How many genomes did I just squash?

Yesterday was a good day for catching up on the literature; not only did I finally get around to the IL28B papers I blogged about yesterday, but I also took a run through the genome fusion paper which is being seen as the fitting marker of the end of the "Communicated by" mechanism of PNAS (sample coverage by In The Pipeline and Science, though the latter requires a subscription).

The paper, by Donald Williamson and communicated by Lynn Margulis, takes the position that " in animals that metamorphose, the basic types of larvae originated as adults of different lineages, i.e., larvae were transferred when, through hybridization, their genomes were acquired by distantly related animals". This is a whopper of a proposal and definitely interesting.

Margulis is famous for proposing the endosymbiont hypothesis to explain mitochondria and chloroplasts and other organelles. The gist of it is that some ancestral eukaryote took in a guest species and in the long run integrated it fully into its operations so that the two could not be separated. An important observation which this explained is the fact that mitochondria and chloroplasts have their own genomes, which encode (almost?) entirely for proteins and RNAs used in these structures. However, their genomes do not encode many of the proteins required -- indeed in metazoans such as ourselves only a tiny pittance of genes are encoded by the mitochondrial genome. A further observation which fits into this framework is the curious case of Cyanophora paradoxa, a photosynthetic organism whose chloroplast-like structure is surrounded by a rudimentary cell wall.

When I was an undergraduate, there was still significant controversy on the validity of the endosymbiont hypothesis. I remember this well, as I wrote a term paper on the subject. What really nailed it down was the careful comparison of gene trees in the cases where the same function is required both in the organelle and in the cytoplasm and both are nuclear encoded. In the vast majority of these cases, the two are evolutionarily distant from one another and in the case of chloroplasts the gene whose protein goes to the chloroplast looks more like homologs in cyanobacteria and the copy producing cytoplasmic protein looks more like homologs in non-photosynthetic eukaryotes. There are some fascinating exceptions, such as cases in which one gene does double duty -- via (for example) alternative splicing or promoters including or excluding the chloroplast targeting sequences.

Margulis and others have tried to extend this notion to other systems. There are definitely other success -- unicellular organisms which appear to carry three genomes & the always challenging to classify Euglena, which appears to be a genome fusion. But there have also been some prominent non-successes, such as the eukaryotic flagellum/cillium. Also when I was an undergraduate a Cell paper made a big splash claiming to find a chromosome associated with the basal body, the organelle associated with flagellum synthesis. However, this work was never repeated and the publication of the Chlamydomas genome failed to find such a chromosome.

After reading the paper at hand, I'm both confused and disappointed. The confusion is embarassing, but the paper goes into a lot of detail on taxonomy and gross development of which I'm horribly ignorant. But, conversely the disappointment comes from what I do understand and how cursorily that is treated. And since it is the stuff I understand which is the route Williamson proposes to test his hypothesis, that is a big let down.

A key part that I do understand (minus a few terms I hadn't encountered before), with my emphasis:

Many corollaries of my hypothesis are testable. If insects acquired larvae by hybrid transfer, the total base pairs of DNA of exopterygote insects that lack larvae will be smaller than those of endopterygote (holometabolous) species that have both larvae and pupae. Genome sequences are known for the fruitfly, Drosophila melanogaster, the honeybee, Apis mellifera, the malarial mosquito, Anopheles gambiae, the red flour beetle, Tribolium castaneum, and the silkworm, Bombyx mori: holometabolous species, with marked metamorphoses. I predict that an earwigfly (Mercoptera Meropeidae), an earwig (Dermaptera), a cockroach (Dictyoptera), or a locust (Orthoptera) will have not necessarily fewer chromosomes but will have fewer base pairs of protein-coding chromosomal DNA than have these holometabolans. Also the genome of an onychophoran that resembles extant species will be found in insects with caterpillar or maggot-like larvae. Onychophoran genomes will be smaller than those of holometabolous insects. Urochordates, comprising tunicates and larvaceans, present a comparable case. Larvaceans are tadpoles throughout life. Garstang regarded larvaceans as persistent
tunicate larvae, and, if so, their genomes would resemble those of tunicates. But if larvaceans provided the evolutionary source of marine tadpole larvae, their genomes would be smaller and included in those of adult tunicates. The genome of the larvacean Oikopleura dioica is about one-third that of the tunicate Ciona intestinalis, consistent with my thesis

Williamson is obviously not an expert on genomics, but Margulis should have known better and pushed him to improve this section. In the "communicated by" path, the academy member can basically hand-pick the reviewers and is supposed to act as an editor would.

The first problem is a rather naive view of genome size and evolution. Genome sizes vary all over the map even within related species; Fugu to salmon is several fold as is fruit fly to malaria vector. The latter pair is particularly relevant since these are both dipteran insects, and therefore in the same bin by Williamson's standard (as stated in the quoted text). Now, that is overall genome size; if you restrict to protein coding regions these pairs are more similar, which leaves some wiggle room. But, by the same token the Oikopleura and Ciona genomes contain about the same number of genes (~15-16K).

But furthermore, his hypothesis should be quite testable right now, at least in a basic form. If a genome fusion occurred, then genes active in larval stages and genes active in the adult should show different gene trees if they are homologs. Given that there is a lot of data to annotate which Drosophila genes are active when, this should be a practical exercise. While I leave this as an exercise for the student, I would point out that it is already known that in Drosophila many proteins are active in both phases. This can probably also be tallied in some fashion. I'm guessing that the fraction of genes shared between stages will be quite large, which would not be very supportive of the fusion hypothesis.

Should a paper like this get into a journal such as PNAS? Given what I've written above, I think not, simply on its demerits. On the other hand, crazy hypotheses do need a place to go because they are sometimes the right hypotheses -- Margulis's formulation of endosymbiont hypothesis had very tough sledding on its path to the textbooks. However, in the modern world there is a place for odd speculations and journeying outside your expertise. It's called a blog!

Williamson DI (2009). Caterpillars evolved from onychophorans by hybridogenesis. Proceedings of the National Academy of Sciences of the United States of America PMID: 19717430

Quite unlike Caesar's Wife

Massachusetts is buzzing with the news that the Mass Biotech Council, an industry group, had closed in a candidate to replace the ethically challenged former politician who had resigned as the previous president. The big news isn't only who it is, but the fact that the same person has been cleverly multitasking by nearly simultaneously interviewing for the MBC job & writing the Patrick administration's big biotech program. Uh, oh.

It's truly sad. Biotech generally has a good public reputation and is viewed as different than Big Pharma. Squandering that good will by even appearing to be engaged to double-dippers is disappointing. Many more shenanigans like this & biotech will be viewed as just another big business playing the corrupt political gain for private benefit at public expense.

The Globe has also reported that the MBC is looking less-and-less like an organization run by biotech executives and more-and-more like a pure lobbying group. I've attended some MBC-sponsored seminars and they were quite good. I'm not naive enough to think that lobbying isn't useful, but it is equally naive (but in the other direction) to allow it to take over.

It isn't hard to see how that slippery slope is entered. Millennium once sponsored a role-playing simulation, and Tom Finneran (the former MBC head who resigned after being convicted of corruption) is a charming guy. He'll charm your socks off. He'll activate every charm-induced promoter in your genome. But he also made the MBC look to the public like just another cushy landing for a charming pol.

When Imagination Trumps Science

I recently finished an interesting book that was a pure impulse item at the local library -- those scheming librarians put books on display all over to snag the likes of me! Imaginary Weapons is the saga of various Department of Defense funded efforts to develop a new class of weapons based on some exotic physics, efforts that are characterized by the steady flow of funding to a scientist of dubious quality to work on a phenomenon that is unrepeatable. My tax dollars at work!

The book is flawed in many ways, and some squishy details at the beginning set me on edge. There is also a lack of a good description of the exact topic being discussed (clear isomers of hafnium), and the author all too often uses 'hafnium' as a shorthand for 'hafnium isomer', even when she is discussing nearby the ordinary, stable form of hafnium. There is also an excess focus on the strange setup of the key experimenter, who uses salvaged dental X-ray equipment for the crucial test. This is probably not the right gear, but the question why is never explored.

The key figure running the 'experiments' (to use the word charitably) is constantly updating what the doubters should have found to reproduce his experiments. "I know signature X was in the paper, but I now know you should look for Y". Negative controls -- forget about it; they were flatly refused.

The truly sad part were the enablers at DARPA, the Defense Advanced Research Projects Administration. DARPA is supposed to fund longshot stuff, and so it could be argued this work was appropriate initially. But to keep sinking money into a clear incompetent, that is the travesty.

The author actually interviewed most of the participants in the fiasco on both sides, but she really missed the golden opportunity. When asked why this research kept being funded, despite criticism from anyone with standing in the physics community, the answer was always that the applications were so promising and it was DARPA's job to fund high-risk, high-reward science. The question that apparently went unasked is 'why this topic'? Why pour so much money into hafnium isomers, rather than zero point energy or antimatter or antigravity? Once you've decided to ignore the recognized experts in a field, how do you go from there? Of course, one can hope this works as 'push polling' to reconsider the meaning of science, but more than likely the next budget request would include funds for the research arm of the Jedi Knights.

Supporting important science that isn't initially respected is a challenge. Biology has plenty of examples of scientists who fought orthodoxy and ultimately were proven correct: Mendel (genetics), Roux (oncogenic viruses), Prusiner (prions), Langer (drug release systems), Folkman (angiogenic factors), Marshall (H.pylori & ulcers), Brown (microarrays) & Venter (whole genome shotgun is just a tiny list. But it is also important to balance that against the stuff that was dodgy then and is still dodgy now, such as Moewus and Kammerer and a host of others. Even if what you claimed to do is eventually done, that doesn't mean you were right -- the claim of cloning a mouse in the 70's has nothing to do with the reality of cloning a mouse in our time. What separates the good fringe science from the crankery is an attention to the criticism, not ignorance of it. I've heard both Langer & Folkman speak, and they clearly kept addressing their critics concerns in their papers. These pioneers also weren't just right; they had done their science well. Mendel found the right laws & his data was generally good; in contrast the uniparental mouse of the 70's is still a fraud despite mammalian cloning ultimately playing out.

Bad work in the guise of science, either outright fraud or self-deception (what Feynman termed 'cargo cult science') will probably be with us forever. Great travesties have been perpetrated claiming to be scientific (e.g. the Tuskeegee syphilis horror). This year's big investigation is bubble fusion; last year's was cloning & next year it will be something else. Reading about science gone wrong isn't much fun (well, the N-ray expose is fun to contemplate!), but it is necessary.

Here a pedia, there a pedia

There's a lot of science blog activity debating the utility of Wikipedia (e.g. Eye on DNA, Wired Science, Science Roll, Epidemix), and I've never been one to not jump on a good bandwagon. In general, I think the various viewpoints agree more than they disagree, but there is a significant divergence of opinion on whether Wikipedia can be saved from itself. I will boldly and decisively plant my flag in the mushy middle.

I find Wikipedia very useful as a general reference (and often link to it from here), but it is clearly flawed. The anonymous nature has always given me the willies. In general, I have found the information pretty good, but often maddening. For example, I was looking up a particular branch of Protestantism today (in the interest of general knowledge), and unfortunately the entry was written by a true believer (and not flagged) -- surprising, since usually WP bends over backwards to flag everything not written in a neutral style. A friend once asked me for some help for her daughter's high school project on serotonin, and I was surprised to find the Wikipedia entry lacked any history of its discovery (but did I edit it then -- no! -- however, it does look like its gained a little bit on the history). Some Wikipedia entries have absurd levels of depth, whereas others are too shallow.

Back in grade school the library always had multiple encyclopedias, which often had different strengths and levels of detail. At home we had both Junior Brittanica and Encyclopedia Brittanica, though both purchased before my entry into this world. I quickly learned that my then favorite topic was badly truncated, with the big one ending during the early Mercury shots and the Junior set going into Gemini (I think). Wikipedia is amazingly up-to-date, with events showing up there before the newspaper with the same info can hit the street. But in any case, the world is probably best served by competing encyclopedias.

An alternative to Wikipedia has been launched called Citizendium, and the model has some interesting differences from Wikipedia. Contributors will be non-anonymous and a much more limited in number, and generally chosen for recognized authority. Alas, Citzendium is pretty limited in coverage. Looking at my last post, things are pretty bad. 'Ailuropoda' brings up nothing, whereas the first hit for 'panda' is to an article on creationism (those poor hypercute ursids, commandeered for pseudoscience!). 'Dodder' brings up articles on horizontal gene transfer. Wikipedia's article on serotonin is flawed, but Citizendium's is non-existent, though there are articles on neurotransmitters and Julius Axelrod. Even more striking, 'Watson-Crick' pulls up nada. Yikes!

What is potentially interesting is that Wikipedia is on a 'copyleft' model, which theoretically means Citizendium could (and plans to) use Wikipedia as a major building block for their effort. So, it is possible that Citizendium will evolve to largely be a buffered version of Wikipedia, slower to be updated and smaller in scope, but with the worst excesses filtered out. Of course, the copyleft also means Wikipedia can raid Citizendium for the improvements. Let's hope this works out to a virtuous cycle.

For the sake of completeness I feel I must include the other heavily publicized encyclopedia effort, but I can't recommend it. Conservapedia is an explicitly ideological view of the world. In particular, it attempts to be even-handed towards various branches of creationism. So the article on the speed of light (at this time of writing) touches on the 'minor' problems it creates for young earth creationism and cites only a creationist tract, but doesn't discuss at all Michaelson-Morley. We learn that kangaroos originated in the Middle East. Now, if you dig you can find that some folks who like the general concept but not the anti-science are trying to contribute

Wikipedia is flawed, but what to do? The eager can try to reform Wikipedia or lead the expansion of Citizendium. But if Don Quixote is your hero, then perhaps you'll try to keep Conservapedia on the straight-and-narrow.

Clearing the Gene Patent Thicket

The gene patent issue, which I addressed once before, continues to boil. Derek Lowe has two good back-to-back posts (with another anticipated) on the topic, triggered by a Michael Crichton OpEd piece in the NY Times. A few weeks back there was another opinion piece in the Sunday NY Times, which Hsien Hsien Lei has covered over at Genetics & Health(NY Times articles require free registration).

There are really two classes of concerns, and concern holders, in the debate. At the one end you have the Crichtons and many others who feel that any sort of patenting of genes is improper and immoral. At the other you have a lot of people (such as myself) who believe certain gene patents are appropriate, but that there is a lot of confusion generated by the legacy of past gene patents.

I can understand some of the concern of the Crichton camp. It is true that genes are natural monopolies -- in general, one can't invent around them easily if the goal is genetic testing. On the other hand, some of Crichton's complaints are simply those that are generally levied against any intellectual property protection in biomedicine: that it creates 'unnecessary' costs and unequal access to lifesaving information. But, as last weeks approval of the MammaPrint microarray-based breast cancer diagnostic test reminded, private companies do bring important health innovations to market. Without premiums for the investors to cover the very high risk of failure, such innovations might never reach market.

As an aside, the issue of failure in biotech is nicely covered in another of Lowe's postings, though Xoma? What pikers! Only 0.75B gone through in 25 years -- that's only 0.03B/year. I'm pretty sure a certain company in Cambridge that burned off closer to 1.5B in about 12 years, and Celera must have done even better than that in terms of bucks per year.

There are some other issues to consider in this space. If patent law is altered to exclude gene patents, will it exclude multigene tests? If I make a small change in a protein therapeutic, ala Aranesp, is that patentable? Are other purified preparations of natural products, such as natural-product derived pharmaceuticals, still patentable?

For those of us who feel that gene patents are appropriate, but under well defined restrictions, the current situation is clearly a mess. During the genomics gold rush, companies flooded the patent office with applications. The general assumption was that these patents would probably be worthless -- but that nobody could take the chance that the courts & Patent Office would decide otherwise. Until one was litigated, nobody knew how things stood -- and nobody felt they could afford to wait around and potentially find themselves naked. From the regulatory ambiguity of the time sprung a gazillion patents. The paralegals used to book me for an hour at a time just to sign patent forms -- since I wrote the software that tag things as 'worth' patenting, I was a co-inventor or sole inventor on many dozen applications. Most of my applications are dead, but there is a horrible mess out there.

Now these patents would just be irritating if they only gave fodder to writers, but there is a real cost to society of them. I was at a Celtics game recently with a friend and a bunch of his buddies, several from his law firm. One specialized in biotech law and was quite confident that none of those genome era patents would hold up under legal assault. But it is that very risk of litigation that hangs a cloud over everything. If you are working on these genes, prudence says that you must review all of those patents, and perhaps worry about them even though they are junk. The same sort of uncertainty that led to these patents continues to make them a problem.

So, I would like to make the following proposal. It won't interest the 'gene patents are evil' crowd, but I will claim it would make good public policy. An organization should be set up and funded with the goal of retiring mass numbers of the gold rush patents. At regular intervals, the organization would hold a Dutch auction to buy up blocks of patents. You couldn't sell them individual patents, only large batches. Once purchased, the organization would have the patents cancelled (if that isn't available in the current law, then that would require some legislation). Or, the organization would somehow be a legal black hole for the patents, forbidden to ever sell them or defend them in court. Not only would the regular auctions slurp in patents, but they would establish a market value for the patents -- and so profitable companies might just donate blocks of patents instead of selling them to reap tax benefits.

The last thing one would want to do is create more incentive for junk patents. The regular auctions would be capped so that these patents would be selling for cents on the dollar spent to get the patents in the first place. Only patents of a certain age range would be taken, perhaps nothing younger than 5 years old. Nobody's going to make a profit on this, but for companies stuck with lots of essentially worthless patents, this is free money. But because it is delivering a value to society, by reducing the overhead imposed by all those patents, I would argue it is a worthwhile expenditure.

This approach wouldn't solve the junk patent problem, and it clearly wouldn't address the patents that biotech executives think do have value. The controversial ones will all fall in that category, as they are controversial precisely because they can transfer money to entrepreneurs. Public debate about patenting is healthy & appropriate, but let's think carefully about unexpected consequences.

Meow. Achoo! Meow. Achoo! -- a bit longer

For reasons other than predicted, namely an unexpected round of furniture moving, a couple of ideas for this space will continue to stay ideas. But there is an interesting article in The Scientist (you may need a free subscription) on the company which claims to have produced a hypoallergenic cat (to much media fanfare), but has yet to actually produce such a cat for inspection. For those hoping to obtain such a cat, the article would suggest that it will not be exploring your catnip patch anytime soon. As for me, I need to take a catnap...

The Incredible Shrinking Bacterium

How's this for an ecosystem niche: 30-50C (84-122F), pH -0.5 to 1.5. micromolar arsenic & copper and nearly molar iron. That's the witches brew found in an abandoned mine in California. Last week's Science (alas, subscription will be required to read) contains a paper describing one of the archeans that lives in a biofilm in the midst of that awful solution. The bug was identified initially as a novel 16S rRNA sequence in a metagenomics sequencing project. Further sequencing pieced together 4Kb from this bug and another 13K from a related species.

The 16S sequences contain some significant mismatches from commonly used 'universal' rRNA primers, which shows a big advantage of metagenomics for discovering novel organisms: it is unbiased.

Things get really interesting when in situ hybridization was used to localize the bugs -- they are the tiniest well documented organisms yet, roughly 244nM x 175 nM -- a volume of <6nM^3 -- vs. about 20nM^3 for the previous record holder. As they comment, if half the cell is occupied by ribosomes it works out to about 350 ribosomes -- and not leaving much room for anything else.

It is interesting that the paper studiously avoids mentioning nanobacteria or nanobodies. Nanobacteria are microscopic structures which have been claimed to be self-replicating and putatively linked to various biomineralization processes and diseases, but their existence is controversial. Nanobodies are even smaller structures claimed to be biological in character.

I had been thinking about nanobacteria recently in the context of looking at some internet lists of controversial ideas that have become accepted. Nanobacteria struck me as one of the shakier contenders, and a quick Entrez Search (try this) appeared to confirm the concern. In particular, there is a paucity, particularly in recent times, of papers in well known journals. This doesn't mean the hypothesis is wrong, just that calling it accepted is a stretch.

Nanobacteria had a huge spotlight thrown on them when it was claimed that structures in a Mars-derived meteorite resembled nanobacterial fossils. Given the shaky nature of nanobacteria, I wouldn't have wanted to hang my revolutionary theory on it, but NASA went ahead.

What is particularly striking about the nanobacterial story is the lack of confirmed DNA data from such a beast. My Entrez search didn't seem to find any, and the Wikipedia entry states that the only claimed nanobacterial sequence is too close to a common contaminant to be believed, especially since no reagent-only PCR control was run.

If nanobacteria are anything like conventional lifeforms, they should have nucleic acids in them. A metagenomics run through a nanobacterial preparation should find something; in the absence of getting a novel sequence (and confirming that sequence's location in the nanobacteria by in situ), one would be forced to invoke non-nucleic acid life-like forms ala prions -- or honorably admit defeat. In other words, do exactly what this new paper in Science did. Perhaps nanobacterial hunting should be proposed the next time someone is giving away next generation sequencing runs, though I think I know one even better I'll write up here at some unspecified time in the future.

GAO Weights in on Drug Discovery

The Government Accountability Office, or GAO, recently publicly released its report to Congress entitled "New Drug Development: Science, Business, Regulatory and Intellectual Property Issues Cited as Hampering Drug Development Efforts". At 52 pages (including all appendices), there is a bunch to read, and I won't claim to have fully digested it. I certainly might comment further on it at a future date.

Note: if you are reading the electronic version, add 4 to all my page numbers to find the right one with Acrobat; it numbers in its count the various header pages that aren't given roman numberings in the report. I had initially used the Acrobat numbers, so if any turn out wrong try subtracting 4 from the page number.

One graph I am grappling with is Figure 1 on page 8, which shows the attrition of compounds through the development pipeline. The starting line is marked with 10,000 compounds yielding one final drug at the end. The plot certainly deserves showing up on Junk Charts, as it is not what it could be (and what such an important topic requires). For example, several stages are marked with numbers of compounds, but these label trapezoids with no clarity whether the number represents the start or the end of the stage. I'm guessing that the 10K number is estimating initial screening hits (counting in failed programs). The preclinical trapezoid is labeled "250 compounds" -- so that would be 40:1 hits to something (leads?). I'd better quit -- the more I stare at the graphic the more infuriating I find it.

Figure 6 (p.15) shows the depressing statistics: increasing R&D spending but a flat rate of New Drug Applications (NDAs) and especially NDAs for novel molecules (New Molecular Entities, or NMEs). Personally I'd prefer these as two vertically arrayed graphs & both in the same format (why bars for one but lines for the other?), but it does make the point.

Figure 5 (p.17) is the sort to enrage drug industry critics: 68% of all NDAs are not for NMEs. One thing not made clear in the methodology is whether generic drug applications (ANDAs) or supplementary applications (sNDAs, such as for additional indications) are in these numbers.
It would make no sense to include them, but given the high number of non-NME NDAs in their numbers I am suspicious. I'll confess that I'm not fully conversant in the classification scheme used here (any enlightenment attempts welcome!). For example, where would the next statin fall? Nexium? One wonders whether the classifications are really particularly useful.

In the Internet age, it is a travesty that the report isn't accompanied by computer-readable tables of all the data used. This really wouldn't be very difficult, the data is all public information, and would certainly allow other authors to vet the results or bring in their own analysis methods.

One more complaint: the PDF is apparently set so that copying can't be performed out of it! Aaargh!

One section I was planning to blockquote extensively was the section on translational medicine. The report cites one trouble area (p.27) as

... a shortage of physician-scientists, also known as translational researchers--who possess both medical and research degrees and thus the expertise needed to translate discovery -stage research into safe and effective drugs--was seen by panelists and other experts as a fundamental barrier to increasing the productivity of drug development. ... Experts attribute this shortage to a variety of factors, including lengthy training and relatively lower compensation for physicians who are also scientists, compared to those in clinical practice. In addition, researchers, including those in academia, have noted that academic institutions have not taken the initiative to provide financial incentives, such as scholarships, for medical students to pursue these research interests.

Even prior to reading a related discussion on In The Pipeline, I had been thinking out a different strategy. There should be better incentives for Ph.D.-M.D.s (which I'm pretty sure is what the report was tracking), but any program to create more will take a while, and some in it will choose other careers or interests. If you really want to expand the translational medicine pool, then start thinking about option beyond a very narrow credential list. Perhaps the most obvious would be to develop training programs to add skills to existing M.D.s, without forcing them to go the full Ph.D. route.

Slightly more radical woudl be the notion of developing translational medicine nurse-practioners -- after all, nursing training is very focused on patient care & patient observation, and would therefore be very suitable for careers in clinical medicine. The news is often filled with stories of nurses leaving the profession for various burnout reasons -- perhaps this option would keep some of these highly skilled persons in the field.

Going farther out, a lot of translational medicine is around developing and analyzing biomarkers. Again, nurses have many of the appropriate skills, particularly in observing side-effects that may be biomarkers (such as skin rashes observed both for EGFR inhibitors and bortezomib). Other biomarker development projects involving new assays fall clearly in the domain of med techs -- in my college internship I was in a lab staffed mostly by med techs, and that crew would have made an excellent biomarker pursuit team.

Perhaps the most interesting part of the report is the section of suggestions, beginning on p.35
. Tightly summarized they are:

1. Industry-government-academia collaborations to systematically analyze drug failures, develop validated biomarker inventories, and prioritize diseases


2. Bigger push in academia for translational medicine specialists (as commented on above)


3. FDA incentives & disincentives based on importance of a new drug: innovative medicines get the push, the me-tos discouraged. One proposed method would be basing patent life on the innovativeness & clinical value of a drug

Well, I'm out of steam. Comments?

Gene Patents

Today's Parade magazine has an article titled "How Gene Patents are Putting Your Health at Risk". The topic of gene patents deserves public scrutiny & debate, but better coverage than this article.

Featured prominently (with a picture in the print edition) is Michael Crichton, whose new book has been touched on previously in this space. Crichton in particular makes a number of concrete statements, some of which are a bit dubious.

First, let's take the statement

A fifth of your genes belong to someone else. That’s because the U.S. Patent Office has given various labs, companies and universities the rights to 20% of the genes found in everyone’s DNA— with some disturbing results.

. The first sentence is just plain wrong, and given its inflammatory nature that is very poor journalism. Nobody can own your genes -- genes, as natural entities, are not themselves patentable. What can be patented are uses of information in those genes. That is a critical, subtle distinction which is too often lost. What can be patented are uses for genes, not the genes themselves, just as I could patent a novel use for water, but not water itself.

Time for the full disclosure: I am a sole or co-inventor on 11 issued gene patents (e.g. U.S. Patent 6,989,363) , many of which are for the same gene, ACE2. Many more gene patents were applied for on my behalf, but most have already been abandoned as not worth the investment. Those patents attempted to make a wide range of claims, but interestingly they missed what may be the key importance for ACE2 (we never guessed it), which is that it is a critical receptor for the SARS virus.

Many of the gene patents do illustrate a key shortcoming of current patent law. When filing a gene patent, we (and all the other companies) tried to claim all sorts of uses for the information in the gene. These sorts of laundry lists are the equivalent of being able to buy as many lottery tickets for free. A rational system would penalize multiple claims, just as multiple testing is penalized in experiment designs. The patent office should also demand significant evidence for each claim (they may well do this now; I am no expert on the current patent law).

Another one of Crichton's claims deserves at least some supporting evidence, plus it confuses two distinct concepts in intellectual property law

Plus, Crichton says, in the race to patent genes and get rich, researchers are claiming they don’t have to report deaths from genetic studies, calling them “trade secrets.”

First, just because some idiots have the chutzpah to make such claims doesn't mean they are believed or enforceable. Second, such claims have nothing to do with gene patents -- such claims could exist in any medical field. Finally, trade secrets and patents are two different beasts altogether. In a patent, the government agrees to give you a monopoly on some invention in return for you disclosing that invention so others may try to improve on it; a trade secret must be kept secret to retain protection and should someone else discover the method by legal means, your protection is shot.

The on-line version also includes a proposed "Genetic Bill of Rights". I would propose that before enacting such a bill, one think very carefully about the ramifications of some of the proposals.

Take, for example,

Your genes should not be used in research without your consent, even if your tissue sample has been made anonymous.

. What exactly does this mean? What it will probably mostly mean is that the thicket of consent hurdles around tissue samples will get thicker. Does this really protect individual privacy more, or is it simply an impediment which will deter valuable research? Will it somehow put genetic testing of stored samples on a different footing than other testing (e.g. proteomic), in a way which is purely arbitrary?

Another 'right' proposed is

Your genes should not be patented.

.
First, an odd choice of verb? "Should"? Isn't that a bit mousy? Does that really change anything? And what, exactly, does it mean to patent "your genes"?

On the flip side, I'm no fan of unrestricted gene patenting. All patents should be precise and have definite bounds. They should also be based on good science. Patents around the BRCA (breast cancer) genes are the most notorious, both because they have been extensively challenged (particularly in Europe) and because the patent holders have been aggressive in defending them. This has led to the strange situation in (at least part of) Europe where the patent coverage on testing for breast cancer susceptibility depends on what heritage you declare: the patent applies only to testing in Ashkenazi Jews.

In a similar vein, I can find some agreement with Crichton when he states

During the SARS epidemic, he says, some researchers hesitated to study the virus because three groups claimed to own its genome.

It is tempting to give
non-profit researchers a lot of leeway around patents. However, the risk is that some such researchers will deliberately push the envelope between running research studies and running cut-rate genetic testing shops. Careless changes to the law could also hurt companies selling patented technologies used in research: if a researcher can ignore patents for genetic tests, why not for any other patented technologies.

Gene patents, like all patents, are an attempt by government (with a concept enshrined in the U.S. Constitution) to encourage innovation yet also enable further progress. There should be a constant debate as to how to achieve this. Ideas such as 'bills of rights', research exemptions, the definitions of obviousness and prior art, and many other topics need to be hashed over. But please, please, think carefully before throwing a huge stone, or volley of gravel, into the pool of intellectual property law.

Long enough to cover the subject, short enough to be interesting.

That was the advice my 10th grade English teacher passed on when asked how much we should produce for a writing assignment. The context (a woman's skirt) he gave was risque enough to get a giggle from 10th graders of the 80's; probably the same joke would get him in serious hot water today -- unless perhaps he pointed out that the same applies for a man's kilt.

A letter in a recent Nature suggests that the same question that vexed me in my student days also bedevils the informatics world. The writer lodges a complaint against MIAME (Minimum Information About a Microarray Experiment), a standard for reporting the experimental context of a microarray experiment. MIAME attempts to capture some key information, such as what the samples are and what was done to them.

The letter writer's complaint is that this is all a fool's mission, as one cannot possibly capture all the key information, especially since what is key to record keeps changing. All reasonable points.

The solution proposed made me re-read the letter for a hint of satire, but I'm afraid they are dead serious.

How should we proceed? Reducing the costs of microarray technology so that experiments can be readily reproduced across laboratories seems a reasonable approach. Relying on minimal standards of annotation such as MIAME seems unreasonable, and should be abandoned.

.

At first, this just seems like good science. After all, the acid test in science is replication by an independent laboratory.

This utterly ignores two facts. First, by depositing annotated data in central databanks the data can be mined by researchers who don't have access to microarray gear. Second, most interesting microarray experiments involve either specialized manipulations (which only a few labs can do) or very precious limited samples (such as clinical ones); replication would be nice but just can't be done on those same samples.

This "the experiments will be too cheap to database" argument has come up before; I had it sent my way during a seminar in my graduate days. But, like electricity too cheap to meter, it is a tantalizing mirage which fades on close inspection.

Metagenomics backlash.

Metagenomics is a burgeoning field enabled by cheap sequencing firepower -- which grows cheaper each year. You take some interesting microbial ecosystem (such as your mouth, a septic tank, the Sargasso sea), perform some minimal prep, and sequence everything in the soup. The results find everything in the sample, not just what you can culture in a dish.

Now in Nature we can see the backlash -- angry microbiologists irked at uneducated oafs stomping their turf. One complaint (scroll to the bottom) is the oft used term "unculturable species" -- i.e. the new stuff that metagenomics discovers. Quite appropriately, the microbiologists cry foul on this aspersion against their abilities, as the beasties aren't unculturable, just haven't been cultured yet.

The new letter says 'Amen' and goes on to gripe that sequencing unknown microbes is no way to properly discover biological diversity, only culturing them will do.

IMHO, a lot of this is the usual result of new disciplines with eager, arrogant new members (moi?) wading into the domain of old disciplines. According to my microbiology teaching assistant, a molecular biologists is defined as "someone who doesn't understand the biological organism they are working with". Similar issues of "hey, who's muscling in on my turf?" beset chemistry, as illustrated in this item from Derek Lowe's excellent medicinal chemistry blog.

These sorts of spats have some value but aren't terribly fun to watch. Worse, the smoke & dust from them can obscure the real common ground. There is already at least one example of using genome sequence data to guide culture medium design. Perhaps future metagenomic microbiologists will make this standard practice.