
The Heroes of CRISPR - jseliger
http://www.cell.com/cell/fulltext/S0092-8674(15)01705-5
======
a_bonobo
Comments on PubPeer are very negative about the undisclosed conflict of
interest of OP's author:

[https://pubpeer.com/publications/D400145518C0A557E9A79F7BB20...](https://pubpeer.com/publications/D400145518C0A557E9A79F7BB20294#fb44022)

~~~
skosuri
According to cell, he did disclose it and they chose not to use it because he
didn't have a personal financial stake [1]. As a note, Doudna's review also
had no conflict of interest despite her personal stake.

1\.
[https://twitter.com/stephenfloor/status/688466159021064192](https://twitter.com/stephenfloor/status/688466159021064192)

~~~
Gatsky
Doudna's article is a typical scientific review written by someone intimately
involved in the research. She doesn't try to teach 'important lessons', or
outline the history of CRISPR, nor does she draw on unquoted 'personal
interviews and other materials'. Everything is referenced, you can go and read
each paper she cites. You can also compare her review to countless others
written by her colleagues and patent opponents. Scientific reviews are
invariably invited by the journal, with authors chosen based on their research
interests and scientific output.

Lander's article is a completely different beast. I highly doubt Cell cold
called Eric Lander and asked him to write a campfire history of CRISPR.

It is clear the Cell has a liberal COI policy in any case. I can't find COI
mentioned anywhere, even to say that there aren't any.

~~~
skosuri
But reviews at Cell are academic papers; they are peer reviewed. Doudna has
direct financial conflicts, it should have been disclosed. The viewpoints are
usually solicited and not peer reviewed (at least ones I've been involved
with), and are often meant to have an individual's biased and perhaps
provocative viewpoint. Regardless, I think most of the COI argument is a
little silly. None of these folks are particularly motivated by the money.

------
mortenjorck

      Finally, the narrative underscores that scientific 
      breakthroughs are rarely eureka moments. They are typically 
      ensemble acts, played out over a decade or more, in which 
      the cast becomes part of something greater than what any 
      one of them could do alone.
    

An excellent closing paragraph. Even if the majority of the technical concepts
in this paper were beyond my grasp, I did take this much away from it.

------
perugolate
This is as partisan as inviting emperor palpatine to write a historical
perspective to fill in the back story of the fall of the republic and the rise
of the empire.

------
jallmann
Really great article, especially for someone like me who only has a layman's
understanding of the biology involved. Thinking out loud:

In computer science terms, the method scientists use to discover and
characterize genes (CRISPR, etc) seems akin to studying the assembly of a
program, occasionally splicing chunks of assembly into other programs, and
observing changes in the output after running. This sounds like a huge slog,
and it is amazing that the method works.

One interesting thing from the article was that, even after determining the
function of CRISPR, scientists still had difficulty in understanding the
mechanical/chemical means of its behavior: the gene is a black box, and its
expression can only be deduced when observing its effects after running.

Have there been attempts to characterize genes on a more basic level, eg by
modelling how a given nucleotide sequence encodes a protein, and deducing its
function from there? Is our understanding of protein folding still inadequate?
Or would reconstructing a protein's physical structure still not give us
enough insight into its intended function?

~~~
reasonattlm
Evolution produces promiscuous reuse of component parts, and everything is
linked to everything else: a cell is a bag of interacting feedback loops in
solution. At a detail level, researchers still only have a sketch of the high
points of cellular biochemistry. Any particular protein may have numerous
roles, and scientists continue to uncover new important roles for even very
well known proteins, those studied heavily for decades in some cases.

Modeling is prevalent and helps. Deducing function with any accuracy requires
much better and more comprehensive models of cellular biochemistry, however.
Those models lie decades of work from here, meaning that altering genes and
watching the outcome in mammalian cells and individuals will be the primary
mode of exploration and validation for a while yet.

------
reasonattlm
So it is today technically possible to run a gene therapy in adult humans via
CRISPR and some recent innovations in vectors with a good expectation that
tissue coverage is going to be what you want it to be - i.e. enough cells take
up changes for it to work. (See for example
[http://today.duke.edu/2015/12/crisprmousedmd](http://today.duke.edu/2015/12/crisprmousedmd)
for the good tissue coverage angle).

This is going to be next year's medical tourism, analogous to the progression
of stem cell therapies from the turn of the century.

There are a few really obvious candidates, such as myostatin and follistatin
to greatly increase muscle growth - and at least one person who has had that
done already, c.f. BioViva. To do this all you need are the connections. Buy
into a biotech startup company, make the arrangement with a lab in Mexico or
Thailand and off you go. If you knew the right people, you could be on a plane
tomorrow and the beneficiary of elective gene therapy the day afterwards.

It can't be overstated how easy CRISPR makes this. It is easier even than
induced pluripotency, and that spread like wildfire through the labs when it
emerged.

The more interesting thing to me is that there are probably a hundred less
obvious, poorly studied, poorly followed up, but very interesting genetic
alterations that could be done, and probably will be done largely outside the
institutions of medical research. This is what happens when cost falls. Any
single gene is fair game now. Want great resistance to ischemia/reperfusion
injuries? Knock out PHD1 [1]. Want your aged liver to function as well as it
did when you were young? Add more lysosomal receptors. [2] Want to have
permanent operation of the benefits of fasting and exercise in the form of
upregulated autophagy? Increase AMPK levels [3]. And so on and so forth
through scores of genes. Maybe many of them will work as the studies suggest,
maybe not.

[1]: [http://www.vib.be/en/news/Pages/-VIB-researchers-discover-
po...](http://www.vib.be/en/news/Pages/-VIB-researchers-discover-possible-
strategy-against-stroke.aspx)

[2]:
[http://www.nytimes.com/2009/10/06/science/06cell.html](http://www.nytimes.com/2009/10/06/science/06cell.html)

[3]: [http://www.salk.edu/news-release/how-the-cells-power-
station...](http://www.salk.edu/news-release/how-the-cells-power-station-
survives-attacks/)

------
ericb
It seems like one thing that CRISPR brings to the table is find and replace,
or find and delete.

As a layman, this would seem ideal for treating any sort of cancer... Just
find the distinct sequences and delete?

What bad news do I not (yet) know that makes it much tougher than I'm hoping?

~~~
a_bonobo
Sadly, cancer goes way beyond some broken DNA, in cancer cells you have
polyploidy = several chromosome copies, these copies break up in weird ways so
that some chromosomes are joined to others and other random mixing, you can't
fix that using CRISPR

You could, however, identify regions of DNA which make your cells more
susceptible to the transformation, but CRISPR is still more unstable than the
OP makes you think - in the highly debated human CRISPR experiment (using an
older protocol) the scientists started with 86 embryos, of which 71 survived,
of which only "a fraction" was successfully transformed, and in another
fraction of that the proper target was hit but only in mosaics (with non-
transformed cells remaining), in the remaining successful transformed cells
the new DNA was inserted in the wrong position (potentially creating a new
disease). See Carl Zimmer's take here:
[http://phenomena.nationalgeographic.com/2015/04/22/editing-h...](http://phenomena.nationalgeographic.com/2015/04/22/editing-
human-embryos-so-this-happened/) There's a lot of hype which IMHO damages the
technology, it's much more finicky than it's usually presented

~~~
jamescostian
Another thing to consider is that one could use CRISPR to make lives worse.

What if someone gave Michelle Obama a very high chance of breast or ovarian
cancer by giving her BRCA1 or BRCA2[0]? What if a dictator's competition got
sickle-cell anemia all of a sudden, or lost their sickle-cell anemia before
their trip to a malaria zone (which is also bad[1])?

[0]
[http://www.ncbi.nlm.nih.gov/pubmed/12677558](http://www.ncbi.nlm.nih.gov/pubmed/12677558)

[1]
[http://www.cdc.gov/malaria/about/biology/sickle_cell.html](http://www.cdc.gov/malaria/about/biology/sickle_cell.html)

~~~
icegreentea
If you could manage to give someone gene therapy, they're already screwed.

Consider that the only reasonable mechanisms for gene therapy on grown animals
is to infect them with a virus (or something similar). If you can infect
someone with a virus, they're already dead.

~~~
Ultimatt
Sure but altering their genome subtly so that it appears natural it becomes
impossible to police as the murderer is very far removed from the murder.

------
Gatsky
Anyone that thinks this is a great article should read below, where the
'heroes' themselves say there are factual errors that were either not checked
or not corrected. Lander really dropped the ball with this one.

[http://www.the-
scientist.com/?articles.view/articleNo/45119/...](http://www.the-
scientist.com/?articles.view/articleNo/45119/title/-Heroes-of-CRISPR--
Disputed/)

------
peter303
I guess with all these contributions, where do you draw the line for the
inevitable Nobel Prize? When these structures were first discovered? Or when
some could use them for genevediting?

~~~
skosuri
Possibly both. Either way, tons of people always get left out.

------
Gatsky
First of all, why is a Lander writing this? What qualifies him to reconstruct
the history of CRISPR? He doesn't do CRISPR research. Historical reviews are
always written by the people that actually did the research because A) who
else really knows what happened and B) we are interested in their perspective.
So Lander's qualification is what exactly? That he's an important person who
knows what DNA is?

The article itself also absolutely stinks. First an ad hoc justification why
this article is important consisting of nothing more than platitudes about
science, then evocative descriptions of the weather in Santa Pola,
progressively more brief descriptions of other sicentists' work followed by a
long section at the end which could be a slightly edited version of the
closing remarks from the Broad Institute's patent attorney in their dispute
against the other CRISPR developers.

This in particular, stinks:

"The history also illustrates the growing role in biology of “hypothesis-free”
discovery based on big data. The discovery of the CRISPR loci, their
biological function, and the tracrRNA all emerged not from wet-bench
experiments but from open-ended bioinformatic exploration of large-scale,
often public, genomic datasets. “Hypothesis-driven” science of course remains
essential, but the 21st century will see an increasing partnership between
these two approaches."

What 'growing role'? Biology has always been largely hypothesis-free. Which
hypothesis was being tested when DNA was discovered? They were trying to fit a
model to the data, not testing out their ideas about how DNA should look.
Penicillin was discovered by accident, where was the hypothesis there? And the
importance of bioinformatic exploration? How does this: "Using his word
processor, Mojica painstakingly extracted each spacer and inserted it into the
BLAST program to search for similarity with any other known DNA sequence"
support the importance of bioinformatics? Manually pasting 4500 sequences into
BLAST? Surely this is an example of progress DESPITE any substantial
bioinformatics.

I can't see why this was written except to further the agenda of the author
and his institute, and to color history to support their legal claims. I can't
see how this was published except through nepotism, eminence based science and
the kind of shameful arrogance and entitlement that only academics have the
luxury to cultivate. Maybe Lander thought he was setting the record straight,
but that isn't his privilege.

~~~
skosuri
Wow, This is a lot of anger. I for one appreciated the viewpoint (taken with
an eye that it is his view). Anyways, for what it's worth, Lander's lab has
done a bunch with CRISPR's so your initial premise is flat out wrong [eg.,
[http://www.ncbi.nlm.nih.gov/m/pubmed/24336569/](http://www.ncbi.nlm.nih.gov/m/pubmed/24336569/)
]. Second, I remember when they figured out that they were targeting phage. I
was working with some Cyanobacteria that had a bunch of crispr loci as well. I
do remember distinctly it being one of the first times that a whole new bio
came from large part from informatics. (Another being lncRNA ultra conserved
elements). Anyways, I really don't get the viciousness of this response.

~~~
Gatsky
"Lander's lab has done a bunch with CRISPR's"

[http://www.ncbi.nlm.nih.gov/pubmed/?term=CRISPR+AND+Lander+E...](http://www.ncbi.nlm.nih.gov/pubmed/?term=CRISPR+AND+Lander+ES%5BAuthor%5D)

There are 5 citations. 2 are reviews. 2 are original research: one in Jan
2014, another in Nov 2015.

A similar search for Jennifer Doudna reveals 44. Feng Zhang has 43. Maybe he's
been doing years of CRISPR work in secret, but I don't think my premise is
'flat out wrong' \- he isn't the person to write the definitive history of
CRISPR.

Second - the human genome project is surely the key example of an entire field
that could not have been birthed without informatics - Celera genomics doing
the shotgun assembly showed everyone how important it was beyond a doubt. This
all happened in 2000. Lander is saying this isn't enough to convince us all
how important bioinformatics is. In 2016, when bioinformatics is so
ubiquitous, he finds the need to cite Mojica copy pasting 4500 sequences
manually from microsoft word into a BLAST search in 2003 as another seminal
example to make sure we all get it? This doesn't strike you as even a little
disingenuous or ad hoc?

I guess we have different ideas about how problematic it is if someone tries
to rewrite history while it's still happening.

~~~
skosuri
1\. You said, "He doesn't do CRISPR research." If you are going ad hominim,
it's usually better if you get your facts right.

2\. FWIW, I think you are largely rewriting history by your comment. The
dominant feeling I remember about the HGP at the time was that it wasn't worth
it and we didn't learn any new bio. This feeling is still widespread... And
biology has always been "hypothesis free"??? Really? Anyways, both of these
points were largely ancillary imo to the early history of the field that I
thought was an interesting viewpoint.

~~~
Gatsky
We're just two guys arguing on the internet now, but here we go again.

1\. To me, just having your name on a paper does not equal 'doing research in
the field'. In the cases of these 2 papers, he is neither the senior author,
nor does the first author come from his lab. He doesn't actually cite any of
his own papers in the review, after all.

2\. I'm not rewriting history because I'm talking about what people think
about bioinformatics in the present because of the human genome project.
Lander's point is that CRISPR informs our opinion about bioinformatics today,
and I'm disagreeing this is a valid point etc etc see above. I agree with you
that at the time HGP happened the reaction was lukewarm. But whatever you want
to say about the impact on humanity, it is indisputable that the HGP has
enabled so much science that relies on bioinformatics, and elevated
bioinformatics to a key part of modern life science.

Not going to get into the hypothesis free argument here, but the issue is
essentially that in biology it is often impossible to specify all the
necessary details of the model you are hypothesising about, which means that
hypotheses have poor generalisability and reproducibility. This means that any
progress we make isn't by virtue of falsifying hypotheses, but more by
observation and investigation of phenomena which may have been observed by
chance. Just the act of making a hypothesis does not make a science
'hypothesis driven' \- those hypotheses actually need to contribute in a
material fashion to the accumulation of knowledge or more importantly,
insight.

------
Moshe_Silnorin
The patent thicket surrounding it is looking quite daunting, which I find
mildly enraging. However, I have mixed feeling on biotechnology. Weaponized
biotechnology looks to be getting disturbingly cheap; maybe these absurd
government-granted monopolies will do some good in slowing this down.

~~~
api
Terrorists aren't going to balk at patent infringement.

