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Yves here. Maybe I am an old fuddy duddy, but I see way too little precautionary principle at work with the implementation of technologies like gene editing.
By Nathanael Johnson (@savortooth on Twitter). Grist’s senior writer and the author of two books. Originally published at Grist
Two heifers at the University of California Davis. One of these cousins has the genetic code to prevent horns from growing and one does not. Photo by Alison Van Eenennaa
For the last few years, writers and scientists have marveled at the potential for gene editing to allow farmers to grow more food on less land and allow more of the earth to grow carbon-sucking forests and savannas.
The main advantage of gene editing is precision. It’s right there in the name: Instead of dealing with the randomness of breeding, or the rough power-tool work implied by the term “genetic engineering,” the “editing” suggests that scientists could now change the letters of genetic code with the same ease that a writer corrects typos.
But in late July, FDA scientists found a chunk of bacterial DNA in gene-edited calves, prompting people to wonder if this precision tool wasn’t as precise as advertised. That hopeful vision of a gene-edited future — verdant with pesticide-free, carbon-sequestering crops — flickered.
On Monday, the scientists studying these gene-edited cattle published a paper in the journal Nature Biotechnology explaining what happened. Essentially, this new paper tells us that gene editing precisely tweaked specific letters of DNA, exactly what it was supposed to do. But scientists also used older, cruder tools, and one of those caused the genetic typo. Even so, the end result might be that gene-editing slides into the muck of controversy over GMOs.
To be clear, the cows at the center of this study have nothing to do with creating more productive, pest-resistant foods. The scientists had edited their genes in stem cells, which grew into calves without horns. Farmers usually remove the horns to prevent cattle from injuring each other — goring is a real danger.
When I visited the University of California Davis in 2015, I saw a pair of these black-and-white bull calves standing and chewing in an outdoor pen, like ordinary but adorable bovines. Unlike other calves, however, they wouldn’t have to suffer through a painful dehorning operation, in which a veterinarian burns out their horn buds.
Some cows are naturally hornless: Angus and Hereford breeds, for instance. But those are beef cattle. For dairy you want Holsteins or Jerseys, and these champion milk producers are more carefully bred than the winners of the Westminster dog show. If you started crossing muscled Herefords with black-and-white Holsteins, it would take decades of breeding to move the hornless trait into the dairy line then weed out all the beefy traits.
What if you just plucked a single gene and moved it into dairy cows? With gene editing, you could tweak dairy cows without messing up their finely tuned milk-producing DNA so that they would no longer have to endure dehorning. The Minnesota-based company Recombinetics tried this using a technique called TALENS (you might have heard of CRISPR — this is just a different version of the same thing).
To run with the editing metaphor, Recombinetics basically took out the DNA that laid out instructions for “HORN” and replaced it with 202 letters of DNA that said “HORNLESS.” But first, they attached it to a bacterial plasmid — think of it as a sub-cellular copy machine — that would reproduce this strand over and over again (HORNLESS, HORNLESS, HORNLESS!). Then they injected all those copies into a cow cell — that gave one of those copies a much better chance of bumping into the one spot in the DNA that read HORN. This is where things went wrong. Instead of just replacing HORN with HORNLESS, the plasmid also folded into the cell’s DNA so that it read something like HORNLESS-COPYMACHINE-HORNLESS. That genetic information went into an egg, which went into a cow’s uterus, and, in 2015, grew into a hornless calf. No one noticed until years later.
The calves I saw at Davis were there to be studied by Alison Van Eenennaam, an animal geneticist. Funded by a U.S. Department of Agriculture program to assess the risks of biotech, her team first verified that the hornless trait was being passed down through generations of cattle. “Basically, we found that Mendel knew his shit,” said Van Eenennaam (that’s Gregor Mendel, the scientist from the 1800s who described how traits are inherited).
With this new paper, Van Eenennaam’s team showed that the bacterial plasmid had also been passed down to some of the calves, again following the rules of genetics 101. It doesn’t seem to be causing a problem — it’s fairly normal for DNA from germs and viruses to work its way into genomes (the human genome is about 8 percent virus DNA), and critters can usually just roll with it. But because these cattle had DNA from a bacteria, it meant they were genetically modified organisms, or GMOs in the eyes of government regulators. That, in turn, meant they would have to undergo years of testing. A giant corporation like Bayer could afford that, but not a small startup like Recombinetics. The FDA is now treating gene-edited animals like new drugs, requiring multiple rounds of safety testing, which effectively puts an end to the quest to make hornless dairy cows. Longtime opponents of biotechnology think that would be a good thing. Friends of the Earth recently released a report with Janet Cotter, who runs the consultancy Logos Environmental, condemning gene edited animals.
“The scientific evidence shows that gene editing, particularly in animals, is far from precise.” Cotter said in a statement. “Instead, it can produce unintended changes to genetic material and disrupt genetic processes. Such effects could have far reaching consequences for food safety, so these applications will require a rigorous assessment if they are to be used in agriculture.”
It would be easy enough to screen out plasmids before putting gene-edited eggs into a cow’s womb. That’s a routine procedure, said Van Eenennaam. But she worries that won’t quell fears that gene editing is sloppier than expected. Treating gene-edited animals like drugs is not proportionate with the risk, Van Eenennaam said, and would prevent breakthroughs that might help us meet the challenge of climate change, whether it’s cows that don’t belch methane, or corals that can survive heat., Van Eenennaam said.
“The debate has pretty much blocked the technology in animals through my whole career. I was hoping gene-editing would be different,” she said. “I have students who are excited about gene editing for disease-resistance — but now I feel like it’s Ground Hog Day. Here we go again.”
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Very timely post. If I read everything right, I do believe they are using CRISPR-Cas9 genome editing technology, and that is a technology/science I do track. At least in the National Academy of science incident database on CRISPR-Cas9, the news has been troubling. Ya, if they could just stop making mistakes and get it right. Mind you we have no idea what’s going on in China (well some, I say it’s dangerous), Russia, and India. In the US, protocols have been set, and only so far – 5-6 times out of 100, things didn’t stop as they should. God only knows what Trump thinks this is all about, but it’s his guys with oversight of the (fed) labs and fed funding. Then we have guys like Bill Gates thinking this a neat way to change the genome of bugs that cause disease. What possibly could go wrong.
Bill Gates also wants to shoot sulfates into the atmosphere to alleviate global warming…apparently he doesn’t realize that we’ve just spent 40 years trying to get them out of the atmosphere to reverse the 60s acid rain problem, wherein the atmospheric sulfates from Midwest coal plants would fall in as sulfuric acid rain on New England…
& yes, removing those sulfates did exacerbate global warming…there’s no simple solutions
So we’ve traveled down the path to destruction by implementing technological fixes without understanding the secondary and tertiary effects of that technology. The solution is to apply even more technological fixes, in areas where our knowledge is even more incomplete, and hope the unforeseen secondary and tertiary effects don’t do in the planet even more completely and quickly than the other technological fixes?
What will it take for us to acknowledge how limited and imperfect our knowledge is and that the only safe and rational approach is to take a step back from technology?
Hear, hear.
Another old fuddy duddy here.
“What will it take for us to acknowledge how limited and imperfect our knowledge is and that the only safe and rational approach is to take a step back from technology?”
Since that is not the only safe and rational approach, it would require a failure of analysis.
In a useful risk analysis, one does not start with the axiom that ‘any possible risk’ is the same as ‘too much risk’. If you really applied that as the appropriate standard, you would never stir out of your room, and you wouldn’t eat most food.
I did discuss this with a friend, who is a molecular biologist which she switched into after earning an undergraduate degree in the biochemistry of food.
She did say that there are definitely major problems with GMOs, gene editing, etc. She also said such things were perfectly safe to eat.
The biggest problems that really exist revolve around legal and cultural issues.
Copyright, for example, is broken in the US, in oh so many ways. In respect of a copyrighted GMO, at least when I talked to her some years ago on this issue, was that a company with a copyrighted GMO could sell the GMO to a farmer, and if pollen from that GMO blew into an neighbouring field, the company could seize the resulting crop on the grounds that it breached their copyright. I don’t remember if there were additional penalties to the pollen receiving farmer.
An example of the cultural issues would be sex selection, where a human genome was edited to produce mostly or completely male children, or where an organism was modified to produce that effect in that organism.
The third problem is not with the GMO itself, but in elevated levels of pesticides that the GMO makes safe for the plant.
Things to remember include:
(1) Most people are remarkably poor at risk analysis, and they become much more so as they leave the realm of common every day life events. The average person does not internalize, for example, the difference in risks between car travel and air travel, though that is a sufficiently used example that many have heard the general answer to that.
Different example: Some people are worried about flu vaccine causing Guillain-Barre syndrome (medical data here:
https://www.mayoclinic.org/diseases-conditions/guillain-barre-syndrome/symptoms-causes/syc-20362793
and thus avoid flu vaccination. The irony is that in the worst version of such events (probability varies with specific annual versions of the vaccine) the probability of having this syndrome triggered by a vaccination is one or two orders of magnitude less than it being triggered by getting the flu.
(2) Levels for risk in public standards are often set more for political and legal than for scientific or practical reasons. In a lot of cases they are far more risk-averse than justified by any logical analysis – but it lets the politicians head off potential criticism.
Our knowledge is not completely perfect about anything scientific.
Indeed, the highest form of scientific knowledge, a theory, is at most provisional, as the best answer that has not yet been falsified. Any theory may fall tomorrow. There is no absolute scientific truth.
In fact we know that some of our most studied and fundamental theories are flawed in ways we have not been able to correct. A notable example is that we have never succeeded in reconciling the theory of gravity and quantum mechanics into an overall unified field theory.
Mathematics, as well, does not permit absolute knowledge in a completely defined formal mathematical system. There will always be truths we cannot prove and falsehoods we cannot disprove. For an overview, search Godel’s Incompleteness Theorems, and choose the reference that matches your mathematical background. For a related phenomena, look up the ‘halting problem’.
At one point I had to be able to prove both of those, but I haven’t done that sort of algebra for a long time.
Bottom line? We never have perfect knowledge, and if we think we do, or must, we are fooling ourselves.
Being a collector of aphorisms and quotes, I have a favourite that may apply to some of these situations:
“As far as the laws of mathematics refer to reality, they are not certain; and as far as they are certain, they do not refer to reality.” — Albert Einstein
In a way, this is another version of ‘the map is not the territory’.
I hope I haven’t bored you, the philosophy of science is a personal interest, and one I consider important in understanding the nature, requirements, and limitations of science.
Confused. I just read a 1990s book by Edward Steele (Australian geneticist) wherein he explained that under normal cell division (I think he was talking about somatic cells and the theme of the book was that it was indeed possible to inherit acquired characteristics) there are certain proteins that check the sequences and clean up the errors with very high accuracy. But if this janitorial mechanism does exist in the mechanics of the cell nucleus what will happen when splicing really gets going? Will it overwhelm the normal conservative maintenance of our genes and their ability to fix many of the “typos” that occur? Will that function die off?
If you prohibit gene editing by responsible people working in regulated environments, you are going to get gene editing by irresponsible people in unregulated environments – such as China. The benefits are too pronounced to “prohibit”.
The alternatives to using gene editing are also potentially harmful – think of pesticides killing all the bees because you weren’t willing to edit resistance into your plants. Or millions of people starving to death because you deprived yourself of the essential tools you needed to feed yourself.
It’s important to differentiate between “technology used responsibly so people don’t get hurt and don’t starve to death” and “technology used irresponsibly to advance the financial interests of corporate monopolies.”
Please don’t interfere with responsible people working in regulated environments.
So-called responsible people working in so-called regulated environments developed the pesticides that are killing all the bees. Apis mellifera has been around for millions of years. It is taking modern responsible humans only a few decades to destroy them.
It’s important to differentiate between “technology used responsibly so people don’t get hurt and don’t starve to death” and “technology used irresponsibly to advance the financial interests of corporate monopolies.”
GMO and the use of gene technology, particularly in agribusiness (not farming or agriculture) are technical solutions for problems that shouldn’t exist. And they do not work. Biological systems from the individual cell to an ecosystem to the biosphere are systems with an essentially infinite number of nonlinear equations and variables. Evolution (without us) provides what we need, and that includes traditional agricultural breeding practices, with plants and animals. RoundUp-ready seeds produce super weeds and profits for the makers of glyphosate. Golden rice has failed to alleviate vitamin A deficiency for those who need it. I understand the allure of technology, but when it comes to agriculture this is mostly fool’s gold. Norman Borlaug got it largely wrong and his so-called Green Revolution has led to the production of commodity crops like maize and soybeans, which has in turn made possible industrial meat production. We read a lot about how bad cows and pigs are for the environment. No. CAFOs are bad, for the animals, and the environment. Not to mention our humanity.
> If you prohibit gene editing by responsible people working in regulated environments, you are going to get gene editing by irresponsible people in unregulated environments – such as China.
I suspect that irresponsible people in unregulated environments are going to do whatever they want regardless of what anyone else does. The so-called “responsible people” don’t have a very good track record, since what they produce is cows contaminated with antibiotic resistance DNA markers (this is DNA we very much do not want to spread around) and various other outcomes they said were impossible.
There are more alternatives to gene editing than drowning the landscape in a sea of pesticides. Those alternatives would likely involve fewer profits for gigantic corporations, though.
“..Please don’t interfere with responsible people working in regulated environments..”
In our neoliberal, Wild West present?
pass
I keep bees and I grow food. So I need food plants that will resist pests without being dowsed in poisons.
If you liked what monopoly agribusiness did to traditional plant breeding and small seed companies, you’ll love what Chinese dictators are about to do to your genes.
That’s where we are right now. Refusal to invest in public research has brought us here. It is probably too late to bring this work back to transparent public research environments. The training and technology are already mostly happening elsewhere.
We didn’t like corporate greed-driven decisionmaking, but at least we could see it. Now we can’t see it. These decisions are being made in the dark by dictators and kleptocrats. Today.
I suppose the best we can hope for at this point is a series of really spectacular disasters caused by closed society decisionmakers.
And we will still have to use the technology. Maybe then we will be conscious of how and why.
I, as a bee keeper wonder about the long-term viability of these charming gifts of nature. In my personal experiance, I’m currently having to deal with viral issues (Curly-wing/K-wing specifically) in my hives … which means my colonies very well may not survive the winter, if there are no nurse bees to tend the queen until spring arrives .. and even then … ??
Now, there are vapor treatments one can use to kill varroa mites within the hive .. which are the main disease vector involved, but that’s predicated on human vigilance ANNUALLY to try to maintain hive viability .. with all the imputs needed thereof. My feeling, is that the honeybee, or in fact ANY bee species thus affected, will have to evolve to deal with such issues .. either through better hygenics by the bees themselves .. or by mutation over time to counter what is a big problem .. man-made bio-cides notwithstanding. I do have concerns that some profit-oriented genius will bio-engineer a super honeybee, supposedly to eliminate said pest/disease, dare I say even pesticide mortality … only to create NEW unintended consequences as a result of genetic interferences. I’m sure the Bill Gateses of the World are on it as I type !
I mean, just look what tech alchemy did for the Mosquito ….
“Trust us.”
Sorry. We tried that before, and got a world saturated in poisons and radiation. Genetic manipulation could easily be worse, because it’s the nature of life to proliferate.
I am still waiting for the results of human cloning, because it is prohibited it should be happening in shady labs and we should see the results any day now!
If CRSPR is that imprecise, then it should be banned and we need to go back to the drawing board.
Donald Trump and Boris Johnson? Both does seems to suffer from the ‘Bladerunner syndrome’; that after only 5 short, but intense, years of activation, their systems seems to be running down and they are rapidly losing their mental faculties.
The other alternative to your Frankenlaboratory world is for governments to ban the use of pesticides and adopt organic agriculture on a mass scale. That would also, as a bonus, sequester carbon in the soil, something that mass chemical GMO agriculture does not do.
http://www.perennialsolutions.org/carbon-sequestering-agriculture-global-warming-solution-piece-remove-co2-from-atmosphere-organic-garden.html
Millions of people are starving to death right now because of problems with food distribution and crops being grown to feed cattle or produce corn sugars. Corporate takeovers of farming to produce crops designed to tolerate yet more pesticides are another reason GMOs are a fraud. Haven’t even mentioned terminator seeds that don’t reproduce or the expensive licensing of seeds that goes a long way toward people starving.
The precautionary principle is now virtually unknown among those who see money in CRISPR-Cas9, and anything and everything else, in biology, chemistry, and physics. But this has always been a problem among scientists, who should not, but repeatedly, mistake technology for knowledge and wisdom, with mind boggling alacrity. 45 years ago it never occurred to the nascent gene jockeys that it might not be a good idea (I simplify) to put what we now call oncogenes in bacteria that inhabit the human gut. The Asilomar Conference of 1975 was the result, and that was the year I got my first research job as a 19-year-old. The regulations that came out of Asilomar were mild, but effective. It turned out that the technology was biologically benign, but the “system” worked. CRISPR is the natural outcome of recombinant DNA research, and is potentially dangerous. But “can implies ought” among $$-eyed scientists. This may not end well, if we are still around to notice. Personally, I blame the Bayh-Dole Act of 1980 for most of this.
https://en.wikipedia.org/wiki/Asilomar_Conference_on_Recombinant_DNA
Well, it’s not life is going to find a way…
I am a scientist. I am in favor of gene manipulating … but am wary of what we are doing now. When we manipulated genes through cross-breeding and other techniques, nature vetted each stage of the change. If we crossed something and it became nonviable, that cuts off that avenue of approach … possibly for good reason. If we do a molecular gene splicing, we skip over all of the steps (if there were even steps–how one mates a salmon with a tomato hasn’t been demonstrated) in which nature has veto power.
I think Yves call to the Precautionary Principle is well taken. We should be going very, very slowly in implementing these things (not necessarily on the research). The profit motive is not a good arbiter of whether or not we should proceed with these high risk implementations.
Gene editing / CRISPR is increasingly being used to coax microbes into producing stuff we want, often cheaply, and without the nasty and polluting chemicals currently used to make it – if we can.
Try here, and if you’re short of time, scroll down / search for Table 1 Industrial Microbes Engineered Using CRISPR-Cas Systems.
Of course there will be mistakes, and of course the ‘Forces of Evil’ will seek to use this technology for evil. The same goes for pretty much any technology ever invented.
Relevant to this, I stumbled across a chain of links that led me to a history of eugenics in the 20 th century. Did y’all know our beloved Mr. Keynes was an advocate of eugenics, right into the 40’s? It was standard fare for political tendencies on both the right and left until just after WWII. I fear with the non-solutions offered by neoliberal capitalism, and the continuing retrenchment of its power, once we start hitting the big resource constraints of the 21st century, it’s only a matter of time before eugenics comes back full-throated. “Precision
gene tech” is sure to be a part of the argument about why “this time it will be different”.
To be sure, but if you ask me, that has little to do with science.
Eugenics translates very roughly as good genes. Its supporters assumed that their genes were not only good, but better than everyone else’s. There’s nothing whatsoever scientific about that assumption, any more than there is in the assumption that Hitler had better genes than say Katherine Coleman Goble Johnson.
The Chinese have already produced genetically modified humans (three in fact, with one having an error in the gene editing). The researcher responsible broke their local rules and was punished.
https://www.cnbc.com/2019/05/21/china-awaits-third-genetically-modified-baby-amid-questions-of-crisprs-ethics.html
I take genetic engineering in the context that every single person has about 30 novel mutations in their genome at birth. These often cause reductions in fitness, sometimes in cruel and spectacular ways. Nature is even messier than genetic engineering in how it handles the integrity of DNA and that has been the primary mechanism of evolution for the last few billion years, the mistake. Sexual reproduction speeds things up a little, epigenetics smooths out the bumps. Over time life has developed new mechanisms to make evolution more effective. Human selective breeding and now genetics are just the latest additions and even with the inevitable errors and unexpected side effects it is vastly more powerful than anything that came before.
The country that takes the risks and consequences with genetic engineering will likely get first mover advantages that force everyone else to follow or be left behind. I suspect China will be the one to take the lead since their culture is a lot less squeamish about such matters. Imagine a human population that expresses cellulase in their digestive system, allowing them to survive on sawdust?
Some thoughtful commentary here on the entire question of genetic manipulation of human germlines, opinions gathered from some of the biggest names in the field. It seems as though any pro forma cautionary caveats take second place to the “benefits” side of the ledger, as usually is typical of those scientists right on the cutting-edge of a “breakthrough” area of research. First come the published articles in prestigious journals, then more big grant money rolls in, scientific awards mount up, talk of “Nobel-quality” bodies of work, etc., and then and only then are there any discussions of potential downsides to the new technologies. Societal vetting and regulation of these techniques lag light-years behind implementation, and it’s usually after some catastrophic failure or misuse of these emerging genetic “tools” that people get serious about controlling the applications.
Any timeline for the article I posted re: “Experts Debate….Gene editing” to emerge from “moderation”? Merely curious.
>it would take decades of breeding to move the hornless trait into the dairy line then weed out all the beefy traits. What if you just plucked a single gene and moved it into dairy cows? With gene editing, you could tweak dairy cows without messing up their finely tuned milk-producing DNA so that they would no longer have to endure dehorning.
Ah, the reader is meant to believe this is for the good of the animal, despite the admission one sentence earlier that the technology is preferred because it avoids the investment of time it would take to accomplish said goal the safe and proven way. This is a lazy and inexcusable use of a dangerous, error-prone technology as a shortcut (in this case, literally) when it isn’t necessary.
I don’t equate the exercising of caution and restraint here as being old-fashioned or fussy. It shows better judgment than those who are hand waving away the surety of “typos” for a quick fix.
This extract from the next-to-last paragraph of this post stood out:
“It would be easy enough to screen out plasmids before putting gene-edited eggs into a cow’s womb. That’s a routine procedure, said Van Eenennaam. But she worries that won’t quell fears that gene editing is sloppier than expected. Treating gene-edited animals like drugs is not proportionate with the risk, Van Eenennaam said ….”
The problem with gene editing is the same problem with virtually every area of Science, Business, Medicine or Government touched by applied Neoliberalism. I read “easy enough to screen” as adds cost to the process, and “treating gene-edited animals like drugs” reads as controlling entry of new ventures into the genetic modifications Market.
The invasion of Copyright and Patent concerns into Science, has slowed and stifled advances in technique and knowledge. If gene-editing using CRISPR is so hit-or-miss perhaps it could be refined — but how will that progress if every step of the way teams of scientists working on the same problems work behind cypher locks and a code of secrecy to protect their potential Copyright and Patent interests? The Nobel Prize has also done its part in this. Research contracts in place of research grants did their part to build a pathological conservatism into what is studied and who receives support to study it — typically those most senior, most aggrandized, most self-promoting, and perhaps furthest removed from the work of Science by their entrepreneurial efforts in obtaining funding. What is the pay-off to ‘investors’ to support improvements to CRISPR? Those improvements would have to ride on top of the basic patent. A new, better process would be valuable but why should those holding the CRISPR patent allow research into a new or better process until they have every penny squeezed out of their sunken investments in CRISPR. [Is it really a such a stretch to imagine that the holder of CRISPR patent is a large enough entity to twist arms where research monies are distributed?]
I guess the Jonas Salk-s in Science are all gone the way of George Bailey-s in Banking.