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Comment: Re:Breach of Contract not necessarily IP infringem (Score 1) 372

by mauthbaux (#39585535) Attached to: The Supreme Court To Rule On Monsanto Seed Patents
Okay, I really need to start reading TFAs and stop posting during the hours when I should already be asleep.

So as some have pointed out, there was no contract between Monsanto and the farmer in question. So this does go back to an IP infringement case, contrary to my previous post. However, I do stand by my previous statements regarding the need for refuge areas, and the need to monitor GM crops to ensure they are in compliance with refuge requirements. Consequently, the farmer in question is potentially dealing a regulated crop while flouting the associated regulations. But then again, I'm not privy to every detail of the case, and may as well be talking out of my ass.

Comment: Breach of Contract not necessarily IP infringement (Score 2, Informative) 372

by mauthbaux (#39582009) Attached to: The Supreme Court To Rule On Monsanto Seed Patents
As I understand it, the issue with the replanted/cleaned seeds is a matter of intentional breach of contract rather than one of patent infringement. When you purchase their seeds, you purchase a license with them that prohibits the replanting/cleaning of the seeds. So whether or not IP was infringed is essentially irrelevant to the stipulations of the contract itself.

Monsanto discusses the topic on their FAQ concerning Food Inc. http://www.monsanto.com/food-inc/Pages/default.aspx

There's also a practical reason behind preventing the cleaning and replanting of seed. Since these seeds contain a pesticide (Bt derivative), a necessary step to maintaining the efficacy of the pesticide is planting a refuge (non-GM section) as part of the crop. If the whole crop expressed the pesticide genes, we could expect resistance to develop very quickly, but by adding in refuge areas the selective pressure decreases. The size of the refuge varies depending on the mix of proteins being expressed, and is determined by the EPA. These non-GM refuge seeds are sometimes mixed in with the GM ones at specific ratios. By cleaning/replanting the seeds, the ratio of GM to non-GM seeds changes, and the size of the refuge is no longer controlled. This creates a situation similar to the over-prescription of antibiotics that we're all familiar with; resistant pest strains will appear much more frequently. So there are reasons other than simple greed behind these contracts.

Disclaimer: I'm currently employed at Monsanto, but contracted through a third party. I am not authorized to speak on behalf of the company, and my comments should not be interpreted as such.

Comment: Bit of an Explanation... (Score 4, Informative) 30

by mauthbaux (#39004729) Attached to: FDA Unveils Biosimilars Guidance
Since there seems to be a bit of confusion here, allow me to explain (inadequately I'm sure) why different manufacturing processes for biologics result in non-identical molecules even though the DNA sequence and folding of the amino acids is the same.

One of the primary differences is in the glycosylation of the protein. This is where sugar groups of various structures are attached to the outside of the protein and act as a sort of label to the body (distinguishing self from non-self proteins), and even within the cell itself (identifying where the protein should be placed inside of the cell). Different organisms each have their own system for attaching and interpreting these sugar groups. For instance, typical yeast Saccharomyces cerevisiae has a glycosylation profile that will cause the human immune system to attack it eventually - which will make you have an adverse reaction not only to the drug that you're taking, but any other drug produced in the same organism. The yeast Pichia pastoris has a glycosylation profile that is superficially similar to a human one, making it less likely to cause an adverse reaction, but the organism is locked down by patents. Furthermore, there's some evidence that the glycosylation is affected by the health of the cells in the culture, and the media that you're culturing them in. Frequently we'll just coat the proteins in polyethylene glycol and hope for the best.

The other place that variation occurs is in the purification processes that are used to separate the drug molecules from everything else. Many of the purification processes will alter the glycosylation profile or the folding of the protein. They're also generally rather lossy, in that the purer the protein you want, the less of it you'll end up with, and the more it will cost. We used to attach tags to the proteins so that they were easier to purify (his6 was a common one), but then there were concerns that the tag itself would become the target for an immune reaction (which, like the glycosylation, would make a person resistant to not only the drug they were taking, but any other drug that used the same tag), so the practice has been mostly discontinued.

The simple fact is that biologics will always result in mixed batches of molecules, and different manufacturing processes do directly affect that mix. The trick for biosilmilars will be to ensure that their mix is functionally similar enough to the original one; which will likely require clinical trials - meaning that cost savings won't be nearly so drastic as it is with small molecule drugs. While we've figured out how to make DNA translate to a protein of our choosing, we're not nearly as knowledgeable about how to manipulate sugar groups in a similar manner. Progress is being made for sure, but we're not there yet.

Comment: similar tech using proteins instead of genes (Score 1) 209

by mauthbaux (#37394166) Attached to: Training an Immune System To Kill Cancer
There's a company called Argos therapeutics http://www.argostherapeutics.com/ which uses proteins harvested from cancer biopsies to do the same thing. Last I checked, they were in phase 2 clinicals (efficacy testing). This is as close to personalized medicine as anyone is really able to do right now. Disclaimer: the only tie to the company that I have is that I interviewed there a couple years ago (didn't get the job unfortunately).

Comment: Re:Inflation (Score 1) 696

by mauthbaux (#36933266) Attached to: Seigniorage Hack Could Resolve Debt Limit Crisis
As I understand it, the typical American has more debt than they do fungible assets. Inflation only means that they'll have less relative debt burdening them. Of course, there's a multitude of other less desirable consequences of hyperinflation, but I'm sure a competent marketing company could make the public welcome such changes.

Disclaimer: I'm not an Economist; not even one of the armchair variety.

Comment: Re:Posted AC, any Biologists here? (Score 1) 550

by mauthbaux (#36805914) Attached to: Re. medication requiring a prescription:
This isn't a topic that I'm honestly all that familiar with (neither the lab in a box nor HGH specifically), but I can offer some speculation.

For HGH, you're lucky in that it's actually a protein, since producing proteins with a specific structure is relatively straightforward. To grow your own, you'll need the gene in a plasmid or some other vector. For a eukaryotic host (CHO or yeast typically), you can clip the gene out of any human cell and put it in (this is far more difficult than I'm making it sound). For a prokaryotic (bacterial) host, you'll need to extract RNA from pituitary gland cells, make cDNA, and then insert that into the vector. Prokaryotic hosts are easier to work with, but do present problems with the immunogenicity of the end product; eukaryotic hosts are generally less stable over several generations and pickier about their growth conditions, but do generally provide the post-translational modifications that will keep the stuff from making you sick. Chances are that someone has already constructed a plasmid with the gene in it; which can save you a lot of effort. Get the plasmid with the gene, pop it into a suitable host, and start growing it. Purifying it afterwards can be simple or complicated, and unfortunately that's not my area of expertise. Growing the organism could be done in shake flasks, which would put it well within the capabilities of a DIYer, but purifying is more complicated. Your best bet for purifying is to use a protein A column loaded with anti-HGH antibodies, and then doing an acid elution to pull the product off the column. It's not cheap, and it's easy to mess up, but it can be done. Again though, purification isn't my area of expertise.

Now, concerning the lab in a box, the idea does sound rather appealing. What you have to realize is that synthesizing a DNA construct, getting it into a microbe, and then getting the microbe to grow while maintaining that construct are 3 different processes. Right now, for most of the oligos, primers, and other DNA constructs we need, we outsource the synthesis. Short ones (20bp or so) come back quickly, but a custom 170bp sequence that we designed took around 3 weeks to be delivered. HGH has 191 amino acids, which means that the DNA sequence is 573 base pairs long; minimum. The longer the sequence, the more likely the chances of introducing errors, and the longer it will take to synthesize in usable quantities. If there's not too many introns in the gene, PCRing it out would be the approach that I'd take, but that would add unnecessary complexity to the lab in a box concept. Anyway, before this turns into too long of a rant, the problem that you're still going to run into is in purifying the resulting protein. Some proteins are easier to purify than others, and there are some ways to make it easier (his6 tags for instance), but I'd still be very hesitant to use anything produced this way as a therapeutic. Still, a system that could pop out a microbe with a specific transgene would be very useful. For simple genes, yeah, I'd think it would be fairly plausible. If you want to synthesize something complex though such as chaperonins, or molecules that require extensive post translational modifications, I can't imagine anyone pulling it off without a firm understanding of the underlying molecular biology. Hopefully I've answered your questions.

Comment: Re:Posted AC, any Biologists here? (Score 4, Interesting) 550

by mauthbaux (#36786928) Attached to: Re. medication requiring a prescription:
Biologist here, and currently employed by a major pharma company.
From what I've seen, the major cost in developing new treatments is in clinical trials. The R&D work is comparatively cheap. The major obstacles for a DIYer in developing a treatment are 1: producing and purifying enough of the substance to test. 2: demonstrating that the treatment is safe (phase 1 of a clinical trial) and 3: demonstrating that the treatment is effective (phase 2 of a clinical trial). As a DIYer, the typical clinical trials can be supplanted with trials in animal models (if available) until a major pharma company buys it up to fund the actual trials. The process can be expedited a little bit if you get what's known as "Orphan Drug Status" (i.e. nobody else is working on this illness since there's probably no money in it) which can grant you additional funding, and streamlines the FDA's approval process; but it's still not a guaranty of any sort.
Now, if a DIYer comes up with an effective treatment, and can produce it consistently at reasonable concentrations, then open-sources the formulation and production method, I'd still expect the FDA to step in to try and regulate it. Concerning your penicillin example, even though the molecule and production methods are well known, it's not something that the average joe can produce at home (not at therapeutic doses anyway), and it's still not something that can be sold over the counter. DIY biotech therapeutics is a good starting point, but it won't get to market without FDA approval, which, thanks to the cost of clinical trials, basically requires corporate sponsorship.

Comment: Re:"Health Care" (Score 1) 642

by mauthbaux (#35843002) Attached to: Need a Receipt On Taxes? The Federal Tax Receipt
I'll admit, it's technically not zero coverage. But assuming something rather severe happened to my health, I'm still faced with the choice to either A: die. or B: bankrupt both myself and my immediate family (as well as possibly my extended family) for the foreseeable future. Honestly, I'm not a cruel enough person to choose B. I know there are instances where the costs get covered, and I do personally know people that have had that happen, but I also personally know people who have been forced to sell their houses over medical debts of relatives.

Comment: "Health Care" (Score 2) 642

by mauthbaux (#35837104) Attached to: Need a Receipt On Taxes? The Federal Tax Receipt
Personally, I'm still rather irritated that a significant portion of my taxes went towards 'health care', and yet I still have zero coverage. I realize that this particular discussion has been beaten to death around here, so don't feel like you have to reply. I just want to complain about it somewhere.

Comment: Re:Pirated copies are good for viewing... (Score 1) 199

by mauthbaux (#35109210) Attached to: Piracy Boosts Anime Sales, Says Japanese Government Study
In a lot of cases, I'd agree with you. Unfortunately, the release schedule stateside is fairly ridiculous. Take Soul Eater for example. Originally broadcast in high def in Japan, episodes were subbed and sent to the streaming sites within a couple of days. Funimation took nearly a year after the original broadcast to start releasing the DVDs (in SD) here in the states. High-def legitimate versions of the series are still unavailable (nearly 3 years after the original broadcast).

Example 2: FLCL.. 6 episode series, 24 minutes each. Originally released here for $30 a disc, and each disc contained only 2 episodes. Do the math, and you end up paying around $0.63 per minute... At the same rate, the first season of the series "Fringe" would cost $630.00 instead of the $30 (approx) it's currently retailing for. Corporate greed and obscene levels of markup drive a lot of us to find other means of acquiring entertainment. It's gotten better recently, but still not on par with domestic releases.

Honestly, I've got a couple hundred legally purchased anime discs on my shelves. There's a lot more that I would purchase if it were available, but there simply no reasonable commercial means of acquiring it.

Comment: Re:Central Dogma? (Score 4, Interesting) 196

by mauthbaux (#34168584) Attached to: Central Dogma of Genetics May Not Be So Central
Actually, as I was taught it (which, I will readily admit, could be wrong), Central Dogma is in fact the proper term, though the definition has been tweaked over time.
Originally it stated something along the lines of, One DNA gene is transcribed into one RNA transcript, which is then translated into one protein.
The discovery of antibodies threw that concept out the window. Variability in intron splicing and recombination means that a small handful of genes can yield a huge variety of protein products (See VDJ recombination).
Yet another twist was added with the discovery of retroviruses which reverse the direction of transcription, turning RNA into DNA. Previously we had thought the central dogma to be unidirectional.
The more we learn about life's mechanisms, the less surprised we are when exceptions to the rules are discovered. Evolution really is the ultimate hacker; constantly expanding the usefulness of very simple resources.

Also, kudos on the evangelion reference.

Comment: Re:What? (Score 1) 414

by mauthbaux (#33181456) Attached to: Genetically Modified Canola Spreads To Wild Plants
Sounds nice in theory, but it's not as easy as you make it appear. First of all, modifying a plant is far more difficult (due primarily to the cell wall) than modifying a bacteria or animal cell. Viral vectors are limited by transgene size and target species, and gene guns are somewhat of a crap shoot. Add in plants' very high tolerance for polyploidy and polysomy, and it becomes quite difficult to add in an effective kill switch.

So, major structural changes that would prevent cross-breeding are out because
1: the knockout/knockin transgenes are simply too large for available vectors.
2: pollination efficiency would likely drop through the floor, making it ultimately unsustainable.
3: assuming you used the structures of some existing species, you now have to worry about your other transgenes spreading to those species as well (admittedly, this is unlikely, but still needs to be considered).
Artificial Chromosomes are out because plants will happily tolerate most all of the mismatch errors which would kill animal cells.
Making a gene metabolically expensive so that it confers no evolutionary advantage (and thus would not be preserved in wild populations) is essentially asking your crops to fail. You could compensate with more fertilizer, pesticide and water, but the extra maintenance required would defeat the purpose of growing GM crops in the first place.
Killswitch genes perhaps? They have plenty of their own problems too.

So, what mechanism would you propose?

TL;DR Breeding incompatibility with wild crops sounds nice in theory, but it's problematic to implement. Also, sorry if my rant is illogical/incoherent, It's the weekend, and my brain's on break as well.

Comment: agreed! (Score 3, Interesting) 71

by mauthbaux (#29654283) Attached to: Startup Offers Pre-Built Biological Parts
First, I agree completely. I can't tell you how much time a program like that would save.

I'd just like to add in a quick feature request. It would be very nice if it could take the .ab1 files from sequenced clones and quickly align and compare them to the theoretical construct, and then indicate what needed to be done differently. For example, "your inserts are forming concatemers: adjust their concentration relative to the vector during the ligation step, or treat them with CAP (alkaline phosphatase)." or "this particular sequence has internal cut sites: use this restriction endonuclease instead."

The software that I'm using now does allow you to figure out situations like the above, but all it does is alignments; Analyzing the reasons why something didn't work out takes guesswork, and the comparisons prettymuch have to be done manually. For the concatomers example, I'd have to back to my original insert sequence, make a text document of the DNA sequence, import multiple copies into the program, reverse a couple of them (sense/anti-sense), and then manually align the second and third copies. It's very time consuming when it really shouldn't be.

Comment: Plasmids kinda do this already. (Score 2, Interesting) 71

by mauthbaux (#29654197) Attached to: Startup Offers Pre-Built Biological Parts

'I'm interested in transitioning biology from being sort of a craft, where every time you do something it's done slightly differently, often in ad hoc ways, to an engineering discipline with standardized methods of arranging information and standardized sets of parts that you can assemble to do things.'"

To some extent, this is already done with common bacterial strains, and the plasmid vectors we already use. Most of the plasmids we use in the industry have specific sets of features such as multiple cloning sites, inducible repressors, ORIs, antibiotic resistance sites etc... You need a plasmid that has a kanamycin resistance gene, high copy number, will add a His tag to your product, and lacks cut sites for a particular restriction enzyme? It's likely in the catalogues already. And if what you're trying to assemble is already in the catalogues, it's a target that may not be worth pursing anyway, since you're unlikely to get a publication or a patent off of it.

The approach he seems to be pushing here seems to be analogous to buying a car piece by piece rather than as a pre-assembled package. The difference is that while average joe has no idea how to fabricate a synchro for his transmission, your average molecular biologist is already quite adept at designing primers and cloning fragments out of a cDNA library. The hard part for the scientists is then characterizing, validating and optimizing the expression of their target; and then later demonstrating the functionality of the product. To continue the analogy, it would be showing that the car ran, was reliable, and was safe for the passengers. Having readily available gene circuits (the famous lac operon for instance) may help with the planning and initial development, but it really won't speed up the bulk of the work we do.

I'll readily admit that many of the expression/knockout constructs are somewhat ad hoc in nature, but interoperability isn't typically a concern. The thing is that evolution is a pretty laissez faire system where "duct tape and bailing wire" construction is more often the rule than the exception. Nature cares about what works, not about what conforms to standards (codon-amino acid translation being the biggest exception that comes to mind). As a result, expression systems have to be tailored to the organism that they'll be expressed in. For instance, bacteria cannot express functional mammalian genes unless the introns are removed from the sequence first. Sufficiently large yeast proteins will cause an immune reaction because the glycosylation patterns are recognized as foreign. Many genes won't be expressed very well at all unless the regulatory elements in the flanking sequences are also included. Once you start looking at things like inducible expression and tissue-specific expression, things get even more complicated, and more varied between species. In short, it's complicated, and the idea of instituting standards to achieve interoperability between expression systems is pretty much a pipe dream.

In short, I have my doubts about the plausibility of this plan, and I'll be mighty impressed if he pulls it off.

Never appeal to a man's "better nature." He may not have one. Invoking his self-interest gives you more leverage. -- Lazarus Long

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