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.

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.

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.

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:

• 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! :-)

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.

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.