Oct 08 2015

CRISPR and a Hypoallergenic Peanut

Anyone with a child in school is probably aware of the need for peanut free zones. You get a notice when your child returns from school on the first day stating that at least one child in their class has a peanut allergy, which means nothing with peanuts gets sent to school for your child’s lunch. If you are a parent of a child with a peanut allergy you understand how important and serious this is – your child is literally one errant Snickers bar away from death.

The general consensus is that food allergies have been on the rise in developed countries, although studies show a wide range of estimates based upon study techniques. A US review found the prevalence of self-reported peanut allergies ranged from 0-2%. A European review found the average estimate to be 2.2% – around 2% is usually the figure quoted. In a direct challenge study, at age 4, 1.1% of the 1218 children were sensitized to peanuts, and 0.5% had had an allergic reaction to peanuts. That means there are millions of people with peanut allergies.

So far there is no cure for the allergies themselves. Acute attacks can be treated with epinephrine, but there are cases of children dying (through anaphylaxis) even after multiple shots. The only real treatment is to obsessively avoid contact with the food in question. Peanuts, tree nuts, and shellfish are the foods most likely to cause anaphylaxis.

There is, however, a potential solution. Researchers have been working for years on developing a cultivar of peanut that does not cause allergies. Attempts to achieve this through conventional breeding and hybridization have failed and does not seem likely to succeed. The only real hope of a hypoallergenic peanut is through genetic modification. We are, in fact, on the brink of achieving this goal, but anti-GMO fears are getting in the way.

There are 7 proteins that have been identified in peanuts that cause an allergic reaction. The allergic reaction from peanuts is entirely an IgE mediated Type I hypersensitivity response. The proteins crosslink with the IgE antibodies, which then bind to mast cells and basophils (cells in the immune system) causing a significant inflammatory response that clinically causes the allergic reaction. One peanut contains about 200mg of protein, and as little as 2mg is enough to cause objective symptoms of an allergic reaction.

What makes a food protein an allergen is interesting. About 700 amino acid sequences have been identified that help confer allergenicity to protein. These protein segments allow the protein to survive processing and digestion, and allow the protein to bind to IgE antibodies.

In 2005 a study was published showing that it is possible to silence the gene for the Ara H2 protein, the primary allergenic protein in peanuts. A 2008 follow up by the same team showed decreased allergenicity of the altered peanut. So where are our hypoallergenic peanuts? This is a complicated question, and I don’t think I can give a full answer.

The delay in marketing a hypoallergenic peanut seems to be due partly to technical issues – it turns out to be a lot more difficult to make the necessary changes than at first thought. However, it also seems to be due to the anti-GMO campaign, which has been scaring away investors and making politicians gun-shy.

Meanwhile, scientists have developed a new technique that promises to revolutionize genetic engineering, called CRISPR – Clustered regularly interspaced short palindromic repeats. This is a system found in procaryotes as part of an adaptive immune system against viruses. The system can be used for relatively cheap and easy gene editing.

Chloe Gui, a scientist with Aranex Biotech, is working with CRISPR technology to identify and then edit out the genes for the major allergenic proteins in peanuts. CRISPR is more precise than older techniques and has the potential to succeed in the goal of an allergy-free peanut. Gui, however, complains that the investors the startup needs to complete their research is difficult to come by because “GMO” has become a bad word. Further, GMO regulations have not yet accounted for CRISPR technology, creating uncertainty in the market.

Conclusion

Peanut allergies are a real and serious health concern. We have in our grasp the technology to essentially eliminate the problem from the world, as thoroughly as smallpox has been eliminated. We can simply edit allergenic proteins out of cultivated peanuts. Conventional breeding has failed to accomplish this, and it doesn’t seem likely that it will be able to.

This is simply an extension of the past several thousand years of altering the plants and animals in our environment to make them more suitable for human consumption. Just about everything you eat has been massively altered through human intervention. Now we have the technology to make precise specific changes.

Irrational fears of this new technology, fueled by pseudoscientific propaganda, have created a significant negative attitude toward GMOs in the public. This is a great example of how misplaced fear can lead to negative outcomes. People will literally die from peanut allergies because the solution is delayed or rejected due to unwarranted fears.

18 responses so far

18 Responses to “CRISPR and a Hypoallergenic Peanut”

  1. carbonUniton 08 Oct 2015 at 9:12 am

    At least they would not be frankenpeanuts, with non-peanut stuff added, just allergens suppressed. I wonder if that matters to the anti-GMO crowd?

    The bit about the 700 amino acid sequences that confer allergenicity to protein got my attention. I wonder if it would be practical to make allergy pills that contains these allergens in very minute quantities. One would give these to children to train their immune system to accept these allergens. One would work up to higher levels unless there was trouble. I’m guessing that the problems with reactions would make those with vaccinations look like nothing though…

  2. RickKon 08 Oct 2015 at 11:31 am

    Until there’s a hypoallergenic peanut, it is important to know that desensitization therapy does work and works well for peanut allergy. Several years ago it was attempted, and the story we heard from our allergist was that at least one patient died during trials.

    What has changed is there are now companies that can produce peanut flour with highly consistent, dependable levels of peanut protein. So dose measurement can be very precise.

    Our daughter had a severe reaction to peanuts at age 3 (ambulance, respirator, nightmare). Throughout most of her school years we did the full-court-press on peanut free areas, hand washing, eli-pens, training administrators and field trip chaperones, and limiting food to only carefully selected products and homemade foods or sweets from Vermont Nut Free.

    A few years ago we heard about a desensitization trial near Hartford that had good results and so we gave it a try. Worked like a charm.

    The doc started with a very tiny amount of peanut flour mixed in something yummy like pudding. The first dose was under supervision in the clinic, then she would take that same dose for 2 weeks. Then we would go back to the clinic, get the first exposure to a higher dose under supervision, followed by 2 weeks at home. Rinse. Repeat

    (It got very interesting carrying pre-measured vials of powder on a family trip to Central America. We had to get doctor’s notes in English and Spanish.)

    Now after dinner each night she takes her maintenance dose – 3 peanut M&Ms – to keep the allergic response from re-developing. While she’ll probably never be able to eat a package of Nutter Butters, she can go off to college no longer worrying about accidental exposures (so long as her roommates don’t munch all of her “medicine”).

    Finally, the “peanut butter gap” in our family pantry was easily filled with a “Soy Nut Butter” product that tastes just fine.

    While this breakthrough in genetics will be wonderful for reducing the dangers of peanut allergy, the more critical challenge is understanding why these allergies form. It feels like a problem that can be avoided almost entirely once we can understand why these immune responses get mis-directed. I haven’t read the literature in the past couple years, but it did seem like there was some combination of environmental and developmental factors leading to IgE food allergies.

    Thanks for this topic, Steve – it is one that is very close to home.

  3. Banzai Otison 08 Oct 2015 at 12:13 pm

    If you’re a RadioLab fan, they did a cool episode on CRISPR: http://www.radiolab.org/story/antibodies-part-1-crispr/

    If you’re not, you should be, so have a listen anyway 😉

  4. Bruceon 08 Oct 2015 at 2:52 pm

    As a father of two children with nut allergies (including coconut which is not recognised as a common allergen here in the UK so it is not bolded on ingredients lists) this is really interesting to me. Unfortunately the NHS is not going to green light desensitisation therapy until a phase 3 trial has been done, so it won’t be available here for a while.

    I love the idea of GM to solve this issue… but yeah… anti GM rhetoric is a big problem.

    I agree with RickK in that finding out why these allergies form is more critical though.

  5. MaryMon 08 Oct 2015 at 2:58 pm

    At Halloween I buy bags of Reese’s peanut butter cups, just to sniff the bag when I open them…. And then I’m sure to have them on hand when the trick-or-treaters come, because I can’t eat them.

    I dream of a Reese’s #GMO peanut butter cup. A lot. But this would thwart my Halloween strategy.

    I use sunflower butter as a replacement. I have yet to find sunflower butter cups, however.

    I”ll be the first in line to test these if they come out. Sign me up.

  6. goldmund52on 08 Oct 2015 at 3:44 pm

    RickK:You said. “While this breakthrough in genetics will be wonderful for reducing the dangers of peanut allergy, the more critical challenge is understanding why these allergies form.”

    Check out the hygiene hypothesis. Feed your infants peanut butter!

    N Engl J Med 2015; 372:803-813February 26, 2015DOI: 10.1056/NEJMoa1414850. Randomized Trial of Peanut Consumption in Infants at Risk for Peanut Allergy.

  7. RickKon 08 Oct 2015 at 4:09 pm

    goldmund52 – Yep, saw that. Exact opposite of what they were saying when our daughter was born.

    I also think we may see something like “sanitized dirt” or “baby bacteria” or “pediatric parasites” or some other safe way of exposing developing children to harmless versions of bacteria and parasites to help tune the immune systems even in a sterile environment.

  8. Willyon 08 Oct 2015 at 5:44 pm

    Side Comment: Do go see “The Martian”. Excellent.

  9. Johnnyon 08 Oct 2015 at 6:26 pm

    “This is simply an extension of the past several thousand years of altering the plants and animals in our environment to make them more suitable for human consumption. Just about everything you eat has been massively altered through human intervention.”

    I very much like this taking a look at the broader picture, and I’ve seen it in several of your blogposts. It gives perspective and (this is slightly irrational) a more story-like feeling (or narrative) to it.

    I have nothing to add to the meat of the content here, just wanted to deliver my appreciation of this one facet. 🙂

  10. hardnoseon 08 Oct 2015 at 6:31 pm

    GM peanuts would not solve the problem and could make it even worse. There would still be regular peanuts around in the world, and a person who is allergic to peanuts could mistakenly eat the wrong kind.

    It’s easier to avoid peanuts altogether than have to determine if a peanut is safe or not, when they look exactly the same.

    Yet another dumb GMO marketing idea.

    Someone else mentioned desensitization, and if you want to help kids with peanut allergies it makes more sense to focus on improving desensitization methods.

  11. arnieon 08 Oct 2015 at 7:13 pm

    Perhaps we’re seeing the first instance where the “GMO” label on a food (peanuts) will imply “good/safe” and the “organic” label will imply “bad/danger”. How deliciously ironic.

  12. jsterritton 08 Oct 2015 at 11:08 pm

    @hn

    “There would still be regular peanuts around in the world, and a person who is allergic to peanuts could mistakenly eat the wrong kind.”

    Why, oh why, would there be “regular peanuts” around? You are such a contrarian and science-hater (and dim bulb) that you can’t even conceive of a world with an improvement in it. A non-allergenic peanut cultivar would instantly replace its “conventional” counterpart in every peanut product in every regulated market in the world. Certainly, it would eliminate the offending legume in the US in every peanut-containing product (including peanuts). Only Tylenol-tampering, Unibomber types like you would hoard dangerous allergenic peanuts to hand out at Halloween. A cursory statistical analysis shows a net saving of untold lives and an ideal replacement for the current ad hoc peanut-avoidance scheme.

    Only you could hate on nutritious, delicious lifesaving technology like the one discussed here.

    Sorry, kids.

  13. thequarkon 09 Oct 2015 at 3:04 am

    This needs to be a thing yesterday. Very cool but sad it isn’t mass-market yet.

    I have one curiosity, though: What does this protein do for the peanut plant? Would taking it out make it harder to produce them en masse or even make viable peanuts at all? Naively, I’d think it does *something* for the plant that grows them.

  14. Steven Novellaon 09 Oct 2015 at 7:26 am

    quark – often when we make plants safer for humans, we make the plants more vulnerable to pests. The potato is a good example – that family of plants produced a natural pesticide that makes humans sick. We bred them to have lower amounts, which makes them safer to eat, but more vulnerable to pests. But this is not a deal-killer – we just adapt the agriculture to compensate.

    I’m not sure what the net effect would be for peanuts, but probably not a significant problem. Allergy itself (unlike toxicity) may be incidental, and not necessary for the plant.

    Desensitization is fine, and this is a good option also, but it’s not perfect. I think false choice statements (why put fluoride in the water, just have people brush their teeth) are almost always misguided. For public health using multiple methods is almost always best.

    Further, even without 100% penetration of the non-allergenic peanut, it would still reduce the risk of accidental exposure because there will be fewer allergenic peanuts out there, and someone with an allergy should still avoid all peanut products unless they are explicitly labeled as non-allergenic (until we have 100% penetration).

  15. RickKon 09 Oct 2015 at 8:57 am

    While the idea of a safer peanut is great, and would make many people breathe easier (figuratively and literally), I actually don’t think it will work out.

    The peanut producers have not felt the impact of allergy fears. There’s been such a backlash against what many perceive as over-concerned parents and overly-sensitive kids, that peanut allergy is more often than not a punchline. So already we have large numbers of parents who simply don’t agree with putting limitations on their kids’ food just so some other kid at the table won’t have a reaction.

    Add to that the anti-GMO hysteria, and you have a lot of reasons for peanut producers to do nothing.

    Given the hype of peanut allergies, the peanut industry has spent relatively little (peanuts, you might say) on allergy research.

    Finally, there is the problem of how to market and profit from the “safe” peanuts. You can’t say they’re safe for allergic kids to eat – there’s too much liability there. All the “safer” peanuts will do is reduce the chances of a bad reaction. Nabisco doesn’t dare try to entice peanut free schools and peanut allergic kids to buy their “safe” Nutter Butters because one publicized reaction blows the whole thing up.

    So it is not surprising that this hasn’t come to market. I think the only way to use this advancement to make the world a little safer is to mandate (through government or voluntary industry organization) a shift to the safer variety, but keep all the same warning labels and controls in place that are there now.

  16. MikeLewinskion 09 Oct 2015 at 6:02 pm

    Note that in the US the Safe and Accurate Food Labeling Act of 2015 as passed by House of Representatives (H.R.1599) explicitly forbids claiming a food derived from a GE plant is safer or higher quality. I suspect that this clause was inserted to give the appearance of balance, as an olive branch to opponents. Unfortunately I think it’s as troublesome from First Amendment perspective as the existing GMO labeling laws.

    There’s also another possible cause of recent increases in peanut allergies that I never would have thought of… dry roasting.

    https://www.washingtonpost.com/news/to-your-health/wp/2014/09/21/could-the-dry-roasting-process-trigger-peanut-allergies-yes-says-a-new-oxford-study/

    I’m just bitter that Dunkin Donuts says their products may contain peanuts, but I can’t actually order a peanut-sprinkled doughnut. In fact almost no one makes them anymore. I’m not allergic, but this is still a reason for me to cheer on CRISPR/Cas9 (and others).

  17. Sylakon 09 Oct 2015 at 7:32 pm

    Huuum barbecue Crisper and peanut.. Oh wait, CRISPR. My mistake. Lol, another nice technology using what nature provide us. Yes, this natural.

  18. zorrobanditoon 11 Oct 2015 at 2:23 pm

    There would still be regular peanuts around in the world, and a person who is allergic to peanuts could mistakenly eat the wrong kind.

    There is an interesting parallel here with almonds.

    The original wild almonds were poisonous. They contained cyanide.

    But long ago a mutation occurred, perhaps more than once? and the resultant almonds were not poisonous. (How exactly did anyone figure this out?!?) And so began the cultivation of almonds. But at first they had to be careful not to allow these “tame” safe almonds to be accidentally cross-bred with the original poisonous kind, for obvious reasons.

    However, over time we got it sorted out. We could do the same with peanuts, which are only dangerous for some people, not, like cyanide, for everyone.

    All that granted RickK is probably right. There are no specific people or businesses which would stand to make money off this proposed modification of the peanut, so it probably won’t be done any time soon.

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