A nice item in GenomeWeb about a new NIH initiative that's just brilliant -- using omics to try to solve rare disease mysteries. I've blogged on this topic before, and it's an obvious way to go -- particularly since the price of these genome studies is dropping so precipitiously.
As noted by the patient named in the report, finding a cause is not (alas!) the same as finding a treatment. But if many patients with mystery diseases are screened, there will almost certainly be some clues that do lead to useful remedies. It is also important to remember that very rare syndromes often shed important light on very common disorders. For example, a large number of rare tumor syndromes have illuminated key cellular mechanisms broadly relevant to tumorigenesis -- von Hippel-Lindau, neurofibromatosis, and many others. Having some molecular clue to the disease is infinitely better than a baffling list of symptoms.
Monday, May 19, 2008
Monday, May 12, 2008
When you care enough to send the very best DNA
Yesterday was Mother's Day, and while searching for a card I spied what looked like a double helix on the front of one card. Finding this odd, I checked the card in detail -- and indeed it was DNA!
DNA is clearly in the public consciousness -- years of Law & Order and CSI have ensured that, but I found it striking that the image of a double helix is deemed recognizable by as mainstream & middlebrow a company as Hallmark.
A nice twist is the card actually bore a message along the lines of 'even though you didn't give me any DNA...' -- a card for mother figures, not birth mothers. So this isn't a sign of rampant DNA deterministic thinking, but rather the imprint of DNA on the public (or at least corporate) mind
DNA is clearly in the public consciousness -- years of Law & Order and CSI have ensured that, but I found it striking that the image of a double helix is deemed recognizable by as mainstream & middlebrow a company as Hallmark.
A nice twist is the card actually bore a message along the lines of 'even though you didn't give me any DNA...' -- a card for mother figures, not birth mothers. So this isn't a sign of rampant DNA deterministic thinking, but rather the imprint of DNA on the public (or at least corporate) mind
Tuesday, April 29, 2008
A missed creative science opportunity?
Either Science or Nature (I can't find the item now) had a blurb noting that a Chilean observatory will play a prominent role in an upcoming James Bond movie -- the hideout of the villain (original press release here). A bit later in the item it is mentioned that the observatory will basically be simply compensated for its costs.
Given the state of public science funding, it's too bad they didn't extort something more. This isn't somebody's production-costs-charged-to-my-personal-Visa indie film, but 007 himself. Budget never seems to matter much in those films, so why not extract a bit of cash?
The movie is at least titled 'Quantum of Solace', so maybe that's some science there. If the observatory could have held out a bit longer, perhaps they could have gotten something better. Imagine, for instance, the effect on interesting young males in science if Bond's love interest was an astronomer, with a requisite seduction scene taking place around a telescope! Imagine the classic Bondian double entendre opportunities!
Ah well, perhaps it's just jealousy. Nobody builds funky buildings for biologists in stunningly scenic locations (the Salk Institute perhaps excepted). Q's gadgets haven't yet involved synthetic biology (I suppose it doesn't film well) -- alas, no devices made from codons.
Given the state of public science funding, it's too bad they didn't extort something more. This isn't somebody's production-costs-charged-to-my-personal-Visa indie film, but 007 himself. Budget never seems to matter much in those films, so why not extract a bit of cash?
The movie is at least titled 'Quantum of Solace', so maybe that's some science there. If the observatory could have held out a bit longer, perhaps they could have gotten something better. Imagine, for instance, the effect on interesting young males in science if Bond's love interest was an astronomer, with a requisite seduction scene taking place around a telescope! Imagine the classic Bondian double entendre opportunities!
Ah well, perhaps it's just jealousy. Nobody builds funky buildings for biologists in stunningly scenic locations (the Salk Institute perhaps excepted). Q's gadgets haven't yet involved synthetic biology (I suppose it doesn't film well) -- alas, no devices made from codons.
Monday, April 28, 2008
Space, the final bio-frontier?
In case it hasn't been obvious from the occasional post, I am a spaceflight aficionado. As a very young child I watched some of the last moon landings. Many hours of play were spent imagining riding a rocket, playing with toy rockets, and building Lego spaceships.
At some point I realized I really didn't quite have the Right Stuff. Clearly I was never going to cut it as a pilot (I carry scale models of Hubble's corrective lenses on my nose daily), and in the end my scientific interests weren't really going to support traveling to space. So it became purely an observational hobby, though the dream has been rekindled a bit by the notion of buying a rocket ticket (alas, 2001 has come-and-gone without the vision of 2001). When Millennium changed travel agents a few years back & we needed to fill out new travel preference forms, I put Virgin Galactic as my preferred carrier.
A more inner struggle, one reflected in much of the space community, is the appropriate role of humans in space, or perhaps more pointedly, of government funding of humans in space. It is one thing for some gazillionaire to pay multi-millions to take a joy ride (anyone want to spot me $50M for a week PLUS a spacewalk?); it's another for governments to continue to spend billions to put people up there. Manned flight is thrilling, but robots tend to get more data.
An item in The Scientist (free registration may be required) points to this debate again, and close to my scientific home. Lobbying is firing up again for biology research in orbit, and given that the company (Spacehab) lobbying for it builds manned research gear, they're pushing the manned angle.
Space research has yielded many earthly benefits, but they're mostly in areas such as communications & remote sensing. It is difficult to really prove a case for very many other areas. Spaceflight remains rare, unpredicable & expensive, three qualities that few like to associate with their research programs.
Two biotech claims are advanced to support space research. One is the long-standing issue of crystallography -- the claim is that crystals for X-ray diffraction studies can be grown in space that are either higher quality than ground samples or which simply can't be made on the ground. The other is a very new claim of vaccine research.
If anyone knows of a good, balanced (not in the Fox News sense!) review of space-based crystallography, I'd love to have a pointer. I'm not in that community, but my general impression is that while useful data has been collected on space-grown crystals, it really hasn't taken that community by storm. Perhaps if flights were cheap & frequent it could, but other approaches such as high-throughput condition screening have had a bigger impact.
The vaccine claims are based on a paper published last year in PNAS (also covered in The Scientist) which found that spaceflight changed some key gene expression programs in Salmonella and that the space-flown bugs were more virulent. A quick scan suggests that the paper is reasonably well done on the transcriptional profiling side (both biological & technical replicates). But, it also points to the challenge of space research -- when is the next flight opportunity to determine how general the effect is?
I do believe there are a lot of fascinating fundamental questions to ask about biology in space. Many would be in the developmental & cellular world: to what degree does gravity influence various developmental processes. Some other research might be less about space & more about behavior: Skylab astronauts had spiders spin webs, and it took a number of trials for the spiders to learn to do it in Zero-G. It could be a fascinating way to study such behaviors & how an animal adapts to a changed environment. But, most space biology questions have an importance scaled to our commitment to manned presence in space. I'm a bit skeptical that the Salmonella experiments really help understand virulence on the ground (or more importantly, are going to be generally relevant -- but sometimes it doesn't hurt to be lucky!), but I'd sure want that line of work driven hard if I was going to spend months in space!
At some point I realized I really didn't quite have the Right Stuff. Clearly I was never going to cut it as a pilot (I carry scale models of Hubble's corrective lenses on my nose daily), and in the end my scientific interests weren't really going to support traveling to space. So it became purely an observational hobby, though the dream has been rekindled a bit by the notion of buying a rocket ticket (alas, 2001 has come-and-gone without the vision of 2001). When Millennium changed travel agents a few years back & we needed to fill out new travel preference forms, I put Virgin Galactic as my preferred carrier.
A more inner struggle, one reflected in much of the space community, is the appropriate role of humans in space, or perhaps more pointedly, of government funding of humans in space. It is one thing for some gazillionaire to pay multi-millions to take a joy ride (anyone want to spot me $50M for a week PLUS a spacewalk?); it's another for governments to continue to spend billions to put people up there. Manned flight is thrilling, but robots tend to get more data.
An item in The Scientist (free registration may be required) points to this debate again, and close to my scientific home. Lobbying is firing up again for biology research in orbit, and given that the company (Spacehab) lobbying for it builds manned research gear, they're pushing the manned angle.
Space research has yielded many earthly benefits, but they're mostly in areas such as communications & remote sensing. It is difficult to really prove a case for very many other areas. Spaceflight remains rare, unpredicable & expensive, three qualities that few like to associate with their research programs.
Two biotech claims are advanced to support space research. One is the long-standing issue of crystallography -- the claim is that crystals for X-ray diffraction studies can be grown in space that are either higher quality than ground samples or which simply can't be made on the ground. The other is a very new claim of vaccine research.
If anyone knows of a good, balanced (not in the Fox News sense!) review of space-based crystallography, I'd love to have a pointer. I'm not in that community, but my general impression is that while useful data has been collected on space-grown crystals, it really hasn't taken that community by storm. Perhaps if flights were cheap & frequent it could, but other approaches such as high-throughput condition screening have had a bigger impact.
The vaccine claims are based on a paper published last year in PNAS (also covered in The Scientist) which found that spaceflight changed some key gene expression programs in Salmonella and that the space-flown bugs were more virulent. A quick scan suggests that the paper is reasonably well done on the transcriptional profiling side (both biological & technical replicates). But, it also points to the challenge of space research -- when is the next flight opportunity to determine how general the effect is?
I do believe there are a lot of fascinating fundamental questions to ask about biology in space. Many would be in the developmental & cellular world: to what degree does gravity influence various developmental processes. Some other research might be less about space & more about behavior: Skylab astronauts had spiders spin webs, and it took a number of trials for the spiders to learn to do it in Zero-G. It could be a fascinating way to study such behaviors & how an animal adapts to a changed environment. But, most space biology questions have an importance scaled to our commitment to manned presence in space. I'm a bit skeptical that the Salmonella experiments really help understand virulence on the ground (or more importantly, are going to be generally relevant -- but sometimes it doesn't hurt to be lucky!), but I'd sure want that line of work driven hard if I was going to spend months in space!
Sunday, April 27, 2008
Bizarre inanity from the financial analysis world
In general I try to ignore the various bleatings of stock pickers. Given the mountain of evidence in favor of the efficient market hypothesis, claims of successful stock picking should be generally lumped in with schemes for perpetual motion machines.
However, sometimes something truly ludicrous crosses my eyes & keeps them crossed. I've previously http://omicsomics.blogspot.com/2007_06_01_archive.html, but now I get to pick on someone calling a stock a buy.
The stock is (surprise!) Millennium, which Zacks.com is diligent to inform us is still a buy in their opinion. When I saw the headline I did a double-take, and then had to read the article. It's just as bizarre as I expected. The author describes a complex analysis leading to a target price of $25, miraculously the same as what Takeda is offering. They note all sorts of good news which might occur to Millennium.
But that's irrelevant, as Takeda has set the price for MLNM: $25/share. Given that MLNM has accepted the offer, the price ain't going higher without another bidder -- and unlike eBay auctions bidders don't tend to swoop in at the last minute. Indeed, Zacks isn't saying "buy this because the price will go higher". Yes, MLNM is currently priced a bit south of $25, but that's because there is really a difference of getting $25 when the deal closes versus getting money today. The gap prices in the transactional costs, the time value of getting (or giving) money now, and the tiny risk the deal won't go through -- but Zacks doesn't comment on any of those. Nope, according to them you should buy because MLNM might have good news!
It should be noted that Zacks in Feb called MLNM a buy with a target of $18. Either they got lucky or they really can pick. However, nowhere do they explain how the calculations really changed between then and now -- supposedly they plugged new numbers in and got a new value. But which numbers changed & why? No talk there.
However, sometimes something truly ludicrous crosses my eyes & keeps them crossed. I've previously http://omicsomics.blogspot.com/2007_06_01_archive.html, but now I get to pick on someone calling a stock a buy.
The stock is (surprise!) Millennium, which Zacks.com is diligent to inform us is still a buy in their opinion. When I saw the headline I did a double-take, and then had to read the article. It's just as bizarre as I expected. The author describes a complex analysis leading to a target price of $25, miraculously the same as what Takeda is offering. They note all sorts of good news which might occur to Millennium.
But that's irrelevant, as Takeda has set the price for MLNM: $25/share. Given that MLNM has accepted the offer, the price ain't going higher without another bidder -- and unlike eBay auctions bidders don't tend to swoop in at the last minute. Indeed, Zacks isn't saying "buy this because the price will go higher". Yes, MLNM is currently priced a bit south of $25, but that's because there is really a difference of getting $25 when the deal closes versus getting money today. The gap prices in the transactional costs, the time value of getting (or giving) money now, and the tiny risk the deal won't go through -- but Zacks doesn't comment on any of those. Nope, according to them you should buy because MLNM might have good news!
It should be noted that Zacks in Feb called MLNM a buy with a target of $18. Either they got lucky or they really can pick. However, nowhere do they explain how the calculations really changed between then and now -- supposedly they plugged new numbers in and got a new value. But which numbers changed & why? No talk there.
Thursday, April 17, 2008
Scrambling E.coli
On a more scientific and interesting note, a new paper in Nature reports on what happens to E.coli if you mess with its regulatory network in a big way. Not only is the paper interesting, but fellow blogger Pedro Beltrao is one of the authors.
The paper takes various promoters and various transcriptional regulators and reassorts which are attached to which. Nearly 600 such combinations were constructed in wild-type E.coli, meaning that the same regulator was also present in its normal regulatory context. The regulators tested also had GFP downstream, so fluorescence could be used to get a rough guide to the level of transcription in the construct.
It is perhaps surprising that most such rewirings are viable; only a few couldn't be built. But, all sorts of perturbations in growth patterns were observed. Some were even more fit than wild type.
Bacteria generally appear to be genetic carpet sweepers, taking in all sorts of genes & trying them out. While most of those genes will be structural, some will be regulators which may bind to existing regulatory motifs (or random motifs in promoters) and activate those genes. Perhaps it is not surprising that E.coli can tolerate many rewirings, as such rewirings must frequently occur naturally -- and activators are often located near the potentially useful genes they activate. If you get the good stuff, you are likely to import an activator, so its useful to be able to adjust to it.
The paper takes various promoters and various transcriptional regulators and reassorts which are attached to which. Nearly 600 such combinations were constructed in wild-type E.coli, meaning that the same regulator was also present in its normal regulatory context. The regulators tested also had GFP downstream, so fluorescence could be used to get a rough guide to the level of transcription in the construct.
It is perhaps surprising that most such rewirings are viable; only a few couldn't be built. But, all sorts of perturbations in growth patterns were observed. Some were even more fit than wild type.
Bacteria generally appear to be genetic carpet sweepers, taking in all sorts of genes & trying them out. While most of those genes will be structural, some will be regulators which may bind to existing regulatory motifs (or random motifs in promoters) and activate those genes. Perhaps it is not surprising that E.coli can tolerate many rewirings, as such rewirings must frequently occur naturally -- and activators are often located near the potentially useful genes they activate. If you get the good stuff, you are likely to import an activator, so its useful to be able to adjust to it.
Death, Taxes & Shareholder Lawsuits
With depressing predictability, the Takeda purchase offer of Millennium has been followed by the filing of a shareholder lawsuit claiming that the MLNM Board of Directors has breached their fiduciary duty.
It is hard not to see this as anything other than a shakedown attempt, figuring that the companies would rather pay to see it go away. Or even more unscrupulous, somebody being conned into suing to provide a revenue stream & publicity for some shady lawyers. Or perhaps a bit of both.
Such a suit ignores the fact that Takeda is buying MLNM for a 50% premium over the previous days price. That price was lower than the recent peak, but not by much -- the Takeda offer represents about a 30% premium over the highest price in many years -- indeed, it was 6 years ago it was so high. So, MLNM was hardly sold cheap.
Of course, there are three other ways the suit could claim merit: either MLNM sat on some explosive positive information, the market was persistantly undervaluing MLNM by a lot, or MLNM directors colluded with Takeda. All highly unlikely.
Such suits are all too commonplace. They simultaneously demean & clog the legal system. Real corporate malfeasance does occur, but this ain't it.
It is hard not to see this as anything other than a shakedown attempt, figuring that the companies would rather pay to see it go away. Or even more unscrupulous, somebody being conned into suing to provide a revenue stream & publicity for some shady lawyers. Or perhaps a bit of both.
Such a suit ignores the fact that Takeda is buying MLNM for a 50% premium over the previous days price. That price was lower than the recent peak, but not by much -- the Takeda offer represents about a 30% premium over the highest price in many years -- indeed, it was 6 years ago it was so high. So, MLNM was hardly sold cheap.
Of course, there are three other ways the suit could claim merit: either MLNM sat on some explosive positive information, the market was persistantly undervaluing MLNM by a lot, or MLNM directors colluded with Takeda. All highly unlikely.
Such suits are all too commonplace. They simultaneously demean & clog the legal system. Real corporate malfeasance does occur, but this ain't it.
Friday, April 11, 2008
The Day AFter
Okay, a day of reflection, buzz -- and two articles in the Boston Globe on the Millennium buyout. One leads from the front page & is a pretty neutral news item. But in the business section is a second piece that works on the theme that genomics was overhyped and has under-delivered. And who hyped it? "Nobody did more to raise those unrealistic expectations than Mark J. Levin"
Oh, really? Okay, I'll confess to not being a neutral bystander. I like Mark. He inspires you. He's also down-to-earth. He's genuine. And yes, he did tout genomics in general and Millennium in particular. But William Haseltine at HGS and Randy Scott at Incyte were hardly shrinking violets. J.C. Venter would never be confused with J.D. Salinger when it came to media access. Drs. Collins, Hood & Lander were hardly silent.
The article is actually a strange mix. It actually starts out with some balance, with an academic commenting how much genomics has forever altered basic biology. There are blurbs from Steve Holtzman (credited in the article as being a key architect of Millennium's business strategy) and Nick Galakatos (whose MLNM employment goes unmentioned), both sobered up but still convinced (as I am) that genomics continues to make an impact on medicine.
The article also repeats the canard about Millennium's drugs not being from genomics. Yes, the two marketed cancer drugs (Velcade & Campath) have very little to credit to genomics (not that we didn't try with Velcade!). On the other hand, unremarked is the pipeline of compounds that Takeda is presumably paying a lot for -- most if not all of those have some genomics heritage, though it is fair to say none of them can only trace back. That's the complexity ignored in articles such as this: genomics has perhaps failed to revolutionize drug discovery, but it has certain become many of the threads in the warp & woof of the drug discovery loom.
The other question that goes unasked is who exactly collaborated in hyping genomics? Hint: remove the silent 'e' & you get Glob. During Millennium's rise the Globe was remarkably charitable to Millennium, with many glowing pieces & routine coverage of every little deal on the front page of the business section. Only well after the genomics bubble burst did that cozy relationship noticeably cool, and indeed through stories such as the failed AnorMed acquisition attempt it seemed to be gone. Perhaps we in the genomics companies were hawking moonshine & snake oil, but the Globe certainly wasn't digging under then. Now, of course, they feel the need to bend over backwards the other way.
Oh, really? Okay, I'll confess to not being a neutral bystander. I like Mark. He inspires you. He's also down-to-earth. He's genuine. And yes, he did tout genomics in general and Millennium in particular. But William Haseltine at HGS and Randy Scott at Incyte were hardly shrinking violets. J.C. Venter would never be confused with J.D. Salinger when it came to media access. Drs. Collins, Hood & Lander were hardly silent.
The article is actually a strange mix. It actually starts out with some balance, with an academic commenting how much genomics has forever altered basic biology. There are blurbs from Steve Holtzman (credited in the article as being a key architect of Millennium's business strategy) and Nick Galakatos (whose MLNM employment goes unmentioned), both sobered up but still convinced (as I am) that genomics continues to make an impact on medicine.
The article also repeats the canard about Millennium's drugs not being from genomics. Yes, the two marketed cancer drugs (Velcade & Campath) have very little to credit to genomics (not that we didn't try with Velcade!). On the other hand, unremarked is the pipeline of compounds that Takeda is presumably paying a lot for -- most if not all of those have some genomics heritage, though it is fair to say none of them can only trace back. That's the complexity ignored in articles such as this: genomics has perhaps failed to revolutionize drug discovery, but it has certain become many of the threads in the warp & woof of the drug discovery loom.
The other question that goes unasked is who exactly collaborated in hyping genomics? Hint: remove the silent 'e' & you get Glob. During Millennium's rise the Globe was remarkably charitable to Millennium, with many glowing pieces & routine coverage of every little deal on the front page of the business section. Only well after the genomics bubble burst did that cozy relationship noticeably cool, and indeed through stories such as the failed AnorMed acquisition attempt it seemed to be gone. Perhaps we in the genomics companies were hawking moonshine & snake oil, but the Globe certainly wasn't digging under then. Now, of course, they feel the need to bend over backwards the other way.
Thursday, April 10, 2008
Sayonara Millennium?
Boy, if today's news can't break me out of my blogging neglect, then nothing can. Japanese pharma Takeda is buying my old shop for a 50% premium, putting MLNM's share price to a level it hasn't seen since before the Cor merger mistake & market cap at a level unseen since the genomics bubble.
Reports are still coming in, but apparently Takeda is really buying the company -- it is not a raid for the pipeline assets but an attempt to get more or less the whole enchilada. Retention plans are rumored to be in place & it's claimed Dunsire will be staying on. On the other hand, time will tell if Sidney Street will soon feel like a tepanaki table (at least I got the cuisine right this time!) with the chef twirling a large cleaver. A lot of the key folks from Cor were supposed to drive MLNM forward, but they pretty much all bailed after a while.
Management always wanted to get a Japanese deal going, but nothing ever seemed to go beyond secretive hints. Finally, it comes in and it is the ultimate deal.
Many thoughts spring to mind, and perhaps I'll try to cover some later. But in particular, was this the result of a deliberate selling attempt or just some talks that blossomed? Two years ago MLNM refused to sell to an unnamed suitor (though one friend of mine joked about it with a lawyer at a local biotech & decided he'd love to play poker with the lawyer, given the size of the 'tell'); this time Takeda was apparently welcomed with open arms. It will be interesting to see what the merger materials say about the timeline of the deal.
Another key question is how tightly will Takeda attempt to integrate with Millennium? MLNM isn't the same loose place it was when the CEO dressed in drag every October (and just before I got there the high jinx bordered on Animal House), but it still had a soupcon of a laid back atmosphere. Last time I was in the lobby there was a display of each year's T-shirt; not your usual corporate display. I haven't had much dealing with Japanese companies, but this certainly doesn't fit the stereotype. Perhaps Takeda will see the wisdom in a largely hands-off approach, much like Warren Buffett does with his acquisitions -- the parent company funds the subsidiaries but otherwise just acts like a typical board member (though with Buffett, that's still a bit activist). Notable Buffett companies include a prominent local furniture store (where you can go to the movies or try to get free furniture if the Sox sweep the Series again) and the one insurance company unafraid to admit to a reptilian quality.
On the other hand, in theory the greatest value comes from integrating -- cross synergies, reduced duplicative effort, etc. My skepticism of such an approach scales with the distance both physical & cultural, so I doubt it would work. I've recently heard from a former colleague now in a large multi-national pharma how badly its integrated, and it's a company which has had years to do so & common language and nationality.
In any case, I'm sure the weekly sushi day in the cafe will be more popular than ever.
Reports are still coming in, but apparently Takeda is really buying the company -- it is not a raid for the pipeline assets but an attempt to get more or less the whole enchilada. Retention plans are rumored to be in place & it's claimed Dunsire will be staying on. On the other hand, time will tell if Sidney Street will soon feel like a tepanaki table (at least I got the cuisine right this time!) with the chef twirling a large cleaver. A lot of the key folks from Cor were supposed to drive MLNM forward, but they pretty much all bailed after a while.
Management always wanted to get a Japanese deal going, but nothing ever seemed to go beyond secretive hints. Finally, it comes in and it is the ultimate deal.
Many thoughts spring to mind, and perhaps I'll try to cover some later. But in particular, was this the result of a deliberate selling attempt or just some talks that blossomed? Two years ago MLNM refused to sell to an unnamed suitor (though one friend of mine joked about it with a lawyer at a local biotech & decided he'd love to play poker with the lawyer, given the size of the 'tell'); this time Takeda was apparently welcomed with open arms. It will be interesting to see what the merger materials say about the timeline of the deal.
Another key question is how tightly will Takeda attempt to integrate with Millennium? MLNM isn't the same loose place it was when the CEO dressed in drag every October (and just before I got there the high jinx bordered on Animal House), but it still had a soupcon of a laid back atmosphere. Last time I was in the lobby there was a display of each year's T-shirt; not your usual corporate display. I haven't had much dealing with Japanese companies, but this certainly doesn't fit the stereotype. Perhaps Takeda will see the wisdom in a largely hands-off approach, much like Warren Buffett does with his acquisitions -- the parent company funds the subsidiaries but otherwise just acts like a typical board member (though with Buffett, that's still a bit activist). Notable Buffett companies include a prominent local furniture store (where you can go to the movies or try to get free furniture if the Sox sweep the Series again) and the one insurance company unafraid to admit to a reptilian quality.
On the other hand, in theory the greatest value comes from integrating -- cross synergies, reduced duplicative effort, etc. My skepticism of such an approach scales with the distance both physical & cultural, so I doubt it would work. I've recently heard from a former colleague now in a large multi-national pharma how badly its integrated, and it's a company which has had years to do so & common language and nationality.
In any case, I'm sure the weekly sushi day in the cafe will be more popular than ever.
Thursday, March 20, 2008
Do you prefer tomatoes or tomatomatoes?
My print version of Science showed up and the cover looks more like some foodie rag. I guessed wrong at first that they were peppers -- right family, wrong fruit. Nope, they are tomatoes.
I like growing tomatoes, though end-of-season output far outpaces my ability to consume them. It's fun growing different varieties, as there are so many different shapes, colors, sizes and flavors. Of course, all of the yard grown ones whip the store cardboard versions. On the other hand, it's hard to grow them around here this time of year -- though I once did have a rampant cherry tomato plant in the tearoom at Harvard (with bunsen burner supports & such staking it up!), though I didn't get any tomatoes until it dawned on me that I needed to play honeybee for the blossoms. When I interviewed at Millennium, someone had a tomato plant growing in the sequencing area (I'm sure the lab safety folks wouldn't let that happen any more!).
Anyway, the Science cover is for an interesting paper showing that a local gene duplication led to elongation of the fruit in one variety. Longer genes, longer fruit! The duplication is recent and was triggered by a retrotransposon, which altered the transcriptional environment around the gene. Cool!
I like growing tomatoes, though end-of-season output far outpaces my ability to consume them. It's fun growing different varieties, as there are so many different shapes, colors, sizes and flavors. Of course, all of the yard grown ones whip the store cardboard versions. On the other hand, it's hard to grow them around here this time of year -- though I once did have a rampant cherry tomato plant in the tearoom at Harvard (with bunsen burner supports & such staking it up!), though I didn't get any tomatoes until it dawned on me that I needed to play honeybee for the blossoms. When I interviewed at Millennium, someone had a tomato plant growing in the sequencing area (I'm sure the lab safety folks wouldn't let that happen any more!).
Anyway, the Science cover is for an interesting paper showing that a local gene duplication led to elongation of the fruit in one variety. Longer genes, longer fruit! The duplication is recent and was triggered by a retrotransposon, which altered the transcriptional environment around the gene. Cool!
Thursday, February 21, 2008
History better learned late than never
I've always been interested in history, and the history of science is no exception. I thought I knew a bit about the history of DNA sequencing, so it was a bit of a rude surprise to read the obituaries on Wed for Dr. Ray Wu and discover that he had published one of the first DNA sequencing methods, a method that is credited with being the forerunner of Sanger sequencing. I was totally unaware of this history.
Sadly, the Wikipedia article on DNA sequencing doesn't cover this at all.
A bit of Medline hunting, aided by Dr. Wu's page at Cornell, found a few articles in PubMed, most sans abstracts and few with full text (Somebody PLEASE arrange legally to get classic J Mol Biol as free full text!). Luckily there are a few papers -- this NAR paper and an earlier PNAS one. If I'm reading it correctly, then it involved 2D analysis of digestion maps, which I had heard of so perhaps my historical knowledge isn't totally deficient.
The one question that occurs is why didn't Dr. Wu stay in the DNA sequencing business. I wonder if he left any thoughts -- was it just not interesting enough or did Sanger & Gilbert just jump ahead so he felt like it wasn't the right place to be. Whatever his reasons it can't really be criticized -- Wu had quite a publication record and appeared to be active essentially to the end of his life. It would just be interesting to understand why he took the direction he did.
Sadly, the Wikipedia article on DNA sequencing doesn't cover this at all.
A bit of Medline hunting, aided by Dr. Wu's page at Cornell, found a few articles in PubMed, most sans abstracts and few with full text (Somebody PLEASE arrange legally to get classic J Mol Biol as free full text!). Luckily there are a few papers -- this NAR paper and an earlier PNAS one. If I'm reading it correctly, then it involved 2D analysis of digestion maps, which I had heard of so perhaps my historical knowledge isn't totally deficient.
The one question that occurs is why didn't Dr. Wu stay in the DNA sequencing business. I wonder if he left any thoughts -- was it just not interesting enough or did Sanger & Gilbert just jump ahead so he felt like it wasn't the right place to be. Whatever his reasons it can't really be criticized -- Wu had quite a publication record and appeared to be active essentially to the end of his life. It would just be interesting to understand why he took the direction he did.
Friday, February 01, 2008
Microsoft's irritating limits
Okay, it’s really time to face facts – there’s no avoiding the issue. I am a creature of habit, but the good ones tend to wax and wane with a rarely changing backdrop of the bad ones. Posting regularly to this forum was a good habit, but one which has been scarcely seen for a while.
For the explanations, you can round up the usual suspects. Work pressures. Holiday madness. Routines once disturbed being hard to reform. But in the end, those are just excuses which must be actively combated. Or perhaps it is a lack of passion? And how can passion be rekindled? What will put a new burr in the saddle – well (to badly mix metaphors), perhaps something to get the blood boiling: a good old-fashioned screed.
Now, there are whole websites devoted to griping about Microsoft. Perhaps everything I say has been said before. And, perhaps it is all obsolete carping – for reasons good and perhaps not-so-good I’m still using the previous version of Office. But, given that most of these problems have persisted through so many versions during a decade-and-a-half, I’m not optimistic.
Now, I’ve picked a very broad target. Easy to hit. Like an archer trying to hit the ocean with an arrow while standing in the foam. But I’ll try to focus.
I could gripe almost endlessly about Bill’s Army’s graphical choices. How poor contrast, cluttered charts are the defaults. I won’t (today, at least) go into that, but suffice to say it would be unhealthy for everyone concerned if I were to be trapped in an elevator with the Excel Charts programming team.
No, today I won’t focus on cluttered vision but on a limited vision, when Microsoft has a good idea but then shackles it bizarrely. When it gives the user choices, but insists on giving them very few.
Excel is a workhorse for myself and my colleagues as a data organization, filtering & delivery tool. This has been a habit acquired way back in graduate school and carried through many iterations. I often gravitate towards Excel for taking structured notes, with it’s relentless row-and-column layout forcing useful order. It’s also easy to take those tables and move them into other programs, and in my current post I’ve discovered Excel’s facility for slurping data out of relational databases. All great stuff.
Now, once you’ve got a mess of data in Excel you’d like to sort, filter & highlight it. Naturally, Excel can sort data, the handy Auto-Filter can filter it, and conditional formatting can highlight cells. But they are all broken in the same way: for reasons numerological or otherwise you can do any of these on only 3 criteria each. Sort on three columns. Have three different states to filter on format on.
Now, to pretend to be fair, with Auto-Filter that restriction is per-column, so in a many columned spreadsheet I can filter each column with three criteria -- except when it gives me only two - -I swear it happens, though I can’t remember when , as I’m usually too busy swearing. But, if you wish to see in your dining spreadsheet when you ate Thai, Italian, German or Fusion, you are out-of-luck.
A work-around, of course, is to compute columns with groupings. This can be useful, especially since you can’t save those filter settings for reuse later, but such columns quickly become a visual headache. A few can be useful, but in my hypothetical dining spreadsheet I really won’t want one column for every possible combination of cuisines!
The visual issue brings up another half-way measure: pane splitting. A useful way to deal with so many columns or rows is to split the panes horizontally or vertically (or often both) – but you can have only one split! So if I want to compare data in columns A,Q and BC, I’m out of luck – unless I copy columns or laboriously hide (and later unhide) the columns in between. One help is to make the top row or first column so it doesn’t scroll offscreen – except that blocks out pane splitting!
Now, somebody might be churlish enough to suggest that these limits are rationally chosen and have to do with tradeoffs. Hogwash! Spotfire has a spectacular interface for limiting a field all different ways, with different idioms for choosing (checkboxes, sliders, radio buttons). And if you are having problems with splitting too many ways not working well with various windowing components (such as scrollbars), it’s not like the company doesn’t have its paws in both areas.
A related class of shortcomings, but not quite in the same category, comes around Excel’s functions. If you want to add or count things conditional on some column, there are the COUNTIF and SUMIF functions. But what if I want a conditional AVERAGE? Well, that at least can be gotten from COUNTIF and SUMIF – but no such luck if I want QUARTILE or MEDIAN or STDEV such ways. Why isn’t there a function APPLYIF?
Similarly, I’ve recently gotten hooked on Pivot Tables, which are handy for summarizing data. Basically, a Pivot Table can give you summary statistics on some cross-reference of fields in rows – for example, I could easily see in my eating out spreadsheet the sums of cuisines versus the months of the year. Naturally, these statistics include sum, count, average, stdev, min, mean – but no MEDIAN or QUARTILE . Aargh!
Alas, for the moment I must let my blood boil. When in a company environment, there is an advantage to having a lingua franca, even if it is a flawed one. Plus, what alternative do I have? Perhaps some of this is better in OpenOffice, but I’m not optimistic – my previous experience (though at least a year old) with OO was that it generally aped Microsoft’s flaws & introduced some new ones. Yeah, with more time and energy I could fix that myself, given that it’s open source, but wasn’t the limits of personal time and energy how I opened this article?
For the explanations, you can round up the usual suspects. Work pressures. Holiday madness. Routines once disturbed being hard to reform. But in the end, those are just excuses which must be actively combated. Or perhaps it is a lack of passion? And how can passion be rekindled? What will put a new burr in the saddle – well (to badly mix metaphors), perhaps something to get the blood boiling: a good old-fashioned screed.
Now, there are whole websites devoted to griping about Microsoft. Perhaps everything I say has been said before. And, perhaps it is all obsolete carping – for reasons good and perhaps not-so-good I’m still using the previous version of Office. But, given that most of these problems have persisted through so many versions during a decade-and-a-half, I’m not optimistic.
Now, I’ve picked a very broad target. Easy to hit. Like an archer trying to hit the ocean with an arrow while standing in the foam. But I’ll try to focus.
I could gripe almost endlessly about Bill’s Army’s graphical choices. How poor contrast, cluttered charts are the defaults. I won’t (today, at least) go into that, but suffice to say it would be unhealthy for everyone concerned if I were to be trapped in an elevator with the Excel Charts programming team.
No, today I won’t focus on cluttered vision but on a limited vision, when Microsoft has a good idea but then shackles it bizarrely. When it gives the user choices, but insists on giving them very few.
Excel is a workhorse for myself and my colleagues as a data organization, filtering & delivery tool. This has been a habit acquired way back in graduate school and carried through many iterations. I often gravitate towards Excel for taking structured notes, with it’s relentless row-and-column layout forcing useful order. It’s also easy to take those tables and move them into other programs, and in my current post I’ve discovered Excel’s facility for slurping data out of relational databases. All great stuff.
Now, once you’ve got a mess of data in Excel you’d like to sort, filter & highlight it. Naturally, Excel can sort data, the handy Auto-Filter can filter it, and conditional formatting can highlight cells. But they are all broken in the same way: for reasons numerological or otherwise you can do any of these on only 3 criteria each. Sort on three columns. Have three different states to filter on format on.
Now, to pretend to be fair, with Auto-Filter that restriction is per-column, so in a many columned spreadsheet I can filter each column with three criteria -- except when it gives me only two - -I swear it happens, though I can’t remember when , as I’m usually too busy swearing. But, if you wish to see in your dining spreadsheet when you ate Thai, Italian, German or Fusion, you are out-of-luck.
A work-around, of course, is to compute columns with groupings. This can be useful, especially since you can’t save those filter settings for reuse later, but such columns quickly become a visual headache. A few can be useful, but in my hypothetical dining spreadsheet I really won’t want one column for every possible combination of cuisines!
The visual issue brings up another half-way measure: pane splitting. A useful way to deal with so many columns or rows is to split the panes horizontally or vertically (or often both) – but you can have only one split! So if I want to compare data in columns A,Q and BC, I’m out of luck – unless I copy columns or laboriously hide (and later unhide) the columns in between. One help is to make the top row or first column so it doesn’t scroll offscreen – except that blocks out pane splitting!
Now, somebody might be churlish enough to suggest that these limits are rationally chosen and have to do with tradeoffs. Hogwash! Spotfire has a spectacular interface for limiting a field all different ways, with different idioms for choosing (checkboxes, sliders, radio buttons). And if you are having problems with splitting too many ways not working well with various windowing components (such as scrollbars), it’s not like the company doesn’t have its paws in both areas.
A related class of shortcomings, but not quite in the same category, comes around Excel’s functions. If you want to add or count things conditional on some column, there are the COUNTIF and SUMIF functions. But what if I want a conditional AVERAGE? Well, that at least can be gotten from COUNTIF and SUMIF – but no such luck if I want QUARTILE or MEDIAN or STDEV such ways. Why isn’t there a function APPLYIF?
Similarly, I’ve recently gotten hooked on Pivot Tables, which are handy for summarizing data. Basically, a Pivot Table can give you summary statistics on some cross-reference of fields in rows – for example, I could easily see in my eating out spreadsheet the sums of cuisines versus the months of the year. Naturally, these statistics include sum, count, average, stdev, min, mean – but no MEDIAN or QUARTILE . Aargh!
Alas, for the moment I must let my blood boil. When in a company environment, there is an advantage to having a lingua franca, even if it is a flawed one. Plus, what alternative do I have? Perhaps some of this is better in OpenOffice, but I’m not optimistic – my previous experience (though at least a year old) with OO was that it generally aped Microsoft’s flaws & introduced some new ones. Yeah, with more time and energy I could fix that myself, given that it’s open source, but wasn’t the limits of personal time and energy how I opened this article?
Thursday, January 17, 2008
Portrait of a scientist
Judah Folkman's passing this week was a sad event. I got to hear the great man speak -- at Millennium's spectacular internal seminar series 'Innovators in Medicine' -- and he was great -- inspiring, friendly, insightful. He will be missed.
Folkman was well known for having enduring brutal ridicule around his angiogenesis hypothesis. In his talk, he mentioned that he kept a room at his lab wallpapered with the years of rejection notices for grant applications and journal submission, using it to remind his students and staff that such difficulties could be overcome. One of the obits even published the crack that angiogenic factors exist 'only in the mind of the principal investigator'.
It was good to see the Globe reprint, although buried inside a section (the lead on the obituary did make the bottom of the front page) a wonderful portrait of Folkman. I don't know how long the article will remain free, but a smaller image shows up with the search. Folkman is shown framed by a lab bench with a face mixing weariness and thought. He did have quite a face! Not a movie star face, but one rich in features and details.
It isn't easy to think of good scientific portraits. Most departmental shots are straight formal shots, if not near mugshots. A few sterotyped poses predominate: for example, googling on Folkman yields some standards: hand on chin thoughtful, looking up from a microscope, teaching in front of a blackboard, listening to a colleague.
One classic is the shot of Watson & Crick with their model, though the photographer had Crick point with a slide rule, a tool utterly alien to the work. Any favorites out there? What are the best photos which illustrate the character and nature of a scientist?
Folkman was well known for having enduring brutal ridicule around his angiogenesis hypothesis. In his talk, he mentioned that he kept a room at his lab wallpapered with the years of rejection notices for grant applications and journal submission, using it to remind his students and staff that such difficulties could be overcome. One of the obits even published the crack that angiogenic factors exist 'only in the mind of the principal investigator'.
It was good to see the Globe reprint, although buried inside a section (the lead on the obituary did make the bottom of the front page) a wonderful portrait of Folkman. I don't know how long the article will remain free, but a smaller image shows up with the search. Folkman is shown framed by a lab bench with a face mixing weariness and thought. He did have quite a face! Not a movie star face, but one rich in features and details.
It isn't easy to think of good scientific portraits. Most departmental shots are straight formal shots, if not near mugshots. A few sterotyped poses predominate: for example, googling on Folkman yields some standards: hand on chin thoughtful, looking up from a microscope, teaching in front of a blackboard, listening to a colleague.
One classic is the shot of Watson & Crick with their model, though the photographer had Crick point with a slide rule, a tool utterly alien to the work. Any favorites out there? What are the best photos which illustrate the character and nature of a scientist?
Tuesday, January 15, 2008
Watching the returns
I'm probably going to stay up later than I should tonight watching the returns. Yep, I'm a junkie for the stuff -- it's just so exciting seeing history being made. The multitude have spoken, and now it is just time to watch.
However, I don't mean paying attention to my ex-governor and former first lady in a bipartite Midwestern state. I was a serious political junkie as a youth, but that has cooled -- not that it isn't important. No, these are the really important returns: new sequence data.
I've been involved with one project here for a long time, with a leading role. The project has been interesting -- as in the bittersweet toast "May you live in interesting times". Ups & downs, trials & tribulations, lights at the ends of tunnels that turned out to be oncoming freights. All sorts of traps I laid for myself & walked into.
But now, after all that, the thing is actually WORKING! Well, maybe. 'Cause the proof is in the pudding, and the pudding is made of BigDye. In Sanger we trust.
So, I have my little database query set up & every so often I ping for an update. Now, the great sequencing system runs autonomously & in batches, and I don't have the wherewithal from home to see where each of my precious plates is in the stacker (the only sure way is to examine the apparatus & we don't have a webcam installed), so an element of suspense is present. I know how many reads were called up for each clone, so I'll know when it's done.
So I sit here, trying to resist pinging again. It's unlikely that another plate has loaded & processed since the last ping. Just hold out one more minute. NOW! Nope, no new data. I can wait. Sure I can. Just another minute...
However, I don't mean paying attention to my ex-governor and former first lady in a bipartite Midwestern state. I was a serious political junkie as a youth, but that has cooled -- not that it isn't important. No, these are the really important returns: new sequence data.
I've been involved with one project here for a long time, with a leading role. The project has been interesting -- as in the bittersweet toast "May you live in interesting times". Ups & downs, trials & tribulations, lights at the ends of tunnels that turned out to be oncoming freights. All sorts of traps I laid for myself & walked into.
But now, after all that, the thing is actually WORKING! Well, maybe. 'Cause the proof is in the pudding, and the pudding is made of BigDye. In Sanger we trust.
So, I have my little database query set up & every so often I ping for an update. Now, the great sequencing system runs autonomously & in batches, and I don't have the wherewithal from home to see where each of my precious plates is in the stacker (the only sure way is to examine the apparatus & we don't have a webcam installed), so an element of suspense is present. I know how many reads were called up for each clone, so I'll know when it's done.
So I sit here, trying to resist pinging again. It's unlikely that another plate has loaded & processed since the last ping. Just hold out one more minute. NOW! Nope, no new data. I can wait. Sure I can. Just another minute...
Thursday, December 27, 2007
A Vertex by the sea?
If one thinks like a builder, it is not difficult to scan the prime biotech zone in Cambridge and see it full at some point. I remember bicycling to the Harvard Medical School in the 90's past an empty zone with just a couple of lone buildings; those buildings are now thickly surrounded, save some parkland. There are still some parking lots that might be made over, but in general there isn't a lot of free space left. Some single-story buildings might go (someone must be eyeing the boarded up saloon up the street from Novartis, but not those close to residential land -- which is a lot of them -- and there isn't much room up. Between a general Cantabrigian disdain for high rises & fire department restrictions on where labs can go, up is not a great option for biotech.
Throughout the zone there are also other uses for what space there is. MIT owns much of the land, and must be wondering whether it will be hemmed in. Urban planning has shifted away towards favoring a variety of uses, and so some of the new development in the zone has gone to residences, hotels & shops -- a good thing, too! Hopefully ways will be found to preserve some of the grittier older businesses, the car repair shops & such that are so convenient. But space must be found, or the biotech industry will stagnate.
There is a lot of open space to the far east, where once a large railroad yard sat in the netherlands between Cambridge and Charlestown. New buildings are springing up there & the developers have already advertised in biotech real estate sections.
However, others are thinking of a really big conceptual leap. In a Globe article before Christmas it was revealed that Vertex is contemplating moving their entire operation to new buildings to be constructed at Fan Pier. This is an area just off the center of Boston and on the waterfront, and which is in an area which is becoming a magnet for development. Better road connections, thanks to the Big Dig, a new transit line, a new federal courthouse, and the new convention center have led to other businesses, such as restaurants and hotels.
It's not hard to see the attraction of the place. Walkable to downtown Boston and a short walk to the transit hub (intercity & commuter train, bus, subway) at South Station. Within site (across the water, traversed by a tunnel) of the airport.
The obvious uses of this space were offices (particularly legal ones; the courthouse is next door) -- but biotech? I wouldn't have thought of it, but somebody did. It's a bold move, one to announce that Vertex has arrived as a FIPCO (Fully Integrated Pharmaceutical Company). The developer has already started acquiring permits around buildings suitable for lab space. And the location has other perks -- nearby Red Line access to the Harvard & MIT campuses, so it's almost like being in Cambridge. The new transit line doesn't yet go many places, but if a proposed tunnel is dug it could connect to the Longwood Hospitals area.
Despite all the hubbub in Cambridge, Boston itself doesn't host much biotech. I think there is some incubator-type space over in Charlestown and maybe some bits elsewhere, but mostly the main city plays a subsidiary role. Remote sites such as a derelict state hospital have sometimes been proposed, but nothing much has happened -- perhaps this could jump-start other unconventional locations for biotech in the Hub of the Universe.
Throughout the zone there are also other uses for what space there is. MIT owns much of the land, and must be wondering whether it will be hemmed in. Urban planning has shifted away towards favoring a variety of uses, and so some of the new development in the zone has gone to residences, hotels & shops -- a good thing, too! Hopefully ways will be found to preserve some of the grittier older businesses, the car repair shops & such that are so convenient. But space must be found, or the biotech industry will stagnate.
There is a lot of open space to the far east, where once a large railroad yard sat in the netherlands between Cambridge and Charlestown. New buildings are springing up there & the developers have already advertised in biotech real estate sections.
However, others are thinking of a really big conceptual leap. In a Globe article before Christmas it was revealed that Vertex is contemplating moving their entire operation to new buildings to be constructed at Fan Pier. This is an area just off the center of Boston and on the waterfront, and which is in an area which is becoming a magnet for development. Better road connections, thanks to the Big Dig, a new transit line, a new federal courthouse, and the new convention center have led to other businesses, such as restaurants and hotels.
It's not hard to see the attraction of the place. Walkable to downtown Boston and a short walk to the transit hub (intercity & commuter train, bus, subway) at South Station. Within site (across the water, traversed by a tunnel) of the airport.
The obvious uses of this space were offices (particularly legal ones; the courthouse is next door) -- but biotech? I wouldn't have thought of it, but somebody did. It's a bold move, one to announce that Vertex has arrived as a FIPCO (Fully Integrated Pharmaceutical Company). The developer has already started acquiring permits around buildings suitable for lab space. And the location has other perks -- nearby Red Line access to the Harvard & MIT campuses, so it's almost like being in Cambridge. The new transit line doesn't yet go many places, but if a proposed tunnel is dug it could connect to the Longwood Hospitals area.
Despite all the hubbub in Cambridge, Boston itself doesn't host much biotech. I think there is some incubator-type space over in Charlestown and maybe some bits elsewhere, but mostly the main city plays a subsidiary role. Remote sites such as a derelict state hospital have sometimes been proposed, but nothing much has happened -- perhaps this could jump-start other unconventional locations for biotech in the Hub of the Universe.
Thursday, December 20, 2007
Getting my hands wet
My undergraduate days were full of laboratory work. I got involved in student research as an undergraduate, spent a xmemorable summer being unsuccessful at DNA sequencing, and enrolled in a new very laboratory-intensive program. Between my mishaps in my coursework & my mishaps in my independent work, eventually it was suggested (and I didn't need much convincing) that maybe I could combine my hobby of computer programming with my focus on biology in some useful way.
After that, labs were on the radar intermittently. My department at Harvard insisted I do one 'wet' rotation, and so I spent a very enjoyable spring in a fly lab, mostly sorting flies & mutagenizing some but also mapping some transposon insertions by in situ hybridization. I also was a teaching assistant, and one year that meant running lab sections. My committee once seemed on the verge of insisting I do some lab work & I started cooking up a suitable experiment involving in vivo footprinting of DNA binding factor sequence preferences, but nothing ever happened.
At Millennium I failed to follow up on a golden opportunity, one that I rue to this day. Soon after joining one of the senior Mass Spec guys invited me to consider spending some time learning the equipment. Now, I had used a 'toy' mass spec as a high school intern to find the leak in some high vacuum equipment (successfully, which led to figuring out that you-know-who had inadvertantly put it there!) -- the spec is built into the instrument & you run a Pasteur pipet hooked to a helium tank around all the suspect spots -- when you see the helium spike, you've found the leak. Plus, my father worked on electronics for a mass spec that got a one-way trip into the Jovian atmosphere, so I had an interest in the things. Alas, I never quite followed through.
Later, it was suggested & I had started making concrete plans to learn how to work the HTS screening robotics at Millennium. Those plans were being laid when I got the pink slip (alas, they don't actually print the letter on pink paper!).
So, it is with some pride I can report I actually did some lab work yesterday. After several polite invitations from our headmistress of sequencing, I spent a bit of time observing & doing some 'scut work' -- having asked for as much as they dared give me. I labeled plates, recored them into the Laboratory Information Management System (LIMS) & later helped load & unload the robot preparing them. I sealed the plates (with a polite admonition that I was being too gentle with the roller). I also got to load the thermocyclers, select the right program & then unload them when done.
Not exactly the solo conquering of megabases that my imagination whipped up, but still very informative. You don't just pour DNA in one end of the sequencer and get data out the wires at the other end; there's a lot of manual tracking & care involved, even in a highly automated modern sequencing laboratory. It actually turns out that the process I observed will be upended in the near future for a much less hands-on, much higher throughput one. And, I couldn't help thinking of the various next-gen technologies, where you just do away with all those 96 or 384 well plates & instead run much larger numbers of sequencing reactions in a much smaller area.
It's all very different than when I was trying to use Sequenase, single channel pipettors, radioactive S35 & slab gels nineteen years ago. And one difference in particular relates to the title of this entry -- no water baths! You don't actually get your hands wet anymore -- nice dry thermocyclers do all the incubating instead.
After that, labs were on the radar intermittently. My department at Harvard insisted I do one 'wet' rotation, and so I spent a very enjoyable spring in a fly lab, mostly sorting flies & mutagenizing some but also mapping some transposon insertions by in situ hybridization. I also was a teaching assistant, and one year that meant running lab sections. My committee once seemed on the verge of insisting I do some lab work & I started cooking up a suitable experiment involving in vivo footprinting of DNA binding factor sequence preferences, but nothing ever happened.
At Millennium I failed to follow up on a golden opportunity, one that I rue to this day. Soon after joining one of the senior Mass Spec guys invited me to consider spending some time learning the equipment. Now, I had used a 'toy' mass spec as a high school intern to find the leak in some high vacuum equipment (successfully, which led to figuring out that you-know-who had inadvertantly put it there!) -- the spec is built into the instrument & you run a Pasteur pipet hooked to a helium tank around all the suspect spots -- when you see the helium spike, you've found the leak. Plus, my father worked on electronics for a mass spec that got a one-way trip into the Jovian atmosphere, so I had an interest in the things. Alas, I never quite followed through.
Later, it was suggested & I had started making concrete plans to learn how to work the HTS screening robotics at Millennium. Those plans were being laid when I got the pink slip (alas, they don't actually print the letter on pink paper!).
So, it is with some pride I can report I actually did some lab work yesterday. After several polite invitations from our headmistress of sequencing, I spent a bit of time observing & doing some 'scut work' -- having asked for as much as they dared give me. I labeled plates, recored them into the Laboratory Information Management System (LIMS) & later helped load & unload the robot preparing them. I sealed the plates (with a polite admonition that I was being too gentle with the roller). I also got to load the thermocyclers, select the right program & then unload them when done.
Not exactly the solo conquering of megabases that my imagination whipped up, but still very informative. You don't just pour DNA in one end of the sequencer and get data out the wires at the other end; there's a lot of manual tracking & care involved, even in a highly automated modern sequencing laboratory. It actually turns out that the process I observed will be upended in the near future for a much less hands-on, much higher throughput one. And, I couldn't help thinking of the various next-gen technologies, where you just do away with all those 96 or 384 well plates & instead run much larger numbers of sequencing reactions in a much smaller area.
It's all very different than when I was trying to use Sequenase, single channel pipettors, radioactive S35 & slab gels nineteen years ago. And one difference in particular relates to the title of this entry -- no water baths! You don't actually get your hands wet anymore -- nice dry thermocyclers do all the incubating instead.
Monday, December 17, 2007
The Nine Circles of Basel
Human society has long had a fascination with large human enterprises. Complex governmental systems, with ministers and sub-ministers, seem to appear in the literature of each civilization (at least the few I have sampled). Confucius's Analects are largely about how to properly govern. Those nine rings of Dante's Inferno don't just run themselves, but clearly have a hierarchy of devils managing them. Throughout history, churches, governments and the military have had organized systems of managers and sub-managers. While these are often the bane of our existence, we do occasionally get such joys as the novel Catch-22 or the movie Brazil -- and the terrors of 1984. (Does some professor somewhere teach a course in the Literature of Bureaucracy?)
According to the few sources I have read, modern corporate bureaucracy can largely trace its origins to the boom of railroads in the mid-1800's. Railroads required organization, or at a minimum freight would rot in the wrong place and at worst expensive rolling stock would be destroyed in collisions (the loss of the passengers & crew being not much concern of the railroad barons). Many of the American railroads were run, particularly after the American Civil War, by men with strong military experience, and so organized structures grew. And grew. And grew.
The Wall Street Journal carries an item (which, as the one silver lining to the Murdoch takeover, is free) that a key focus of Novartis' announced job cuts is to eliminate bureaucracy. Dr. Vasella, the CEO, was shocked (shocked!) that a mid-level manager in one Novartis division had 6 levels of employees below him, and believes this is too many.
I used to joke at Millennium that I was routinely being demoted. This was obviously so, as the number of people between myself and Mark Levin kept growing. When I joined, around 250 employees, there were two people interposed, but at times it was at least four or five. I reported to a group leader, who reported to the informatics head, who reported to the technology head, who reported to the CSO, who reported to Mark. At various times the higher levels would shift, but like the beach which does the same it rarely changed my routine existence. We'd get invited to different meetings, my impertinent emails would irritate different superiors, but overall it took some digging to find the real changes -- and by the time you did, the next reorganization would be upon us.
Six levels at first glance seems like a lot. If each manager had 10 reports, then that's a million employees, right? Much more than the employment of Novartis (calculated from another report at around 100K. Vasella has apparently decreed that no division shall have more than six layers of reporting (hmm, with a few layers at HQ, that would be how many levels total? :-). Suffering from the sclerotic plaques of bureaucracy? Apply the statin of restructuring!
I'm no fan of bureaucracy -- I have a particular talent for botching official forms -- but I hope that Vasella & his staff think carefully about the unintended side-effects of such a crusade. Too many layers stifle innovation. But too few may have consequences as well.
My jaundiced history of corporate organization leaves out some of the other drivers of layers. Yes, 6 layers should be sufficient to support 1 million employees -- if each manager has precisely 10 reports. Even that many is too many for some Human Resource experts' tastes, but more importantly sometimes a manager should have fewer. Someone might be a great manager of three but horrible at seven. Or you do really need 3 mass spectroscopists managed by one senior one -- but that's it. Also, some layers of management are a way to train & retain valued employees.
At first thought, the main danger of a blanket edict is that the organization will adjusted to fit the management dictum, not the other way round. Procrustes as organizational expert. While that is certainly not a foreign mode of operation for large companies, it is hardly what you want to encourage! Second, the organization will be stifled in new ways: sorry, we can't enlarge this successful organization without blowing it up, as we've hit our depth chart limit. Furthermore, the asterisks are likely to start rolling out -- and with them additional warpings of the original goal. Summer interns -- they don't count. Full-time contractors -- nah. Outsourcing -- well, of course not! And as routes to avoid limits are found, they will be used -- whether they make overall sense or not.
Is there an alternative? It's hard to say. Like most management mantras this paring, if applied judiciously, might be a good thing. Loosening up rules to minimize how far purchasing requests must percolate upwards are good. Identifying where additional layers are not adding expertise but only inertia is good -- but inertia tends to be in the eye of the beholder (or perhaps, bestopper). Legal requires such as Sarbane-Oxley don't exactly encourage a free hand either -- the shareholders like to know how you're spending their money, and if not them then Capitol Hill.
Of course, one solution is to work in a very small company. Then there can't be too many layers between you and the top, unless the company has a completely linear organizational structure! That's not to say that small companies don't face the same human & informational challenges or solve them easily, but too many layers of managers tends to be low on the worry list.
According to the few sources I have read, modern corporate bureaucracy can largely trace its origins to the boom of railroads in the mid-1800's. Railroads required organization, or at a minimum freight would rot in the wrong place and at worst expensive rolling stock would be destroyed in collisions (the loss of the passengers & crew being not much concern of the railroad barons). Many of the American railroads were run, particularly after the American Civil War, by men with strong military experience, and so organized structures grew. And grew. And grew.
The Wall Street Journal carries an item (which, as the one silver lining to the Murdoch takeover, is free) that a key focus of Novartis' announced job cuts is to eliminate bureaucracy. Dr. Vasella, the CEO, was shocked (shocked!) that a mid-level manager in one Novartis division had 6 levels of employees below him, and believes this is too many.
I used to joke at Millennium that I was routinely being demoted. This was obviously so, as the number of people between myself and Mark Levin kept growing. When I joined, around 250 employees, there were two people interposed, but at times it was at least four or five. I reported to a group leader, who reported to the informatics head, who reported to the technology head, who reported to the CSO, who reported to Mark. At various times the higher levels would shift, but like the beach which does the same it rarely changed my routine existence. We'd get invited to different meetings, my impertinent emails would irritate different superiors, but overall it took some digging to find the real changes -- and by the time you did, the next reorganization would be upon us.
Six levels at first glance seems like a lot. If each manager had 10 reports, then that's a million employees, right? Much more than the employment of Novartis (calculated from another report at around 100K. Vasella has apparently decreed that no division shall have more than six layers of reporting (hmm, with a few layers at HQ, that would be how many levels total? :-). Suffering from the sclerotic plaques of bureaucracy? Apply the statin of restructuring!
I'm no fan of bureaucracy -- I have a particular talent for botching official forms -- but I hope that Vasella & his staff think carefully about the unintended side-effects of such a crusade. Too many layers stifle innovation. But too few may have consequences as well.
My jaundiced history of corporate organization leaves out some of the other drivers of layers. Yes, 6 layers should be sufficient to support 1 million employees -- if each manager has precisely 10 reports. Even that many is too many for some Human Resource experts' tastes, but more importantly sometimes a manager should have fewer. Someone might be a great manager of three but horrible at seven. Or you do really need 3 mass spectroscopists managed by one senior one -- but that's it. Also, some layers of management are a way to train & retain valued employees.
At first thought, the main danger of a blanket edict is that the organization will adjusted to fit the management dictum, not the other way round. Procrustes as organizational expert. While that is certainly not a foreign mode of operation for large companies, it is hardly what you want to encourage! Second, the organization will be stifled in new ways: sorry, we can't enlarge this successful organization without blowing it up, as we've hit our depth chart limit. Furthermore, the asterisks are likely to start rolling out -- and with them additional warpings of the original goal. Summer interns -- they don't count. Full-time contractors -- nah. Outsourcing -- well, of course not! And as routes to avoid limits are found, they will be used -- whether they make overall sense or not.
Is there an alternative? It's hard to say. Like most management mantras this paring, if applied judiciously, might be a good thing. Loosening up rules to minimize how far purchasing requests must percolate upwards are good. Identifying where additional layers are not adding expertise but only inertia is good -- but inertia tends to be in the eye of the beholder (or perhaps, bestopper). Legal requires such as Sarbane-Oxley don't exactly encourage a free hand either -- the shareholders like to know how you're spending their money, and if not them then Capitol Hill.
Of course, one solution is to work in a very small company. Then there can't be too many layers between you and the top, unless the company has a completely linear organizational structure! That's not to say that small companies don't face the same human & informational challenges or solve them easily, but too many layers of managers tends to be low on the worry list.
Thursday, December 13, 2007
Corporate DNA
Hsien-Hsien is frequently asking 'What's in your DNA?', and a correspondent of mine recently pointed out that "it's in our DNA" is becoming a bit of a corporate cliche. Indeed, there is at least one TV advertising campaign on those lines, though the ad writers would be disappointed to find out I can't name the company.
Now, I'm not always responsive to suggestions for blog posts, but since the writer shares both my mitochondrial & Y-chromosome genotypes, I was more easily swayed.
The question posed is this: what do companies asking this really mean, or more specifically what might it mean that they don't intend (very Dilbert-esque). Presumably they are trying to make a statement about deeply embedded values, but what does it really mean to have something in your DNA? For example, do they mean to imply:
Now, many of these statements may well be true about a given company, but is that what you really want to project?
What's in my company's DNA? Well, that's easy -- it's what the customer ordered! :-)
Now, I'm not always responsive to suggestions for blog posts, but since the writer shares both my mitochondrial & Y-chromosome genotypes, I was more easily swayed.
The question posed is this: what do companies asking this really mean, or more specifically what might it mean that they don't intend (very Dilbert-esque). Presumably they are trying to make a statement about deeply embedded values, but what does it really mean to have something in your DNA? For example, do they mean to imply:
- A lot of our company is unfathomable to the human mind
- There's a lot of redundancy here
- Often we often repeat ourselves often repeatedly, often repeating repetitiously.
- We retain bits of those who invade our corporate DNA, though with not much rhyme or reason
- A lot of pieces of the organization resemble decayed portions of other pieces of our organization
- Some pieces of our organization are non-functional, though they closely resemble functional pieces of related organizations
- Most of our organization has no immediate impact on routine operations, or emergency ones
- Most of our organization has no immediate obvious purpose, if any
- Our corporate practices are not the best designable, but rather reflect an accumulation of historical accidents
Now, many of these statements may well be true about a given company, but is that what you really want to project?
What's in my company's DNA? Well, that's easy -- it's what the customer ordered! :-)
Monday, December 03, 2007
What Cell Is This, Who Laid To Rest?
With the holiday season upon us, I break out my seasonal music. So it is only fitting while I ponder various versions of Greensleeves that the NIH is finally starting to lay down the lay about the identity of cell cultures.
Cell cultures are great, but the problem is most of the cells pretty much look the same -- especially when growing in a culture dish. Now, I'm sure folks expert in the field will say they can distinguish many of them even without a microscope, but the fact remains that errors have frequently occurred and more than a few published studies are wrong because their cell culture wasn't what they thought it was. At my previous posting we burned a lot of effort on one large dataset that turned out to be useless for just this reason.
The prod in this case was an open letter by a number of researchers, and the response will apparently be to encourage referees to downgrade grant proposals and such which do not authenticate their cultures. 'bout time.
At Millennium we had licensed the Ingenuity database, which is a spectacular collection of biomedical facts culled from the primary literature (spectacular, but neither perfectly correct nor comprehensive, but amazing nonetheless). When gearing up for a big experiment on cell line X, we might try to pull all the knowledge of the database derived from experiments on cell line X -- the level of detail which Ingenuity provides. Of course, some of these would be contradictory -- and I found other cases where two published experiments were claimed to be precisely the same, but with very different results. The letter cites estimates that 20% of cell cultures are the wrong thing, which might explain a few of these.
Particularly in cancer research, this lack of a critical control is downright stupid. Nowadays, a somewhat pricey but powerful cell typing method are SNP chips. These will clearly disambiguate mouse from human (you won't get much signal if from the wrong species!), but can also probe deletions & copy number variation (though not balanced translocations). Given that most tumor cell lines are pretty fouled up in the DNA operations & maintenance department, expecting these cell lines to be stable is pretty unreasonable. Particularly if the experimenter is deliberately selecting for something (such as adherent growth, or growth in the absence of specific factors, or such), checking for major changes just makes sense -- and will also catch sneaky invaders who might take over such a culture.
Science published a good news article on the topic last winter -- alas, it will require subscription access.
Cell cultures are great, but the problem is most of the cells pretty much look the same -- especially when growing in a culture dish. Now, I'm sure folks expert in the field will say they can distinguish many of them even without a microscope, but the fact remains that errors have frequently occurred and more than a few published studies are wrong because their cell culture wasn't what they thought it was. At my previous posting we burned a lot of effort on one large dataset that turned out to be useless for just this reason.
The prod in this case was an open letter by a number of researchers, and the response will apparently be to encourage referees to downgrade grant proposals and such which do not authenticate their cultures. 'bout time.
At Millennium we had licensed the Ingenuity database, which is a spectacular collection of biomedical facts culled from the primary literature (spectacular, but neither perfectly correct nor comprehensive, but amazing nonetheless). When gearing up for a big experiment on cell line X, we might try to pull all the knowledge of the database derived from experiments on cell line X -- the level of detail which Ingenuity provides. Of course, some of these would be contradictory -- and I found other cases where two published experiments were claimed to be precisely the same, but with very different results. The letter cites estimates that 20% of cell cultures are the wrong thing, which might explain a few of these.
Particularly in cancer research, this lack of a critical control is downright stupid. Nowadays, a somewhat pricey but powerful cell typing method are SNP chips. These will clearly disambiguate mouse from human (you won't get much signal if from the wrong species!), but can also probe deletions & copy number variation (though not balanced translocations). Given that most tumor cell lines are pretty fouled up in the DNA operations & maintenance department, expecting these cell lines to be stable is pretty unreasonable. Particularly if the experimenter is deliberately selecting for something (such as adherent growth, or growth in the absence of specific factors, or such), checking for major changes just makes sense -- and will also catch sneaky invaders who might take over such a culture.
Science published a good news article on the topic last winter -- alas, it will require subscription access.
Sunday, December 02, 2007
Metastasis research deficit?
The Boston Globe had an article starting on the front page (briefly free, then will require $$) titled 'Critics blast slow progress on cancer: Say costly drugs do little to extend lives'. As with most newspaper articles the piece is short on hard data and longer on quotes. The most data-rich element is a graphic on the front page comparing 5-year survival rates for isolated vs. metastatic cancers (colon 89.8% vs. 10.3%; prostate: 100% vs. 11.9%; lung: 49.1% vs 3.0% & breast: 98.0% vs. 26.7%).
Two data items of interest that are here. First, an author who is "writing a book on the 'dysfunctional' cancer research industry' claims that 0.5% of federal research dollars have gone to studies of metastasis. The other is that 92% of cancer drugs entering human testing fail to make it to market.
If that 0.5% number is correct, it is most unfortunate. Early detection is great, but there needs to more focus on preventing metastases and treating them once they occur. There is a quote from Judah Folkman that some promising initial results have been seen using angiogenesis inhibitors to prevent metastasis, but they are clearly very small studies.
A key point that the article hammers on is that cancer researchers have constantly been promising that cures were around the corner, and yet that hasn't been realized. It cites the 36-year war on cancer, which was promoted as ending cancer by the bicentennial in 1976. More recently, now FDA commissioner Andrew von Eschenbach was proposing eradicating cancer by 2015.
What the article fails to explore is that we can't really know if we are about to have a sharp turnaround. As the article states, the long term survival mark is 5 years -- which means we won't know if the new drugs of 2007 had a real impact until pretty close to 2012. It also fails to explore the idea that extending lives by 'a few months' may be the initial signal, but that further optimization may extend that -- or that drugs are initially tested in desparately ill populations, where the deck may be highly stacked in the tumor's favor. In earlier patient populations, more notable gains may be practical.
Personally, I think that proposing to eradicate cancer by some time in the very near future is a recipe for disaster: again, given that 5-year survival is the key benchmark, eradicating cancer by 2015 would either mean (a) nearly perfect early detection [for cancers where that is nearly synonymous with a cure] and/or (b) eradicating cancer with the drugs in current late-stage testing, since only they could hit the clinics in a big way by 2010 so that 5-year survival could be measured by 2015. The former is just not realistic, and there's no great buzz from the industry that something is there to fulfill role b. Instead, researchers should set more reasonable expectations based on what is realistic. New tools for exploring cancer genomes & personalizing treatment will (IMHO) start making an impact -- but not for 5-10 years as they are tuned & troubleshot.
One other interesting note: amidst bemoaning flat U.S. government support for cancer research, it is noted that various patient-driven organizations are pumping money in or setting up key resources (such as a myeloma tissue bank set up by the Multiple Myeloma Research Foundation). What is interesting, and will hopefully continue, is some of these private organizations trying to invest in proposals that are kind of 'out there'. According to the article, the Komen foundation (breast cancer) has announced plans to invest $600M "to find wild ideas that will break the mold". That's some serious money, and if it is used to fund the 'unfundable' it will probably mean a lot of money going for failures -- and a few spectacular advances. If patients are impatient with research progress, funding what the establishment doesn't is a good way to express that frustration -- and maybe make a huge difference.
Two data items of interest that are here. First, an author who is "writing a book on the 'dysfunctional' cancer research industry' claims that 0.5% of federal research dollars have gone to studies of metastasis. The other is that 92% of cancer drugs entering human testing fail to make it to market.
If that 0.5% number is correct, it is most unfortunate. Early detection is great, but there needs to more focus on preventing metastases and treating them once they occur. There is a quote from Judah Folkman that some promising initial results have been seen using angiogenesis inhibitors to prevent metastasis, but they are clearly very small studies.
A key point that the article hammers on is that cancer researchers have constantly been promising that cures were around the corner, and yet that hasn't been realized. It cites the 36-year war on cancer, which was promoted as ending cancer by the bicentennial in 1976. More recently, now FDA commissioner Andrew von Eschenbach was proposing eradicating cancer by 2015.
What the article fails to explore is that we can't really know if we are about to have a sharp turnaround. As the article states, the long term survival mark is 5 years -- which means we won't know if the new drugs of 2007 had a real impact until pretty close to 2012. It also fails to explore the idea that extending lives by 'a few months' may be the initial signal, but that further optimization may extend that -- or that drugs are initially tested in desparately ill populations, where the deck may be highly stacked in the tumor's favor. In earlier patient populations, more notable gains may be practical.
Personally, I think that proposing to eradicate cancer by some time in the very near future is a recipe for disaster: again, given that 5-year survival is the key benchmark, eradicating cancer by 2015 would either mean (a) nearly perfect early detection [for cancers where that is nearly synonymous with a cure] and/or (b) eradicating cancer with the drugs in current late-stage testing, since only they could hit the clinics in a big way by 2010 so that 5-year survival could be measured by 2015. The former is just not realistic, and there's no great buzz from the industry that something is there to fulfill role b. Instead, researchers should set more reasonable expectations based on what is realistic. New tools for exploring cancer genomes & personalizing treatment will (IMHO) start making an impact -- but not for 5-10 years as they are tuned & troubleshot.
One other interesting note: amidst bemoaning flat U.S. government support for cancer research, it is noted that various patient-driven organizations are pumping money in or setting up key resources (such as a myeloma tissue bank set up by the Multiple Myeloma Research Foundation). What is interesting, and will hopefully continue, is some of these private organizations trying to invest in proposals that are kind of 'out there'. According to the article, the Komen foundation (breast cancer) has announced plans to invest $600M "to find wild ideas that will break the mold". That's some serious money, and if it is used to fund the 'unfundable' it will probably mean a lot of money going for failures -- and a few spectacular advances. If patients are impatient with research progress, funding what the establishment doesn't is a good way to express that frustration -- and maybe make a huge difference.
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