
Teenager's sickle cell reversed using a treatment to change his DNA - _nh_
http://www.bbc.com/news/health-39142971
======
Symmetry
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](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.

~~~
ralfd
> 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.

~~~
true_religion
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.

------
criddell
Will this change potentially be transmitted to his children?

~~~
quotemstr
Unfortunately, human germline modification is still taboo here:
[https://motherboard.vice.com/en_us/article/scientists-
argue-...](https://motherboard.vice.com/en_us/article/scientists-argue-the-us-
ban-on-human-gene-editing-will-leave-it-behind)

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

~~~
Moshe_Silnorin
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](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.

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

~~~
Moshe_Silnorin
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.

~~~
texthompson
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?

~~~
stavrus
This might particularly interest you:
[http://www.lettersofnote.com/2012/08/why-explore-
space.html](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?

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

~~~
jfarlow
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...](https://www.ncbi.nlm.nih.gov/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Click%20on%20image%20to%20zoom&p=PMC3&id=4779296_fig-3.jpg)

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

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

~~~
splike
CRISPR is typically delivered via a lentivirus.

~~~
jfarlow
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/](https://serotiny.bio/notes/proteins/cas9/)

------
danielmorozoff
here is the nejm paper in the article:
[http://www.nejm.org/doi/10.1056/NEJMoa1609677](http://www.nejm.org/doi/10.1056/NEJMoa1609677)

~~~
jfarlow
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](https://serotiny.bio/pinecone/part/10803)

A short little writeup I did about the mutation:
[https://serotiny.bio/notes/proteins/hbb/](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...](http://osp.od.nih.gov/sites/default/files/1164_bluebirdbio.pdf)

------
hutzlibu
"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 ...

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

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

~~~
Waterluvian
Aha my mistake.

------
beerbaron23
Would this apply to thalassemia too?

------
aptidude187
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?

~~~
red75prime
Real life gattaca would be quite boring. Protagonist would have failed
practical aptitude tests or some such.

~~~
true_religion
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.

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

