Love all of the TWIx podcasts and find them to be a great soundtrack for long hours with the epifluorescent microscope. While listening to TWIV 232, when you asked about APOBEC proteins in Old World Monkeys, I thought for sure someone would mention the work of Michael Emerman’s lab. I’ve attached their PLOS Pathogens paper from earlier this year examining the co-evolution between Old World Monkey APOBEC3G and SIV Vif proteins. In this paper, they state that SIV may have an origin in Old World Monkeys perhaps over 12 million years ago. Enjoy, it’s a very nice read.
Jordan T. Becker
Graduate Research Assistant – Nathan M. Sherer Lab
McArdle Cancer Biology Program
University of Wisconsin – Madison
This paper is nice but it focuses exclusively on APOBEC3G (with little regard to other 6 family members). We were discussing the differences between the genetic make-up of each species; In any event, I wish we had a bit more time to discuss functions and do the topic more justice.
Vince (and crew),
I wanted to write some thoughts in regards to an issue discussed in Episode 231 (Hepaciviruses and pegiviruses in bats and rodents, w/ Kapoor, Quan and Lipkin).
During the discussion, you (Vince) sought clarification on the definition of zoonosis. Ian offered the definition as a recent animal-to-human transition, particularly when we know the origin. You all came to be satisfied with that parameter – I agree. Though, I think your larger esoteric thought exercise was under-engaged by your colleagues – in theory, aren’t all human viral pathogens zoonoses?
I wonder though if this discussion touches on a larger evolutionary question of speciation itself. Could we not envision a viral system in arms-race balance with an evolving primate lineage – co-evolving with its host population through transitional stages of hominoids, up and through sapiens? The virus species becomes increasingly diverged and isolated from sister viral taxa as it adapts to its host population while the host population simultaneously becomes reproductively isolated from its own sister taxa? This could clearly be a non-zoonosis origin. The virus did not come from a opportunistic cross-species event, but was always present within the population. Together they now just stand in a different ecological-evolutionary space.
The origin of poliovirus could well fall within the scope of a non-zoonosis co-evolution theory. We see evidence of poliomyelitis in antiquity (Egyptian art) suggesting a long-term human co-evolution. Given its fecal-oral transmission being primed for close-association group dynamics, perhaps it has long thrived within primate tribes. And perhaps agriculture and population growth facilitated its continued success in humans whereas common ancestor strains in other primates were lost stochastically over time (or are yet to be found) due to the comparative under-success of their hosts.
Questions of what are speciation events and what mechanisms facilitate them are still so difficult in evolutionary theory. But we further know so little of the role of pathogens on this process. However, we do know one critical transition brought on by a virus – syncytin. The most significant evolutionary transitional event in mammals was the result of a retroviral co-evolution. How many other evolutionary speciation events have been viral-driven? Could a viral system have facilitated the developmental transition to complex body forms during the cambrian explosion? There may well be numerous smaller-scale viral burdens have forced host populations into isolation, resulting in speciation events. Probably happens regularly in bacteria-phage systems.
Loved the discussion of new viral survey results. I often describe my research focus as: defining constraints in viral adaptation. In a recent meeting with my PI I told him this may be a poor choice. As we continue to survey more of the global virome, its clear… there are none (constraints). We’re surrounded.
Postdoctoral Research Associate
Paul Turner Lab
Dear Team TWIV:
As I write its 62oF, 16oC and cloudy in Chapel Hill, North Carolina. Chapel Hill is home to a great college basketball team and many outstanding virologists.
First, thank you all for a wonderful podcast. I try to stay current while catching up on back episodes on my commute. I’m so hooked that when my six year-old daughter sees me using earphones, she asks if am I listening to This Week in Virology (a card she made for me is attached).
As background, I am a PhD organic chemist who studied under Ronald Breslow in the Department of Chemistry at Columbia. For more than 20 years, I’ve been practicing biotechnology patent law. I’ve worked both in a diagnostic company and in law firms. I’m writing because I think you missed the boat regarding few aspects of your TWIV #230 discussion of gene patents.
At the outset, thank you for correctly identifying the inconsistency with regard to the U.S. Government position that patents on cDNAs should be allowed. A similar inconsistency exists in the ACLU’s disingenuous argument that they aren’t challenging short sequences such as PCR primers. Isolated cDNAs and primers will match exactly the sequences of human BrCA1 or its complement. If the Supreme Court invalidates the Myriad patents on isolated DNAs encoding human protein “W”, there is absolutely no reason why the same “law of nature” rationale would apply to invalidate a patent on an isolated DNA encoding a plant protein “X”, a bacterial protein “Y”, or a virus protein “Z.” Similarly, isolated DNAs encoding probes and primers or cDNAs corresponding to natural sequences, would be invalid.
However…my rare moment of disagreement with the TWiV podcast has to do with the fact that all of you are so opposed to DNA patents. One reason may be that it’s axiomatic to practicing patent attorneys that you can’t patent an idea. You can only patent an invention. Unfortunately, the question presented to the Supreme Court, “Are human genes patentable?” is an idea. Moreover, it is a carefully-crafted catchy idea designed to appeal to emotions…emotions that scientists and doctors are not immune. It provides Luddites and anti-technology activists with fodder using charged statements such as Michael Wosnick’s misguided “Patent My Jeans, NOT My Genes!” Myriad didn’t patent a gene, no one can. Both scientifically and legally you cannot patent a gene. Moreover, the question presented leads to a muddying of the four discrete legal requirements for a patent: it must be new (35USC§102); it can’t be obvious (35USC§103); must provide a recipe (35USC§112); and must be statutory subject matter (35USC§101).
Myriad received a patent for a new, an unobvious, and a useful defined molecule, a new chemical entity (NCE), never seen before as of their filing date, namely “An isolated DNA coding for a BRCA1 polypeptide, said polypeptide having the amino acid sequence set forth in SEQ ID NO:2.” At a molecular level the isolated DNA has been both (i) covalently modified by precise cleavage out of the chromosome 17, and (ii) purified from other cellular materials (enzymes, structural proteins, lipids, other nucleic acids…). I can read SEQ ID NO:2 and know exactly what Myriad discovered; what products would infringe the patent; and suggest ways to design around their patent (see Amgen v Transkaryotic Therapy (TKT) a homologous recombination work around; or the various PCR patent amplification work arounds). Thus fulfilling the Article I, section 8, clause 8 constitutional goal of promoting the “useful arts.”
Roll back the clock to the time of Myriad’s patent filing, no one had a clue as to (a) its specific chemical composition/sequence; (b) the exact chromosomal location where the DNA corresponding to this molecule could be found; or (c) whether or not BrCA1 would have any value as a clinical diagnostic. The 350 million people walking around the U.S. with the BrCA1 gene in their cells aren’t infringing Myriad’s patents. Those individuals never “isolated” DNA having the BrCA1 sequence. Contrary to the brief by Dr. Eric Lander, gene fragments or pseudogenes in blood are not “isolated.” Furthermore, those arguments relates to whether BrCA1 DNA is new (35USC§102) or obvious (35USC§103) not 35USC§101. Similarly, next generation sequencers never “isolate” any DNAs rather they sequence short fragments 100 to 200 base pairs.
The scope of protection provided by chemical composition matter patents is enormously broad. It covers any use whatsoever. Pfizer’s Viagra® patents cover making, using, selling…Viagra for any purpose. Many academic scientists and academic law professors find this huge breadth unsettling. However, while Viagra enjoys its twenty year term, other pharmaceutical companies may make their own independent patent protected products to mimic Viagra’s therapeutic effect. When the twenty year term is up, the drug becomes generic and can be bought for pennies. If you can’t patent “isolated DNA”, others could readily come up with alternative methods to design around the Myriad patent portfolio. These two misconceptions (scope and designing around) have led brilliant scientists such as Drs. James Watson and Eric Lander or the American Medical Association to oppose Myriad’s isolated DNA patents. It has also led to a plethora of academic law professors, government lawyers and academic/government scientists with no research, development, or commercialization experience to oppose isolated DNA patents.
Since the early 1980’s the biotechnology industry in the U.S. has thrived. Somewhat like vaccines, their success may have given way to complacency with regard to patent protection. Many leading companies have built their global successes around patents on isolated human nucleic acids. A couple of leading examples include: the Amgen DNA patents on erythropoietin (Epogen®); the Genentech patents on tissue plasminogen activator (Activase®); and the Biogen/Idec patents on interferon beta (Avonex®). The ability to patent genetically engineered organisms thanks to Diamond v Chakrabarty and the passage of the Bayh-Dole act helped these inventions to succeed. Similarly, the creation of a specialized appellate court for patents, the Court of Appeals for the Federal Circuit, helped assure a predictable scientific/legal/business environment for these biotechnology successes. None of these companies would have invested the huge resources required for research, development, validation, clinical trials, and marketing to healthcare professionals, if they didn’t have defined patent protection.
Myriad was overly aggressive in their assertion of their patent rights. As a diagnostic testing company lawyer, I would have strongly urged them not to sue providers of second opinion cancer testing. In general suing your customers or end-users is a bad idea. Here with women already having positive diagnoses for increased risk of breast cancer, it’s an awful business move to sue second opinion testing providers. In addition, Myriad never asserted that scientists could not do “research” with BrCA1 DNA or the BrCA1 sequence, rather they enforced their patents against commercial diagnostic testing providers. Hard cases may make bad law.
If the Supreme Court invalidates the Myriad DNA patents, universities will no longer invest their scarce resources into new patent filings on human isolated DNAs (contrary to the landmark Bayh-Dole act). Next in the innovation food chain, startups and venture capitalists will no longer invest. If a startup doesn’t have defined patent rights, why invest only to launch your new product and then have some giant diagnostic, pharmaceutical or biotechnology company steal your lunch. As Alan observed, one big problem facing commercialization of great academic discoveries has been referred to as the valley of death (http://www.nature.com/news/2008/080611/full/453840a.html). Universities, startups, and big companies won’t invest in a highly uncertain but promising discovery, if they can’t recover their investment by having a monopoly for a “limited period of time” at the end.
Lastly, it is the job for congress to change the law, not the Supreme Court. Courts can only decide real cases not theoretical challenges. Dr. Ostrer’s challenge (the lead plaintiff backed by the ACLU et al.) is stale and his harm de minimis. Thus, there is no real case or controversy with Myriad. If the Supreme Court wishes to whittle away at patent protection in the medical arena, they should hire an expert economist to educate them on the business/innovation implications or force licensing as the courts did in 1944 for Vitamin D (Vitamin Technologists, Inc. v. Wisconsin Alumni Research Found., 146 F.2d 941, 944 (9th Cir.). Alternatively, Congress should make biotech patents hard to enforce as congress did in 1996 for medical procedures, e.g., Lasik eye surgery (35USC§287(c)) or the Executive branch should exercise the “march in” rights under the Bayh-Dole act.
Thanks for reading. If you want to read more, the American Bar Association has posted the briefs for all sides of Myriad case (http://www.americanbar.org/publications/preview_home/12-398.html).
Chapel Hill, NC
I’m writing this email as a follow-up to TWiV 230 on gene patents, and specifically to Vincent’s comments about his own “useless” patents. Vincent, as you know, I have been working as a science advisor in a patent law firm since last July, and as I understand it, a good (and “honest”) lawyer would probably have advised you against pursuing any patents. As Alan pointed out so eloquently, there is really no point in patenting a product, unless your product has some sort of commercial value. If you’re not planning on making money on your invention (and knowing you, I assume you didn’t), it makes no sense to apply for a patent, because the cost of prosecution will far outweigh any future financial gain.
According to the U.S. Constitution (Article 1, Section 8, Clause 8) the main purpose of patent law is “to promote the progress of science and useful arts, by securing to authors and inventors the exclusive right to their respective writings and discoveries”. This exclusivity is meant to stimulate invention and disclosure of invention in the sense that the patentees, and those who fund the inventor’s work are stimulated to make the investments of time and money, being comfortable in the fact that once they complete their invention and get a patent on it, they will have a limited period of time of exclusivity with respect to practicing the invention. This makes a lot of sense if you think of it like this: let’s say a company spends $100 million developing a new pharmaceutical. Upon obtaining a patent, those investors can rest somewhat assured that the competitors (the generics) can’t immediately come on the market and copy what they did without having to spend the $100 million in cost, and thereby be able to underprice them. That being said, without patents, a lot of valuable drugs would never come to market or even be invented, because investors would find no motivation to fund the work. And we all know how valuable money is when it comes to research!
My firm works with a lot of small start-up biotech and pharmaceutical companies, and we are actually trained to advise our clients about the value of a potential patent, as well as the lack thereof. Of course, some clients still choose to go ahead and claim their invention, even if it doesn’t really make sense in the long term, but I chalk that up to vanity. Vincent, I’m sorry you’ve had such a negative experience with lawyers! But they’re really not all bad, I promise!
P.S. We’ve had a really cold spring in Atlanta, it’s currently 59 degrees Fahrenheit, and windy.
Tom writes: (subject line: US Patent System FU)
In TWiV #230, you talked a bit about the US Patent system. Here’s a bit of Follow Up.
Try Goggling “US Patent System Broken” to tap into a very lively discussion of patents in the context of information technology.
If you want a Viewer Pick, I’d suggest
This is an article from last June, during a Apple / Android patent battle. It provides a good overview of the current patent landscape, along with photos of troll dolls, a tiger over a bloody carcass, and Jabba the Hut’s caged monster from the second Star Wars movie.
The last paragraph echoes what I’ve been hearing for over 15 years: “There are often literally dozens of duplicate patents on a specific technology. And there are literally tens of thousands (or more) patents that should not have been granted due to their obviousness.”
At one time I heard that the US Patent Office was thinking about a public “peer review” Wiki system, where they could elicit subject matter experts’ help with patent examination. Not sure how that’s working out.
– Tom in Austin
Yes, I’ve written to you previously. And you can change the subject line’s ending … I just couldn’t resist, after your earlier using, and then dropping, that term. It seemed so fitting for this email’s topic. :