Monday, 7 December 2009

Nano Nano the Panacea. What will be hidden in Pandoras Nanotech Box?

Nano Nano the Panacea. What will be hidden in Pandoras Nanotech Box?

I was watching a swedish/norwegian professor on TV who was estolling the virtues of the brave new nano world on friday. Nanotech will do everything apparently and alter how most anything manufactured interacts with our persons and personal bits. She meant the latter in a more formal medical way, but here in lies my take on nanotech.

Nanotech can be in some areas, the new marie curie playing with the "wonder stuff" which breifly radioactive material was.


My issue is that with many applications we will create carbon, silicon and metallic based nanoparticles which are not biodegradable and in their initial applications to products require no bio-safety testing.

Issues, which I will go into with explanations of my concerns later, include

  • Chronic Allergies
  • Subcell, cell-surface and perimembrane biological disruptions ( READ CANCER caused by nano technology)
  • Other issues with the non specific immune system reactions
  • Issues with how natural process in the body and environment clean up, transport or horde nanoparticles
  • In respect of the last, long term and unanticipated bio environmental dammage caused by nano particles

Why do I set such an alarmist tone?

Let's think about an area which you may call "micro" technology, or rather the seemingly wonderful technology which contained a pandoras box of issues eminating from the micrometer level.

Picture if you will, mid way through the last century and films promoting the wonder stuff which was fireproof and could be woven into pipe lagging or even fire proof suits for workers. You've got the picture: Asbestos.

The problem on a micro scale with asbestos was known about - roman slaves in their rock-wool mines died mysteriously young- some of what we now call asbestosis- the scarring of the lungs caused by massive exposure to the fibres as dust.

But asbestos held a far more worrying threat which casts it's shadow down to nanotechnology today. In theory just a single fibre of asbestos ( five microns long and less than three microns √ł) can cause a rare disease which in fact is the very one from which Cancer ( the crab) derives it's name. The insidious "mesothelioma". In advanced stages this manifests itself as inflamed, red strands of new tissue radiating from just below the rib cage through the ribs, a bit liek a king crab. The "new growth" is of course what we call generically cancerous tissue.

The exact biological mechanism is known and for further reading, but to summarise the small fibre is picked up by a type of roving immune cell which tries to engulf and destroy it, only to be empaled upon a two ended spear, then itself becoming a dangerous chemical bomb filled with free radicals and enzymes otherwise threatening to normal lung cells. It soon impales a lung cell and seeds a cancer.

Okay, this exact mechanism is maybe unlikely from nanoparticles which are very much smaller. BUT it shows how an inert, non biological particle eliceted a disease which would still today be unanticipated if it were a new substance.

Cellular machinery is biochemical I hear you say, not prone to mechanical interuption. Well that is not the case. Intracellular machinery utilses biochemicals ( primerily ATP) as a fuel to effect many mechanical operations, and I believe most of these remain un-illuciated today.

In ways analogous to those which we see when asbestos fibres interupt a biological, primary immune mechanism so could some nanoparticles do the following:

  • Block up cell membrane mechanisms- receptors, transport channels, formation of new cells- distuptions to all of which are linked to cancer.
  • Interfere with intercellular mechanisms: mecahnical 'substrates' cells grow along- causing defects in foetuses- or disrupting the immune system in this way.
  • Illiciting or interfering directly with antibody mediated immune response; antibodies interact at the nano and pico / √•mstrong levels. People of course have allergies to fairly inert substances like copper, cobalt, chromium. This happens at the nano level.

Will nano-techies not design us out of this issue, or will the particles not be contained or washed off easily?
Nanotechnologies, which are not a food or medical device, require no biological safety testing. In any case there may be new problems which are not currently screened for in tests, or cancers, cell damage or unborn defects may take longer to show than current cell based assay and animal testing would detect.

We can choose not to buy nano, just like GMO, right?

WRONG inert, non degradable nano particles will start to build up in our environment and bodies after it is widely employed in paints, cleaning substances, coatings and in of course clothing or medical devices ( laterly will get some level of saftey, but that is not gauiranteed if deiseases take years to incubate or accumlation occurs by unknown processes)

So what do I recommend: At the moment there should be a biohazard due dilligence for any nanotechnology which is

  • not proven compeletly biodegraded, by a safe mechanism to safe residues
  • non encapsulated, non covalently bound to a larger substrate - ie potentially airborne
  • anything to be used in proximity to the skin, airways etc MUST be trialled at least by ADMETOX.
  • An immediate moritorium on production of paints, coatings etc where the above are not satisfied.

Tuesday, 3 November 2009

A Brief History of the Technologies of Life!

I had the occiasion to be at a dinner with a then senior manager at Invitrogen corp, Charles Golightly, who is no longer with the company.

Being a former mol biologist ( coming in handy once in a while) I was encaptivated by his fortelling of a remarkable set of entrepreneurial escapades.

From his verbal reconaissance, having often dealt with GIBCO and invitrogen reps, and some sources on the web I have been able to put together a bit of a history which is unofficial and uncomfirmed.


Now I write this for the very irony that the name "life technologies" was far too good to go away. It's back and saying the same thing it did before, moving to do stuff for our own life quality, understanding of biology, and improvement of health . In fact this "near to patient" is hardly new to the corporation, which has either ditched or pulled out of several 'close to patient' routes before. It seems that "mol biol tools" scientists, business men and product/programme managers are a little shy of the FDA and all the paper work which comes with it.

In Two Years Time Biotech is 60

It all probably began with Helen A's cervical cancer -tumour cells in 1951 ( look it up on google) She was an anonymised afrocaribean US citizen whose cancer cells were found to be not only growing in culture outside the body, but seemingly "immortalised". Wikipedia cite them being from an specific woman, and as now in many countries the cells where taken and utilised without consent or rights to commercial uses. Strains of her cells are saving lives today and widely used in advanced research and production of diverse proteins for research purposes. This was most likely the start of the 'consumer need' to have media in which to grow cells in vitro

A decade later and two biologists, Bob and Earline Ferguson, inherited their parents farm on the Grand Island - on the river near Buffalo, NY state. Amongst the live stock were some goats and they found they could tap the blood and extract a serum useful for growing various cell types in. They soon found a market and founded, in true ACME style, the Grand Island Biological Company : GIBCO. Incorporated by 1963.

Gibco grew quietly and diversified around their core media and nutrients media for cell culture. The farm house apparently stood in the midst of GIBCOs large production facility which dominates the island today, right into the 1990s when it became a bit of a liability.

Rather quaint eh? Bunch of goat farming proto hippies becoming the biggest biotech company of the 1970s. They were in the area of fairly simple blood extracts, vitamins, sugar/protein block solutions and so on. I guess few even in Buffalo knew what they did, and with the fetal bovine serum being a major money maker, it wasn't for the squemish I guess! Still big, high margin business today, FDA approved! However in the field of molecular biology- enzymes as tools, there was little activity before the advent of BRL on the scene.

Later in the 70s some time, Bathesda Research Laboratories was founded in a GARAGE and a back room of a real estates agent rented through someones wife or husband. They set about making the new and highly useful "restriction enzymes" which cut DNA up at usually specific sequence, and they brewed up bacteria, macrophages and other cells to harvest these from in small bioreactors. The simple business model was scalable in repeating these reactors on a small, hand to mouth expansion model and also in offering many new products from the "home brew" extraction process. When I was a geneticist, BRL restriction enzymes were worth many times the value of gold by weight! I seem to remember 500 GBP for like maybe a microgramm.

As they expanded, they were loathed to move their bioreactors for fear they might upset the bugs and lower yields, but by 1982 VC were well on board and the now large concern with large problems.

The First Big Biotech -Founded in 1983 by Merger

Although you wouldn't maybe glean this from and VC history of what they know as Biotechnology- whacky new drugs and the supply chain in that area - the merger of these companies above would create the first major biotech company, before most VC were out of nappies. Life Technologies was founded in 1983 by the merger of Bethesda Research Laboratories, Inc. and GIBCO Corp., a subsidiary of Dexter Corp. GIBCO was an amalgam of some 40 businesses acquired over a 15-year period by North American Mogul Products Co., a firm incorporated in 1915 that changed its name to Mogul Corp. in 1968 and was acquired by Dexter in 1977. GIBCO had sales of $77.3 million and net income of $4.5 million in 1982.


Remember DEXTER!

Bethesda Research, by contrast, at that time coudl be described was a struggling private company that, according to its chairman, Frederick Adler, was within a week to ten days from filing for bankruptcy in 1982. ( source, new york times) Adler, described in a Barron's news story as a "flamboyant venture capitalist and turnaround artist," laid off about half of the company's 500 employees and lopped off marginal research and unprofitable product lines. According to Adler, Bethesda Research was on the verge of launching an initial public offering of its own when it merged with GIBCO. It became profitable during the last quarter of 1983.

Dexter took a 64 percent stake in newly formed Life Technologies. The first chairman was Adler and the first president was M. James Barrett, a microbiologist who Adler had lured to Bethesda Research from SmithKline. The firm originally had headquarters at GIBCO's old offices in Chagrin Falls, Ohio. Net sales came to $91.4 million and net income to $3.7 million in 1983.

In 1985 Life Technologies was producing and selling more than 3,000 products used in scientific and medical research, human health diagnostics and treatment, biotechnology, and industrial applications. Among its units, the Invenex Laboratories division, located in Orlando Florida, was specializing in the production and sale of small-volume parenteral solutions such as nutritional supplements, electrolytes, antihistamines, antibiotics, diluents, anticholinergics, and generic diuretics. This division was sold to LyphoMed Inc. in 1985 for $39.5 million in cash and notes.

In 1986, the year it went public with an offering of about seven percent of its outstanding common stock, Life Technologies believed itself to be the leading supplier of sera and other cell-growth media. It was also a leading supplier of enzymes and other biological products necessary for recombinant-DNA procedures. In December of that year the company completed the sale of its Sensititre product line to Radiometer A/S, a Danish instrumentation company. By then the company had moved its headquarters to Gaithersburg, Maryland. In 1987 the company signed a technology transfer and licensing agreement with Toray Industries of Tokyo. This agreement conferred on Toray exclusive marketing rights in Japan, Korea, and Taiwan for products based on Life Technologies' nonisotopic DNA technology for detecting hepatitis B and human papillomavirus (HPV), with the company receiving a sum of $2 million over three years.


Invitrogen Corp was founded by the charismatic californian, Lyle Turner with partner Joe Fernandez, around 97 and inc. 1989. 11 years later they would be in the lear jet set and even some of their warehouse guys were millionaires on their share options.

Lyle was supposedly the guy who was a researcher and sick of pippetting, titrating and so on just to get the right qauntities of REs, buffers, acids and so on and struck on the business idea of launching new mol biol products as kits, with small vials of reagents enough for a defined amount of reactions. Now this was a stroke of genius, because everyone was used to buying in bulk ( 500ml is often way "Bulk" quantity when used for a 50 ul reaction) to get a reasonable deal per gramm or ml, or just because chemical companies like sigma didn't bother making small vials for limited reactions. As I remember pre IVGN, there was always hydration of powders and contamination of liquids and lots of people using out of date 500ml bottles of this and that or having labs full of home brewed bottles made up to starndard solutions from powder, used for a month and then "just kept handy". Science was shit back then BTW. Real lab rat conditions.

The company initially found success with its kits for molecular cloning— notably, The Librarian, a kit for making cDNA libraries, and the FastTrack Kit for mRNA isolation from biological samples.


Now they grew, and had pot on the table at board meetings, and probably golfed from their lear jet eventually. In 1999 though, there was a lot of economic turmoil and DEXTER corporation was open for stock market raids by the nasty capitalists. However someone advising or acting with Lyle and Joe, spotted the weakness of the WHOLE dexter company on the "street" and the opportunity to use Invitrogen's cash positive and high share value to lever enough to 'eat the bigger fish". Which they did- they got life technologies out of dexter in 2000.

Lyle soon realised no doubt that the tail could not wag the dog- Life Tech had loads of personnel, world wide, and a heavy sales and support organisation. Ivgn was small, fast acting, big on the branding front with funky advertising and the use of DM over shoe leather sales forces.

Life tech had 'gateway' vectors and many tipped this to be synonymous with Windows, just for CLoning. Lyle and Joe wanted gateway , maybe for a while, but probably got it too late.


Any idea that they would get a 'fusion synergy' by inhereting the Life Tech sales force would soon evapourate in the first of many take over clashes. Life tech sold some pretty basic stuff, and all the best sellers sold on volume of GIBCO products- My opinion is that they couldn't sell gateway, weren't maybe incentivisced to do so, and missed the biggest window of opportunity at companies like AMGEN who were validating second generation vectors for volume proiduction already.

Their reps and managers were a mixed bunch but not very up on mol biol- many had been with the company for years, some got in with "biology degrees " ( i knew a PM who had probably never used a micropippetor) and it seems others were not even biology majors. I know- I have met many of them and spoken to their sales managers in the 90s as I thought about workign in sales there. Life tech reps were rather dull types with 'foot on throat' sales managers - I often met them at conferences, the managers that is, and they were a strange bunch to be working selling to scientists. DOuble glazing sales management seemed to be better suited to some of their aggressiveness. All opinion from meeting a spectre of them.

SO the IVGN tail could not wag the dog, and any other small company like Probes which came on board and tried, would be eaten up eventually. Invitrogen kept the "life technologies" label as a strap-name under all their stuff, for a while at least. By this take over, and integration of all those mol biol products from IVGN, the beast changed nature in how consumers (scientists) viewed the company. All the big deals they could get on the GIBCO end were done or could be done, by the old gaurd team there, who stacked genetic institutes, warehouses and probably garages with gibco product all on pull forward sales and large discounts way back when.

Rather than this , very soon into the 200os , invitrogen became percieved as the wallmart of biotech research tools. Management still believed they had a raft of new cutting edge products and ever higher margins, and that innovation, platform solutions and high technical service was essential. Consumers however put up with the odd thawed product because it was easy to order, and the catalogue was cool to shop from over coffee in the departmental library. It took Greg Lucier about three years to understand that the corporation was good at logistics and shop front, consumer business on a micro- granular scale, and not at big deals and near patient stuff.

Thereafter new companies were assimilated as are brands sold on the shelf under their own makers name at wallmart to some extent, with packaging being at least standardised to mother invitrogen branding. "life tehcnologies" was dropped around 2003 I think. Too much clutter.

Now we have come full circle - Life Technologies Corp. and the company is still tilting at the windmills of near patient care, whilst gene-therapy never really takes off and many of the big medical protein production deals are validated and locked in. Almost thirty years ago GIBCO BRL sold off nearly all their 'near patient' therapeutic divisions and earlier acquisitions. There is a big old doggy in their and it sure as hell isn't letting the tail wag it of the hearth rug o f mol biol research IMHO.