By Kevin Davies
July 11, 2012 | Since emerging from bankruptcy Chapter 11 in early 2010, Kari Stefansson and his colleagues at Iceland’s deCODE Genetics have kept a relatively low profile, save for a steady stream of top-notch peer review publications in leading journals.
Things are looking up for the mercurial Stefansson, who is once more running the company. Last month, Stefansson’s daughter, a striking ex-model named Solveig Karadottir, married Dhani Harrison, the son of the late ex-Beatle George Harrison, just outside London with Paul McCartney and Ringo Starr in attendance. And this week, Nature publishes a major new study from deCODE describing a rare variant in a known Alzheimer’s gene that actually confers protection against the disease, and possibly a broader spectrum of age-related cognitive deficits.
|deCODE CEO Kari Stefansson
Although too rare to have relevance as a diagnostic, the deCODE team has pinpointed a major functional role for the protective variant in the APP (amyloid precursor protein) gene on chromosome 21, which has important implications for drug development efforts against Alzheimer’s disease.
“It’s a great paper, there’s no doubt it is right,” says John Hardy, neuroscientist at University College London, who first discovered mutations in the APP gene cause early-onset Alzheimer’s disease two decades ago.
“It shows that long-term inhibition of BACE can prevent amyloid-driven disease,” meaning not just Alzheimer’s but potentially other cognitive declines including Down syndrome. As for drug development, “it’s definitely a shot in the arm,” says Hardy.Not that deCODE has any intention of getting back into the drug discovery game directly. “We’re going to stay closer to our core competence, which is genetics,” says Stefansson. “We’re coming out of Chapter 11 and our business strategy is based on projects much closer to our core competence.”
“We expect that we will turn this [finding] into a commercial collaboration with one of the big pharmaceutical companies,” Stefansson adds, noting that deCODE currently has collaborations with Genentech, Pfizer, and Novartis.
Lessons in Longevity
Sounding relaxed and in good spirits, Kari Stefansson spoke at length with Bio-IT World about the significance of deCODE’s latest discovery and how it fits into deCODE’s broader thinking.
“If you think about a meaningful lifespan, you can expand lifespan but without cognitive function it becomes pretty meaningless. You can argue that conservation of the function of the brain puts a roof on meaningful lifespan,” says Stefansson, a neurologist by training.
deCODE has been studying the genetics of longevity since the company was founded in the 1990s. Indeed, in the company’s first major publication, Stefansson’s team showed that Icelanders who reach 90 years of age are much more related to each other than control groups, suggesting there is a genetic component to becoming a nonagenarian.
“This is important,” says Stefansson. “You’re asking the genetic effect to rise above 90 years of environmental influences. This is the biggest stress test you can put on genetics. So what is it? What are you inheriting for this ability to live to 90? Are you ducking disease genes or inheriting a positive asset?”
Over the years, deCODE has gathered strong evidence for the existence of one or a few “positive assets” in the Icelandic population to promote longevity. “So this is a genetic asset conferred to you by a relatively simple genetic mechanism, probably via one gene,” he says.
Importantly, Stefansson says the new APP discovery was not hypothesis driven. Rather, it fell out of a systematic analysis of every new DNA variant discovered by whole-genome sequencing in 1,800 Icelanders (at the time) scanned against 1,500 phenotypes. (deCODE has currently amassed some 41 million SNPs in the Icelandic population.)
“We came across this APP variant in 0.5% chromosomes in Iceland, so it’s carried by 1% of the population. If you take the whole population as a control, this decreases your risk of Alzheimer’s disease by a factor of 5. If you use as controls 85-year-old cognitively intact people, you decrease the risk by a factor of 7. So this variant confers a very large protection against Alzheimer’s disease.”
The protective APP variant, known as A673T (the substitution of a threonine residue for an alanine at position 673), is caused by a simple C-to-A base substitution in the APP genetic code. The frequency of the rare variant is about 0.5% in Scandinavian populations, less elsewhere (including the United States). Stefansson admits he doesn’t know the significance of that observation. “The common variants are the ones that generate normal human diversity and are selected for. Rare variants are relatively new,” he says.
The A673T mutation sits adjacent to a well-known cleavage site targeted by the enzyme beta secretase (BACE1), which cleaves APP from the plasma membrane of the neuron. This results in the formation of amyloid protein deposits, widely considered to be the chief culprit in Alzheimer’s disease.
Several big pharma companies have been working for 15-20 years at developing BACE1 inhibitors, but Stefansson says there has been no proof of concept. “They have not been able to demonstrate that if you block beta secretase, you can slow down Alzheimer’s disease,” he says. In the Nature paper, the deCODE team, working with Genentech, shows that the A673T mutation decreases cleavage and amyloid formation by 40-50%. “So we have provided industry with the proof of concept. If you indeed succeed in blocking beta secretase, you will slow down Alzheimer’s disease.”
Even more interesting, says Stefansson, is what his colleagues have learned by studying the rate of cognitive decline in Icelanders aged 80-100 in the nursing home population, which is tested several times a year for cognitive function. Not surprisingly, there is a slow but steady decline in cognitive function, but the APP variant slows down that cognitive decline. In other words, says Stefansson, “It protects against age-related cognitive decline in the elderly who do not have Alzheimer’s.”
“The implication there is that if big pharma finally develops an effective inhibitor of beta secretase, it should not only be given to those at high risk of Alzheimer’s disease, it should probably be put into the drinking water!”
“I’m not joking, not at all,” he continues. “I think it makes infinite sense to use for people who become sufficiently old who suffer age-related cognitive decline. Remember originally, the pharma industry developed statins to treat very high blood lipids. Now we have started to give Sstatins to people who were previously considered to have normal blood lipid levels, because it has been demonstrated that you can prevent a normal decline in vascular health by treating statins to a very large percentage of the population.”
Stefansson’s team plans to measure the plasma level of APP in individuals with the A673T mutation to provide an indication of how far clinicians should take the plasma level when treating patients in clinical trials before seeing a therapeutic effect. They’ll also consider the question of the optimal timing of administering BACE inhibitors – at birth? 50? 70? Stefansson’s colleagues are performing cognitive testing on mutation carriers of all ages to determine at what age cognitive function in A673T carriers and controls part ways. “That is the age at which you should not delay treatment,” he suggests.
The APP study is but the latest high-profile result in a string of recently published discoveries from deCODE include the discovery of several medically relevant DNA variants: one such variant increases the risk of sick sinus syndrome (a common risk factor for pacemakers) by a factor of 12; another increases the risk of ovarian cancer by factor of 8; and others on gout, skin cancer, and brain cancer.
Stefansson turned from musing about longevity to outlining future priorities for the new deCODE.
“We have fully sequenced now about 2,500 Icelanders, and publishing paper after paper about discoveries coming out of sequencing. As in everything, the proof is in the eating. We’re managing and mining these data effectively. There’s nothing miraculous about it, but it hasn’t constituted any destructive discovery in IT. We have reasonable software system to gather, store, and manage these data. We’re making a lot of discoveries out of them.”
“A lot has been written of late about the difficulty of managing manage all the data from whole genome sequencing. Analysts at big banks such as Goldman Sachs have been making bold statements about how important informatics inventions will be in biology because they will constitute the next disruptive discoveries coming out of biology, giving the impression that for the moment, this is an insurmountable difficulty in medicine. And that is just a crock of s—t!”
Stefansson says there are about 20 recently formed companies trying to develop software for genome sequencing interpretation, which he says deCODE has already achieved.
“We’re going from genotypes to phenotypes, not from a disease and looking for a variant. There are many companies trying to sell the scientific community methods to manage WGS data to make discoveries, and other companies trying to market software systems to manage clinical systems. And we have this all in place.”
Stefansson also says that deCODE plans to begin marketing later this year its system for managing sequence data, both for discovery and clinical sequencing – as well as release diagnostic tests in areas such as developmental disorders, prenatal testing, and cancer. Some of this may be done through spin-out companies.
deCODE’s principal sources of revenue comes from collaboration with big pharma, diagnostics tests, and scientific grants. ”Future growth will come from projects that will help integrate genetics into healthcare: software systems, diagnostic tests, and the way in which we help the pharma industry to use genetics.”
We have sequenced the whole genomes of 2,500 people. We have genotyped about 120,000 Icelanders with an Illumina chip. We can impute whole genome sequence down to variants with less than 0.1% frequency into about 370,000 Icelanders -- there are only 320,000 living today!”
“We basically have the whole genome sequence of an entire nation.”
deCODE has formed a collaboration with the National Hospital of Iceland to impute the genome sequence of all patients over the past 3 years (~300,000) and ask: in what indication, in what disease would WGS have the biggest impact on the selection of treatment and outcome? “Rather than doing it on a priori assumptions, we’ll do it by data mining,” he says. “Rather than doing it on a handful of people, we’ll do it on the basis of the whole nation. That shouldn’t take more than a year. We’re in a privileged position.”
With that, Stefansson has to leave for another meeting, but not before he signs off with a trademark flourish. “I think, Kevin Davies, you should just hop on a plane and come and look at the pipeline. You might learn something!”