Another Alzheimer's Setback

The late-stage clinical trial failure of Eli Lilly's Alzheimer's drug semagacestat does not necessarily mean the end of the line for the 'amyloid hypothesis', which holds that the best way of tackling Alzheimer's is by blocking the formation of the beta amyloid plaques that are pathological hallmarks of the disease. There remain far too many unanswered questions, both about the trial itself and about the wider drug mechanism, for any definitive conclusions to be drawn at this point.

But this latest setback - it follows several other late-stage recent failures, including Flurizan (flurbiprofen; Myriad Genetics) Alzhemed (tramiprosate; Bellus Health) and Dimebon (latrepirdine; Pfizer/Medivation) - further ups the ante on two antibody development programmes that also target beta amyloid, bapineuzumab (Elan, Johnson & Johnson, Pfizer) and solaneuzumab (Lilly). The list of failures is growing, while success remains frustratingly elusive.

Semagacestat works by inhibiting gamma secretase, which is responsible for processing amyloid precursor protein into beta amyloid, the abnormal deposition of which is thought by many to play a key role in the development of Alzheimer's. Bristol-Myers Squibb is also developing a gamma secretase inhibitor, BMS-708163, which is undergoing phase 2 trials.

Data from these studies could help to answer some questions about the Lilly trial. It is unclear whether a class effect is at work or whether semagacestat itself is the problem. Clinical evidence in support of the compound was thin on the ground before it entered phase 3 trials. Lilly relied on biomarker evidence rather than any real indication that it actually worked in patients.

A year ago, one analyst told this writer that the trial wasn't expected to demonstrate efficacy, as the dose was too low. Safety was the main concern. That the drug actually proved toxic for patients bears out this suspicion.

Inhibiting gamma secretase can interfere with notch signalling, which is centrally involved in many cellular communication processes. The increased risk of skin cancer, which Lilly observed in patients receiving the drug, may be linked to disruptions in the notch pathway. One recent review of the topic (Panelos J. & Massi D., Cancer Biol. Ther., 8, 1986-1993, 2009) is baldly titled Emerging role of Notch signaling in epidermal differentiation and skin cancer.

The over-riding problem with nearly every late-stage Alzheimer's drug trial underway at present - certainly those that target beta amyloid formation and deposition - is that blocking beta amyloid formation and/or deposition may be too late for the mild-to-moderate patients who are usually recruited onto drug trials. The damage may already be done by the time they have been diagnosed.

Earlier recruitment - assisted by better biomarkers - could help. But the failure of semagacestat and other drugs shows that our biological understanding of the condition remains hugely incomplete.

Ireland Not Included In Merck Restructuring

No one's talking about it on the Irish media (from what I've heard at least) but I'm sure anyone in the vicinity of Wilton Place this afternoon must have heard some very audible sighs of relief coming from IDA Ireland executives - to say nothing of Merck/Schering-Plough employees in Clonmel, Carlow and in Brinny, County Cork.

Merck has detailed the R&D and manufacturing facilities it will close, following the Schering-Plough acquisition - and its Irish facilities appear to emerged unscathed from the shake-up. That's a major achievement for the local management(s) here. Research facilities in the US, Canada, Denmark, Germany and Scotland are affected; so too are manufacturing sites in Italy, Portugal, Mexico, Brazil, Singapore and the US.

300 ≠ 87

The pharmaceutical industry's great giveaway to the people of Ireland is not quite as generous as it has successfully managed to spin.

Although the Irish Pharmaceutical Healthcare Association (IPHA) claims to have cut the cost of 300 drugs by 40 per cent, the lobby group has displayed all the cunning of a sheep farmer on the Cooley peninsula applying for EU headage grants. There's a lot of double- and even triple-counting going on.

The IPHA's list of products included in the initiative contains multiple entries, denoting different dosages. It also contains different versions of the same drug made by different manufacturers.

In reality, there are, according to my tally, only 87 unique drugs on the list. And as they're all off-patent anyway, they should have been available at rock-bottom prices before now in any case.

The real test of the industry's 'generosity' will be the level of discount it will apply to some of its biggest moneyspinners, which are coming off patent in the next couple of years.

Extraordinary Measures, Extraordinary Story

Biotech gets the Hollywood treatment in Extraordinary Measures, a forthcoming film about a father who doesn't take on the pharmaceutical/medical establishment in order to find a cure for his kids - he becomes part of it. The man in question is John Crowley, CEO of Amicus Therapeutics , whom I met last February while on a study tour of the greater Philadelphia area. More on Crowley's and his family's extraordinary story in Technology Ireland's March/April 2009 issue -it's a rather large, clunky file but go to page 17 for the story.

Plenty of 'smarts' in programme for government

Fianna Fail's and the Green Party's recently revised programme for government is liberally sprinkled with references to the smart economy.

It will, the document confidently asserts, take us to a smart new world, in which we will be smart and work smart - at sustainable jobs supported by smart capital. We will travel to these jobs by a process called smart commuting. This may involve cycling. We will live in smart homes, whose [low] energy consumption will be measured by smart metres (sic). Some people may even be lucky enough (or smart enough) to live in a 'smart town'.

In all, the words 'smart' or 'smarter' appear in the 43-page document 27 times.

Our world will be just so smart, we won't really need stupid old science any more, apart from a couple of settings:-

"We will support Teagasc in enhancing its scientific capacity to enable it to foster science-based innovation on farms and in firms."

"Through sustainable management based on scientific advice, we will work to rebuild fish stocks and maintain the quota fished annually by the Irish Fleet."

That's all folks - those are the sole references to science in the entire document. To be fair, it contains numerous references to research and technology. By why are they so afraid of one 's-word'? And so addicted to another?

Stepping away from a civic science

It's hard to know whether pity, derision or even mild annoyance is the most appropriate response to Tanaiste Mary Coughlan's recent gaffe, when she confused Albert Einstein with Charles Darwin.

Anyone can make a slip of the tongue - presuming that that is indeed what occurred. One strongly suspects, however, that the minister responsible for our science-powered drive to economic utopia, otherwise known as the smart economy, isn't overly acquainted with the work of either scientist. At an individual level that hardly matters. At a societal level, it matters greatly - as Chris Mooney & Sheril Kirshenbaum argue in the snappily titled 'Unscientific America'.

Their work represents a plea to include science in America's common culture. Back in 2003, Mary Harney delivered a similar message, when she occupied the post that Coughlan does now. It is arguably the most interesting speech on science & technology ever made by an Irish politician. (Which isn't saying an awful lot - they're usually pretty dreary.)

In 'Towards a Civic Science: A Mission for the 21st Century', an address to the Royal Irish Academy, Harney called for the creation of a 'civic science', that is, "a science engaged with and invited into the national dialogue"; one that is "responsive to the public and worthy of the public trust"; and one that is "embraced and valued by students, educators, industry and communities and, yes, the government".

It's early days yet, of course. But it's safe to say that that particular mission has yet to be accomplished.

No Irish at iGEM

Now that Ireland finally has a large-scale effort in systems biology underway, maybe it's time to establish a small-scale effort in building genetically engineered machines.

The MIT-hosted International Genetically Engineered Machine competition (iGEM) for students is now in its seventh year - the final jamboree kicks off at Cambridge, Mass., on 30 Oct. However, an Irish team has yet to pull on the green jersey and splice some DNA for the nation - or, ahem, fiddle about with biobrick components for the nation.

Synthetic biology - is it lego for genetic engineers or biology's final frontier? Who knows? But the competition is one good way to get undergraduate students thinking along interdisciplinary lines, as their professors would have it; or thinking along biological hacker lines, as they would have it. Which is, of course, a whole other can of worms.

Science in Europe: siloed and silenced

Europe's efforts to build a knowledge-based society are doomed because of its inability to embrace innovation. Instead, according to Brussels-based scientific public affairs consultant David Zaruk, we are building an "influence-based society", in which policy is determined not by scientific considerations but by "eco-religious fundamentalists".

Zaruk sets out his stall in an extensive and stimulating interview with EuroActiv. He sees the European Commission's silo-based approach to policy as part of the problem - while DG Research is actively promoting scientific research, DG Sanco is actively hampering it through an overly zealous embrace of the precautionary principle.

Speaking at the World Conference of Science Journalists in London back in July, the UK's chief scientific adviser John Beddington was also critical of the absence of a scientific input into the European Union's policy-making process. The European Commission has scientific committees that speak when they are spoken to, he says. But neither the president of the Commission nor any individual commissioners has an independent scientific adviser. "We see real problems there," says Beddington.

But the problem extends beyond Brussels. Ireland and the UK are, he says, the only EU member states with a chief scientific adviser. The contrast between the EU and the USA couldn't be stronger. Barack Obama's administration is packed with heavy hitters, such as Steven Chu, Steve Koonin, Harold Varmus and John Holdren. Where - or, heaven help us, who - are their European counterparts?

What's another year - of declining interest in science?

Science and technology are only guaranteed prominence on the news agenda during two weeks of the year. One is in January, when the BT Young Scientist Exhibition helps to fill the news vacuum created by the post-Christmas lull.

The other is in August, when the leaving certificate exam results become available, and employers' lobby groups like IBEC , ICT Ireland and The American Chamber of Commerce in Ireland line up to complain - or, in lobbyist speak, 'express serious concern' - about Irish students' declining interest in science and maths. It's a wholly predictable annual ritual.

The proposed solutions to this perceived problem include overhauling teaching, establishing incentives - for both science teachers and science students - and improving the 'image' of science-based careers. Interestingly, none of the concerned employers seems to feel the need to work on improving the actual substance of the careers they offer [economic circs permitting].

Better teaching - of any subject - is always a good thing, so if genuine improvements in science education can be made, let's have them. Giving students accurate and useful careers information can only be a good thing too. But pandering to disinterested second-level students and then shoehorning them into unsuitable university courses will not work. Arguably, we're already doing this to an extent.

Of course, the phenomenon is by no means unique to Ireland. It's on the OECD radar as well. But one voice seems to be entirely absent from this debate - that of the students themselves. Why are they opting out of science? Are they wilfully turning their backs on lucrative, rewarding careers? Or do they simply see more attractive options elsewhere?

Maybe science isn't fun

High drop-out rates from third-level courses in science and technology, as reported by the Irish Times this week, elicited the usual chorus of concern. The implicit suggestion is that those lazy, science-averse kids are endangering our future. We need science graduates - truckloads of them - to take us to the 21st century's version of the promised land - the fabled 'smart economy'.

We will get them, so the chorus of concern goes, by changing our teaching methods. Science and education minister Batt O'Keeffe says that making science more "practical" will help to address the issue. Dublin City University, says president Ferdinand von Prondzynski, has introduced a "new framework of student support", which should lead to significant improvements. IBEC, the employers' lobby, says it has "serious concerns" about the way science and maths are taught at second level.

More tellingly, the same organisation also notes that some students may not be equipped to study science. It would be extremely interesting to hear the individual stories behind the bare statistics - why a particular student opted for science in the first place; whether the course matched his or her expectations; and why she or he decided she or he would not or could not continue.

I wonder whether we are now reaping what we sowed. The current crop of science students has - unlike any previous generation - been on the receiving end of a significant state-supported campaign intended to make science seem sexy. One sponsored TV series gave science the MTV treatment (disclosure: I did a very small amount of work on this). Another, also heavily sponsored, adopted a crisp, urgent tone, somewhat reminiscient of an espionage thriller.

We've spent a lot of time, energy and money telling young people 'science is fun' - and maybe even cool. We've neglected to tell them that science can also be a bit difficult - and maybe, for many, not a whole lot of fun at all.

Which Irish motor industry are we talking about?

The Society of the Irish Motor Industry (SIMI) is at it again - complaining on RTE's Morning Ireland about how the slump in sales of new cars is threatening the Irish 'motor industry' and calling on the banks to make credit available to prospective buyers and, bizarrely, for government to subsidise new car purchases - when many people are worried about keeping a roof over their heads.

It baffles me that what is essentially a retail lobby group can present itself as an 'industry' and be accepted as such on the country's flagship current affairs radio programme.

SIMI describes itself as the representative body for "dealers, repairers, vehicle distributors, wholesalers, retailers, vehicle testers and many more important operators within the industry in Ireland". Leaving aside the tautology, what you've got essentially is the sales, distribution & service piece of the automotive industry value chain. There's precious little productive economic activity in there - and certainly none of it is to be confused with the once thriving and now declining automotive components manufacturing sector.

While the current economic collapse is unpleasant for everyone, SIMI's members and their employees included, its woes are the least of our problems.

What is the smart economy ?

To enterprise, trade & employment minister Mary Coughlan, it's whatever you're having yourself.

A reading of her recent speech at the MacGill summer school would indicate that the smart economy is a remarkably flexible instrument, capable of being whatever the minister wants it to be. It has all the attributes she likes - competitiveness, low costs, high skills; it is pervasively innovative; and it kind of reminds her of Stanford University: "The University has spawned some 3,000 companies in high technology and other fields, resulting in the creation of tens of thousands of jobs. It is that type of innovation led environment that our drive for a smart economy must emulate in Ireland. There is no good reason why we cannot."

I can think of $17.2 billion worth of reasons why we cannot. That's the size of Stanford's endowment. Comparisons with Ireland's underfunded and overstretched universities are entirely meaningless. But it never prevents policy makers - or ministers - from making them.

Margaret Pugh O'Mara's 'Cities of Knowledge' is a great place to learn more about the specific set of historical factors underpinning Stanford's success - and to learn why Ireland really ought to find more appropriate role models.