She worked on this technology for years, developing it from it's infancy to in vitro proof. MIT scientists swooped in and within 2 months applied it in-vivo and patented it.
I guess to be rewarded in science you have to be a master in your field and intensely concerned with IP deadlines.
It's really a shame that Berkeley loses licensing on a tech that was 95% developed at Berkeley.
I'm one of those who wonder if these things should be patented.
That being said:
"Swoop in and patented it" is not exactly how it goes. There is a long back story to this with a lot of people discoing stuff to make this possible.[1]
You can watch a video by Zheng (the patent holder) on how CRISPR works if you are curious[2]
I doubt she's livid, they won a lot of research prize money from their research [2]
and she's probably collect money from patents from the company she started with the patent holder "Editas Medicine. Co-founded by the Broad’s Zhang (and also by Doudna, in more collegial days)"[2]
as with most patent disputes the lawyers are the real winners:
"The Broad’s legal costs, paid by Editas, topped $15 million last summer. UC’s, paid by Caribou, have passed $5 million. Neither party has said what they have spent since then."[2]
The article, written by Eric Lander of the Broad Institute, was widely criticized[1][2][...] at its publication for being a veiled attempt to reframe history to support the Broad Institute's patent claims. Note a number of their framing decisions - choosing to group Doudna et. al.'s contributions as #4 in a long list and setting Zheng's contribution by itself in a different color. Seems innocuous when skimming over it, but the choice of what to emphasize and categorize is not objectively deterministic, and this particular framing and coloring was no doubt chosen deliberately. Many think there was purposeful deception behind that deliberate choice.
I don't really have a horse in this race, but I am new to working in the Biology field. I will say that biology seems to depend on the work of many people and is kind of incremental. Its weird that some are getting rich and lots of credit, while a lot of the researchers work in obscurity. That was my take away from the Cell article.
Your first article was a good critique of the Cell article.
The second one was a little hard to take seriously first[1] (plus written by someone from the other side of the dispute), though he does come around to my original point in my original post: "And, as I have long argued, I believe that neither Berkeley nor MIT should have patents on CRISPR, since it is a disservice to science and the public for academic scientists to ever claim intellectual property in their work."
[1]"Lander’s recent essay in Cell entitled “The Heroes of CRISPR” is his masterwork, at once so evil and yet so brilliant that I find it hard not to stand in awe even as I picture him cackling loudly in his Kendall Square lair, giant laser weapon behind him poised to destroy Berkeley if we don’t hand over our patents."
"The work of many people" is literally the title of a paper by Edward Teller that in some opinions had the same kind of aim as we're talking about here for the Lander paper -- minimizing Ulam's contribution to the Ulam-Teller mechanism behind the H-bomb. (I can't tell if that's fair, not least because only the first page is accessible: http://science.sciencemag.org/content/121/3139/267 Background: https://en.wikipedia.org/wiki/History_of_the_Teller%E2%80%93...)
I was reminded of it when Lander's article came out, not just now.
> topped $15 million last summer. UC’s, paid by Caribou, have passed $5 million.
So a $20 million boon for lawyers and who knows how many hours the researchers lost being distracted by legal issues. One wonders how we could rework our legal system so that that kind of funds and that kind of time don't get wasted like this and instead reward both the researchers and the implementers that get it into practically usable form.
In my opinion, an opinion, the Berkeley IP office is a pain and thus its own enemy. They could take a lesson from Stanford and be more of a partner and advocate for faculty and students. They lost Howe (EE105) to Stanford over simply being a pain rather than a resource.
They also value their prerogatives infinitely high which makes them a pain internally. Outside of the BSD case, I'm struggling to think of anything they've done right.
particularly when a lot of the research was achieved by charity funding and tax grants. public funded then privately profited is a disgusting outcome of our current research system.
I would disagree. Securing a patent means that further investment is possible.
Yes, one of the two labs discovered CRISPR. OK, now what? It's not a treatment at this point, it's just a technique. So someone has to invest a ton of money to turn the technique into a therapy for humans. And I would bet that investment will absolutely dwarf what's been spent so far.
Depending on what the other uses are, the patent holder is always able to out-license the patent for specific uses. This is actually pretty common in biotech.
> I guess to be rewarded in science you have to be a master in your field and intensely concerned with IP deadlines.
Dr. Zhang and MIT proved that the Crispr technique would work in plant, animal and human cells. The value of the patents is in that research, not Doudna's in vitro proof.
Doudna took Cripsr from an odd genomic pattern to proof of Cripr/Cas9 being a bacterial immunity complex complete with proof of mechanism.
Transferring that body of work over to in-vivo is trivial in comparison to what she did. Transferring genes from one organism to another is run of the mill molecular biology.
Transferring that body of work over to in-vivo is trivial in comparison to what she did. Transferring genes from one organism to another is run of the mill molecular biology.
This tech has been around for years. Monsanto wouldn't exist without molecular biology. We'd still be extracting insulin out of farm animals if molecular biology hadn't allowed scientists to grow it in yeast.
You're mistaking traditional cell bio libraries with CRISPR, crispr takes a two year process and makes it two weeks. It's really quite a significant change.
The tech is really not the same, it's the difference between hand braided core-ram and re programmable memory. It's a huge difference.
The process of putting the CRISPR genes in a cell and making them target a given gene is trivially simple and undergraduates around the world are doing it every hour (if not more). The Broad group did a little more than that, but it's nothing compared to UC's group's pioneering effort, and amounts mostly to breaking a certain part of the functionality and doing some very standard tests.
The tool is extremely effective, as you say, and was primarily "designed" via natural selection. The researchers (1) discovered it, teased out its mechanism of action, and its programmability, and (2) did standard molecular bio techniques to show that it works across several oragnisms.
This ruling is based on the fact that the original inventors didn't throw the genes into cells, publish, and (most importantly) apply for patents before the Broad group did. Whether it would work in those other cells was a crapshoot and doesn't represent any significant creative work, and a minor work of science. The importance is the result - we know it works in those cells.
Source: I also work in this field. This ruling is absurd.
Doudna definitely deserves all the credit for clarifying the mechanism and modifying the system for sgRNA instead of the original two RNAs.
But what Zhang did was not trivial. He did not just take Doudna's system and threw it into a mammalian system. He modified the system so: 1) codon optimized (not very hard, I know). 2) Added two localization signal sequences so it goes into the nucleus. 3) And most importantly, he modified the system (nuclease to nickase) so mismatch repair (homology based repair) occurs more frequently than non-homologous end joining. These modifications are not trivial and probably took a lot of trial and error.
Just because crispr is so simple to perform now doesn't mean there wasn't a lot of effort on both Doudna and Zhang's part.
Personally, I believe both of them should have been on the patent. For me, Doudna came up with the Ford model T and Zhang iterated and extended it into a Ferrari.
> Transferring that body of work over to in-vivo is trivial in comparison to what she did.
If this was the case then she would have won the patent fight. The Patent Trial and Appeal Board thought otherwise. Did you read their 51-page decision?
She worked on this technology for years, developing it from it's infancy to in vitro proof. MIT scientists swooped in and within 2 months applied it in-vivo and patented it.
This is wrong.
It's really a shame that Berkeley loses licensing on a tech that was 95% developed at Berkeley.
Sigh, it's the PCR patent story all over again [1].
As always, government and charity funded researchers are spending government and charity funds on fighting each other for the right to make a fortune from the fruits of government and charity funded research. 20 years later the patents expire, and all that's happened is you've slowed down medical progress. What a great legacy for Eric Lander and the Broad. Punks.
This is a question I've asked many times and never got an answer, when you donate "for the cure" does that cure end up patented and sold back to you? That seems more like Kickstarter without the rewards than charity to me.
The Broad licenses the technology. So, perhaps it's slowed down because people have to pay money to use it, but on the other hand, the technology is available, and the inventors derive some revenue from it.
That's not entirely correct. It's right of first refusal. Here is the terminology:
However, after an initial period, other companies may apply to license certain CRISPR IP for use against genes of interest not being pursued by Editas. Specifically:
(i) a third party interested in an individual gene target would provide a bona fide development plan,
(ii) Editas then has a pre-defined period to decide whether it intends to pursue the gene of interest and to commit funding and launch a program, and;
(iii) if Editas is not already working on the gene of interest and chooses not to launch a new program of its own within this period, the IP may be available for licensing by Broad, Harvard, and MIT to the third party.
I wouldn't call it "fair reasonable and non-discriminatory", but it's not entirely exclusive.
Note that they make the tech completely free to the academic community.
Right of first refusal is very different from exclusive licensing. The development plan issue is handled by grownups at companies with hundreds of millions of dollars of funding and they already developed development plans.
One argument is that getting a patent ensures exclusivity to use the technology. In turn, that drastically improves the likelihood of getting a return on any investment dollars. And finally, that attracts a lot more capital than a non-profit or gov't funded agency could typically get.
Like PCR, CRISPR is a relatively simple technology. It doesn't require billions of dollars of R&D to make it useful. Less useful gene editing tech (Zinc fingers, TALENS) have already been used in clinical trials. So just like PCR or that blood Myriad Genetics gene patent on BRCA1, patents hinder progress, make research more expensive, and impair new companies from getting started.
The problem is most tech-transfer departments that universities have actually lose money after paying the lawyers[1] is taken into account. Public research should belong to the people who paid for it -- the public.
Apparently the following (humble and honest) statement made by Doudna to a UC system magazine[1] hurt their case[2]:
>Says Doudna, "Our 2012 paper was a big success, but there was a problem. We weren't sure if CRISPR/Cas9 would work in eukaryotes-plant and animal cells." Unlike bacteria, plant and animal cells have a cell nucleus, and inside, DNA is stored in a tightly wound form, bound in a structure called chromatin.
Maybe universities shouldn't be businesses, and what might be a prevailing way to edit genes for quite some time shouldn't be controlled. Perhaps this should be in the commonwealth. I've been to university talks where the presenters declined to answer certain questions because they'd violate the business interests of the school. In other words, the other researchers could not learn about the presenter's discovery and innovation. I think universities should be about advancing and sharing knowledge.
Is "sharing" equivalent to "giving for free the hard work to the private industry"?
Most of the time the system works as intended. The researchers do their research on public money, most of what they do becomes public knowledge through papers, if something noteworthy is found, it's patented and licensed and the university gets its cut. The system kind of fails sometimes at giving the researchers (in plural, not just the tenured rockstar) its due, but many times are the scientists the ones that open an enterprise to work it out.
In this case, it's not that system that has failed, it's that different universities are fighting over who has the right to license it. I have no horse in this race, but this it's probably going to become even more common, as improvements on existing technology become smaller and it's harder to tell who deserves the full credit.
This is 100% paid work, nobody is working for 'free'.
MIT is well known for the second form of patient troll where you look for years of very promising research done by someone else, make minimal change using government funds, and then get to lock things up for 20 years.
Worse there is now a huge incentive to find some other trivial change to get around this patent thus costing the field 100's of times more than their initial 'effort'.
I have mixed feeling about biotechnology, though. On one hand I'm a big fan of human genetic engineering for increased IQ which is looking extremely possible in the near future (hopefully something that will be available here in Singapore before I have kids), on the other hand as these techniques get cheaper and easier to use we may get to the point where any madman with an IQ over 145 could kill hundreds of millions. Nick Bostrom asks this question in his book: if building a nuclear bomb turned out to be trivial, like putting sand in a microwave, would human civilization have survived? We will find out if synthetic biology keeps advancing. Or maybe this is my nightmare and the patent system will slow down progress enough to save humanity.
human genetic engineering for increased IQ which is looking extremely possible in the near future (hopefully something that will be available here in Singapore before I have kids)
I wouldn't hold your breath. Intelligence is not a single gene you can turn on or off. We don't know enough about what genes to modify (even if we could modify them).
It's polygenic, like height. People who I read in the space of cognitive genomics, such as Steve Hsu and Razib Khan, agree it's looking increasingly plausible. It would require modifying hundreds of alleles. Embryo selection is possible now, just not useful until we have a million genomes tagged with their donors' IQ. 1 of 10 embryo selection give you about 8 IQ points per generation. Hsu thinks Crispr will obsolete embryo selection before it's in wide use.
He also said the following:
>I think there is good evidence that existing genetic variants in the human population (i.e., alleles affecting intelligence that are found today in the collective world population, but not necessarily in a single person) can be combined to produce a phenotype which is far beyond anything yet seen in human history. This would not surprise an animal or plant breeder — experiments on corn, cows, chickens, drosophila, etc. have shifted population means by many standard deviations (e.g., +30 SD in the case of corn).
Or maybe if you put too many IQ-associated alleles in one person you wind up with a psychotic wreck. We don't know how these genes interact, if they do, nor by what mechanism they work. And unlike with corn, you can't just guess until something works; experimenting with actual humans would be a major ethical breach, and there's no animal models of human intelligence. Progress on that front is possible but unlikely in this century.
> Progress on that front is possible but unlikely in this century.
I agree in a way, but every time this comes up I point out that in East Germany they would have pounced on this technique and built a secret base in the wilderness to work on it. I say East Germany because it is a matter of historical record, what they put their athletes through.
So I'm saying that progress on that front is possible but unlikely in this country, where we consider a major ethical breach to be something to be avoided entirely, not just hidden.
You're talking about a country which prepared to biowarfare by dropping bacteria on its own civilian population (including San Francisco Bay Area[0]) to see what happens, without telling anyone. A country that has its own movie industry creating story after story of its military experimenting on people, to the point it's pretty much became a trope.
So no, I wouldn't be so sure this couldn't in principle happen in the US of A.
The future is the same no matter how long it takes. Advancing slowly doesn't prevent the results of advancement. It just increases the likelihood that something else is advancing faster than you. We should rather humanity destroy itself than lose a fight to a more advanced civilization.
If we can slow down biology enough, the AIs will conquer us and keep us as pets. They'll keep us from destroying ourselves with genetic reprogramming the same way we keep dogs from nagging their own wounds: With a cone collar. But this will be some kind of virtual cone collar that blocks CRISPR research.
Something can be said for allowing "enough" time for wisdom to develop, instead of rushing forwards without adequate consideration.
How long is "enough" though, and what stimulus is needed for get that wisdom in place? Probably some form(s) of failure, though I've not thought on it further.
The article doesn't mention Eric Lander's controversial article a few months back, but this outcome certainly seems like what he might have been working toward. Is it considered to have given any weight to their case?
Of course this is what he was hoping for, that was obvious at the time. The particular article was almost certainly not given any weight during the case, it's just a restatement of their general argument.
You are absolutely right. But, since I called it an article, and linked to the article in Cell (via HN), I'm a bit lost as to what you're trying to tell me. Sorry, is the premise of my question weird or something?
I don't know the whole backstory of Crispr or all the people involved, I just know it sounded amazing when I first heard about it on Radiolab, and then it got mired in this fight over credit and rights. I'm wondering if Lander's piece was influential in this first victory, and whether this outcome was part of his intent in writing it.
You take public money to do research, any fruits from that money belong to the public. You don't get to start companies and patent the end result and get rich off of our money. If you purely take private money you work in some startup you can do stuff like this. Even then I would argue that understanding or discovering some biological entity should not be patentable.
> You take public money to do research, any fruits from that money belong to the public
TBF we did try this in the US, and this is exactly how things worked for decades. That rule was eventually shot down for a whole host of reasons.
> If you purely take private money you work in some startup you can do stuff like this
How about this scenario:
Person A invents something using public money.
Person B creates a start-up using Person A's invention.
Person C needs said invention, and can only get it from Person B, who charges them for it.
In other words, if the fruits of the labor are going to be extracted by someone, shouldn't that someone be the person who made the actual discovery (assuming they're willing to do the business side as well)?
We've been having this discussion on HN for years now, and I haven't seen many workable alternatives to the current system as it applies to pharma.
A lot of this boils down to risk and risk mitigation. Because the monetary outlays and failure risks are so considerable to shepherd a technology through the entire life cycle from conception to commercial availability, big pharma has to be extraordinarily selective about where they place their bets.
They generally do not invest in early stage developments. In fact, these days, we have to find partners or spin out startups to help further the research to even get to the point that pharma wants to talk about licensing.
The patent protections allow the time to get to that point and ensure our partners that they will have some protection to assure revenues (assuming the technology even makes it to market) sufficient to offset the costs associated with the various phases of clinical trials.
It's by no means a perfect system, and there are some slightly different models out there. Singapore, for example, requires the research dollars to be reimbursed upon commercialization. That is a fairly small ecosystem to analyze, however, when compared to the scale of US investment via agencies like the NIH and NSF.
Edit to add disclaimer: We have patents licensed to the company referenced in this article (Editas).
In fact, the patent system comes close. If what you contributed was inventive and new, you get a patent on that slice of what you invented. For someone to commercialize the whole thing, they may need to pay both parties (essentially both parties who had a part to play in the "discovery" will be paid for their work). In many cases like this, the parties have to cross-license each other (pay each other or license each other for their respective patents).
That is actually what the article says.
"An appeals board of the patent office ruled that the gene-editing inventions claimed by the two institutions were separate and do not overlap."
"Ultimately, companies wanting to apply Crispr for use in medicine, agriculture or other fields might need licenses from both the Broad Institute and the University of California, a lawyer for the university said. ..."
The usual result is that no creative applications of the new technology are legal until both patents run out in 20 years.
Or that a foreign nation that didn't accept the patents becomes the only center of innovation and the nation that paid for it becomes a backwater.
One or both of those happened with steam engines, sewing machines, and aeroplanes. Humanity was not better off.
It was narrowly averted in photography, automobiles, and computer software by governments invalidating the pioneer patents in the field for the benefit of mankind.
I hear ya, especially on aeroplanes (it turns out the Wright brothers were kinda jerks). It's such a shame that, due to the current nature of political discourse, it seems that the only two plausible options are (a) artificial and stifling patent monopolies or (b) expropriation by the state.
There seems to be a very sensible, but verboten, middle ground here: government funding of socially beneficial research and, if a significant public benefit can be demonstrated, compulsory state acquisition under the condition that just compensation is given.
The traditional explanation for the economic usefulness of patents is that it incentivizes public disclosure of discoveries, and prevents trade secrets from dominating the innovation economy. (Imagine if the cure to cancer was kept as secret as the recipe for Coca Cola!)
The odd part of this case is that it might cause researchers to hold back from publishing their discoveries until they're sure their own institution can 'squeeze out all the juice' and best monetize the novel finding.
On the other hand, perhaps it incentivizes more classical research institutions to employ top teams of researchers who can prototype the 'medicine' part of a biomedicine discovery as quickly as possible. In truth, there are a lot of amazing discoveries at the ground level of molecular biology, which plausibly could revolutionize human health, but are still waiting decades later to be shown to be practical.
I believe the government should apply eminent domain to key technologies that promise wide-scale advancement for society. Technologies like CRISPR are far too powerful and have far too much potential to be confined to control by a single entity.
I would imagine that this would go on to appeal and be in the courts for years if it decades. Especially once the parents actually produce royalties. No?
She worked on this technology for years, developing it from it's infancy to in vitro proof. MIT scientists swooped in and within 2 months applied it in-vivo and patented it.
I guess to be rewarded in science you have to be a master in your field and intensely concerned with IP deadlines.
It's really a shame that Berkeley loses licensing on a tech that was 95% developed at Berkeley.