.

The cattle became the poster animals for a new era of genetic engineering.

But this miracle was hit by a massive setback.

As Michael Slezak discovered, that didn't end the project.

The next chapter of this scientific fiasco would continue, quietly, in one non-descript paddock just outside Melbourne.

Duration: 36min 21sec
Broadcast: Sun 15 Mar 2020, 8:05am

ALICE BRENNAN: Hey there. Welcome to Background Briefing. My name is Alice Brennan.

(Sound of laboratory door opening)

MICHAEL SLEZAK: Cool, so this is it?

ALEX KELLY: This is it. This is the (inaudible) lab.

ALICE BRENNAN: The ABC's national science, technology and environment reporter, Michael Slezak, recently visited a lab in Sydney called Biofoundry.

It's set up to do some stuff like editing the DNA of organisms.

Now, that sounds high-tech, but this place is actually run by amateurs who call themselves 'biohackers'.

ALEX KELLY: This is pretty cool, man. This is – Alex recently donated this to the lab. So this is a class two biological safety hood.

ALICE BRENNAN: So, Michael, who runs this place?

MICHAEL SLEZAK: So there's Meow-Ludo Disco Gamma Meow-Meow. He's the founder. And that's actually his name.

And the day I visited another biohacker was there, too. His name is Alex Kelly.

ALEX KELLY: This is a gel transilluminator, which is going to...

MICHAEL SLEZAK: So before I knew it, they'd put a white coat on me.

ALEX KELLY: Very importantly, you're doing science…

MEOW-LUDO MEOW-MEOW: So you need to wear a lab coat.

ALEX KELLY: …so you need to wear a lab coat.

MICHAEL SLEZAK: I have to wear a white lab coat. All right. Is that just to make me look silly?

(They laugh)

ALEX KELLY: No, it's good practice.

MEOW-LUDO MEOW-MEOW: Good practice.

MICHAEL SLEZAK: OK.

ALEX KELLY: We'll get this started because this will take a little while.

MICHAEL SLEZAK: Yeah. So, what do you mean by "get it started"? What are you doing?

MEOW-LUDO MEOW-MEOW: What you're doing.

ALEX KELLY: Yes.

MICHAEL SLEZAK: What I'm doing. OK. Yeah, so I'm doing it. All right, cool.

ALEX KELLY: So you're about to create your first GMO.

ALICE BRENNAN: You're making a genetically modified organism?

MICHAEL SLEZAK: Yeah! So they tell me that we're about to genetically modify a nasty e-coli [bacterium], to make it do something useful.

ALICE BRENNAN: And this is the same e-coli as you find in ailments like gastro or urinary tract infections, right?

MICHAEL SLEZAK: Yeah. But they want to modify it so that it produces human insulin.

ALEX KELLY: That right there is purified plasmid DNA that contains the gene to produce human insulin.

ALICE BRENNAN: Michael, how do you actually do that?

MICHAEL SLEZAK: Well, first we need a way of delivering the new DNA: kind of like a tiny little gene delivery van.

ALICE BRENNAN: And this 'delivery van' is a way to get all up inside the e-coli?

MICHAEL SLEZAK: Yeah. So they pull this little 'delivery van' out of the fridge – and actually, it looks less like a delivery van and more like a small vial of clear liquid. It's called a plasmid.

MEOW-LUDO MEOW-MEOW: OK. So you want to be working underneath this flame…

ALICE BRENNAN: So this plasmid is like a little delivery van, as you've said. But what is it really?

MICHAEL SLEZAK: Well, interestingly, this little gene delivery van is made from bacteria, because bacterial DNA easily slips in and out of cells.

ALEX KELLY: The plasmid is just like an accessory genome. It's an extra file that it can access.

MICHAEL SLEZAK: So this plasmid goes into the cell and gives the e-coli some extra DNA, which it then uses to start making human insulin.

ALEX KELLY: When we put them onto the heat bath, the rapid change in temperature will actually suck the plasmid DNA (makes sucking noise), straight into the cell.

MICHAEL SLEZAK: And after a few minutes, they tell me that's exactly what I'm doing.

ALEX KELLY: Oh, we're got to do that. All right. Four… You ready? Grab the tube.

MICHAEL SLEZAK: What do I do with it after that?

ALEX KELLY: Put it back in the ice. Go. Done. Nice. And that is now modified.

MICHAEL SLEZAK: So I just made a GMO?

ALEX KELLY: You just made in a GMO.

MEOW-LUDO MEOW-MEOW: How does it feel to make your first GMO?

MICHAEL SLEZAK: It's terribly exciting. (Laughs) It's cool. No, it's really cool.

ALEX KELLY: So you just created an insulin-producing bacteria.

MICHAEL SLEZAK: OK.

ALEX KELLY: So this bacteria now…

ALICE BRENNAN: Forgive my ignorance, but I had no idea that amateurs could actually do this kind of thing so easily.

MICHAEL SLEZAK: Yeah. So this kind of genetic modification is pretty easy to do. And nothing we've done here is even really regulated by the Australian gene tech regulations. It's considered too safe to worry about.

But Alex and Meow would like some of our regulations relaxed a bit more.

ALEX KELLY: My friend Sebastian, who lives in New York City in his mum's apartment: he calls himself a flower designer. And his entire thing is: he's trying to create a bluer pigment for flowers. And I think that is just the coolest thing.

ALICE BRENNAN: But unfortunately for Alex, right now he can't create his own flower pigments.

MICHAEL SLEZAK: No, but these are the kind of dilemmas facing regulators, because this revolution in gene editing is making modifications like this easier and easier.

And at the same time, the technology is getting more and more powerful.

Here in Australia, some of our regulations are getting looser; and that is worrying activists and a group of experts, who say gene-editing mistakes could cause unimaginable consequences.

ALICE BRENNAN: Michael, you've investigated one example of a gene-editing mistake?

MICHAEL SLEZAK: Yeah. So this is a pretty wild story. It's a story that involves what we'll call 'miracle cows'. But those cows turned out to not be just cows but, technically, part bacteria.

And I'm going to tell you about how those cows ended up here in Australia.

ALICE BRENNAN: But actually, your story starts in the US?

US AUDIO ENGINEER: How's that on level? I have them all the way up.

MICHAEL SLEZAK: Yeah, that's right.

ANTONIO RAGALADO: I can hear you, yep.

MICHAEL SLEZAK: It starts with a US tech journalist.

ANTONIO RAGALADO: My name is Antonio Regalado. I am a reporter at Technology Review and I cover research on genetics and genetic engineering: and specifically when that genetic engineering involves a human embryo.

MICHAEL SLEZAK: So several years ago Antonio is sniffing around this frontier of gene editing.

ANTONIO RAGALADO: That's my specialty.

MICHAEL SLEZAK: And he finds something huge.

ANTONIO RAGALADO: Everybody's heard about it by now.

MICHAEL SLEZAK: In fact, he finds the biggest story yet in gene editing.

REPORTER (AP News, Nov. 2018): A Chinese researcher claims to have helped make the world's first gene-edited babies.

ANTONIO RAGALADO: Twins born in China with their genomes edited with CRISPR, the gene editing super-tool. So that was kind of the scoop of a lifetime.

MICHAEL SLEZAK: But what's important for our story is what he finds on the way to that scoop of a lifetime.

ANTONIO RAGALADO: So in the late spring of 2014, I start to get in touch with the companies that were already editing large animals, right: pigs and cows.

MICHAEL SLEZAK: Because, he figures, if you're going to try something on humans you'd probably try on a bovine or a barnyard animal first.

ANTONIO RAGALADO: So I literally started calling the animal engineering companies to get an idea of how this technology worked in a kind of non-controversial scenario.

And Recombinetics was one of them.

(Excerpt from YouTube promotional video from Biotechnology Innovation Organization)

INTERVIEWER: Using the latest science and technology to develop more humane ways to raise livestock and other animals.

(Excerpt ends)

MICHAEL SLEZAK: Recombinetics is a US biotech start-up.

(Excerpt from YouTube promotional video from Recombinetics)

IAN FRIENDLY: This will play a role in solutions for all of the most thorny problems in society.

MICHAEL SLEZAK (voiceover): To be clear, Recombinetics' core business is just modifying animals. As far as I know, it doesn't have ambitions to move on to humans.

PERRY HACKETT: We're talking about feeding the world, saving individuals and making the types of medicines and therapies that are going to extend our lives and make the lives that we lead far better. Recombinetics actually covers all three of these.

(Excerpt ends)

MICHAEL SLEZAK: The company says it all began when its founder, Scott Fahrenkrug, visited a farm a decade ago and saw animals being dehorned.

(Excerpt from YouTube promotional video from Biotechnology Innovation Organization)

TAMMY LEE: …mechanically, and it's a very nasty process. And he looked at that and thought: what could we do to use technology to prevent that from happening?

(Excerpt ends)

MICHAEL SLEZAK: You see, dairy cows grow horns naturally. But the horns are dangerous. They can harm, or even kill, other cows. So farmers de-horn them or dis-bud them.

I went to a dairy farm just outside Sydney to see what it's really like – and it is pretty nasty.

(Sound of calf lowing)

Farmers gouge the horns out of young calves like this one with a hot iron.

(Sound of cattle walking on platform)

Or, if the animal is older, they just cut them off.

ANTONIO RAGALADO: Scott Fahrenkrug just had this kind of idea that was a brilliant idea: to use genome editing technology to introduce what I'm going to call the "no horns recipe" into cattle that do have horns.

MICHAEL SLEZAK: This "no horns recipe" already exists in cattle like the Angus breed, which most of us have eaten, and it could be bred naturally into dairy cattle – but it would take decades to do it properly.

What Scott Fahrenkrug and Recombinetics are proposing is to speed it all up through gene editing. That way, they could do it in one generation.

So they want to just take the gene from a cow that doesn't grow horns and pop it in a top dairy cow.

ANTONIO RAGALADO: That was the absolute brilliance of gene editing.

MICHAEL SLEZAK: In 2014 Recombinetics owns patents for a process called TALENs. It's similar to CRISPR: a way of targeting a specific part of the genome.

But here's something important to know. The vehicle that delivers the genetic changes is a little ring of bacterial DNA. Just like the tiny delivery van I used with the biohackers, this vehicle is not bovine: it's bacterial.

So they put this bacterial DNA, mixed with the no-horns cow DNA, into the bull.

Recombinetics does this and everything's going great. The genetically modified calves are born and they seem perfect.

They – and the company – hit the big time.

(Excerpt from American Broadcasting Company news story, YouTube, Dec. 2016)

CHRIS EGERT: About an hour north-east of here, at a nondescript research farm at the University of California Davis, are two very important cattle.

These cattle are cloned.

So is it cool to be able to see them in person?

TAD SONSTEGARD: Yeah, for sure. (Laughs) It's great to see that we've actually been able to make something using our technology and make something better than it was before.

(Excerpt ends)

ANTONIO RAGALADO: Wired had a cover story about the CRISPR revolution and on it was one of these cows, so they put the cow on the cover. So it literally became the symbol of the promise of gene editing.

MICHAEL SLEZAK: The cattle were also on the front page of the New York Times and featured in a bunch of TV news pieces.

ANTONIO RAGALADO: And the headline or the cover language says something like, you know: "CRISPR could lead to a better world or a more humane world. And will we let it?"

MICHAEL SLEZAK: Back at the paddock, the animals seem incredibly… normal.

ALISON VAN EENENNAAM: So we had the two bulls and they were… they didn't grow horns. It's not a very interesting characteristic.

MICHAEL SLEZAK: Alison Van Eenennaam is an animal geneticist from UC Davis. She's the one raising them, so she keeps checking on them.

ALISON VAN EENENNAAM: Every day they didn't grow horns. And so after you've done that 10 days in a row, it's like: OK, I'm done here.

MICHAEL SLEZAK: But Allison wants to make sure there are no hidden problems with the GMO calves.

ALISON VAN EENENNAAM: We additionally did full genome sequencing of them all, We were being very comprehensive.

MICHAEL SLEZAK: And they don't find a single problem. It's a huge breakthrough and a massive win for the company.

Now, Recombinetics just needs regulatory approval to take the technology to market.

And if anyone has doubts about GM animals, this is the perfect thing to change their attitude.

The Recombinetics founder, Scott Fahrenkrug, is hoping these cows will shift hearts and minds. And Antonio says it kind of worked.

ANTONIO RAGALADO: A lot of people are against genetically modified anything. And with this particular application, I think he was able to split the opposition.

You know, a lot of the people who are against GMOs may also be members of PETA or something. So I thought it was politically clever to kind of lead with this concept of the hornless cattle.

MICHAEL SLEZAK: Alison Van Eenennaam says she got involved in the project for that very reason: shifting hearts and minds.

ALISON VAN EENENNAAM: So I think, you know, the science communication suggests that the way to try to address these things is to touch people where their values are.

And I think most people would have a shared value of decreasing animal pain and having healthy animals and plants. And so I guess, to me, you know, can we change the narrative?

MICHAEL SLEZAK: That's the first thing that made these animals powerful political tools in the GMO debate: framing genetic engineering as animal welfare.

But it's not the only value of these miracle cows.

They have another very important role to play in the GMO debate because, even before they hit the big time, Recombinetics was making interesting claims about these cows.

They were claiming that they weren't even really GMOs.

ANTONIO RAGALADO: The goal is, at all costs, to get away from the GMO debate. That's the goal.

MICHAEL SLEZAK: Recombinetics wanted to avoid the onerous regulations: the expensive checks and tests that you're forced to go through if your products are classified as a GMO.

According to the scientists involved, these animals were not "genetically engineered" or "genetically modified:" instead, they preferred the term "precision bred."

ALISON VAN EENENNAAM: I see a real effort to conflate the two and use the term GMO to say, "Oh, that's all the same thing." And it's like: actually, they're pretty different.

MICHAEL SLEZAK: The argument is that GMOs have traditionally used genes from a completely different species – say, a human – to transplant into a totally different organism, like a mouse.

But with the Recombinetics dairy cattle, they're only taking genes from within the same species, a cow, and giving them to another type of cow. And that, they say, happens in nature all the time.

So they say "precision breeding" is just taking nature to the next level: making breeding more precise.

ALISON VAN EENENNAAM: "Precision breeding" is used because if we're not using editing, we're just hoping that nature makes an alteration that gives a characteristic to an animal.

So 'genetically modified organism' is a non-specific term. And as a scientist, I can't stand non-specific terms.

MICHAEL SLEZAK: If Recombinetics could avoid GMO regulation and just call their cattle "precision bred," that would open up markets around the world.

ANTONIO RAGALADO: These are marketing terms. They're not scientific terms. These are marketing terms whose purpose is to indicate that this process is controlled, accurate; that the scientists are the master of it.

Of course, it didn't turn out to be that way.

MICHAEL SLEZAK: The first sign that there was something wrong with these miracle cows came in the winter of 2019.

ALEXIS NORRIS: So it was actually snowing that day. And so I was snowed in at my cabin in the woods in Pennsylvania.

MICHAEL SLEZAK: Dr Alexis Norris was trapped, so she decided to try to do some work from home.

ALEXIS NORRIS: And my co-workers were my three pugs: so, you know, really helpful for the bioinformatics support.

MICHAEL SLEZAK: Alexis is a bioinformatician at the Food and Drug Administration in the US. That's the agency that regulates genetic modification of animals.

At the time she was developing some new software for the FDA: basically, a computer program that would help analyse genetic data.

Luckily, from that cabin in the woods, she was able to remotely control these powerful supercomputers that she needed to do her work.

ALEXIS NORRIS: I started developing the pipeline in December. That's... once you get access to a powerful computer cluster, then you can start making a lot of progress.

MICHAEL SLEZAK: She had the program ready to go and just needed to test it with some really good quality data.

ALEXIS NORRIS: The goal was – or the intention was to make sure that our method confirmed the known results.

MICHAEL SLEZAK: She was just looking around for some genetic data to test the program on; and she just happened to find the full genome of the gene-edited bulls.

ALEXIS NORRIS: And then we move on to the next bioinformatics analysis method.

MICHAEL SLEZAK: So anyway, she plugged the bulls' data into her new program.

ALEXIS NORRIS: Um... and that's when I saw it.

MICHAEL SLEZAK: What she saw shocked her.

ALEXIS NORRIS: And I did not believe it. It took a few days to think that I wasn't... that there wasn't something that I was missing.

MICHAEL SLEZAK: But Alexis was right. She'd found something that shouldn't be there. She'd found a tiny amount of bacterial DNA in the bull.

The discovery risked throwing all Recombinetics' work on the cattle out the window.

ALEXIS NORRIS: I noticed that there were DNA sequences from the data that didn't match the cow and they matched the plasmid.

MICHAEL SLEZAK: OK. So, remember: the plasmid is that tiny little 'delivery van' made of bacteria, that transports the new gene into the original DNA.

I used a plasmid to do my gene-editing experiment with Meow and Alex.

And Recombinetics was using a plasmid to do their gene-editing too.

But the plasmid DNA had somehow been left behind and it was now a part of the bull.

A little more than a millionth of the bull's genome was bacterial DNA: only a tiny bit, like about 4,000 letters among the 3 billion letters of its natural DNA.

So the bull was actually part-bovine, part-bacterium.

And this disturbing discovery was made a good five years after the gene-editing was done, completely by accident, while testing a computer program.

ANTONIO RAGALADO: It's almost as if the IT person, you know, is going through the system and finds the error.

All the promises, the insistence by this company that they had this kind of clean, swift technology and that they could guarantee that the product was all cow, was not true.

They had accidentally inserted this piece of bacterial DNA in there and they hadn't even realized it.

So far from being a precision animal, in fact it contained a mistake; and a mistake that had kind of far-reaching consequences.

MICHAEL SLEZAK: For Recombinetics, the consequences were swift.

Plans that were ready to go, including breeding the beasts in Brazil, were cancelled.

They could only avoid GMO regulations if they were all-cow. But these animals were part-bacteria, so by any definition they were GMOs.

It seemed like the whole project was over.

ANTONIO RAGALADO: My impression is that this is the end of the hornless cattle project, which is too bad because, as Scott Fahrenkrug said in our first interview: like, this would be good for the animals. They wouldn't have to get dehorned.

MICHAEL SLEZAK: But it was the end for the cattle, too.

ANTONIO RAGALADO: My understanding was they were all going to an incinerator.

MICHAEL SLEZAK: But that wasn't the end of the project, at all.

In fact, I've discovered that the next stage is being carried out right here in Australia.

(Sound of car interior)

MICHAEL SLEZAK: So we left Melbourne at about 8:00am this morning and we're heading two hours west to Camperdown, to see these genetically modified cows.

Back before Alexis got snowed in in Pennsylvania that day, Recombinetics froze semen from one of the bulls and sent it here to Australia.

Dairy cows at a facility run by a company called Total Livestock Genetics were inseminated with that semen.

In all, 11 calves were born. All 11 were hornless – and all 11 were GMOs.

Then the mistake was discovered.

But quietly, here in the Victorian countryside, they've continued to do research on the beasts.

There's apparently five of them on this farm and, as far as I'm aware, no other journalist has been there. No other journalist has reported about how they're going, what they're doing there.

So I'm really keen to see what they look like and what the plans are; what Recombinetics are planning to do with these genetically modified cows.

(Sound of alighting from car; sound of an open field)

MICHAEL SLEZAK: So we've arrived here at the paddock. And look, it looks like a paddock you'd see on any farm around Australia.

It's got a fence around it. It's been raining, so it's quite green. It's lined with trees.

The only difference is here at the front, where the gate is. Sitting on the gate is two signs and each of those signs says: "Biohazard." And it's got the classic symbol; the biohazard symbol.

(Sound of gates opening)

TAD SONSTEGARD: Hey.

MICHAEL SLEZAK: Hey, g'day. I'm Michael Slezak from the ABC.

TAD SONSTEGARD: Hey, Michael.

MICHAEL SLEZAK: Tad?

TAD SONSTEGARD: Yeah.

MICHAEL SLEZAK: Hey, g'day. Michael. How are you going? Nice to meet you.

(Voiceover) Tad Sonstegard heads up the livestock programs at Recombinetics. He has agreed to show me around the research facility and he's accompanied by the team from Total Livestock Genetics.

After a short chat, we get back in the car and drive around their facility to see the actual cattle.

(Sound of farm gate opening)

MICHAEL SLEZAK: Oh, is this them?

UNIDENTIFIED MAN: Yep, this is them.

MICHAEL SLEZAK: Ah.

UNIDENTIFIED MAN: Tad shows great joy and...

TAD SONSTEGARD: Yeah. My babies.

MICHAEL SLEZAK: Are the cows a biological hazard?

TAD SONSTEGARD: Well, we don't consider them a true biological hazard.

MICHAEL SLEZAK: On the side of the paddock are five cattle. They're young. They're about seven months old, apparently. And they're not little calves, but they're not fully grown either.

It shouldn't be a surprise, but it is a bit of a let-down: the calves really do look just like any other black-and-white dairy cows.

The screw-up in their father's genetic editing didn't seem to change how they looked - and especially not these particular animals.

There are only five calves in this field, but 11 were born here.

It turns out that after Alexis in the US discovered the mistake, Recombinetics tested the genomes of all 11 of the calves here and killed the six that were found to have the bacterial DNA.

So the remaining ones, despite being GMO, despite being gene edited, are as far as we know 100 per cent bovine. No known bacterial DNA is in their genomes.

And in farming speak, they're "polled": that means they have the no-horns gene.

But actually, there is one side effect.

TAD SONSTEGARD: He has the double eyelashes for sure.

UNIDENTIFIED MAN: Yeah.

TAD SONSTEGARD: That one does. So polled animals have double eyelashes, which is why they're even more pretty than a regular one.

MICHAEL SLEZAK: Instead of having the normal single row of eyelashes, they have two rows. It almost looks like they've got a false pair of eyelashes above their normal ones.

It's pretty cute, really and it's a feature of Angus cattle, the cows the hornless gene was taken from.

TAD SONSTEGARD: So clearly polled and double eye lashes, which is all natural phenotypes.

MICHAEL SLEZAK: Standing in this paddock with these happy, seemingly normal, hornless cows, I can see why genetic engineering could be an attractive solution.

It starts raining and we head over to a concrete pen to shelter from the rain. There are swallows flying all around, making a bit of a racket.

(To Tad Sonstegard) There were headlines around that said things like, you know, "It was a major screw-up;" people saying things like, "It's part-bacteria, part-cow." What do you make of those responses?

TAD SONSTEGARD: I think that's an editor telling the person who wrote the article to get clicks or views. So it's sensationalism.

There's plasmids in all of our micro-organisms that we use for cheeses and beer and other foods. There's no real risk to it. It's certainly not what we wanted.

MICHAEL SLEZAK: What does seem relevant about it, though, is that it appears to undermine some of the claims made about them: that they're not transgenic, for instance; that it's the "precision"...

TAD SONSTEGARD: Right, but again, this is not what... we would never have commercialized that animal, especially with that event.

MICHAEL SLEZAK: At the time, until it was discovered, you appeared confident that there was no mistakes with the editing.

TAD SONSTEGARD: Yes.

MICHAEL SLEZAK: And now you're kind of saying, "In the future we'll be confident again that there won't be mistakes."

TAD SONSTEGARD: Yes. I'll be very confident again that there is no mistakes, because it depends on what tool we're using and what is in the mix that is being put into the editing.

MICHAEL SLEZAK: What can you say to people to regain trust?

TAD SONSTEGARD: The process that we go through is going to be regulated.

They're always going to ask us the question: "Was any material inserted that you didn't want into the genome?" So we have to answer that question.

That's part of the process, so I can confidently say it'll be taken care of.

MICHAEL SLEZAK: But before the mistake was found, Recombinetics argued that those kind of regulatory hurdles shouldn't apply to these animals.

And in the end, it was only by accident that the regulator did pick up the mistake.

So one thing I was curious about when I found the calves here was: why Australia? Why did they send them here?

I found some clues in a set of slides that Recombinetics presented to the United States Department of Agriculture.

In this presentation, Recombinetics outlined what it called its "global plan" to bring this technology to market.

I've got that presentation in front of me and on one of the slides it describes the global plan.

On that slide is a map of the world with pins on top of various countries: Brazil, Argentina, Canada and Australia. It describes those as "focus countries" because of the regulations they have.

And it says that the coordination of early adopters – these focus countries – will drive global business models.

It seems pretty clear that it's all about finding countries where regulations are more relaxed. And they figured Australia was one of them.

Back when this presentation was put together, at the start of 2019, Australia's regulations were up in the air and a proposal that would have been very good for Recombinetics was on the table.

It would have allowed their brand new cows to be considered non-GMO.

Recombinetics had previously written submissions to the Office of the Gene Technology Regulator, arguing for that outcome.

So was Recombinetics targeting Australia because it looked like it might have more permissive regulations?

(To Tad Sonstegard) Why did you decide to bring the technology to Australia?

TAD SONSTEGARD: I think it's important, actually, to introduce it into every place where livestock are raised. It provides a proof to people, so they can see that the animals are not really any different than the animals they have. And it's also a way for us to test the regulatory systems in each country.

MICHAEL SLEZAK: That said, the cattle haven't been introduced into every country or lots of countries. Why Australia?

TAD SONSTEGARD: Well, Australia is a place where polled or the lack of dehorning could be very useful.

MICHAEL SLEZAK: Is there anything to do with the regulatory regimes? I mean, that must be a, influence when you're deciding…

TAD SONSTEGARD: No. No, I don't think so.

MICHAEL SLEZAK: Despite the problem with the editing, Tad still says what they do isn't risky.

(To Tad Sonstegard) So is it a safe, no-risk method, do you think?

TAD SONSTEGARD: For me, in my opinion, yes. There's no risk.

MICHAEL SLEZAK: In the end, Australia didn't relax its regulations in a way that would have allowed the cattle to be considered non-GMO – error or no error.

Because the process involved inserting new genes into an animal, the cattle were GMO under our definition.

But there have been other changes, like if you do what's called "gene knockouts": only taking genes out instead of putting them in. As of October last year, that's no longer considered a GMO in Australia.

And now there's a huge debate about how we should regulate these knockouts and other gene-editing techniques.

In one corner, most of the scientists who use this technology say it's safe.

MARK TIZARD: My name is Mark Tizard. I work at CSIRO: the Australian Animal Health Laboratory in Geelong

MICHAEL SLEZAK: Mark has been involved in advising the regulator on a different review of regulations and supports the changes that have been made.

(To Mark Tizard) Do you think there's anything to worry about?

MARK TIZARD: From a personal point of view, I think that this is pretty safe technology. There's nothing in this that concerns me.

MICHAEL SLEZAK: He says he has full confidence that regulators will pick up any problems with genetic modifications – and that scientists wouldn't want to do anything dangerous anyway.

He says the mistake that happened in the Recombinetics cattle isn't something you'd see today, five years on, because the technology is now far more advanced.

MARK TIZARD: If you think about, for example, your iPhone: the iPhone of five years ago didn't have face recognition or thumbprint recognition. It didn't have a nice, big screen. It had poor battery life. It wasn't waterproof. It didn't have wireless charging.

That's five years in the space of the life of the iPhone. In the five years since this was conducted, a whole new set of tools have come along.

MICHAEL SLEZAK: In the other corner of this debate is a smaller group of scientists and civil society groups, who aren't nearly as relaxed about these changes to Australia's regulations.

JACK HEINEMANN: I'm Jack Heinemann, professor of genetics and molecular biology at the University of Canterbury.

MICHAEL SLEZAK: Jack Heinemann is based in New Zealand. He's worried that, if some of these things are no longer considered GMOs in Australia, the regulator won't be paying them much attention.

He says that means mistakes could go unnoticed.

JACK HEINEMANN: You can make unsafe things using gene technologies. I think you can do that on purpose, but that's not really what we're talking about here.

I also think you can do it, though, by accident.

MICHAEL SLEZAK: Jack has worked in genetic engineering labs for years and he's advised regulators around the world, He's also worked with groups like Greenpeace, who are sceptical of the technology's safety.

He says the case of the GM cows shows that mistakes can happen – and they can go unnoticed.

JACK HEINEMANN: The company and its collaborating public sector scientists were claiming that they had confirmed, extensively and comprehensively, that the addition of unexpected DNA just didn't happen.

MICHAEL SLEZAK: Jack says he doesn't know if this particular mistake could pose a health issue, or some other problem. But he wants regulators to at least have a look, to make sure.

JACK HEINEMANN: I can't tell you if there's a specific harm. The issue would be that, if we don't look, we don't find it until after it's released.

And that's the importance of regulation: we look before it's released.

MICHAEL SLEZAK: When Australia deregulated some types of GMOs, one of the main reasons given was that organisms modified in those ways were "indistinguishable" from non-GMOs.

But Jack says that's a stretch.

JACK HEINEMANN: No. They're not right because, first off, you don't know that they're indistinguishable unless you've looked.

MICHAEL SLEZAK: For what it's worth, the Office of the Gene Technology Regulator didn't want to be interviewed for the story.

But it said it consulted widely when it changed the rules and it maintains these sorts of applications of gene technology are no more risky than traditional ways of breeding.

But Jack says almost anything could go wrong with this sort of gene editing, which could hurt the environment or people.

And the solution is to have regulators just look.

JACK HEINEMANN: Now the chances of that: I don't know if they're large or small. But fortunately, if we regulate and do a risk assessment, I don't have to speculate on whether they're large or small.

MICHAEL SLEZAK: Even advocates of gene-editing technology like Mark Tizard say it is possible GM foods could end up containing new chemicals that people are allergic to.

MARK TIZARD: Allergens is the only thing that people could legitimately be concerned about.

But as has been mentioned before, the natural variation that occurs during sexual reproduction causes these small changes all the way through. And in the 10,000 years we've been growing cattle, there's only a handful of things that have led to unwanted consequences for consumers.

JACK HEINEMANN: It's true that mutations are happening all the time in nature, but it's misleading to extrapolate from the types of mutations that occur in nature and their low frequency, widely distributed appearance around the world; and the highly concentrated process of amplification that goes on in the commercial production of products from gene technologies.

MICHAEL SLEZAK: In the end, most experts agree the likelihood of harm from any particular genetic modification is low.

But the question seems to be whether or not regulators should just make sure there's not going to be any harm, before the modifications are released.

JACK HEINEMANN: I don't think that products are necessarily unsafe. I think that there is a really good reason – and as a geneticist, I really believe there's good reason – to investigate the products we make.

I still subscribe to the idea that we should be humble in our claims about how much we understand life.

MICHAEL SLEZAK: I asked the FDA why the US hasn't taken a similar approach to Australia. Why are they still regulating these 'gene knockouts', even though no new genes are being added?

HEATHER LOMBARDI: There is still a potential for mistakes. Any time you're going in and you're cutting the DNA and then relying on the cells to repair it properly, there can always be error.

MICHAEL SLEZAK: That's Dr Heather Lombardi, the head of Animal Bioengineering at the FDA. She works with Dr Alexis Norris, who discovered the screw-up in the cattle's DNA.

HEATHER LOMBARDI: So, you know, it's a biological system. You know, there are things that can happen that are sort of out of your control.

MICHAEL SLEZAK: Tech journalist Antonio Ragalado says your approach to these things really depends how cautious you want to be about what you don't yet know.

He thinks the Recombinetics cows probably aren't really dangerous. They are just a disturbing demonstration that we don't always really know what we're doing.

ANTONIO RAGALADO: Plasmid or not, are these animals a danger to those who would eat them or drink their milk? No.

The danger is the unexpected. It's what we don't know about the consequences of genetic engineering in general. We can't point to a health consequence, but there could be consequences we haven't thought of.

I mean, is it a worry? I'm worried if scientists sort of assert things that aren't true. That worries me because: what else could happen? Or where could it go?

MICHAEL SLEZAK: The newly relaxed regulations in Australia could open the door for another invention by Recombinetics.

One of their latest innovations is heat-tolerant cattle.

TAD SONSTEGARD: One of our genetic solutions for thermal tolerance we can apply to dairy animals and be considered as a non GMO after consultation.

MICHAEL SLEZAK: They have made these new heat-tolerant cattle without adding in DNA. They've only taken DNA out.

So in Australia, those wouldn't even be classed as GMOs: that is, assuming that this time there aren't any screw-ups.

And as for those miracle cows, lazing around in the field: well, obviously they'll still be regulated as GMOs here.

But Recombinetics has plans for them.

TAD SONSTEGARD: So the males we're not going to keep for breeding and we can't eat them, because they're experimental animals. So they'll have to be sacrificed. That's just the way that it goes.

With the females, we probably have to put in a protocol, but we would ask that we could inseminate them with normal Holstein semen and generate calves. And then we would collect milk to show that it's equivalent to normal milk.

MICHAEL SLEZAK: If all goes to plan for Recombinetics, one day you could be drinking milk from one of these genetically dehorned cows – the miracle cows without the genetic mistake.

Recombinetics thinks this is just the start of what commercial gene editing will do.

TAD SONSTEGARD: I think it's going to have a huge impact on agriculture: not only in livestock, but in plants as well.

So you're talking about making the next generation of crops for the Green Revolution, that are going to be drought-tolerant, disease-resistant; and the next generation of animals that are going to have better animal health, better animal wellbeing: and we'll be able to stop some of the diseases that are in livestock.

MICHAEL SLEZAK: Background Briefing's sound producers are Leila Shunnar and Ingrid Wagner. Sound engineering by Isabella Tropiano.

Fact-checking by Benjamin Sveen. Additional production by Penny Timms and Gina McKeon.

Supervising producer is Tim Roxburgh. Our executive producer is Alice Brennan.

And I'm Michael Slezak, the ABC's national science and technology reporter, from the Specialist Reporting Team.

You can hear us on the ABC Listen app, or subscribe to Background Briefing wherever you get your podcasts.

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