Now that we've made economical the tools to sequence, search, and have some understanding of an organism's genome, we're reaping fast rewards in learning what the natural world is actually capable of in terms of astounding feats of nano-engineering. There's a massive nanotechnology textbook in our ecosystem's genomes that's a few orders of magnitude more impressive than our best semiconductor patents.
The CRISPR system here was discovered in a single-celled organism that likes brine water - a tool it used to intercept hijackers. The 'standard' Cas9 that is being used extensively in the rest of the CRIPSR stories comes from the bacteria that causes strep throat. Studies are now mining the genomes of organisms found in 'mud pits' and 'pond scum' to find all sorts of smaller, faster, more efficient variants of Cas9. And that's just for the single purpose of editing a genome.
The capabilities of proteins found (off the top of my head) in jellyfish, in sulfur springs, in colored algae, in electric eels, in little pond creatures, in HIV, in waterbears, etc. are all depositing huge amounts of technology into our collective knowledgebank. We have been given a store of 'alien' technologies to sift through that are applicable in every condition to be found on Earth, literally. The cures to many of our ills will not be engineered from scratch, but rather will be adapted from existing technologies found in extant organisms literally scattered across the globe.
This is how 'basic science' works. A magnanimous scientist is curious how a little cell can survive in really salty water, and owing to his curiosity we discover a nanotechnology that can edit an organism's genome. We humans are smart - but not yet that smart.
Which is also a reason we should stop destroying the environment. There is a wealth of knowledge out there we have yet to acquire. If you ran a deep-learning algorithm using an entire planet for 3 billion years, the results would be considered invaluable. Well what is natural selection and evolution but that?
If in a sci-fi novel an alien handed a character their 'magic rock' (iPhone) and they smelted it for its gold content rather than reverse-engineered it's wireless charging, communication, and computation capabilities you would scream at the character for being horribly short-sighted. Such a waste of sophisticated technology laid right in front of them for such little temporary gain.
Why can't we do both . At least smelting until we have enough energy to reverse engineer and then keep smelting space rocks. I think that's actually what we are doing, birds eye view.
Once a species is gone it is gone. Lots and lots of species disappear now and many of them we are not even aware about, let alone any DNA samples taken or research done (e.g. burn down rainforest). So you can't "have both".
> If you ran a deep-learning algorithm using an entire planet for 3 billion years, the results would be considered invaluable. Well what is natural selection and evolution but that?
>The capabilities of proteins found (off the top of my head) in jellyfish
Flashbacks to that "Can a protein originally found in jellyfish improve your memory? Our scientists say yes!" commercial I've heard a million times without even setting out to watch TV. I was skeptical at the time, but I guess this means such a thing is at least in the realm of theoretically possible.
Edit: turns out that specific thing was still illegitimate anyway.
I agree, it is extremely short sighted to gut any program that does not produce returns (value defined by a single metric) based on an arbitrary time scale of quarterly reports.
Even endowment for the arts can produce significant impact on how we think and use technology.
Understand, just understand, understand how something works, what makes it tick, in biology, chemistry, physics, mathematics, the economy, etc., just, darn it, UNDERSTAND ....
As we know well from experience and might expect, just understand
is nearly necessary for a huge fraction of fantastic progress and often sufficient or nearly so. The track record is the best of any allocation of resources.
Or toss some rocks into the camp fire and in the morning find some clump at the bottom. Then, try to UNDERSTAND that? That clump is different; what the heck is it? This was the first time saw this; what caused it? Can do that again?
Okay, just used the carbon in the fire to remove the oxygen from copper oxide and leave some copper metal. Start of exploitation of metals for humans ....
"We are the world’s leading packager of patent pools for standards and other technology platforms used in consumer electronics, as well as chemical, eCommerce, education, energy, environment, healthcare and biotechnology, manufacturing and materials, transportation and wireless technology. We developed the pool market space. (view link) Our business model supports a large number of patent users – creating reasonable access and profitable opportunities for all parties."
This feels like the MPEG-LA is realizing that patent pools for video codecs are a short-lived industry and trying to figure out how they can extend their tendrils into something for another 20 years.
MPEG LA, LLC is a firm based in Denver, Colorado that licenses patent pools covering essential patents required[1][2] for use of the MPEG-2,[3] MPEG-4 Visual (Part 2), IEEE 1394, VC-1, ATSC, MVC, MPEG-2 Systems, AVC/H.264 and HEVC standards.
MPEG LA is not affiliated with MPEG, the Moving Picture Experts Group.
Doesn't that mean MPEG LA is affiliated with MPEG?
MPEG creates the MPEG codec standards, MPEG LA is a separate organisation that exists to sell patent licences required to actually implement the MPEG standards. They don't particularly need to be affiliated.
MPEG LA, however, would like you to believe that, seeing as LA is (or at least, was) an abbreviation of Licensing Authority -- something they clearly aren't.
Can somebody explain what exactly the problem is with this? Did they not have a hand in any of the research? Do they provide a genuinely useful service yes/no?
MPEG LA is a for profit firm that has historically specialized in getting huge corporations in a room, the patents surrounding a technology all of them need, and getting them to agree on a standard code to be licensed to everyone: Apple, Cisco, Dolby, Fujitsu, HP, Hitachi, MS, NTT, Panasonic, Samsung, Sony, etc.
They have no biomedical or biochemical expertise. They have no hand whatsoever in discovering or understanding any science at all. It now appears as though they would like to try to get another group of mega-companies in a room to cross license their patents on Cas9 variants - there are as many (natural) variants as there are bacteria out there, and there are a combinatorially large number of synthetic variants on top of those. The Berkeley/MIT faceoff you've likely heard about in the news is over a very broad patent on using Cas9 therapeutically, but the space of natural Cas9 variants is actually broader still than even that patent could cover.
We as a country need to have a conversation about patents and how the policies that work for computer code may not be the same policies that work for small molecules, which may not be the same processes that work for genetically encoded materials. Each of those technologies are all extreme in terms of the cost of R&D, verifiability, producibility, reproducibilty, and longevity. It is difficult to shoehorn each of these technologies into the same patent framework.
"MPEG LA is a for profit firm that has historically specialized in getting huge corporations in a room, the patents surrounding a technology all of them need, and getting them to agree on a standard code to be licensed to everyone: Apple, Cisco, Dolby, Fujitsu, HP, Hitachi, MS, NTT, Panasonic, Samsung, Sony, etc.
"
That's very kind.
They also historically have done everything they can to keep the pool alive by evergreening it, and allowing companies to evergreen it.
They also have done pretty much everything they aren't supposed to since the original BRL the DOJ sent (https://www.justice.gov/atr/response-trustees-columbia-unive...)
"We as a country need to have a conversation about patents..."
People keep saying this about whole host of issues, and it makes me wonder if that's ever happened about anything. Have Americans ever "had a conversation" about any issue and decided anything collectively like that?
They want to earn money, nothing more. No knowledge is gained, no wisdom is earned here. Just plain old money interests at work.
Some call it capitalism, i call it greed.
Such organizations free up people like Jennifer Doudna to spend time in their labs (i.e., their area of expertise) rather than spending time sitting in meetings with lawyers and similar krill from companies that want to license the technology.
CRISPR, Gene Drive, and IPSC biotech is incredible.
Right now I'm killing time until my residency starts and I've been reading recent journal articles relating to each of these.
One of the weirder journal articles I read was about this one group taking fibroblasts from XX and XO (Turner's syndrome) females and XY cells from a male and de-differntiating them into induced pluripotent stem cells. They then re-differentiated the cells into germ cells. Sure, that's not controversial just yet, but then they decided to put the XX female germ cells into a teste. The female germ cells (XX and XO) and the male XY cells all differentiated into cells that could succesfully undergo meiosis. And these cells, could terminally become sperm. That means an XX skin cell could be induced to become a sperm and possibly fertilize an egg from another woman. Of course all offspring would be XX female. This process totally bypasses males.
Anyways, very interesting to me, maybe it will be to others. Here's the journal article.
I know this article I'm posting under is about CRISPR, but I feel like new/controversial biology research could be posted here too. Hopefully anyone reading gets the same feeling of discovery/wonder/incredulity that I had when reading about it.
I didn't read the paper but it's in scientific reports (minimal and rushed peer review, bottom of the barrel nature subjournal)...I'd be a bit skeptical.
It's not exactly anyone's first choice place to publish.
Crispr/Cas9 is not as robust as people make it out to be, but it's promising. (I do some work with crispr/cas9)
It's not the only paper I read regarding IPSC and germ cell induction. The Yamanaka paper has been out since 2007, this kind of work is well established. But, this paper is the only one I can find that has researchers attempting to make sperm from a female. There are other papers regarding iPSCs induced to become female germ cells to oocytes and then IVF producing viable offspring, in mouse, pig, and monkey.
> Crispr/Cas9 is not as robust as people make it out to be, but it's promising. (I do some work with crispr/cas9)
Please expand on this. I feel like CRISPR is being overhyped, and would love to hear form someone educated on the subject as to what its possible limitations are, or at least some of the known challenges ahead.
Cas9 is a protein with two functions: 1) locate a DNA sequence that matches the little RNA it grabs ahold of, and 2) cut that DNA at that location. The first of those functions, it's ability to locate particular and arbitrary sequences, is its comparative advantage against all other technologies we know of. The second, cutting DNA, well, works I guess, but will likely be engineered to be more useful, or turned off in order to make way for other more useful functions.
The protein is special for two different reasons: 1) it is able to locate DNA sequences with very high precision 2) and the sequence it locates can be swapped out as easily as changing the sequence of the RNA it grabs ahold of (trivial to do, can be done in a day, and can cost >$1 per target sequence to swap). Note, it is not special because it can cut DNA - there are lots of proteins that do that, and there are lots of better ways to change or alter DNA once you get to a particular sequence - but Cas9 was originally a self-defense mechanism, so it's evolutionary function in strep throat bacteria was to kill invaders by dicing up their DNA (at particular sequences that strep throat doesn't have).
Cas9 is powerful because it could be used to direct any function at a particular DNA sequence, where the sequence can be altered in the lab quickly and cheaply. As it is a protein encoded by a particular sequence, you can fuse it to other proteins with other functions to build a more powerful machine. (see [1] if you want to play with those sequences yourself.) As an experimental tool it will likely become a foundational tool used all throughout molecular biology - and for that alone is is worth it's fame. Thermophilic polymerase used in PCR is another such tool. As are restriction enzymes. As is GFP. That's the scientist's perspective.
However, Cas9 also previews the capability of directly and arbitrarily editing of a genome - a holy grail of biomedical sciences. Though unengineered Cas9 it's not great at editing a genome (we're not entirely sure why what it does even works) - but some 2-10% of the time it can actually edit a genome with fidelity. And that's good enough for many experiments (though not good enough for therapies). It has off-target cuts, and when it cuts it slices all the way through the double stranded DNA, and if it isn't properly stitched back together you have a broken chromosome. And getting payload DNA to the site that Cas9 cut is still really tricky. It's also a multi-part system (it needs it's little RNA as well as the protein itself), and so it's hard to deliver directly as a therapeutic. So the wild-type Cas9 is likely limited in its direct therapeutic relevance in terms of pure genome editing. But it will be used extensively for its ability to 1) further research quickly and cheaply, 2) prototype what genomic changes would do if they were successful (when you only need 10% efficacy to conduct a study), and 3) act as an engineering platform upon which other functions can be placed, and its own wild-type limitations can be overcome.
It's powerful. It's not perfect, there's lots more engineering to do with/to it. It's not going to get to the holy grail of genome editing all on its own, but it's a very solid platform to start building off of, as well as simply being a solid tool that will become a workhorse of further synthetic biology.
What organisms are you working with? I've known several groups that have had problems recovering heterozygotes because CRISPR-Cas transformation is so efficient in plants.
If it was just 2-10 percent, everyone would still be using Agro.
>"Though unengineered Cas9 it's not great at editing a genome (we're not entirely sure why what it does even works) - but some 2-10% of the time it can actually edit a genome with fidelity."
Can you expand on the part I italicized, preferably also linking to some journal articles?
Cas9 finds, then cuts both strands of DNA. Now you have to flat edges of a braid you must rejoin. This is called Non-homologous end-joining of DNA (NHEJ). The recognition, repair, fidelity, and correct repair during NHEJ is not well understood. Cas9 does no joining, no ligation, no pasting, it only does the snipping. The joining is done 'on it's own' by the cell at some rate, sometimes correctly, sometimes even uptaking an insert into the process. So insofar as Cas9 is doing any 'editing', the repair process is entirely an accidental after-effect of Cas9's targeted DNA breakage.
I quickly looked through your links. The first article you link seems to lack any control group (which we need to assess the proportion of pre-existing mutant cells), the second is primary research but does not mention CRISPR-Cas9, and the other two are review articles that don't contain any quantitative data.
As mentioned, I only looked quickly, but I do not think any will be helpful on the point I am bringing up. Let me know if I missed it.
Frequency of survival is shown in table 2... it ranges from 5/1,000 to 1/100,000. So cell death is a 200-100,000 times more common result than NHEJ using those methods. I have no idea how well that would correspond to the conditions we are interested here, but see no way this paper can be taken to support NHEJ is a more likely result than cell death.
It also says:
"Yeasts, like other eucaryotes, exhibit cell cycle arrest in
response to DNA damage (17)."
Right, so you are just saying no one really understands how NHEJ works at this point.
Have you considered that mechanism (NHEJ) is not even necessary to explain the rise in proportion of mutant cells after the CRISPR-Cas9 treatment? Because while it may happen to some extent, I do not think that is the simplest explanation for what I have seen reported.
I've been thinking this for awhile now, but never bothered to really write it up and keep track... you can check the discussion here (there are some other posts about CRISPR-Cas9 strewn about that thread as well):
https://news.ycombinator.com/item?id=14014098
I have really only read papers other people bring up in conversations online or that get media coverage I come across on this topic. But every single paper I looked into has reported results that fit my explanation just as well as , or even better than, the NHEJ one, and this has been a couple years now...
As far as investor understanding goes the hype is probably under selling the importance of CRISPR. Because it makes lots of functionality reliable, cheap and much simpler. Even if it did nothing novel at all that would be important enough.
the end of men indeed :) as if being automated out of relevance was not enough soon you can take your sperm with you as you retire to the "manly hills"...interesting times ahead.
Did you know that fetal viability outside of the womb now starts right after 21 weeks (although with a currently still low chance of survival)? At some point science will probably start figuring out the mechanics of gestation and - eventually - synthesise the whole process, at which point you could call it 'the end of woman' as well. What's left then? Maybe "The Matrix" was quite realistic, only, we're building it ourselves.
Well the only clinically significant scenario I can think for this kind of thing is for homosexual partners to reproduce with 50% of the genetic material coming from each partner. Right now one partner contributes 50% of the genetic material and the other partner doesn't get to contribute anything.
And creating perfect humans and cloning them in artificial wombs sounds beyond the scope of science at this point. The paper I posted could lead to offspring now (viable or perhaps so epigenetically modified they are doomed -although a germ cell undergoes some demodification in the ovary's environment).
It wasn't supposed to be an alternative future for humans (such as perfect humans), although I could see a total female society having less anti-social personality disorders and less violent crime.
If that actually does happen. Do it in conjunction with backing up the brain. Thus achieving true immortality.
Have bodies that are engineered to live forever, but accidents abound. Should anything happen to you, they'll re-clone you and restore the last brain backup.
Like the cylons did in Battlestar Galactica.
Imagine living for 10s of thousands of years and the only way to truly die is for your genetic material to be disposed of and the backups wiped.
If tech like that were available. I'd happily sign up. Travel the stars and explore the unknown!
Do humans have the same low level immune system bacteria have? It seems like passing immunity between generations would be extremely unlikely, but it could still be useful for offering some immunity to viruses that one has already had.
Would it be possible to introduce a genetic template from a viral disease into an embryo to produce a human essentially immune to that virus?
CRISPR is a solution to just retroviruses. Bacteria through phages actually come under more attack than humans in this way. If you've got a single cell for the next generation you care a lot about this. Humans any old crap can happen to litterally trillions of cells without affecting the germ line. CRISPR itself has capacity to introduce damage to the genome.
So its a balance between error correction and error introduction. In Bacteria its worth it, in humans not so much, especially as we have a bunch of other subtler more complex ways of handling viruses before they get all the way to the nucleus https://en.wikipedia.org/wiki/RNA_interference Bacteria dont have this luxury as their DNA lacks this extra barrier. The biggest difference is simply cells dont matter in a human and can just kill themselves if all else fails.
The rest of the "innate" immune system has similar proteins involved nearly everywhere e.g. https://en.wikipedia.org/wiki/Toll-like_receptor These are the components involved in cell surface recognition of sugars. But much more similar between all animals than animals and bacteria.
Answer to your second question is yes you could add a CRISPR construct with templates for known disease and add artificial immunity. However, finessing this so that CRISPR doesnt cause lots of damage from randomly cutting your DNA throught your life leading to a higher risk of systemic cancers... is a big hurdle.
There is something in humans called Dicer - which is an enzyme that uses RNA to cause RNA interference. It has a role in destruction of viruses that use RNA. Here's a short wiki about it.
This paper claims to have found RNA interference in mammals (https://cl.ly/jq5X). This paper is an attempt to refute the first paper (https://cl.ly/jq5T).
The crux of the debate is that mammals have the interferon system to respond to viruses, so why would they have kept around a system like CRISPR?
The CRISPR system here was discovered in a single-celled organism that likes brine water - a tool it used to intercept hijackers. The 'standard' Cas9 that is being used extensively in the rest of the CRIPSR stories comes from the bacteria that causes strep throat. Studies are now mining the genomes of organisms found in 'mud pits' and 'pond scum' to find all sorts of smaller, faster, more efficient variants of Cas9. And that's just for the single purpose of editing a genome.
The capabilities of proteins found (off the top of my head) in jellyfish, in sulfur springs, in colored algae, in electric eels, in little pond creatures, in HIV, in waterbears, etc. are all depositing huge amounts of technology into our collective knowledgebank. We have been given a store of 'alien' technologies to sift through that are applicable in every condition to be found on Earth, literally. The cures to many of our ills will not be engineered from scratch, but rather will be adapted from existing technologies found in extant organisms literally scattered across the globe. This is how 'basic science' works. A magnanimous scientist is curious how a little cell can survive in really salty water, and owing to his curiosity we discover a nanotechnology that can edit an organism's genome. We humans are smart - but not yet that smart.
(some of those protein technologies we like to talk about here on HN: https://serotiny.bio/notes/proteins/ )