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Drug Industry History

Ten Years After: The Genomics Frenzy

So it’s been ten years now since the peak of the genomics craze in the drug industry. Hard to believe! Looking back on these things, it can be hard to recapture the mood, since regretful hindsight keeps blurring the more painful parts. I know that a lot of companies would, in retrospect, rather have back some of the huge amounts of money they spent back in that era, but for every one of those, there’s a genomics company that wishes that they had something that hot to sell again.
Well, actually, that’s not true in every case, since several of those genomics players haven’t even lasted long enough to look back from this far. But at the time, at the time they looked as if they might end up owning the world. Not everyone believed that, true, but I don’t remember many people with the nerve to say so in public. The strongest misgivings went something like “We don’t know if this is going to work or not, but we have to be ready if it does”, which is a perfectly defensible position.
But that was rare – most of the stuff you heard, at least in press releases and the like, ran to “Genomatronic Corp. announces that it has now filed patent applications (a whopping load of patent applications) on another huge, important swath of the vital human genome (remember, there’s only one!), and reminds the industry that its back walkway is open on Tuesdays and Thursdays for Big Pharma to come crawling up it”. Over at Megapharm, Inc., their opposite number, the fear was quite real that the Genomatronics of the world actually were staking out all the deposits of gold, and that all the drug targets in the world were going to end up owned by someone else – like those other big drug companies that were daily announcing huge deals with Genomatronic et al.
It was easy for panic to set in. How much of the genome could possibly be left by now? We’d better do a deal while there’s something to buy! After all, when you got down to it, these folks were right – there’s only one human genome, and we’re only going to read it for the first time once, and all the drug targets that will ever exist are in there – right? So why would you sit there and watch the competition walk off with all the good stuff? Right?
Well. . .not as right as you’d think. The big splash of cold water, at least as I remember it, was when the Human Genome Project folks announced the total number of human genes, and it came in way below what some people had been estimating – like, ten times less. If you added up all the genes that people had claimed to have filed applications on up until then, it was well in excess of the number of genes that turned out to actually exist. This embarrassing patent excess was one problem (some of which could be explained by multiple filings by different companies), but the unexpectedly small number was the other one, and the more worrisome. How could there be so few genes when we knew there there were a lot more proteins than that? And so the importance of post-translational processes finally began to be appreciated by a wider public. It wasn’t “one gene, one protein” – it was “one gene, a bunch of proteins, and we’re not sure quite how or quite how many”.
Another set of problems came on a bit more slowly. The companies that did the whopper genomic deals came to realize that (1) even 50,000 genes was rather a lot, when you had no idea what most of them did, what pathways they fit into, what diseases they might be associated with, and what might possibly happen if you found a compound that affected their associated proteins, and (2) it didn’t look as if we were going to even get a chance to find out about that last part, because most of these things came up empty when you screened against them anyway. These were (and are) all major problems. We still have only fuzzy ideas of what a lot of genes actually do, and we still have a terrible time finding useful chemical hits against a lot of our new targets – more on these later; they’re perennial topics around here.
You still see breathless articles (particularly in the alternative press) about the amount of your own DNA that’s like, patented and owned by the big corporations, man, but the people who write these articles generally don’t know enough to realize that most of that stuff is irrelevant. The patent office has tightened up severely on its requirements for gene patents, and recent court decisions have called the whole idea of patenting DNA sequences into question (more on this later, too). And at any rate, most of these things would be on track to expire without anyone yet finding out what they might be good for.
So where are we now? So, in the end, there was no genomics gold rush, at least not in the way that everyone thought. The genomics players are out of business, or if not, they had to completely retool and find something else to do. Most of their patent applications were wastes of time and money, since they never issued, were generally hard/impossible to defend if they did, and are mostly heading for expiration without having made anyone a dime. The value of the genome is real, but it’s taken (and it’s still taking) a lot longer to realize it than anyone would have believed in 1999. If anyone was predicting this ten years ago, I missed it. It wasn’t me.
Update: Keith Robison lived it from the inside, and tells the tale.

45 comments on “Ten Years After: The Genomics Frenzy”

  1. Retread says:

    It’s terribly off-topic, but it being Martin Luther King day today, and with our first Black president, how many of you chemists, grad students etc. etc. have a Black colleague?
    In my Ivy League class in the 50s, we had one Black in over 700 individuals. In my medical school class of 125 in the 60s, we had one Black (from Nigeria). There were none that I can recall in grad school at another Ivy League institution from ’60 – ’62.

  2. lucifer says:

    Hey.. smart ivy leaguers also thought that exotic financial instruments (CDO, CDO-squared,various CDS, MBS, various DBCPs to name a few) were going to create a new age of financial engineering and moderation. We all know how that worked out.. Curiously many of these very bad ideas also become ascendant in the last 15 years.
    While we should not reject new ideas, we should always be on the guard for exaggerations, scams, group-think and other assorted BS.

  3. Cellbio says:

    Ah Derek, you bring back some fond memories. I lived through this period at a Biotech, and before that I was trained as a molecular biologist, cloning genes with expression behavior that mimicked oncogene’s temporal induction. I then tried to figure out what these did and found how hard it is to run a research program with every experiment a ” let’s look and see if”. I won’t say I knew the genomics effort would fail so broadly, but I was very skeptical. My favorite pitch came from a Boston Co big in the field, they offered the Venn diagram “proof” of their superior approach, and after applying their special sauce to the boundless opportunities in the genome, they identified, drumroll…the chemokine Rantes! Wow, I would have had to read the literature to know about that one. Another great genomics company is now making innovative albumin fusions, like glp and INF fusions.
    Certainly some good will come from the genome, in terms of products, but another point is worth mentioning, IMO. The post-genome era has lessened the value of molecular biology, and restored the need for classical disciplines like pharmacology, enzymology etc. Still somewhat tough to find these folks (without gray hair), but every molecular biologist I know in the biz has retooled, myself included, to fit elsewhere in the process. I wonder if long time chemists had experienced a thinning of support skills amongst their colleagues through the genomics era?
    The last point I’ll make is how I found it interesting to watch the post-genome shuffle of the pitchmen. After the genome, you could hear the following, ah, well, it’s not the genes that matter, its the mRNAs! Off we go to microarray the world! If we know all the mRNAs in a cell, we’ll know the biochemistry of the cell (actual claim of Science editor). Then off course, it isn’t the mRNAs that do the business, and while the genome may be more limited, the protein diversity of a cell knows no end! By the time we get to Metabonomics, we seem to run out of steam.
    Too bad, because I was ready to launch a new company, Omniome. The company pitch can be made in one slide, one giant circle encompassing the various Venn diagrams of failed companies. We would use all techniques to make drugs, molecular biology, pharmacology, chemistry, and on. The effort could not fail, because it would be made superior to the approach of mortals by spending millions of dollars at McKinsey to yield the phrase “seamless integration” which will be included in every powerpoint and hallway conversation with management, which of course will be purged of anyone capable of independent thought. We will start the company with 10,000 employees, immediately finding “synergies” and electing to outsource, thereby reducing our staff to 5 MBAs with fantastic hair, all of which will receive handsome bonuses for spinning wonderful phrases like, “we are really doing you a favor by accelerating your career development decisions”. Fueled by this success, the management team will move on to partner positions in VCs, where they will set the course for the future of our industry!
    Kidding aside, re the MLK diversity question, in my 26 years (student and industry), I have worked with 2 black scientists, one African American, one Nigerian. Research must be a largely invisible world to the African American community.

  4. Todd says:

    Hey, speaking as a proud African-American, the research world isn’t invisible. I think the problem is one of self-reinforcing influence against it (which is the idea that affirmative action is allegedly working to fight). Since few Black people are exposed to the sciences well, few of the best and brightest get into research. Then, unless you’re like me and don’t mind being the token Black guy everywhere you go, there’s a huge tendency to duck out and do something else even if you do end up there. Like it or not, work is a much more social activity than most people, especially in the sciences, care to admit. That’s why you see a lot of bright African-Americans (a cringe-worthy term few Black people use to refer to themselves in casual convo) heading into law and the business world and less into the sciences, with medicine being an exception.
    In terms of the molecular biology world in which I make a living, it’s interesting how the genomic revolution has changed so much. I know a few years back, I had a lot of questions about how the genome was going to cure this, that and the third. I think the thing is that we don’t have a good naildown as to what causes disease states. With efforts like the cancer genome and the 1,000 genome effort, I think we’ll get better answers. On top of that, the developed techniques haven’t gone for naught, especially when it’s been applied to infection diseases.
    However, two things are clear. One, a lot of hype with this technology was a result of people not knowing what the heck is out there. Two, once we figure this out, I think there is going to be a paradigm shift in how drugs are discovered and tested. The difference is that the shift isn’t going to be as dramatic as thought.

  5. Anonymous says:

    Can anyone name a technology which resulted in a lot of hype which was not a ultimately a ‘dismal failure’ in that it didn’t save the industry and also core a apple? The problem is not the technology, the problem is the mentality that seeks a gold rush. Genomics, like rational drug design, HTS and (wait for it) combichem are tools which are useful to help answer specific questions. Ware the backlash, or we throw out useful techniques. Science is hard – even the revolutions just make more hard work for us!
    Seriously, name a technology that was an absolute, unqualified success.

  6. AR says:

    Yeah – there weren’t many Martin Luther’s back then who voiced dissension during the genes to products era.
    In those days, I worked a biology stint for big pharma and kept asking anyone involved in genomics if evolutionary biology would allow a single gene alone to control the fate of a cell? They couldn’t answer – but more to the point, made it perfectly clear that anyone asking those sorts of questions must be of negligible intelligence. Now, I’m not one to applaud senior management at Big Pharma, considering I was on the sort list of those chosen to be outsourced from a job, but at this particular company, it was senior management that began to question the value of genomics based targeting. That was 2003 or thereabouts. By then, of course, most scientists were involving themselves in a new science candy called siRNA.

  7. MTK says:

    Hindsight in this case truly is 20/20.
    I don’t think the idea was bad or oversold for what was known at the time. It just ended up being far more complicated than anyone thought. Out of naivete or ignorance everyone, including the leading scientists at the time, thought that the phenome and the genome would be neatly correlated.
    As I understand it, when the genome ended up being a lot smaller than thought, that’s when the “Houston, we have a problem” moment came. Since then it’s became clear that even the simple phenotypic changes may be determined through the action of many genes.

  8. eugene says:

    Well, all the patents would expire about 15 years from now, right? So, those big evil corporations still have some time to screw people. The ones that are not out of business that is. I remember back at the time, I was impressed that they were working on the genome and companies were spending so much money on all these patents, I just had a hard time of envisioning how it all would be turned into a drug or cure. I wasn’t even studying chemistry at the time (and didn’t know too much about biochem), and got most of my info from major news organizations, which did not seem to be forthcoming with the details.
    Retread, we have a good percentage of black people in my department — it’s probably very close to the actual percentage vis a vis the rest of the population by now. Not a good percentage of those are American. The people in my lab, it’s the same story. When I was poor and working in factories in Europe, I was working with Africans moving boxes of heavy shit, and I’m now working with Africans doing chemistry in America. And apparently I’m still poor and so are they. Nothing changes.
    Though, my regular chess partner is the same as Obama (one black parent) and he’s American, but he’s not in the same lab and works in a different chemistry field. Unlike me and the African dude in my lab, he also wants to quit chemistry research after the Ph.D. in order to make lots of money.

  9. Jose says:

    MTK wrote, “It just ended up being far more complicated than anyone thought.”
    When will we all learn that this is *always* the case???

  10. Cellbio says:

    I think the point is not that it ended up being far more complicated than anyone thought, but that those that made the grand promises (to get the money!) purposely simplified the project, or spoke from ignorance. This is so common; just think how many times you have heard of a gene, SNP or haplotype linked to disease, with the assertion that therapy would soon follow. This thought is prevalent amongst those that have never done the drug discovery/development work: biology knowledge equals drug, as if the drug discovery development is the easy part. History says otherwise. Look at Sickle Cell as an example. The amino acid variant responsible was determined in 1956, yet it remains difficult to “drug” this disease.

  11. Jared says:

    Blacks would do better to avoid science and improve their economic status through medicine and business. I know several blacks in undergrad at MIT that could have gone to graduate school but went to medical school instead.

  12. philip says:

    The unfortunate truth is that for any new technology/technique/approach to be tried (i.e. money spent) by most scientists, there is an absolute requirement for a raving, lying, over-promising, self-promoting egomaniac to lead the way. That’s just the way it is. Sometimes these guys are brilliant and often self-delusional, but they’re always there. And thus the stage is set for a failure to match the hype.
    Where are we now? We’re waiting for someone to come along who has the brilliant and completely novel idea, that you need chemists to discover new drugs.
    To retread: I worked for a black professor, who was originally from Mississippi, as an undergraduate at UNC in the mid seventies. My first boss after PhD was a black man from Jamaica. Unfortuantely, they comprise about half of the black chemists I’ve known. And it doesn’t seem to be changing much.

  13. Ty says:

    given that, any thought or a bold prediction on the up and coming gold rush which is stem cell/ regenerative medicine?

  14. Sili says:

    How did one go about patenting a gene? I mean, what would have stopped me from just using the corresponding chimpanzee or mouse gene? The only difference between chimps and us is expression of the genes, after all (as we seem to know now).
    Since when did anyone go into Science for the benefits? The question is why so few blacks seem to be driven to ‘find things out’ so to speak? Assuming of course that’s the case. But personally (as a non-American) I can only think of deGrasse Tyson and that physicist with the timemachines off the top of my head.

  15. Chemjobber says:

    I work with one Af-Am chemist; he’s frickin’ smart and has been around the block. In my new position, I’ll be working with another one. During my graduate school days, the smartest grad student in my group was from West Africa, by way of France.

  16. RTW says:

    Lets see – I think about 5 I recall at PD/Pfizer in Chemistry in Ann Arbor. 4 PHD’s and one BS/MS scientist. 3 of the 5 African Americans, one from Ethiopia I think and the other I am not sure what his background nationality. All where male. All very good people. In other departments there where probably about the same percentage.

  17. MTK says:

    I guess thinking back I thought even the best and brightest were envisioning a 100,000 gene genome where genes really did correlate absolutely with some disease states. It wasn’t and isn’t my field of expertise, so I guess my memory isn’t correct.

  18. SRC says:

    To see breaking news from 2019, mentally replace “genomics” with “global warming” and reread the relevant comments.

  19. SD says:

    Derek – Nice blog.
    To what extent do researchers in the field indulge their capacity for sneakiness, if any? Example: I would assume, on the strength of the preponderance of the evidence, that God (whichever one you posit to be responsible for life, if any) is cunning, and not prone to simple, linear creations when complex interlocking ones will do nicely. (I am reminded of the game called “Rubik’s Clocks”, a box with nine interlocking clocks, the goal of which is to set all the clocks to midnight, frustrated by the fact that whenever you move one hand the others move in seemingly random directions.)
    In this context, what that means is that I – deeply paranoid and mistrustful of simple models, hearing Greeks in every horse – would expect the critical information content of the human cell to be “smeared” across multiple structures in the cell, not restricted neatly to a single well-defined container (DNA), and that each structure would have multiple uses and decoding frameworks. DNA would be read forward and backwards, frame-shifted, the information compressed to a level such that single alterations have drastic ramifications, but also made sufficiently redundant (RAID for DNA?) that a single mutation has a sufficiently small chance of accomplishing anything that the business of life can carry on much as usual.
    Observing the failure modes of the human organism – bizarre cancers of unknown or semi-known etiology, genetic disorders, &c. – and observing that many of these diseases seem curiously to hinge on single chance alterations of some portion of the cellular structure, but that these chance alterations are *still* not immediately lethal (either to the cells themselves or to the organism as a whole), the original hypothesis (“distributed information”) seems plausible. Then again, I am a layman in this field (electrical engineer/math with tendrils in biology and chemistry), so perhaps this is a little kernel of crackpottery coming to the fore. >;->

  20. MedChem says:

    To comment 9 Jose,
    Your comments made me laugh so hard! You hit the nail on the head.

  21. SD says:

    Er, suppose I elaborate a bit:
    I have discovered that “sneakiness”, a certain intrinsic mental flexibility and mistrust of rules, is very nearly a requirement for successfully divining and predicting the internal operations of a black box, or for troubleshooting it when it malfunctions, when you have little, no, or conflicting information about it. A willingness to disregard what you think you know is key, for there is nothing else in the world quite so misleading. This is a prominent feature of the psychological landscape of the hacker (in both “white hat” and “black hat” senses), a sort of “try it and see” mentality that operates independent of any internal filter that would quash it on the basis of “knowing” that it isn’t going to work.
    In my experience, however, at least half and possibly a simple majority of those in scientific fields appear to not possess such a mindset in their mental toolkit. (A supermajority of engineers do not.) Maybe I just don’t know the right scientists, though, which is why I ask; is this actually a common trait among life scientists?
    I draw this analogy from my personal experience because I believe that technological systems (electronic/digital/industrial), taken all together, are beginning to approximate the complexity of minor subsets of biological systems, and that there may be useful parallels drawn between certain habits of successful investigators in the respective fields. I have no metric on which to base this belief, of course, but it “seems” correct. I would guess that the Internet as a whole is probably roughly as complex as a single bacterium.

  22. CMC Guy says:

    The quandary is that “traditional” drug discovery is often unreliable and inefficient which motivates the search for alternates and the receptiveness for people (in Science and Management) to the excitement (without always necessary critical evaluation). #5 Anon makes a valid point about the potential usefulness as tools of technologies that were much over hyped as (the next) panaceas. Any help and new ideas should be welcomed and encouraged but proof is in demonstration not theory. #10 Cellbio also correct that complicated message often gets oversimplified in order to sell/raise capital but unfortunately most VCs and other Finance will tune out quickly if dig into heavy scientific rationale.

  23. JSinger says:

    I guess thinking back I thought even the best and brightest were envisioning a 100,000 gene genome where genes really did correlate absolutely with some disease states. It wasn’t and isn’t my field of expertise, so I guess my memory isn’t correct.
    Given that *everyone* in the CSHL GeneSweep contest bet on the high side of the real number — yes, it was everyone from the best and brightest to, well, me. And at least I was in the 60K’s!
    The “correlate absolutely with some disease states” is unfair, though. Everyone realized that would be a complex, statistical problem.

  24. SRC says:

    SD, when I was in grad school a grad student once deflected a question from our PI (a Nobel Laureate), saying that he couldn’t answer because he didn’t have all the data.
    The PI retorted, “Anyone can figure out something when he has all the data in hand. Figuring out something when you don’t have all the data, and half of what you do have is wrong – that’s the trick.”
    Wise man.

  25. MTK says:

    Well JSinger,
    Thanks for the clarification.
    I did “some” disease states. 🙂
    Derek: No temptation to subtitle this post “I’d Love to Change the World”, Ten Years After’s biggest hit song?

  26. milkshake says:

    There is a poignant story about Celera – how they went on buying up companies with the money from their investors, and what they did to their research staff soon after. It shows that you don’t need to be a Big Pharma company to cause some wide-spread damage.

  27. Retread says:

    The comments about Blacks in chemistry match my very limited experience this past fall semester when I audited an introductory PChem course, with 80 students of which about 10 were black. More than half of them were nonUS (Kenya, Nigeria, Mali, and Haiti among them).
    Hype about promised results from research is far from new. The “War on Cancer” was started in 1971 — if we could put a man on the moon, we surely could defeat cancer, etc. etc. Does anyone out there think it has been won? Howard Varmus, Nobel laureate, and former NIH director doesn’t think so. [ Science vol. 312 pp. 1162 ’06 } “The age-adjusted mortality rate for cancer is about the same in the 21st century as it was 50 years ago, whereas the death rates for cardiac, cerebrovascular and infectious diseases have declined by about two-thirds.”
    I agree with #13 Ty — Stem cell research is probably the latest hype. So far it has produced nothing.
    However, I do think that research on microRNAs is likely to be productive, and I hope to have a post explaining why, and why it will mean tons of jobs for synthetic organic chemists, up on Chemiotics in the Skeptical Chymist in the near future.

  28. Cellbio says:

    Gene patents would include the aa sequence, and variants that had the same function. Your move to chimp would not be viable. If you altered the protein in meaningful, non-obvious way, say changing receptor specificity, or extending half-life, then you could hope to have a chance, but the patents were pretty broad.
    MTK, not sure I got your point, but I’ll try to respond. Indeed many argued the case of 100K genes, and most of us believed it and that there would be “land grabs” that would block us from bringing the next insulin/GH/epo forward. That is why many in industry got involved,either as a business venture to grab valuable IP, or as a way for established companies to preserve freedom to operate. But, IMO, anyone who thought the disease information would come flowing forth was just silly (Maybe you were being sarcastic above?) Back then, we weren’t sequencing populations of diseased and normals and looking for correlations, we were sequencing end-to-end to get the basic blueprint, and all the IP you grab along the way.
    A curious thing for me, is that the patent office appears to consider antibodies prior art, so if you own the gene, you own any and all abs, kind of opposite to small molecule targets. Due to the sequencing rush of the 90s,broad ab patents are expring soon, so the barrier to entry in therapeutic antibodies is the hefty cost to make your clinical lot. That explains a lot to me about why Pharma is getting in now. They can pretty much make any antibody they want to fit in with the rest of their portfolio in a therapeutic area and readily understand the value of the investment.
    Retread, hope you’re right about miRNAs, but other than liver and acute use at that, I have my doubts. Hope I am wrong, cause a lot could be done, but that gets me back to the making the drug part (tolerable, effective).

  29. Pat Pending says:

    “How did one go about patenting a gene? I mean, what would have stopped me from just using the corresponding chimpanzee or mouse gene? The only difference between chimps and us is expression of the genes, after all (as we seem to know now).”
    To get a patent on a DNA sequence you first need to show “utility” i.e. what the sequence does, this prevents the patenting of SNPs, assuming the sequence is for a protien the PTO will assume utility and allow you to claim the isolated DNA sequence and the isolated polypeptide that is derived from the DNA sequence. This would be valuable if the protean was EPO, insulin etc. The problem with the mass sequencing and claiming of the human genome was that the PTO wanted utility ie what the sequence did and for some of the genome sequence the companies did not have that information. The PTO also objected to patents with enormous numbers of claims directed to DNA sequences.
    You could patent the chimp gene, for all the good it would do you, if the gene was new, non-obvious over the mouse, human, rat etc. gene and useful in the patent sense. The value of the patent, IMO, would be very limited because why would anyone want chimp protean or an isolated chimp gene on a replication cassette?
    IMO, the perceived value of the human DNA claims was that the DNA would be isolated, a protein obtained from E. coli or yeast and then compounds screened in an assay against the protein. The other value would be if you wantd to sell the protein as a drug.

  30. MTK says:

    My thought, which I may need to change based on the feed back from you and others, was that 10-15 years ago that people, including leading scientists, did believe that some if not many diseases states could be correlated to single genes. Of course, that would have to happen after the genome was mapped, so yes, no one was mapping normal and disease state, but that people thought that was what it was going to become. That vast numbers of new targets, and eventually new therapies, would be unearthed thanks to genomics. We could correlate a certain disease to a difference in a gene, which would lead to the protein that modulates that disease state, and that protein would then be targeted. That was the vision that people were selling back in the 90’s.
    My point, which may be incorrect, was that while we look back now and say that it was just another example of slick salesmanship by entrepeneurs and venture capitalists, that that’s not quite how I remember it. That even some of the best minds at the time thought that vision would be obtainable.
    Now, of course, there were examples of this vision being over-simplified, but as long as a big genome was around, it was still viable to an extent. The smaller genome made this vision less likely since it meant that the there were now less genes per protein than initially anticipated.
    OK, all of the above may be revisionist,i.e. wrong, which is why I appreciate the viewpoints of you and others.

  31. Cellbio says:

    MTK, you are right, it was not just slick salesmanship, though that was a part, both in Industry and by the big NIH guys too, but there was a broad frenzy of belief in this big biology approach. At the time, I read commentaries that compared it too big physics, which come argued was squeezing out the researcher that did not work on a mega project, so some were even questioning the value of sequencing the genome as a goal, as opposed to letting it be solved by individual researchers pursuing genes based on some functional behavior or genetic knowledge.
    In hindsight, hard for any of us to relive the moment purely and not add some revision. I appreciate your viewpoint as well.

  32. Sili says:

    Well, ‘I’ wouldn’t want to patent the chimp gene – I’d use to it to circumvent the patent on the corresponding human one. Sounds like that wouldn’t have jived. Ah well.
    The ‘War on Cancer’ may not have helped us cure cancer, but isn’t the primary source of our current knowledge that there is not such thing as Cancer; it’s a question of cancers?

  33. srp says:

    The thing that has always baffled me is how little people seem to talk about the ribosome. It’s liking seeing a photocopier in action and spending all your time studying the original documents, the copies, and maybe the blank paper and the toner. The mechanism is actually an ingenious and finicky thing, and if you want to know why the copier works sometimes and fails the other times you pretty much have to look inside all those parts labeled A, B, and C and learn about electrostatics and the engineering of paper flow.
    I know there’s been a dedicated group of workers that has isolated many of the functional parts of the ribosome (I read an article in a popular magazine a few years ago–AmScientist or SciAm or some such) but I get the feeling that this work is sort of off to the side. But it’s hard for me to believe that when things go wrong in a cell, as when a copier starts jamming or making bad copies, we can solve the problem by changing the input paper or the toner or hand-correcting the copies after they’re made. And that seems to me like what most of the discussion is like about drug targets and the genome.

  34. Derek:
    Thanks for the post. I have some related thoughts posted
    A few responses to what folks have written here
    1) I agree with the one reply that there was never a claim in the genomics field of some master genes for disease. Indeed, it was much the opposite — the claim was that complex diseases were not due to single genes. Either multiple genes participated, and would make good targets, or what we call one disease is really a syndrome of many diseases with similar symptoms but different underlying causes — and we would tease those apart and find the responsible genes for each subtype. That model certainly holds forth in many cancers — it was true before genomics (in the 1940s there were 2 kinds of leukemia — by the 80s it was 10s of subtypes, I think).
    2) Patents were intended to cover close relatives. One of the still outstanding questions is how much you can get away with, and when people still file sequence patents they often have clauses that step down the percent identity — i.e. claiming 95%, 90%, 80%… For small molecules the main concern was screening, and two workarounds were actually considered — one was to find a homolog that fell outside the bounds of the patent claims — perhaps you could screen the mouse version (which might have been public prior to the patent being filed & therefore prior art). The other would be to find somewhere that the patent didn’t apply & do the screening there — if someone hadn’t gotten coverage in Japan, then screen it there. I was much in favor of building a screening facility on some distant tropical island!
    3) The War on Cancer got oversold on when it would have an impact (hmm, sounds familiar). It’s worth noting that many of the hot genes in cancer research today (Src, Abl, Met, etc) were found around that time.
    4) Understanding the ribosome will advance biology, but will probably have an impact on only a limited number of diseases (e.g. Diamond-Blackfan anemia, which has a direct link) IMO. I think the photocopier analogy is more trouble than it’s worth; after all, few diseases are characterized by a gross derangement of protein synthesis. The other reason that the current models have such favor is that while they don’t work quite like we might want them, there are a lot of drugs which really do make huge differences in human suffering — and in most cases we can pretty confidently state what the molecular target of that drug is and in many cases know what happens downstream of that. The model is used because the model works (to a degree).

  35. Cellbio says:

    srp, take a look at 8 January, Nature, page 161. “Quality control by the ribosome following peptide bond formation” Zaher and Green.

  36. fromsgc says:

    srp, There is a LOT of interest and research in the role of ribosome misfunction.
    Ribosome biogenesys and translational control is now recognized as a main effector of the PI3K->Akt->mTOR pathway in cancer

  37. An esteemed colleague of mine often says:
    “Genomics is like hardcore porn. Shows you everything but tells you nothing.”

  38. Andrew Ryan says:

    “How did one go about patenting a gene? I mean, what would have stopped me from just using the corresponding chimpanzee or mouse gene? The only difference between chimps and us is expression of the genes, after all (as we seem to know now).”
    I had that problem with a mouse gene that had been patented by Yale. Their patent protected anything that was >70% identical at the amino acid level. So we were ready to roll with the horse gene, I think, which was 68% identical. But then it turned out that the patent had lapsed so we didn’t have to worry about it.
    As for blacks in science, my graduate school departmtnt (~50 students) had three, one of which was African. I only knew the two African Americans, but they were both very dumb and lazy with major attitude problems and blamed their lack of success on racism. During my postdoc at Columbia there were zero that I recall. At my current company there is one technician who is black and another biracial out of 60 or so people. She is very nice and seems to do a good job.
    I participated in various programs working summers with high school students and college grads to increase minority involvement in science. They were nice, worked hard and came from good families but they all lacked the required intelligence for the career path. It was sort of the proverbial elephant in the room.

  39. Cloud says:

    Just curious, Andrew Ryan- do you have the same disdain for dumb, lazy white people who blame their lack of success on affirmative action?

  40. Anonymous BMS Researcher says:

    I was among those who thought for sure there were at least 100K genes, based largely on the EST data. I was also involved in some major efforts to exploit novel targets that foundered on the difficulty of getting from novel targets to something on which HTS screening could be initiated. My name is on a gene patent that has been granted, though I can’t say which patent since that might reveal my identity…

  41. S Silverstein says:

    My provocative post in a similar vein is here: Has Bioinformatics Hit a Hard Wall of Stagnation?

  42. befuddled says:

    I think there was good reason for concern among big pharma about the patent land grab that the genomics companies indulged in. And in my opinion, the current patent situation is still bad enough to justify a few “breathless articles”.
    The genomics companies strategies weren’t totally crazy. Consider secreted proteins. They’re usually secreted for a good reason. Some of them tend to be relatively uninteresting carrier proteins like serum albumin. But the novel ones (the more common carrier proteins and digestive enzymes having already been identified) have a fairly good chance of being therapeutically interesting ones, like hormones, interleukins, etc.
    So I think it made a certain amount of sense to do as some of those companies did, and try to identify secreted proteins by their signal sequences. Some of those proteins were likely to be pharmacologically interesting.
    The question in my mind is whether is how easy it should be to patent such a protein of unknown function based on general sequence attributes.
    Of course, the other issue is, we know of (and knew of even before the genomics boom) a large number of hormones, interleukins, interferons, chemokines, etc. with potent physiological effects. How many of those have turned out to be useful drugs?

  43. Andrew Ryan says:

    “Just curious, Andrew Ryan- do you have the same disdain for dumb, lazy white people who blame their lack of success on affirmative action?”
    I couldn’t tell you because I’ve never met one. But as a hypothetical, sure.

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