Genegineering
November 16, 2015 12:21 AM   Subscribe

Humans 2.0 - "With CRISPR, scientists can change, delete, and replace genes in any animal, including us. Working mostly with mice, researchers have already deployed the tool to correct the genetic errors responsible for sickle-cell anemia, muscular dystrophy, and the fundamental defect associated with cystic fibrosis. One group has replaced a mutation that causes cataracts; another has destroyed receptors that H.I.V. uses to infiltrate our immune system."
The potential impact of CRISPR on the biosphere is equally profound. Last year, by deleting all three copies of a single wheat gene, a team led by the Chinese geneticist Gao Caixia created a strain that is fully resistant to powdery mildew, one of the world’s most pervasive blights. In September, Japanese scientists used the technique to prolong the life of tomatoes by turning off genes that control how quickly they ripen. Agricultural researchers hope that such an approach to enhancing crops will prove far less controversial than using genetically modified organisms, a process that requires technicians to introduce foreign DNA into the genes of many of the foods we eat...

Inevitably, the technology will also permit scientists to correct genetic flaws in human embryos. Any such change, though, would infiltrate the entire genome and eventually be passed down to children, grandchildren, great-grandchildren, and every subsequent generation. That raises the possibility, more realistically than ever before, that scientists will be able to rewrite the fundamental code of life, with consequences for future generations that we may never be able to anticipate. Vague fears of a dystopian world, full of manufactured humans, long ago became a standard part of any debate about scientific progress. Yet not since J. Robert Oppenheimer realized that the atomic bomb he built to protect the world might actually destroy it have the scientists responsible for a discovery been so leery of using it.
also btw...
  • Meet one of the world's most groundbreaking scientists - "Zhang was 11 when he and his mother left China and settled in Des Moines, Iowa. A few years later, when he was in high school, she often waited in her car for hours while he worked late in a gene therapy lab. Driving home in the gathering dark one autumn evening, mother and son were struck by the sight of falling leaves, dead and dying after lives measured in mere months. They spoke about how little time anyone has, she recalled, and how easy it is for a life to disappear without the slightest trace that it had ever been. 'It just seemed important to me to try my best to make a difference', Zhang said."
  • CRISPR-Cpf1 - "Cpf1 is a smaller and simpler enzyme (known technically as an endonuclease) than Cas9. That means it will be easier to deliver to the cells whose genes need modifying... as more gene-editing systems are discovered, it will be harder to monopolise their use via the patent system."
posted by kliuless (69 comments total) 42 users marked this as a favorite
 
Agricultural researchers hope that such an approach to enhancing crops will prove far less controversial than using genetically modified organisms, a process that requires technicians to introduce foreign DNA into the genes of many of the foods we eat

That's an interesting point, though I doubt it will work regularly. If the concern is rogue proteins with unknown toxicity or catalytic behaviors, removing coding DNA shouldn't contribute to concerns of food contamination. Unless their catatylic behavior turns a toxin into a nutrient...

Problem is that most every gene is subject to selection, and if natural selection favored keeping something, there might be some parasite or predator we don't know about applying that pressure.
posted by pwnguin at 12:31 AM on November 16, 2015 [3 favorites]


Pwnguin, it isn't always that simple. One of the big problems is genes which are beneficial if heteryzygous but deadly when homozygous. The two best examples of that are the gene for cystic fibrosis and the one for sickle cell disease.

If you have one of the sickle cell genes but its mate is normal, then you have a high resistance to malaria.

If you have one cystic fibrosis gene and its mate is normal, then you are much more likely to survive serious diarrheal diseases (like cholera).

In both cases, being heterozygous has no health consequences. But in both cases, if you have two copies then absent modern medicine you probably won't live to see age 15.

So it turns out there's a prevalence rate where the number of lives lost to the gene equals the number of lives saved by the gene, and evolution ends up homing in on that prevalence rate. In areas of Africa where malaria is more common, the sickle gene is also more common.

And it is thought by some that the reason the cystic fibrosis gene is so common among people of European descent is the Black Death. People with the CF gene would be more likely to survive it.
posted by Chocolate Pickle at 12:44 AM on November 16, 2015 [36 favorites]


This is definitely a thread about human engineering, but I should clarify my comment was about, for lack of a better term, gene deleted food. Hence the comment about toxicity. Presumably you don't care too much about family trees when you're buying GMO seeds with terminator genes.

I will say that removing genes from humans has a whole host of ethical issues beyond 'is it toxic.'
posted by pwnguin at 12:57 AM on November 16, 2015


CRISPR Gene Editing to Be Tested on People by 2017, Says Editas
A biotechnology company says it will test advanced gene-engineering methods to treat blindness.
Editas is one of several startups, including Intellia Therapeutics and CRISPR Therapeutics, that have plans to use the technique to correct DNA disorders that affect children and adults. Bosley said that because CRISPR can “repair broken genes” it holds promise for treating several thousand inherited disorders caused by gene mistakes, most of which, like Huntington’s disease and cystic fibrosis, have no cure.

Editas, which had not previously given a timeline for an initial human test of CRISPR, will try to treat one form of a rare eye disease called Leber congenital amaurosis, which affects the light-receiving cells of the retina.

The condition Editas is targeting affects only about 600 people in the U.S., says Jean Bennet, director of advanced retinal and ocular therapeutics at the University of Pennsylvania’s medical school. “The target that they have selected is fantastic; it has all the right characteristics in terms of making a correction easily,” says Bennett, who isn’t involved in the Editas study.
posted by a lungful of dragon at 1:12 AM on November 16, 2015 [1 favorite]


CRISPR-Cas9 gene editing: Check three times, cut once
Two new studies from the University of California, Berkeley, should give scientists who use CRISPR-Cas9 for genome engineering greater confidence that they won't inadvertently edit the wrong DNA.

The gene editing technique, created by UC Berkeley biochemist Jennifer Doudna and her European colleague Emmanuelle Charpentier, has taken the research and clinical communities by storm as an easy and cheap way to make precise changes in DNA in order to disable genes, correct genetic disorders or insert mutated genes into animals to create models of human disease.

The two new reports from Doudna's lab and that of UC Berkeley colleague Robert Tjian show in much greater detail how the Cas9 protein searches through billions of base pairs in a cell to find the right DNA sequence, and how Cas9 determines whether to bind, or bind and cut, thereby initiating gene editing. Based on these experiments, Cas9 appears to have at least three ways of checking to make sure it finds the right target DNA before it takes the irrevocable step of making a cut.
posted by a lungful of dragon at 1:21 AM on November 16, 2015


Genome Editing with CRISPR-Cas9

This animation depicts the CRISPR-Cas9 method for genome editing – a powerful new technology with many applications in biomedical research, including the potential to treat human genetic disease. Feng Zhang, a leader in the development of this technology, is a faculty member at MIT, an investigator at the McGovern Institute for Brain Research, and a core member of the Broad Institute.

posted by a lungful of dragon at 1:33 AM on November 16, 2015 [3 favorites]


pwnguin: "Presumably you don't care too much about family trees when you're buying GMO seeds with terminator genes."

Good things you can't buy those and never could, then.
posted by Joakim Ziegler at 1:34 AM on November 16, 2015 [3 favorites]


Radiolab did a story about CRISPR a while back.

I found the implications mind-boggling at the time and still do.
posted by Happy Dave at 1:38 AM on November 16, 2015 [2 favorites]


Agricultural researchers hope that such an approach to enhancing crops will prove far less controversial than using genetically modified organisms, a process that requires technicians to introduce foreign DNA into the genes of many of the foods we eat

Perhaps I am too pessimistic, but I dont't see much reason for this hope: a lot of the more emotional arguments against GMOs (messing with fire, slippery slope, non-specific unnaturalness) more or less go for this technique as well.
posted by Dr Dracator at 2:06 AM on November 16, 2015 [6 favorites]


Of course this is 2015 so we can't have nice things without an unseemly patent dispute.
posted by kersplunk at 2:19 AM on November 16, 2015 [6 favorites]


We need to eliminate patents on genetic changes asap.
posted by jeffburdges at 2:19 AM on November 16, 2015 [7 favorites]


This is a consolation prize because no jetpacks?
posted by From Bklyn at 2:44 AM on November 16, 2015


This is a consolation prize because no jetpacks?

About five threads down. Looks like it's 0.1% playtoy only, but you get jetpacks if you have the money now.
posted by Happy Dave at 3:01 AM on November 16, 2015 [2 favorites]


Could we just skip the ethical issues, franken-gene hysterics, uninformed protesters, etc., and go straight to Culture glands?
posted by signal at 3:18 AM on November 16, 2015 [9 favorites]


"This is definitely a thread about human engineering, but I should clarify my comment was about, for lack of a better term, gene deleted food. Hence the comment about toxicity. Presumably you don't care too much about family trees when you're buying GMO seeds with terminator genes."
There is a reason why there haven't really been voices talking about "toxicity" related to GMOs that don't also betray fundamental misunderstandings of the molecular genetics underlying genetic engineering since the 90s. The genetic information of the things we eat is constantly mutating with far more dramatic deletions, insertions, and substitutions than anything we do intentionally without anyone being any the wiser, much less batting an eyelid. Besides, Genetic Use Restriction Technology (GURT), colloquially known as terminator seeds, were developed by the Agricultural Research Service of the USDA and the Delta and Pine Land company in the 1990s, but were never used and likely never will be used. The people who succeeded at selling you a fear of them either didn't know they were never actually a thing, or just as likely didn't care to know.
"I will say that removing genes from humans has a whole host of ethical issues beyond 'is it toxic.'"
What this article is talking about is making somatic mutations, editing cells involved in making the body operate, not making germline mutations that would edit cells involved in heredity. This is honestly no ethically different than administering any other therapeutic. Germline engineering though, is going to be a thing that we are going to need to talk about, this is where the global conversation has started with a lot of the people who were at Asilomar back in the day and new PIs at the forefront of things:

A prudent path forward for genomic engineering and germline gene modification
Genome engineering technology offers unparalleled potential for modifying human and nonhuman genomes. In humans, it holds the promise of curing genetic disease, while in other organisms it provides methods to reshape the biosphere for the benefit of the environment and human societies. However, with such enormous opportunities come unknown risks to human health and well-being. In January, a group of interested stakeholders met in Napa, California (1), to discuss the scientific, medical, legal, and ethical implications of these new prospects for genome biology. The goal was to initiate an informed discussion of the uses of genome engineering technology, and to identify those areas where action is essential to prepare for future developments. The meeting identified immediate steps to take toward ensuring that the application of genome engineering technology is performed safely and ethically.
posted by Blasdelb at 3:53 AM on November 16, 2015 [21 favorites]


"We need to eliminate patents on genetic changes asap."
For better or worse, the Supreme Court is way ahead of you and did this once and for all two years ago: Association for Molecular Pathology v. Myriad Genetics.
posted by Blasdelb at 3:56 AM on November 16, 2015 [3 favorites]


This is fascinating and terrifying.
posted by odinsdream at 5:17 AM on November 16, 2015 [1 favorite]


Yes, a lot of the OMG Frankengene stuff is analogous to the OMG LHC Black Hole Swallow Earth, in that nature's carrying on far more extreme experiments all around us all the time, so the chances of an unexpected and massively bad consequence are very low (and zero for some of the popular ones).

Proliferation worries me, still. Technology does not stay in the hands of the great and the good. It might be fun to think about, say, putting the pathway to psilocybin into an endemic yeast as a fictional device, but I've known people who'dve done it had they had the chance. A moment's thought is enough to draw up a list of actors currently doing very bad things and who might safely be assumed to have motivation and resources enough to do directed genetic engineering of a very dark nature indeed, if the basic tools were accessible and cheap.

“CRISPR is the Model T of genetics,” Hank Greely told me when I visited him recently, at Stanford Law School, where he is a professor and the director of the Center for Law and the Biosciences. “The Model T wasn’t the first car, but it changed the way we drive, work, and live. CRISPR has made a difficult process cheap and reliable. It’s incredibly precise. But an important part of the history of molecular biology is the history of editing genes.”
posted by Devonian at 6:13 AM on November 16, 2015 [5 favorites]


Feng Zhang sounds a lot like Crake.
posted by k5.user at 6:28 AM on November 16, 2015 [8 favorites]


Yes, a lot of the OMG Frankengene stuff is analogous to the OMG LHC Black Hole Swallow Earth, in that nature's carrying on far more extreme experiments all around us all the time, so the chances of an unexpected and massively bad consequence are very low (and zero for some of the popular ones).

It's not that in and of itself CRISPR spells doom, it's that it is a wildly powerful tool (the bounds of which are, to me, entirely unclear) that is very easy and inexpensive to use. And there are a lot of creepy/bad people who might see this as a golden opportunity to do nobody any good.
posted by From Bklyn at 6:47 AM on November 16, 2015


So I had an eye test recently, and when the young optician looked in my eyes she told me I would have a cataract in about 10 years time. Will they be able to tweak my genes to stop this happening? I am old, would that make a difference? (No special snowflake details inside!)
posted by marienbad at 6:47 AM on November 16, 2015


Man, I was not expecting the Shapers to get rolling first. I was completely sure the Mechanists would be the first-round winners.
posted by aramaic at 6:51 AM on November 16, 2015 [8 favorites]


I am way too sleep-deprived to get into CRISPR on Metafilter today.

Suffice to say "Agricultural researchers hope that such an approach to enhancing crops will prove far less controversial than using genetically modified organisms, a process that requires technicians to introduce foreign DNA into the genes of many of the foods we eat" makes me just dissolve into giggles this is already well past "hope" and far into "who will have their crops out before the FDA realizes maybe they should look into this."
posted by maryr at 7:09 AM on November 16, 2015 [1 favorite]


First RUMBLR, now this?
posted by Philipschall at 7:13 AM on November 16, 2015 [2 favorites]


marienbad - No. Sorry.
posted by maryr at 7:20 AM on November 16, 2015


First RUMBLR, now this?

Somewhere in Dalliamsburg, an app for swiping on fried-food trucks has been denied its name.
posted by acb at 7:23 AM on November 16, 2015


Also I just saw Doudna speak and holy shit, did she have some pretty graphics. She had a time lapse of GFP-CRISPR searching the entire genome and you could see it light up where it slowed down because it found the right site even through chromatin and WOW was that awesome.

(also also, hey, Zheng went to the same summer program I did a year after me, he is a year younger than me, that is terrifying, if you're reading this sorry I was on zrsi so much, I was super bored at my job that summer. you better be taking Rickoids in your lab.)
posted by maryr at 7:26 AM on November 16, 2015 [3 favorites]


And there are a lot of creepy/bad people who might see this as a golden opportunity to do nobody any good.

There's almost no human possibility that this cannot be true for, though. This is more like a general ideology than a complaint about this specific technology.
posted by clockzero at 7:35 AM on November 16, 2015 [7 favorites]


But there are vast differences in the potential hams to ease of use ratios for various technologies.
posted by straight at 7:59 AM on November 16, 2015 [2 favorites]


Possibly most singularly appropriate typo ever.
posted by ROU_Xenophobe at 8:06 AM on November 16, 2015 [11 favorites]


"CRISPR Gene Editing to Be Tested on People by 2017, Says Editas"

This is quite interesting to me, as I have LCA. There were some very small studies done a few years ago with a wide age range of participants, but the method of delivery was so rudimentary compared to this.

As far as the ethics go, even as a person who'd benefit tremendously from this sort of thing, I'm still ambivalent.

I can't speak to debilitating or painful conditions that you know, actually physically hurt on a day-to-day basis, but the idea of banishing visual impairment from my life is actually kind of terrifying. When you live seeing things from a different and highly unique perspective your whole life, disrupting that should maybe cause a little inner reflection. The kind of shift a sea change like that could bring about isn't something to be taken lightly, no pun intended.

Also beaten to the startup jokes, damn it. I love this place.

I imagined a disruption of the veggie crisper industry.
posted by Ephelump Jockey at 8:11 AM on November 16, 2015 [1 favorite]


Given the colloquially well-known similarity of human flesh (“long pig”) to pork, I suspect the potential hams are numerous.
posted by acb at 8:16 AM on November 16, 2015 [3 favorites]


Gene modification is a conceptual shotgun shell: You can't really predict the precise impact pattern the shot will take in detail, but you can more or less predict its spread. Electronic theory was similar. Since, say, 1960, advances in electronics have evolved to the extent that they have begun to modify our basic paradigms. The advent of personal computers prepared the telephone's transition from a simple communication device to an electronic personal assistant that gathers and stores information, and links us in real time to anybody anywhere on the planet. We haven't yet developed terms to describe some of the toys that have become possible in the past couple of decades. The modern notion of telephone doesn't much resemble my mother's notion. Movie theatres are archaic remnants, televisions are at the point of obsolescence.

If computer inspired internet, and internet inspired computer viruses, it takes only a small effort to think that gene manipulation ought to wear a cautionary robe. Atomic energy inspired the bomb, and we've spend 60 years trying to hobble that particular genie. The problem for me is that I can't envision the downside of gene manipulation. Will it come from Big Brother or Dr. No?

What I see is a ticket to retard aging and eliminate many diseases. Maybe we can make humans smarter--assuming we can figure out what "smarter" is. It seems to me that CRISPR technology is another genie that, once it has been invoked, won't be easy to put back into its bottle. As a non-scientist I am eager to see how this develops. But I am thankful to not be the one who rubs the lamp.

Make a wish.
posted by mule98J at 8:17 AM on November 16, 2015 [2 favorites]


And it's not like anyone's planning on making big money on this technology. But we can worry about regulatory systems later if we need them.
posted by sneebler at 8:26 AM on November 16, 2015


The New Yorker article is quite clear this is several generations away from success in embryos. But I expect there are PGD/IVF labs that would be more than willing to work with an appropriately funded, interested couple to move this along rapidly. Too bad the ethics and legal sides won't move equally rapidly.

Fewer than half the embryos were edited successfully, and, of those, most retained none of the new DNA that was inserted into the genes. The experiment, which was published in the Beijing-based journal Protein & Cell, demonstrated clearly that the day when scientists could safely edit humans is far off. The CRISPR system also made unintended cuts and substitutions, the potential effects of which are unknown. In other cases, it made the right changes in some cells of the embryo but not in all of them, which could cause other problems. “These authors did a very good job, pointing out the challenges,” Dieter Egli, a stem-cell researcher at Columbia University, said when the study was published. “They say themselves that this type of technology is not ready for any kind of application.”

Unintended cuts and substitutions=caused new mutations/diseases.
posted by beaning at 8:33 AM on November 16, 2015 [2 favorites]


I will say that removing genes from humans has a whole host of ethical issues beyond 'is it toxic.'

This.

"One group has replaced a mutation that causes cataracts; another has destroyed receptors that H.I.V. uses to infiltrate our immune system"

One group hasn't bothered to look at all the unintended consequences this could cause..
posted by prepmonkey at 8:44 AM on November 16, 2015 [1 favorite]


What this article is talking about is making somatic mutations, editing cells involved in making the body operate, not making germline mutations that would edit cells involved in heredity.

Apologies for not reading the article first, as I guess I was imagining IVs or pills. The article itself does suggest CRISPR is not specific enough to miss germline cells:

Inevitably, the technology will also permit scientists to correct genetic flaws in human embryos. Any such change, though, would infiltrate the entire genome and eventually be passed down to children, grandchildren, great-grandchildren, and every subsequent generation.

Perhaps the author is misunderstanding, but I'm not well-read enough in the subject to know how you might apply CRISPR without also hitting up germline cells.
posted by pwnguin at 8:58 AM on November 16, 2015


"CRISPR Gene Editing to Be Tested on People by 2017, Says Editas"

It's not quite CRISPR, but a similar technology used to treat a young girl with a rare form of cancer was reported last week: Gene editing saves girl dying from leukaemia in world first.

This wasn't embryo modification either, but removal and modification of her own immune cells. Conventional treatments had failed; she was going to die otherwise. The modified cells were later destroyed by a second successful marrow transplant, but the modified immune cells allowed her to get there.
posted by bonehead at 9:19 AM on November 16, 2015 [2 favorites]


The New Yorker article is quite clear this is several generations away from success in embryos. But I expect there are PGD/IVF labs that would be more than willing to work with an appropriately funded, interested couple to move this along rapidly. Too bad the ethics and legal sides won't move equally rapidly.
The New Yorker article is not correct on this point. I am aware of multiple gene-edited embryos that have been carried to term and that are one the ground right now. They're not humans, but they're mammals.
posted by wintermind at 11:18 AM on November 16, 2015


I think a lot of the discomfort (besides basic things-man-was-not-meant to meddle with non sequitur) is that we're rapidly expanding genetics from a science to a field of engineering, and, well, do you know any engineers?

(Emacs CRISPR extension by 2020)
posted by PMdixon at 11:20 AM on November 16, 2015 [3 favorites]


The problem is most people are fighting the wrong battles---arguments about "toxic" manipulations and the terminator genes above are good examples of this. There are real, pressing, ethical issues to worry about, but public discourse is about the more cinematic concerns of the earlier types of technology. The review Blasdelb linked above is a good starting point if you're interested.
posted by bonehead at 11:31 AM on November 16, 2015 [1 favorite]


CRISPR/CAS FACES THE BIOETHICS SPOTLIGHT: Here's a report that goes into a bit more of the specifics for a few issues surrounding this technique. Note that it was published after the call in Science for a moratorium on clinical testing, and discusses that paper a bit as well.
posted by bonehead at 11:50 AM on November 16, 2015


PMdixon: "we're rapidly expanding genetics from a science to a field of engineering, and, well, do you know any engineers?"

I can't wait for the 'Real Men edit genes with VIM' holy wars.
posted by signal at 11:52 AM on November 16, 2015 [1 favorite]


It's not quite CRISPR, but a similar technology used to treat a young girl with a rare form of cancer was reported last week: Gene editing saves girl dying from leukaemia in world first.

That treatment uses a similar nuclease technology called TALEN. Our lab uses TALENs to cut out regulatory regions in the human genome, to see how a particular cell type changes or behaves. Some regulatory regions may direct the cell to become a blood cell, or a neuron, etc. Other (broken) regulatory regions may lead to cancer, or aid in tumor growth. Knowing the roles of these regulatory regions in various cell types holds future promise in organ regeneration, cancer treatment, curing Mendelian (single gene mutation) diseases, and so on.

There are a lot of safety, environmental and national security issues around companies like Monsanto using genetic engineering to manipulate our food supply, but as far as helping out sick human beings goes, CRISPR/Cas9 and TALENs are going to have a huge and positive impact.
posted by a lungful of dragon at 12:03 PM on November 16, 2015 [3 favorites]


jesus christ can we stop dicking around and just start cranking out the supersoldiers already
posted by um at 1:39 PM on November 16, 2015 [1 favorite]


As someone with a four year old son who has cystic fibrosis (CF), I have some interest in this. However, it seems that using this technique to edit in-place cells (e.g. the lung cells) which cannot be removed is significantly more difficult than other types of cell (e.g. blood cells).

Certainly the CF charities and doctors don't seem to be discussing this as a potential treatment any time soon; the existing CF gene therapy trials recently were a moderate success but are also a long way from any form of useful medical treatment.

I understand there are ethical concerns about modifying human genetics, but I think there should be room in the eventual regulation of this field for fixing known flaws like CF.
posted by Stark at 2:35 PM on November 16, 2015 [2 favorites]


Real question. Could this save the life of Stephen Hawking?
posted by lumpenprole at 4:46 PM on November 16, 2015


Lumpenprole, it's highly doubtful. The physical brain damage that ALS patients suffer is substantial. Fixing it would require growing a lot of new nerves in place and then rewiring them to something like normal. The brain is the only organ in the body where the structure at the cellular level is critical, and most of that is not controlled by genes.

Doing that to an adult, even one who is profoundly crippled, would probably render the thinking mechanism nonfunctional.

Anyway, his life doesn't appear to be in peril. Most ALS patients die long before they reach his age (currently 73).
posted by Chocolate Pickle at 5:24 PM on November 16, 2015 [1 favorite]


Yes, there are ethical issues with applying CRISPR to humans, but one of those issues is the harm of applying it too late. It's easy to imagine all the ways corporations and ideologues might abuse the technology, and thus regulate and limit its use. Harder to fix cataracts, HIV, and who knows what else after decades of such limits, then look back and realize all the other people we could have helped.
posted by Rangi at 5:46 PM on November 16, 2015 [1 favorite]


I can't envision the downside of gene manipulation.

I see this eventually having huge impact in the area of prenatal genetics and insurance and health care in general, but not always in a good way. I think this risks being one more way for further separation of those with access to knowledge/money/services from those without. And for couples to be forced to make decisions without full information and for women to lose bodily autonomy.

In addition to the clearly genetic disorders discussed here, there are lots of discussions elsewhere on the internet about testing to determine possible genes related to homosexuality, IQ, sport ability, etc-how do those genes factor in? And personally I don't trust PDG docs NOT to go "oh, well, we'll just CRISPR that gene right they way you want it, who am I to say..." when a cash-paying couple asks for ethical ifs. And the "no funding for special needs" legislators will have fun too-why did you not just use CRISPR? And will insurance pay for long term care if CRISPR correction is not chosen?

But yes, done properly there are huge potential upsides. And most scientific advances involve at least one "are you sure you want to do that?" moments.
posted by beaning at 6:30 PM on November 16, 2015


The bad news is that your son will be born with Downs Syndrome. The worse news is that your insurance doesn't cover the fix.
posted by mule98J at 9:02 AM on November 17, 2015


I can't envision the downside of gene manipulation.

A specific, real world concern for the food supply is creation of new allergens, or expanding the range of crops that might cause a specific allergic response. Adding a "peanut" allergy to another kind of food, as a hypothetical example. In any GMO, this would be something that would have to be checked.
posted by bonehead at 9:40 AM on November 17, 2015


A specific, real world concern for the food supply is creation of new allergens, or expanding the range of crops that might cause a specific allergic response.

Yes, but nobody cares about testing the safety of tangelos and pluots, even though they are the result of stitching two whole genomes together randomly. (I actually think there should be minimal testing associated with new hybrids as well as GMOs, or anything where new antigens could be developed. Knockouts of existing genes get a pass, unless they are repressing other genes.)
posted by benzenedream at 10:20 AM on November 17, 2015 [1 favorite]


The bad news is that your son will be born with Downs Syndrome. The worse news is that your insurance doesn't cover the fix.

Down syndrome isn't caused by a mutation. Its proper name is "Trisomy 21", which means it's caused by having a third copy of chromosome 21. CRISPR couldn't do anything about that.

It's caused by a mistake during meiosis resulting in an egg (usually) having one more chromosome than it's supposed to have. (It can be caused by a malformed sperm, too, but a sperm with an extra chromosome is going to be heavy and slow and probably won't win the fertilization race.)
posted by Chocolate Pickle at 11:23 AM on November 17, 2015 [1 favorite]


Re could CRISPR correct chromosomal anomalies,

From http://www.nature.com/cr/journal/v23/n12/full/cr2013135a.html How to correct chromosomal trisomy

Trisomy 21 in human causes Down syndrome, a common chromosome disorder with devastating phenotypes ranging from early death in utero to intellectual disability together with an array of physical anomalies and late-onset diseases. In a recent study published in Nature, Jeanne Lawrence and her colleagues restored normal gene expression in trisomy 21 cells by silencing the extra chromosome using XIST, the non-coding RNA that normally silences one X chromosome in females; this improved growth and differentiation of neural cells, which offers hope that some deleterious effects of the trisomy could be reversed to improve this incurable disease.

And for efforts to correct trisomy 21 and trisomy 18 but with less success, see
http://dnaresearch.oxfordjournals.org/content/early/2015/08/24/dnares.dsv016.full
posted by beaning at 2:22 PM on November 17, 2015


...That is a fascinating idea.

Still wouldn't work in humans unless you did it at the embryo stage, but using Xist is a great idea.
posted by maryr at 2:52 PM on November 17, 2015


Maryr is right: XIST is fascinating and certainly worthy of study, but it probably isn't useful in the real world for Down Syndrome. It would have to be applied in the very earliest stages of development. Most Down Syndrome is detected in the womb by extracting some amniotic fluid and testing loose cells found in it -- and by the time that's even possible, it would be long since too late to do anything about it.

If you used it prior to in vitro fertilization, that might be possible. But in that case, if you detect the extra chromosome, I think in most cases that embryo would just be discarded and they'd make another. (Some people might have religious objections to that, but generally such people aren't going to be using in vitro fertilization because that nearly always involves making extra embryos and discarding the excess ones.)

It would have to be applied before the blastula formed, at the 8- or 16-cell stage when the cells are still undifferentiated. You'd modify one cell, discard all the rest, and then develop an embryo out of that one.

It seems like an enormously complicated (and risky -- it might not work, and it might cause other problems) solution when others are already available which are easier and more sure.
posted by Chocolate Pickle at 4:13 PM on November 17, 2015


The more likely Xist scenario is to engineer neural stem cells with the extra chromosome silenced from the Down syndrome patient, in order to prevent the early onset neuronal degeneration they suffer. Still decades away from a therapy, unfortunately.
posted by benzenedream at 6:33 PM on November 17, 2015


Oh, I completely agree the research as to what percentage of cells in what systems needs to be corrected, etc is all very early and I'd further argue that the full extent of the needed research isn't yet realized. Is correction of all cells needed or can organs/systems be targeted? For some metabolic conditions or cancers, what about correcting a limited number of self-cells and then letting the effect spread- similar to organ, bone marrow or stem cell transplants but without awaiting donors? Most metabolic patients don't need 100% of cells working 100% properly in order to avoid crises; they need specific organ systems to function at certain levels.

As to needing this applied to embryos prior to the blastula stage to correct chromosomal issues, that's pretty much when aneuploidy screening is done in current PGD/IVF procedures. If CRISPR or XIST or similar could be applied at that stage, I expect a significant couples would prefer not to undergo another very trying and expensive round of hormone stimulation, retrieval, anxiety, etc.

This 2012 review has nice enough cites of PGD technical articles but primarily focuses on the ethics of PGD/IVF diagnostics from single gene testing to aneuploidy analysis to aCGH to exome studies. CRISPR related issues are just one more issue to throw into a stew that has been cooking for years.
posted by beaning at 7:06 PM on November 17, 2015


Gene editing the human germline: What are the risks? posted by kliuless at 7:35 PM on November 17, 2015 [3 favorites]


Knockouts of existing genes get a pass, unless they are repressing other genes.

How could you possibly know that?
posted by pwnguin at 7:49 PM on November 17, 2015


Future generations can’t give consent

No one asks to be born. The best we can do is give future generations the best possible shot.
posted by a lungful of dragon at 10:08 PM on November 17, 2015


The Best Possible Shot, that's the thing we're giving them. Wait, no, that's not the thing. We're doing the other thing, the whatcha call it, the global warming crop failures civil unrest mass extinctions thing. The Not The Best Possible Shot thing. The Armageddon thing, that's the thing we're giving them.
posted by five fresh fish at 12:08 AM on November 18, 2015 [1 favorite]


"How could you possibly know that?"
I don't work with Eukaryotes, but this should be super trivial. Just looking at whether whatever you're repressing has DNA or RNA binding domains in hmmer, and double checking that the transcripts produced aren't antisense for other transcripts by BLASTing the complimentary sequence, would do it. That's five minutes of effort. Even then, if you are the type of paranoid that leads people to protest the LHC as something that could END THE WORLD, RNA-Seq or microarrays with a few grand and a few months of a graduate student's time would firmly establish nothing was being differentially expressed but the target.

There is this weird tendency in lay communities to assume that, because they don't understand current scientific models, the scientific models we rely on are either much less reliable than they are or don't exist. Editing genomes is an increasingly trivial thing that has been done routinely in labs for research purposes for the last forty years, its not some kind of nebulous unknown, or even honestly that new.
posted by Blasdelb at 1:38 AM on November 18, 2015 [3 favorites]


There is this weird tendency in lay communities to assume that, because they don't understand current scientific models, the scientific models we rely on are either much less reliable than they are or don't exist.

Welcome to the wonderful world that is explaining risk management to an uncaring and often unreceptive, sceptical and hostile public. You're assumed to be acting in bad faith until you demonstrate otherwise (because enough companies and academics actually are).

To restate, this is the informal back end of the precautionary principle. It's not enough to say something is safe, you have to prove it is so in the most direct way possible, often multiple times, in multiple ways. This is the way a lot of regulations work (or how they try to work). Beyond that is the social licence to use a technology, and that frequently requires more effort than just meeting regulatory requirements.
posted by bonehead at 6:56 AM on November 18, 2015 [2 favorites]


"How could you possibly know that?"

You fund basic science research, ha ha, just kidding, silly me, who would do a thing like that?
posted by maryr at 11:52 AM on November 23, 2015 [2 favorites]


Well, sure. There's a specific definition of gene repression geneticists use that I forgot about, and thus regret the precise framing of that question. I was primarily thinking of the problem in terms of the interactome, which is quite large and undocumented, so not yet amenable to search queries like BLAST and hmmer. It may take another generation before that process is mapped, or understand how much larger a problem domain than a genome it is.

The worry that removing a gene might yield a different result from protein-protein interaction doesn't seem to merit the pocket dismissal given here. But it's definitely not the same as gene repression.
posted by pwnguin at 3:27 PM on November 23, 2015




"Well, sure. There's a specific definition of gene repression geneticists use that I forgot about, and thus regret the precise framing of that question. I was primarily thinking of the problem in terms of the interactome, which is quite large and undocumented, so not yet amenable to search queries like BLAST and hmmer. It may take another generation before that process is mapped, or understand how much larger a problem domain than a genome it is."
This is the level of concern for esoteric outcomes that makes sense for efforts edit patient somatic cells like in the FPP, much less germline cells, but I'm not at all convinced that the interactomics of recombinant mutants would even be meaningfully interesting to look at with yeast two hybrid screens in the kinds of crop species benzene dream was talking about. So long as any hypothetical interaction doesn't impact the viability of the critter, which would be immediately apparent by growing it, why should any hypothetical interaction even matter? We could certainly pull up an armchair and imagine scenarios where perturbations to the interactome could cause some hypothetical harm that would be too subtle to notice, but can we come up with any that wouldn't also be caused much more often by any other method of crop breeding? Just think about it, if anything the more distant the foreign genetic material being used is, the less likely it would be to affect the interactome at all - when we currently cross breed related plants with all sorts of kinky mechanisms for chromosomal recombination and apply gamma radiation to select for whatever within the wildly affected mutants without giving it a second thought.

When we have the luxury of just throwing out non-viable mutants, unlike with human cells, how could this possibly cause a problem we're not already much more vulnerable to? Intended effects in viable mutants are hard enough to pull off with recombinant DNA technology, we don't really have much at all to fear from unintended genetic effects as we've done just fine taking objectively much bigger 'risks'. The more social, environmental, and economic risks worth actually thinking about (and that really should be social, environmental, and economic conversations as those risks are only really tangentially related to the recombinant technology itself) only get harder to have when we our scientific conversations stay stuck in the 90s like this.
posted by Blasdelb at 6:12 AM on November 24, 2015 [2 favorites]


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