Myriad, Mayo and Prometheus: the line between "law of nature" and invention

(by chemicalbilology) Aug 22 2012

Some very interesting litigation has been going down this year, somewhat under the radar for most of us, regarding the patentability of biological products and processes that could have huge implications for both the biotech industry and academic research labs hoping to commercialize their findings.

Earlier this spring, what would look to most people (and even most scientists) as a very dry case made its way up to the Supreme Court. The case was brought by Mayo Clinic (via their laboratory group Mayo Collaborative Services) against Prometheus, a medical diagnostics company. Prometheus own(ed?)(s?) the patent on a certain test offered by the laboratory. This test involved detecting the levels of a certain drug metabolite in order to monitor dosage/predict side effects/etc., and correlate those levels to the health of the patient (i.e. efficacy). Basic pharmacokinetics/pharmacodynamics (PK/PD) type information--thousands upon thousands of people get a similar kind of testing for their coumadin/warfarin levels all the time, This is mainly because there are certain polymorphisms in a couple of enzymes (VKORC1 and CYP2C9) that affect the metabolism and thus blood levels of warfarin in some patients, and if the balance isn't right (and the effective dose ends up too high) the patient's blood won't be able to clot at all, which is a bad thing, obviously. If it's the other way around, the patient won't get enough of the thinning effect and will not get the intended benefit. So everyone who starts on warfarin has to get their prothrombin time and "international normalized ratio" (PT/INR i.e. measures of clotting) regularly checked to make sure the dose is having the intended effect; doctors adjust based on the outcomes of these tests as necessary.

So, Prometheus developed a test for a certain drug metabolite in a certain disease (unrelated to warfarin, that was just a handy example) that was a little more direct: it measured the actual level of the metabolite in the blood rather than a downstream effect of that level. (you could do this for warfarin too, but it's probably a lot cheaper to do the PT/INR test) They also established a correlation between those levels and the outcomes, and patented the whole system. They sold a kit, that made this test simple, to the Mayo labs, and Mayo Labs bought it and used it regularly. Then at some point, somebody at Mayo Labs said, "Hang on, if this is just measuring the level of this metabolite using a machine we already have, let's just put together our own reagents off the shelf and run it without paying all this money for this expensive kit." (something research labs may or may not do all the time... ahem...) As you might expect, Prometheus wasn't very happy about this and it all culminated in some intellectual property litigation. You know, just a little argument that ended up... before the Supreme Court.

Teh SCOTUS' decision ruled, in way-shortened summary, that because a drug metabolite is produced by the body, it is a "law of nature" and is thus unpatentable. This result sent waves through the intellectual property law community because if a diagnostic for drug levels is considered a "law of nature," WHAT ELSE is now going to be challenged as unpatentable?? The entire freaking biotech industry??!

Think, in particular, the ongoing fight about Myriad Genetics' test for BRCA1/BRCA2 mutations. Someone else certainly did. Last week, in an update to this law of nature drama, the U.S. Court of Appeals for the Federal Circuit ruled in favor of Myriad, that because the DNA constructs covered under their patents are cDNAs and other pieces of cloned out material, they are not "natural" and thus don't fall under the "law of nature" definition. This is a key result: it means that the issue isn't necessarily so sweeping and cut and dried as it looked from the opinion that came out of ye olde SCOTUS... and may ultimately end up back there via this Myriad case.

But overall, this whole discussion may end up having the effect that was speculated to be part of the SCOTUS' plan for their dramatic ruling: to better define what constitutes "natural" in the 21st century, where modern biotechnology can generate whole artificial genomes, and exome sequencing (heck, even the cheap kind of sequencing, or good old fashioned GC/MS metabolomics) can help predict who is at risk of a given disease and/or will benefit from a given drug; and to force the biotech world to figure out which and how molecular parts are owned by the individual who produced them (either in their body or from their mind). And us in academia, we better pay attention--because these are our discoveries out there, too, and if we want them to ever see the light of day, somebody is going to have to help us make products out of them. That's pretty hard to make happen without viable intellectual property in place.

8 responses so far

United Airlines loses an unaccompanied minor and doesn't give a crap

(by chemicalbilology) Aug 14 2012

Whoa, this is so whacked out I had to post about it. United Airlines basically lost and ignored a 10 year old for whom they were responsible as an unaccompanied minor traveling with them. The only way it got figured out was through some of their employees breaking the corporate "rules" to do things they weren't supposed to do and help her. You really need to read the full story here:

United Airlines lost my friends' 10 year old daughter and didn't care (Bob Sutton)

One response so far

Clarifobfuscation?

(by chemicalbilology) Aug 04 2012

Maybe I am just feeling obtuse today, but this clarification RE: the time limit on resubmitting applications to NIH does not at all clarify the issue for me. I am more confused now! Before reading this, my understanding was that it was A1 and done, and that the 37 month thing just meant you better get that A1 in within that time frame. But by this statement:

"After thirty-seven months, NIH views a submission as a new application, regardless of whether an unsuccessful resubmission (A1) was submitted during the thirty-seven month time period"

...do they mean that if your A1 doesn't get funded, you can just wait a couple of years and submit it again? I haz a confyuz.

5 responses so far

Annoying Google gaming

(by chemicalbilology) Jul 25 2012

ZOMG, this is really ridiculous: I'm trying to Google multiple reaction monitoring (MRM) proteomics to gather resources and references for a workshop talk I'm giving in a couple of weeks. Searching for "mrm proteomics" brings up a neverending list of permutations of this ONE company's information (including every page on their website individually, as well as two different blogs, one Blogspot and one WordPress, that have the same entries) (I refuse to link to them since that'll just feed their Google beast). You don't even get to the freaking Wikipedia page for it until, like, the third page of the Google results! Sheesh people, I know it's important to get your company's information about there, but that's just obvious game of the Google search algorithm. They must have hired some "get your website in the top of search results!" service. It's just kinda lame.

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Notes from the NIH Regional Grant Seminar

(by chemicalbilology) Apr 18 2012

I spent the day at the NIH Regional Grant Seminar in Indianapolis, and it has been a mix of useful stuff and other things that are too beginner-y for me. Not like I am some kind of NIH expert, but because of the great public service provided by the blogworld via e.g. Drugmonkey and Physioprof and the mentorship of my senior colleagues and advocates, I am already pretty clued in to the basics of the NIH operational model, so sessions describing how peer review happens and what is the job of a PO vs. an SRO aren't all that useful to me in particular. The most interesting part for me is to get to ask questions of the people who are usually just names on policy documents or the internet, and see what kind of a response they have to my and others' questions. Dr. Sally Rockey has had some good sessions and engages fully in each answer she gives.

Something I hope to probe more about tomorrow is the NIH's projected path towards putting their "money where their mouth is" about improving the pipeline issues created by our country's current model for grad school and postdoctoral training, something that this blogosphere is very familiar with. It's clear that they can tell there is a problem, and the data illustrate the problems in various ways:

  • abysmal representation of African Americans in the investigator pool, both as applicants and as funded
  • loss of women PIs at the R01 renewal stage (as described in this paper by Pohlhaus et al)
  • huge reliance on postdoctoral "trainees"--who aren't really getting a training experience towards becoming independent--as research staff on R grants

A dissatisfying element is a tendency to invoke the "well, we can't mandate that institutions do X or Y" about things that it would be HARD to do (like, politically or financially hard)--even though, clearly, NIH and government policy DO mandate plenty of things about how institutions need to operate in order to get their money (ORI, IRB, IACUC). I totally understand that it is their job to toe the line and keep on message; but it seems like a very convenient reason why some things "can't" be changed in ways that might address the diversity issues.

For example, employee-style benefits including family coverage health insurance and family leave for graduate students and postdocs are "allowable costs" on F and T grants; but NIH's official position is that it can only be covered by these grants IF other graduate students and postdocs at the institution get the same options. I know there are plenty of institutions that do NOT provide adequate coverage of these things for any of their grad students or postdocs. At my own institution, I know that the family coverage purchasable by grad students is so expensive, and so poor with respect to cost-coverage ratio, that graduate students often have to put their children on Medicaid (which they easily qualify for!!). This is terrible! And what a barrier this puts up to anyone considering having children while in graduate school--especially women. It's not reasonable to assume that everyone in graduate school or postdoctoral training will have a partner who has a "better" job with "real" insurance. It really should be the responsibility of the training program to provide reasonable, livable coverage for cost-of-living, which in this country, includes health insurance. For postdocs, at many institutions (including mine) they get dropped from their benefits programs as soon as they obtain independent funding through e.g. a K99 or F32 award. What a disincentive to apply, yet putting trainees between a rock and a hard place since independent funding is their currency towards a faculty position, and it has a strong likelihood, again, of affecting trainees (especially women) with families who need to maintain their family insurance coverage.

These kinds of situations seem like a perfect opportunity for NIH to connect the dots between some of the various problems with the training process in the biomedical workforce, to not just allow but provide this coverage to any trainee who obtains funding regardless of what their institution does for others. For one, this would have an immediate impact on and incentive for graduate and postdoc trainees to apply for funding (and for PIs who care about this kind of thing to apply for training grants). For two, NIH could make it a part of the review criteria (either merit review or programmatic decision-making review) to evaluate trainee support at the institution (e.g. insurance subsidies, availability of family leave and benefits), and that institutions that provide poor support for their grad students and postdocs will get dinged for Environment and that this will factor into funding decisions. In principle, it would be cost-neutral, since those costs are already allowed to be budgeted into the "institutional allowance" amount (although, that amount isn't actually enough to cover 'real' insurance either; but it's closer than nothing). Maybe it would provide the nudge that institutions need to make them realize that these things actually do matter, both to the trainees and to NIH. NIH has the power to shift this paradigm, just like it did with new investigator funding rates--they just need to take it on.

 

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Maybe it would help to wear a "man" suit with an elbow-patch jacket or something...

(by chemicalbilology) Feb 10 2012

AAAAAGGGGHHHHHH!!!!!

I'm currently lecturing in introductory organic chemistry; the head of the course is a very experienced outstanding teacher who (literally) wrote the book, and has won many awards for his excellent teaching. He started the course for the first few weeks of lecture. I'm covering lecture for now, and he will pick it up again later in the course (about a month and a half from now).

I messed up carbocation rearrangement today, right at the beginning of lecture. I lost 'em; they were VERY restless and chattery and obviously like "This lady does not know what she is talking about!" It actually turned out that the mistake I made was a very instructive example of a common misconception about the topic that students have, and the ensuing discussion of where I had gone wrong cleared up a lot of questions they had and got everybody to a much better understanding of the topic than if I'd just gotten it right the first time through.

BUT I am pretty sure that it is still going to kill their perception of me as someone they can trust to teach them. Every time I get anything wrong it's like another nail in my "I'm a younger female who doesn't really 'look' like a professor" coffin. I don't have any room to make mistakes, because I'm already having to prove to them in the first place that I can teach them about chemistry.

It's like a Catch-22; I end up sacrificing my dignity in a way that helps them LEARN more, but it might end up adversely affecting their learning overall if it makes them think I can't help them understand things. And it also shows up in their memories as a huge looming perception, so when it comes to instructor evaluation time... what do YOU think happens?

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#iwanttoliveinaworldwhere...

(by chemicalbilology) Feb 08 2012

...postdocs who are pregnant do not have to live in fear of letting anyone know until it's unavoidably obvious. And then don't have to have their jobs held over their heads once it is. Where recent PhD grads never have to feel anxiety about whether their offers for postdoc or other positions will dissolve if they let it slip that they are, or would like to soon become, pregnant (a fear my sister recently experienced). Where postdocs on the TT market (or any other job market for that matter) don't have to feel fear, stress and hopelessness about it, either.

THAT is one thing that could help improve the diversity of the biomedical research workforce. But what will/could the NIH do about it? I know what each and every one of us can do individually about it: work on our inbuilt and resource-motivated biases. But systemically? Hell if I know--brainstorming here...

19 responses so far

My awesome student!

(by chemicalbilology) Oct 27 2011

I am so proud of my visiting high school student (who joined us through a cooperation with Project Exploration and GERI during the summers of 2009 and 2010) Genesis Galan, who won a $25,000 college scholarship!!! Way to go Genesis!

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Michaelis and Menten: when science was scrappier

(by chemicalbilology) Sep 28 2011

ResearchBlogging.orgEnzymes are the chemical engines and machinery of life. They are the catalysts that move things around inside our cells, that break apart proteins and other molecules to either recycle them or get rid of them out of the body. They are the machines that read, translate, replicate and repair our DNA. They are proteins themselves: big long amino acid polymers that glob up on themselves to give three-dimensional shapes with velcro-like molecular surfaces and little sticky pockets for other molecules. In an enzyme, those sticky pockets can do more than just stick (i.e. bind) to another molecule--they can perform chemical reactions on those other molecules. They do this by bringing those molecules so close in space either to other molecules they also bind into their sticky pockets, or to their own amino acid chemical groups, that the atoms in the molecules just can't help but interact and form (or break) bonds with each other. Think of static-y balloons: rub them on your hair, then hold them juuuuust close enough to the wall and they POP on over to stick. Or of how even though you didn't like your college roommate very much at first, you spent enough time in close proximity and eventually bonded and became friends. These kinds of forces happen at the atomic scale, bringing molecules together that otherwise either would not ever get close enough together to react, or who don't really WANT to react but can't help it when they get stuck together in a sticky pocket and stay there together for a long enough time. For molecules, even a few milliseconds can be long enough.

The molecules that enzymes are bringing into sticky pockets and forcing to become friends with themselves or others are called their "substrates." The stuff that gets formed in the sticky pocket is called the "product." How much a given substrate "likes" an enzyme (and vice versa) is governed by the chemical properties of the molecule and how well they are compatible with the sticky pocket. A key aspect of this is that in order to be a good enzyme, a good catalyst, there has to be just the right balance between how much the substrate and product stick to the sticky pocket: if either one of them sticks too much, the enzyme has trouble kicking them out to move on to the next molecule of substrate and therefore can only do the reaction once. How fast the enzyme can go through this process (the "rate" of the reaction) is thus also governed by the stickiness, but additionally by the amount of time it takes for molecules of the substrate to randomly bump into the enzyme when they are both floating around in a solution where at any given time, they may be very, very far away from each other (think trying to find another human in a vacant building vs. a crowded airport). This seems pretty straightforward as a conceptual illustration, but how do we actually quantify this? How do we figure out how fast an enzyme goes with a given substrate, how well a substrate sticks to an enzyme, how well its product sticks to the enzyme, and how to relate any of this to what we want to know about the world and how it works? A fascinating new translation (from the original German) of the paper by Michaelis and Menten that is considered to be the first quantitative description of all of this, along with some commentary and historical contextualization, was published this week in the journal Biochemistry.

In the early 1900s, a Canadian woman named Maud Leonora Menten went to Germany to work with Leonor Michaelis at the University of Berlin. By this time in scientific history, Michaelis and Menten knew that enzymes could perform chemical reactions. They knew approximately that this stickiness of pocket for substrate was a factor in determining the fundamental properties of the reaction (things like its rate and the mechanism by which it occurred). Catalyzed themselves by work from Victor Henri, they hypothesized that there would be a quantitative relationship between the amount of enzyme around compared to the concentration (or density of molecules floating in the solution--trying to find each other in the vacant building or the crowded airport)--but nobody had ever analyzed this properly before. Henri had the basic idea right, but had forgotten to take some key factors into account (things like changes to enzyme products that just happen on their own without the enzyme being involved, and how much an enzyme depends on having the right pH balance in order to work properly) that made it too hard for him to figure it out. In just that one year, Menten worked with Michaelis to set up experiments to test this and to properly control those other aspects that Henri didn't, and collected the data to write the paper describing analyses and equations that transformed the way scientists thought about enzyme function and provided the foundation on which modern biochemistry is built.

All of this was done without even knowing how much enzyme they were working with, just diluting some kind of preparation of it (which, Johnson and Goody point out, Michaelis and Menten didn't even describe in the paper) in different proportions to substrate (which was sucrose) and without having modern molecular analysis tools available. The "readout" (i.e. detection method) of the enzyme activity that Menten used was the optical rotation of the solution she was working with: how much the solution "twisted" some polarized light that was passed through it. The enzyme, invertase, was breaking apart sucrose into fructose and glucose, and removing the bond between them had an effect on the optical rotation. She had to handle the solutions just right and put them in conditions that would minimize the unrelated conversion of the glucose to make sure that those effects wouldn't complicate the analysis. With that scrappy, deeply thought-out experiment, she and Michaelis are a reminder about how much you can figure out with very few resources. This piece of history also illustrates how much discovery of the un'seeable' can come from the basic function of human exploration, even without fancy machines and lots of pre-determined knowledge about a system.

One thing their models don't account for is how enzymes probably ACTUALLY function inside cells, where concentrations and densities of proteins and other molecules are extremely high and dynamic, relative to when they are free floating in solutions. The interior of a cell is like an obstacle course, with strings of stuff and big protein chunks in glommed up 'complexes' everywhere you turn. Molecular distances are measured in Angstroms, where one Angstrom is 1/10th of a nanometer. A typical enzyme protein is, on average, about 4-5 nanometers in diameter (40-50 Angstroms) when its amino acid polymer chain is all velcroed up on itself (i.e. the protein is 'folded').  An enzyme can be sequestered over in one region of a cell (which is about a picoliter, or a billionth of a liter, for a human white blood cell), thousands of nanometers away from its substrates and with protein after protein in between them. Having an obstacle course of proteins between you and your substrate is a lot different from only having a bunch of tiny water molecules filling that distance. Proteins do not get out of your way easily the way water molecules do--however, they do sometimes actively facilitate your travels to bring you to your substrate (through their own enzymatic machinery functioning as kinetic motors). Also, you might just end up next door to some other substrate that you don't like that much, that doesn't stick very well in your sticky pocket, but hey, you're hanging around in the same locale and what the heck. You might crawl from there to some other molecule of another substrate in a complex next door, without ever letting completely go and floating away (the way the traditional understanding of enzyme reaction rates assumes is happening).

These factors and differences play a major role in actual biological enzyme catalysis, and add so much complexity to the system that these simple Michaelis-Menten models break down. It's analogous to the difference between Newton's Law of Gravity and General Relativity. The rates could be either faster or slower than you would expect from how sticky the enzyme pocket is for the substrate (faster because of proximity increases for the substrate, slower because of more chances of sticking to something else nearby including inhibitory, grabby product, and not being released to find another molecule of substrate), and we don't have good ways of measuring these effects to any accuracy yet. This will be the next challenge for biochemistry, to update this model and incorporate all of these complex molecular interactions into a fuller, integrated picture of how these machines work inside the cell. This is, to put it simply, a loooooong way off. But we need to remember as modern scientists how much we can do when we make the best possible assumptions we can with all of the information we have available, are rigorous about defining and remembering those assumptions, and not be afraid to ask these kinds of questions just because they are hard.

Menten didn't stay in Germany--she went to the University of Chicago to complete a PhD degree (because Canada didn't allow women to get PhD degrees at the time--way to go, dudes). She went on to publish other work and be very successful as a faculty member at the University of Pittsburgh--where, surprise surprise, she wasn't promoted to full professor until she was 70 years old and had been there for 26 years. From all accounts available, she was a fascinating person, researcher, doctor and painter, and was multifaceted and accomplished in all aspects of her life. Also interestingly, I don't see any discussion of her family or marital status in the sources I've trolled through (admittedly briefly)--it's nice to know that a woman's accomplishments can be discussed independently of whether or not she had a husband and children. I wonder why I never knew Menten was a woman before now. I'll make sure to tell my students about her.

__________________________________

Johnson, K., & Goody, R. (2011). The Original Michaelis Constant: Translation of the 1913 Michaelis–Menten Paper Biochemistry, 50 (39), 8264-8269 DOI: 10.1021/bi201284u

4 responses so far

My lab equipment

(by chemicalbilology) Aug 26 2011

is like a bunch of bratty teenagers. Every time (every TIME!) we're really getting rolling, a bunch of people are up to speed, we're about the launch off on a bunch of paper-completing experiments...

it's like a beaver dam where little leaks start springing everywhere and everyone has to drop what they are doing and run around trying to stick their fingers in the holes.

And by the time we get it figured out (>$5K later), all the momentum is lost and it is like starting over. Then, the cycle begins again.

3 responses so far

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