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Teenager's sickle cell reversed using a treatment to change his DNA (bbc.com)
211 points by _nh_ on March 4, 2017 | hide | past | favorite | 75 comments

After adenoviruses proved to be dangerous [1] I wonder what sort of virus they're using now?

[1] https://en.wikipedia.org/wiki/Jesse_Gelsinger

Are doctors allowed to use gene therapy in life or death conditions now? In the trial for fixing OTC deficiency that Jesse Gelsinger died in they only administered the trial to people who were capable of living with the disease as opposed to the babies that were going to die in their first year without it. The idea was that a parent faced with the possibility of their child dying painfully couldn't possibly refuse the treatment and therefore couldn't give informed consent.

A key point in the difference that might help explain it:

> On 13 September 1999, Gelsinger was injected with an adenoviral vector carrying a corrected gene to test the safety of the procedure


> Doctors removed his bone marrow - the part of the body that makes blood. They then genetically altered it in a lab to compensate for the defect in his DNA that caused the disease. ...

> A virus was used to infect the bone marrow with new, correct instructions.

> The corrected bone marrow was then put back into the patient.

This was a self transfusion in the lab rather than an injection of a virus. After the virus infected the bone marrow, it would then have been tested to make sure that there are no immune responses with the material and that it is safe to return to the patient.

> The idea was that a parent faced with the possibility of their child dying painfully couldn't possibly refuse the treatment and therefore couldn't give informed consent.

Well ... I get the idea, but I am not sure this is rational. If I have the choice between pizza and no pizza, and of course everyone would choose the pizza, my choice is not uninformed, just because it is too good of a deal.

The idea is that they would agree to anything, including things which has low likelihood of success and could be traumatic to the child simply because the known downside was too great.

People aren't very good at comparing a terrible known condition A, to a merely potentially terrible known condition B.

It strikes me not so much as irrational as that it's the sort of thing an evil mustache twirling bureaucrat would say in a Hollywood movie.

Will this change potentially be transmitted to his children?

Unfortunately, human germline modification is still taboo here: https://motherboard.vice.com/en_us/article/scientists-argue-...

It angers me that a misguided and stringent sense of ethics might slow the deployment of one of the most beneficial technologies ever conceived.

I agree with this, but not a popular opinion. Hence the down votes you are getting. Korea and China don't have the same memetic immune response to such ideas, injecting one's children with growth hormone in hope of increasing future job prospects, for example, is extremely common in Korea. I suspect embryo selection and generic engineering for increased IQ will take off in East Asia first. Then we will be forced to allow it to compete. 50+ more IQ points looks very possible: https://arxiv.org/abs/1408.3421

However, any significant lag could spell the end of American economic dominance. For this reason, I intend to start investing more in Korean firms in the next few decades.

A better way to increase iq would be to raise the socioeconomic level...

Nope. Genetic engineering works far, far better. We've already plucked the low hanging fruit of adequate nutrition, early education, salt iodization, and lead reduction. Anyway, those reduce mental retardation, they don't improve the baseline too much. And the Flynn effect looks to be slowing or reversing. 50 IQ points is huge. It's the difference between a burger flipper and a physics professor. The change to the world when the average 5th grader is mastering chromodynamics is hard to even contemplate.

People in Flint, Michigan still don't have clean water. Lots of other folks in the world also don't have clean water. Doesn't that seem like an easier thing to fix than trying out experimental therapies?

This might particularly interest you: http://www.lettersofnote.com/2012/08/why-explore-space.html

The gist of it is, in 1970 someone asked a director of NASA why billions of dollars were being spent on exploring space when millions of children were still dying on Earth. The response in part explained that NASA's R&D was paving the way for satellites with better weather forecasting, better communications, and better equipment that was making its way into people's everyday lives. While a bit morbid to say, the advancements made by NASA have arguably saved many more lives in the long run.

It's hard to see the point in investing in experimental technology whose payoff is unknown, especially when we have definite problems with feasible solutions. That doesn't mean we shouldn't try. The possible payoffs - cancer cures, age prolongation, enhanced food production, disease and sickness prevention - that can come from investing in gene therapies are just too great to ignore.

As a side-thought, the technological singularity is thought of as the point at which we create an AI smarter than us, triggering a run-away effect of self-improvement. What if we end up doing it to our own race first through intelligence-improving gene modification? Can you imagine the implications of applying that intelligence to solving the rest of our problems?

And if you're interested in helping people in places that don't have access to these things that salt ionization is almost certainly the thing to work on first.


As to Flint that does seem to be finally over now, though goodness knows it went on for a distressingly long time.


doesn't doing both seem more effective

> Genetic engineering works far, far better.

Um, do we know that? Unless I've missed some very interesting research that sounds like an extremely untested hypothesis.

It's untested in the sense that no genetic engineering has been done in humans, yes. (Unless you count gene therapy to cure disease, which is fairly different.)

However, there are some pretty strong reasons to think it would work, at least if we're just talking about improving within the typical range of human ability. Going to the extremes of existing ability and beyond is probably possible too, but there are more unexpected problems that could exist.

Has IQ-improving gene-editing been proven in animals then?

Yes: http://www.sciencemag.org/news/2014/09/human-speech-gene-can.... (That said, you'd need to use a different approach in humans, because we don't have any smarter species that we can copy genes from.)

People are talking more about 15 point gains through embryo selection now rather than 50 point gains. The later might be possible at some point but even the former isn't quite within the grasp of current science.

I think you're putting too much faith into IQ.

Shockley only had an IQ of ~125 (even though he became an eugenicist...).

More importantly, Feynman used his low IQ score (124 I think) to show how useless the IQ test was as a predictor of intelligence.

IQ mean is 100 and stddev is 15. He was in the top 5.5% of human intelligence.

There are tests that don't use a standard deviation of 15. Feynman might have done, for example, the Cattell Culture Fair Intelligence Test[1], which has a standard deviation of 24.

[1]: https://en.wikipedia.org/wiki/Cattell_Culture_Fair_III

What Shockley and (especially) Feynman did is well beyond a 95th percentile of ability.

Ability isn't well distributed to where it can have a maximal benefit in a given field. It's often said that people as smart as Einstein (and Feynman) are currently living and dying on subsistence living farms.

What hasn't been said, but is equally true, is that people as capable in physics as Einstein as currently working as waitresses in No Where, Idahoe. Or they're slaving away as bit-actors in Hollywood because that's what they love.

Or they're sitting behind a computer, typing away on HN, never to know that they're potentially amazing theoretical physicists simply because their 7th grade teacher turned them off to the idea of physics in general so they studied computer science instead.

Until there's some kind of test that tells you your aptitudes at very subject, you'll always have people pick suboptimal paths to excellency and something other than what they absolutely theoretically could have been best at.

There is an ongoing minor controversy around Feynman's IQ score. See Steven Hsu here for some context: https://www.psychologytoday.com/blog/finding-the-next-einste....

> 50 IQ points is huge. It's the difference between a burger flipper and a physics professor. The change to the world when the average 5th grader is mastering chromodynamics is hard to even contemplate.

We will have super smart burger flippers?

Is there any foreseeable way to apply gene editing like this to adults? Could existing adults (us) in the future make use of this type of IQ increase?

Not impossible but much, much, much more plausible with embryos. Modifying billions of neurons is a very, very tall order, and would likely be much less effective after the brain is grown. Embryo selection and modification are almost doable now, we just don't know which alleles to select for or edit in. A gift you can give your children but one you are unlikely to be able to get for yourself.

This is true, as much as I disagree with his ideas. Trying to genetically modify a living adult across many cells is very difficult.

Who's ideas?

IQ test are a proxy for g. They are meaningless when applied to computers.

My point is that the IQ test is meaningless in measuring intelligence....

Here's a neat primer from Vox on some of the social science behind IQ. It's incredibly predictive of people's life outcomes!


That is...much better than I would have expected of Vox.

They really are meaningful. How about we make a deal? You read Intelligence: All That Matters and I'll read The Mismeasure of Man again.

If genetic boosting is actually possible and not fringe bullshit, it's way faster than socioeconomic fixes, which seem to take 10 years per 3 iq points.

It only takes you so far. Mainland China is 99, Hong Kong is 107.

The ethnicity is virtually the same so that is being as close to a controlled parameter as it realistically can be without doing unethical things.

No amount of life quality can raise iq by the magnitude in the parent post.

If we don't try, then we'll have a lot of poor, sick, and unhappy geniuses walking around.

I wonder which types of crime they'll optimize?

Wow. That's amazing. You're actually arguing that we need to keep hoi polloi stupid so that it's easier to control them.

No, he's arguing that we provide the "hoi polloi" with a higher quality of life...

Would it not be the same argument as GMOs, that we don't understand the consequences enough and therefore shouldn't be used? N. Taleb has quite a detailed critique of GMOs, I'm wondering if this is the same to that and if the same concerns apply.

Well what happens when people start modifying people not for illness, but for other characteristics. You start having parents paying for their kids to make them faster, stronger, smarter, etc. You are left with two classes of citizens which might already be the case with wealth inequality. What about athletics with gene doping? It might be inevitable, but you have to think about what might end up happening.

So because some people might benefit and not others, we're all supposed to be stuck with these Savannah-adapted bodies forever? That's the ultimate crab bucket mentality.

That same misguided sense of ethics is becoming rampant everywhere. It might end up completely halting human progress.

Looks at the first Reddit comment on any interesting new technology. There's always someone dismissing the whole idea due to some outlandish risk.

I would like to see reliable, precise modifications before human germline modifications happen. As I understand it, current techniques involve infecting cells, integrating whole foreign genes (or even genomes) into them, and hoping that a beneficial modification comes along for the ride. If every family starts editing their children's genome like this, we'll end up with a whole lot of random crap in our germlines.

CRISPR is better but not there yet, I believe. Let's get all the way to being able to do the equivalent of sed to our germline cells before we start editing.

It's unlikely. The virus used to modify the bone marrow cells would have to stay active after the transplant and infect the rest of his body (specifically his testicles).

It sounds like this research involves somatic gene transfer, in which the change to the genome is not passed on to children:

Gene transfer can be targeted to somatic (body) or germ (egg and sperm) cells. In somatic gene transfer the recipient's genome is changed, but the change is not passed on to the next generation. In germline gene transfer, the parents' egg and sperm cells are changed with the goal of passing on the changes to their offspring.


Isn't that dangerous ? This will allow him to have a normal life, which includes kids, which will need this (potentially very expensive) treatment as well.

Wouldn't you, in order to not destroy the gene pool, want to restrict gene changes to both of those ? Either that or sterilize the patient to prevent transmission of lethal genes ? This treatment is VERY unfair to any children this guy fathers.

Of course I do get that the method used here goes not really support germ transfer (that requires the gene change to happen in vitro)

Just carrying the sickle-cell trait is mostly neutral to highly advantageous depending on where you live, because it confers substantially increased resistance to Malaria.

This is how a trait that is so dangerous when expressed has managed to spread; in regions with endemic malaria, carriers have better survival chances and the difference is sufficient to make up for those who express it and end up dying young.

It is recessive - you need to inherit it from both parents to express it. So it is in fact entirely safe for this man to have children provided he has children with someone who is not a carrier, or ensure appropriate tests are taken during pregnancy.

Most people who carry this trait in developed countries today know about it, because the mechanism is very clear and they will usually know whether or not any of their family expressed the trait, and will have been tested to see if they inherited it. E.g. we had our son tested because his mother is a carrier, but because I am not we knew he could not have sickle cell disease.

My son is a carrier, but all that means is that like the guy in this article, he will want to make sure his partner is tested before having children, and to ensure to decide in advance what to do if both are carriers or if his partner has the disease (such as whether to have an abortion if tests show the child has the disease).

We can expect the number of people with this gene to drop over time because it is now so easy to avoid. But in the meantime a treatment would make a massive difference for those with the disease.

This treatment is VERY unfair to any children this guy fathers.

In order to have the disease you need to inherit bad genes from both parents.[1] Consequently there are many more carriers than people who actually have the trait. So any of this guy's children have at most a 50% chance of having the trait if the other parent of the child doesn't have it, and 0% chance if the other parent isn't a carrier.

I'm sure if we sequenced your DNA we would find a number of potentially very problematic diseases for which you are a carrier. That applies to everyone, nobody has perfect DNA.

in order to not destroy the gene pool

There are a lot of morons in this world; many more being born every day. Many of them manage to reproduce before reaching the point where they would be under consideration for a Darwin Award. In the greater scheme of things this one particular genetic defect isn't seriously threatening to "destroy the gene pool".

[1] https://en.wikipedia.org/wiki/Sickle-cell_disease

This is just a better treatment for sickle cell. Should sterilization be a requirement for any sickle cell treatment?

Part of the beauty of these kinds of gene therapies is that the cost can ultimately be lowered to near-zero levels. These are not drugs that must be taken over a lifetime, but can potentially provide 1-time delivery of the instructions to your own body about how to cure itself. Certainly in the near term the R&D must be paid for (and the marketing, and regulatory burden, and everything else). But in the long term the actual material used to change someone's life forever can cost pennies and a one-time delivery.

This. It would need to affect F2. It won't.

Is this using CRISPR or some other method of editing the DNA?

This treatment does not use CRISPR. It involves the hollowed out and repurposed lentivirus (similar in kind to HIV)[1]. The virus keeps it's own viral 'insert-into-DNA' machinery, but is stripped of its replication machinery as well as the code for its physical shell. The insert-into-DNA machinery is further hijacked so it can insert nothing but the DNA that encodes for the new mutated hemoglobin (HBB [T87Q][2]) that, when the patient's cell reads that new DNA will produce a new version of the protein. That insertion machinery with its new payload is loaded into a viral shell in a lab somewhere (again, its replication machinery and the code for new shells has been gutted).

When this new virus is given to the patients it does indeed infect the patients' cells. It uses its viral machinery to insert itself into the genome of the patient, more or less randomly - and that is not ideal. CRISPR systems are much newer and are being worked on right now, but the technologies you see in use in this article predate CRISPR. CRISPR will only speed up what was here a monumental (and slightly more risky) effort.

Regardless of how the code gets inserted into the genome (lentiviral in this case, CRISPR likely in future therapies), the instruction set to produce the new protein is not only capable of doing the job of the broken hemoglobin, but actually enables the broken hemoglobin to regain some of its function, likely coming very close to actually curing the patient.

In computer terms, someone with sickle-cell disease has a typo in the source code that leads to a buffer overflow error in the oxygen transport module. We found stuxnet can inject live code into a running OS, so we stripped it of its payload, it's ability to replicate but kept its injection capabilities and gave it our hot-fix as its payload. Our patch will be injected into billions of running nodes, inserting a ~500 line patch randomly into the each node's memory stack (yes, that's scary - but if a few of the nodes (cells) go down, it's not a horrible problem, and the current price of doing the patch at all... CRISPR can help here in future versions). That new code provides not only an alternative oxygen transport package, but this new package, so long as its running on >20% of the nodes, actually forces the original code's memory to periodically flush, thus de facto correcting the original typo's overflow bug - allowing both the new package and the old (kinda bug-fixed) package to both now be useful oxygen transport code. No more bug = cure.

The patients had a code regression, and we're applying not just a 1.0 fix, but a very real 1.1 patch on the human hemoglobin instruction set (randomly, into live code, on millions if not billions of cells, using modified HIV technology).

Diagram of the patch's entire injected instruction set (8.5kb): https://www.ncbi.nlm.nih.gov/core/lw/2.0/html/tileshop_pmc/t...

[1] Lentivirus: https://en.wikipedia.org/wiki/Lentivirus

[2] The 'updated' hemoglobin: https://serotiny.bio/notes/proteins/hbb/

Applying the patch directly on production, with no backups, too (!)

This was a great little writeup, and I appreciate you taking the time to make it.

Thank you for this brilliant and detailed explanation showing the differences between CRIPR and the virus method! I haven't seen anyone explain the concept of viruses in the language of buffer overflows! Delightful.

Thank you for applying this to a mental model I can relate to. If there was an equivalent of Reddit gold, I would give you one.

CRISPR is typically delivered via a lentivirus.

The lentivirus has a number of capabilities - insert into cell, insert into DNA, replicate payload, build capsid, encapsidate payload, escape cell. In this particular case the lentivirus was used both for it's 'insert into cell' as well as its 'insert into dna' capabilities - with all others being stripped.

CRISPR (more specifically, Cas9) is another protein machine that locates particular DNA sequences [1]. It can help take over from the lentivirus with respect to the 'insert into dna' capability. But you're right, we still have no better way to get it into the cell than to use a (lenti)-virus's own 'insert-into-cell' machinery. So a lentivirus might be used along with CRIPSR in order to just get CRISPR machinery into the cell.

This is further muddled by the fact that sometimes you actually want the dna that encodes for your CRISPR system to itself be inserted into the genome, and in that case you might keep both the lentivirus's 'insert-into-dna' machinery AND the CRISPR's own 'insert-into-dna' capability.

At the end of the day, lentivirus's capability to insert into DNA is not predictable, and therefore a bit dangerous (if it inserts its payload in the middle of an oncogene in a predisposed cell you could get cancer). CRISPR is a device which promises to bring specificity to the command, making it 'insert-into-dna-AT'. And in that way it could replace the job of lentivirus in the above gene editing technique.

[1] Cas9: https://serotiny.bio/notes/proteins/cas9/

here is the nejm paper in the article: http://www.nejm.org/doi/10.1056/NEJMoa1609677

Ultimately, they are delivering a payload with a slightly modified version of wild-type hemoglobin (a single point mutation from wild-type). Patients with sickle-cell disease have a (different) mutation in their hemoglobin that causes the hemoglobin protein to aggregate, and not carry oxygen. The modified version being delivered to patients is not just a 'corrected, wild-type' version of the protein capable of carrying oxygen more efficiently, but actually carries a synthetic mutation that actually prevents the patient's version from aggregating. So if even 20% of the hemoglobin in the treated patient's blood is of this modified type, then none of their hemoglobin will aggregate, and they should get much of their oxygen-carrying capacity back. This modification to the introduced version of the protein also allows it to be easily identified and tracked to monitor things like its concentration.

The actual sequence and mutation HBB [T87Q] protein: https://serotiny.bio/pinecone/part/10803

A short little writeup I did about the mutation: https://serotiny.bio/notes/proteins/hbb/

A very detailed presentation about Bluebird Bio's therapy (called LentiGlobin BB305) provided to the government: (PDF warning) http://osp.od.nih.gov/sites/default/files/1164_bluebirdbio.p...

"He no longer requires a transfusion so we are quite pleased with that"

I like that language so much more than, than the increasing THIS IS AMAZING, SO AWESOME, WHAT WE GREAT GUYS ACCOMPLISHED!!! even though it would fit here much more, than in the usual context people use it fore ...

I don't think I have ever seen medical professionals speak in the manner you described.

I did not say that, I was talking about other tech branches, startup hype speak etc.

Aha my mistake.

Would this apply to thalassemia too?

Total noob here, is this type of treatment going in the direction of something like in the movie gattaca? Would gene editing also help fully grown adults?

If they have an identifiable deficiency, sure. Sickle cell is a stem cell (erythroblast more precisely) disorder, so fixing the stem cells fixes the disease. If you already have the tissues you want to change, it'll be harder.

Real life gattaca would be quite boring. Protagonist would have failed practical aptitude tests or some such.

He cheated. He had a heart condition but faked his heart rate for the testing so he would be allowed to go into space.

Yes, he could run at the same pace as someone with a better heart, but he was predisposed to arrhythmias even at a normal level of effort.

What an amazing achievement. Finally, the promise of genetic therapy is starting to actually emerge from the lab.

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