Biomedicine

Clive Cookson

deCODE genetics was the biotech industry’s champion at scientific discovery – contributing more research papers to top journals than any other company – but its commercial model was far from successful. In November it filed for bankruptcy protection.

Today, happily, the core deCODE genetics business is resurrected as a private company, with new funding – including some from the venture capitalists who originally backed it in the 1990s.

The Icelandic company’s press release boasts proudly but correctly: “deCODE operates the most productive human gene discovery engine in the world.”

It has discovered an amazing number of genetic variations that contribute to common human diseases, often in collaboration with academic groups. But deCODE’s drug development and DNA testing business brought in less revenue than expected, and the company lost serious money in the 2008 Lehmann Brothers crash.

deCODE founder Kari Stefansson will remain as executive chairman and president of research, joined on a two-man executive committee by new recruit Earl “Duke” Collier, previously executive vice-president at Genzyme.

The company says it will continue to offer deCODE diagnostics disease risk tests, deCODEme personal genome scans, and contract service offerings including genotyping, sequencing and data analysis. “Going forward, deCODE will concentrate on translating its science into medically and commercially important products and services,” it says.

deCODE was not universally popular but I am delighted that this very distinctive Icelandic enterprise will live on and, I hope, contribute more to human healthcare.

Clive Cookson

The most frightening moment of my journalistic career was reporting on the discovery in April 1996 of the link between BSE and CJD. Sensible scientists expressed fears that Britain could be in for a large epidemic of incurable brain disease as a result of people having eaten meat contaminated with mad cow disease.

Those fears persisted as the annual death toll from vCJD – the form of disease linked to BSE – rose to 28 in 2000. Thankfully that year turned out to be the peak.

The annual report of the National CJD Surveillance unit, published this week, shows that just one person died of vCJD last year compared with five in 2007.

The unit’s up-to-date monthly surveillance figures, also out this week, show two vCJD deaths in 2009 and four definite or probable vCJD patients still alive.

There will almost certainly be a few more vCJD cases over the next few years. All are of course horrific tragedies for the patients and their families.

The number may even pick up again if it turns out that prions (the infectious proteins responsible) have been spread through blood transfusions – or if people in different genetic groups, who have not yet succumbed, turn out to be susceptible but with much long incubation periods.

But we have been spared the terrible mind-destroying epidemic that seemed possible in the late 1990s.

Clive Cookson

The relentless process of making the financial associations of medical researchers more transparent has taken another important step forward.

The 12 journals that belong to the International Committee of Medical Journal Editors (ICMJE) have agreed a common format for disclosing authors’ financial interests. They include the world’s best known medical publications such as The Lancet, New England Journal of Medicine, JAMA and BMJ.

The new disclosure form is introduced in a common editorial to be published in forthcoming issues of all ICMJE journals.

The three-page form, which will have to be submitted online by everyone whose name appears on an article, looks quite formidable. But the journals say the common format will actually make life easier for authors by eliminating the need to draw up separate forms for competing journals; they will be able to store it on their computers in partially completed form and just add information specific to the manuscript.

There are four sections. First, authors must state their assocations with any company or organisation that supported in any way the study or paper submitted for publication. Second – and this is the longest and most detailed section – they must specify any financial association with any entity that could be viewed as having an interest in the general area of the submitted manuscript (at any point during the three years before submission).

Thirdly, authors are asked about similar associations involving their spouse or children. And lastly they must disclose relevant non-financial associations.

To guide authors, ICMJE provides an illustrative form completed by Kermit The Frog, co-author of a paper entitled “The effects of Sunstop on the function of sunlight on frog skin slime”. For example, in section 4, Kermit declares: “Tadpole Inc. puts $10,000 per year in the college fund of each of my children and pays for a car that my wife drives on a daily basis.”

Though some authors may regard the exercise as excessively intrusive, it is unfortunately necessary if the scientific integrity of medical research is to be restored after recent scandals, such as the drafting by company-funded ghostwriters of articles that are passed off as the work of independent academics.

The journals will use the form for a six-month trial, before their editors meet in April to modify it if necessary in the light of experience.

Clive Cookson

An interesting clinical trial is under way at Leicester and Loughborough universities, to see whether chemotherapy can be tailored more closely to the needs of the individual patient.

Barry Sharp of Loughborough, the project leader, outlined the move towards “personalised chemotherapy” at the British Science Festival in Guildford.

Compounds based on platinum (cisplatin, carboplatin and oxaliplatin) are used in about 65 per cent of chemotherapy. All patients receive a standardised treatment regime based on their body size and kidney function, although response to the drugs varies substantially.

The aim is to develop a test that clinicians can use before and after dosing, to personalise the regime to maximise benefit and minimise side effects.

Thirty people are taking part in the pilot trial. Researchers take 20ml blood samples and use mass spectroscopy to quantify how much of the administered drug has bound to the target DNA.

They hope to see how the drug dose is distributed through the cells and thereby predict both efficacy and side effects.

If it turns out that test results correlate well with clinical data, then clinicians could for the first time make decisions about dosing on the basis of numerical data from an objective test.

As Dr Sharp says, the benefits to patients in terms of improving effectiveness and reducing harm from platinum chemotherapy are potentially huge.

But at least five years more work will be needed before clear clinical guidelines emerge.

Clive Cookson

Osteoporosis – weakening of the bones – is a Cinderella disease.

It gets remarkably little attention from the public and GPs, in relation to its huge impact on public health: 230,000 people suffer osteoporotic fractures every year in the UK, at a total cost to the NHS and government of £2.3bn.

My colleague Margaret McCartney drew attention to it in her FT column recently and at the British Science Festival in Guildford today osteoporosis specialists were working hard to raise the profile of the disease.

They drew attention to potent new drugs that are due to be licensed later this year in the US and Europe, though there is some doubt whether NHS patients will see much benefit from them, since they may be too expensive to pass the value-for-money tests of NICE, the National Institute for Health and Clinical Excellence.

Neil Gittoes, consultant endocrinologist at Queen Elizabeth Hospital in Birmingham, and David Reid, professor rheumatology at the University of Aberdeen, said the availability of a relatively cheap generic treatment – alendronate, originally marketed by Merck as Fosamax – for about £50 a year in the UK was inhibiting the introduction of more sophisticated osteoporosis treatments.

Other drugs in the same bisphosphonate class, such as risendronate, ibandronate and, most recently, zoledronate exist in longer acting versions which may be superior for some patients. A single injection of zoledronate, sold by Novartis as Zometa, may last for a year. But these alternative bisphosphonates cost five times as much as alendronate.

Denosumab, a monoclonal antibody developed by Amgen, is likely to be licenced later this year. Antibody treatments are more expensive than the most costly bisphosphonates, so it is hard to see denosumab being used extensively in the UK.

Pointing out the high prevalence of osteoporosis, Margaret McCartney quoted the estimate that one in three women and one in 12 men over the age of 50 suffer a fracture due to osteoporosis at some point. According to Dr Gittoes the figures are even worse: one in two women and one in five men over 50 suffer such fractures.

Whatever the true figure, there is no doubt that the medical profession and society as a whole must do more to educate people at a much younger age about the dangers of osteoporosis and the need to keep their bones healthy, particularly through appropriate exercise and diet.

Clive Cookson

The big feature I’ve most enjoyed writing for the FT so far this year is in today’s paper. Please take a look.

It’s about synthetic biology, which is emerging as a really hot field of research.

The most eye-catching project in synbio is what I’ve called biology’s “Frankenstein moment”: Craig Venter’s attempt to create a microbe from scratch, using lab chemicals. (Sorry Craig, I know you won’t relish that phrase.)

More significant are the efforts to re-engineer existing organisms, for applications from biofuels to medicine.

And, to accompany the article, my FT graphics colleagues have constructed an excellent illustration to show how synthetic biology works.

Clive Cookson

If you want a vivid illustration of the way an infectious disease might spread around the world in an era of extensive international travel, take a look at the latest interactive creation by the FT graphics department.

Don’t take the model too seriously. It is an imaginary pandemic and is not based on any epidemiological model of a particular disease.

It’s more a computer game than a realistic simulation. But it does show how variations in the infection rate, virulence and incubation period of the pathogen can affect the course of a pandemic.

Clive Cookson

Nature, the great British science journal, has offered the animal rights movement a new cause. “Posters that feature an endearing marmoset face peering out of a cage and a caption denouncing experiments will make for an emotionally appealing campaign,” it says in an editorial.

Of course Nature, which publishes papers involving animal research in every issue, does not advocate such a campaign.

But its editorial is warning about the implications of an experiment described in this week’s edition. Japanese scientists have created transgenic marmoset monkeys that glow green in ultraviolet light – and passed the added gene for green fluorescent protein (GFP) on to their offspring.

Although several research teams have tried to produce transgenic monkeys that transmit their new genes to subsequent generations, Erika Sasaki of the Central Institute for Experimental Animals in Kawasaki and Hideyuki Okano of Keio University are the first to report success.

GFP, derived originally from jellyfish, is a standard “marker gene” in molecular biology, which scientists use to demonstrate that genetic engineering has worked.  While glowing green marmosets have little practical application, the experiment shows that transgenic monkeys could be important research tools for investigating human diseases, as transgenic mice already are.

The Japanese researchers transferred 80 transgenic marmoset embryos to surrogate mothers. Five healthy offspring were born, which passed the GFP gene on to their own offspring.

Dr Okano told a media briefing that the next step would be to generate transgenic monkeys that carried genes for brain disorders, starting with Parkinson’s and motor neuron disease. Marmosets would be better vehicles for studying such diseases than mice because their brains are much more like those of humans.

Nature supports such research, as does the FT, so long as it offers sufficient benefits, in the form of more sophisticated “models” of human disease, and the experiments are carried out responsibly.

But the researchers must be ready to deal with the broader ethical questions involved and to be open about their use of animals. As Nature notes, that may not be easy for Japanese scientists, who freely admit their dislike of public confrontation.

E.Sasaki et al 2009

Five transgenic marmosets, with feet glowing green in UV light (inset). (Credit: E.Sasaki et al 2009)

Clive Cookson

After talking to Dan Jernigan, one of the top flu specialists at the US Centers for Disease Control here in Atlanta, I feel a bit clearer about current expert thinking about the H1N1 almost-pandemic.

The good news is that the illness is on average similar in its severity to normal seasonal flu or perhaps just a little more virulent. Certainly the virus is nowhere near as dangerous as the new flu strains that have caused the great pandemics of the past, notable in 1918.

What is unusual is the age pattern of infection, which continues mainly to infect children and young adults. In the US, 60 per cent of cases have been in 5- to 24-year-olds.

The new strain is scarcely hitting old people, the main victims of seasonal flu. To some extent this may reflect the pattern with which H1N1 is moving through the community, with schools particularly affected, so that the elderly have been less exposed to the virus.

But tests suggest that older people are still protected to some extent by previous exposure to similar viruses.  This would particularly apply to those born before the 1957 pandemic of H2N2 flu which swept away many of the old H1N1 strains dating back to 1918.

When I told Jernigan that, so far as I knew, I had never had flu, he said I was almost certainly wrong. I must have been infected in the past but the symptoms were not serious enough to register in my mind as flu.

Routine analysis of blood samples shows that 7-10 per cent of the US population – 21m to 30m Americans – is infected with flu virus in an average year.  But many suffer nothing worse than a feverish cold.

So much for the scorn that we hear frequently health experts and others pour on people who complain about flu when the symptoms are supposedly not serious enough. “You just have a bad cold,” they are told. But it turns out not to be true that flu is bound to hit you with a high fever and lay you low for a week.

It seems that the new virus is less likely than seasonal flu to cause very mild cold-like symptoms but that remains to confirmed.

Meanwhile experts such as Jernigan continue to emphasize the unpredictability of new flu strains, while repeating the likelihood that the northern hemisphere will experience a more extensive H1N1pandemic after the flu season begins in the autumn. By then, however, a vaccine against the new strain should be in production.

Clive Cookson

Just 10 years ago one of the dogmas of 20th century neuroscience – that adult humans do not make new brain cells – was overthrown. The discovery at the Salk Institute in California of adult neurogenesis, the creation of neurons, gave new hope to those seeking treatments for brain disease and inspired a great wave of neural research.

Leading investigators of neurogenesis discussed their findings at the BIO conference in Atlanta today, in the most fascinating scientific session I have attended here. The focus was on depression, which affects an estimated 15m Americans and hundreds of millions of people worldwide. As Saundra Maass-Robinson, an Atlanta psychiatrist, reminded us, fewer than half the patients treated with the antidepressant drugs available today “achieve remission” – in other words have their depression lifted.

Depression is a focus for neurogenesis research because neuroscientists, led by René Hen of Columbia University, discovered around 2003 that all antidepressant drugs achieve at least some of their effects by stimulating the growth of neurons in a region of the brain called the hippocampus, which is involved in learning and memory.

The conventional explanation for how antidepressants such as Prozac work is that they increase the production of certain neurotransmitters – brain chemicals such as serotonin that carry signals between neurons. But scientists have long been aware of a paradox here: the drugs change neurotransmitter levels very quickly but their clinical benefits only appear after a few weeks.

Hen’s hypothesis, that the delay in antidepressant action reflects the time taken for new cells to generate in hippocampus, has been confirmed by animal studies, brain imaging and postmortem examination of human brains – and is now widely accepted by neuroscientists.

The research led to the formation of BrainCells Inc (BCI), a biotech company in San Diego dedicated to developing new drugs for depression based solely on stimulating neurogenesis rather than neurotransmitters. Two candidate drugs, discovered by screening hundreds of chemicals to find ones that best trigger the proliferation of new cells in laboratory cultures of neurons, are already in early clinical trials and results will be available later this year, says BCI chief scientist Carrolee Barlow.

Of course if neurogenesis can be stimulated without unacceptable side-effects, there could be many other applications beyond depression. For example NeuroNova, a Swedish neurogenesis company targeting Parkinson’s disease and ALS, will be presenting its work here tomorrow.  

To go from a basic biological discovery to clinical trials within a decade is remarkable. As Barlow says, “this is one of the fastest moving fields I have ever seen in science.”

The world of research

The science blog is no longer updated but it remains open as an archive.

Clive Cookson, the FT's science editor, picks out the research that everyone should know about, in fields from astronomy to zoology. He also discusses key policy issues, from R&D funding to science education. He'll cover the weird and wonderful, as well as the serious side of science.

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