Suing for Alzheimer’s Mouse

Are patents the protectors of innovation or repressors of research?  - Why the academic community can’t make up its mind  

In February 2010, the Alzheimer's Institute of America (AIA) filed lawsuits against several research institutes, one of which was the Jackson Laboratory, for alleged infringement of their patented Alzheimer’s mouse. These unfortunate rodents are engineered to carry a mutant form of the gene for human amyloid precursor protein in their genetic code, a characteristic that guarantees the mice will develop Alzheimer’s disease symptoms. This makes them particularly useful models for studying the development and prevention of the disease in humans. The Jackson Laboratory is a non-profit institute that is funded by the National Institute for Health (NIH) to produce these mice and distribute them to the research community. Herein lies the problem – by distributing the mice (and allegedly making a profit from them, according to AIA), the Jackson Laboratory is infringing AIA’s exclusive right to make and sell their patented invention (35 U.S.C. 271).

Photo: Rama

Both sides accept that these mice are vital to Alzheimer’s research. According to judge Elizabeth Laporte for the US District Court of Northern California, AIA has not disputed Jackson's claim that "prolonging the litigation in this case would harm Jackson and the public by extending the chilling effect of the litigation on mice research on Alzheimer's disease".

An interesting facet to this whole case is how reflective it is of academic science’s love-hate relationship with patents.

In April, we (or maybe just those of us who follow patent news) heard the outrage from the academic community at the European Court of Justice’s Advocate General’s opinion regarding the patentability of human embryonic stem cells (hESC). As explained in an earlier post, the AG found that inventions that used hESC were contrary to ordré public and morality, and as such, unpatentable under European Law. This was unacceptable to much of the academic community. Thirteen prominent academics implored the ECJ to rule against the AG’s opinion in a letter to Nature. If stem cell inventions were ruled unpatentable, the academics argued, stem cell research in Europe would be severely disadvantaged. Selling and licensing patented technology to large pharmaceutical companies gives university and small and medium enterprises an indispensable funding source. Without such funding, the future of stem cell research and potential cures for the millions suffering diseases such as Parkinson’s, would be severely threatened. Being able to patent research is essential.

Yet in the states, a very similar rhetoric is being used to support a completely incompatible point. Researchers are arguing that by enforcing their patent, the AIA is threatening research and essential funding for the development of therapies for a devastating disease. The Jackson Lab has the advantage that Alzheimer’s is an incredibly emotive issue – blocking Alzheimer’s therapies arguably has a lot more sympathy than blocking stem cell research. So much so, that the NIH has come to the rescue, granting the Jackson lab government sanction to use the patent (the US government has the power to commandeer any US patent for it’s own use - within reason). Not being too keen on attempting to sue the US federal government, the AIA dropped their case against the Jackson Laboratory. But not, however, against the other defendants.

To the outside observer, there does seem to be some inconsistency in the academic communities’ approach to patents. Rudolf Tanzi, a researcher studying Alzheimer's disease at the Massachusetts General Hospital in Charlestown, taking to Nature News remarked “I think you need to respect people's intellectual property, but the impact on field if the mice were not freely available would be devastating.” However this same argument could equally be applied to any patented stem-cell inventions. For example, the stem-cell patent in dispute in Europe refers to neural precursor cells produced from hESC – surely if these were not freely available it would be devastating on any field researching potential therapies for neurodegenerative diseases, for example Parkinson's, and indeed, Alzheimer’s.

(Interestingly, the application to patent the original transgenic mouse, Harvard University’s “Oncomouse”, provoked similar ethical opposition as has arisen to the patenting of stem cells. If “Oncomouse”, genetically programmed to get cancer, had been ruled unpatentable due to ethical considerations, AIA’s “Alzheimer’s mouse” would be freely available to use.)

The problem is that the arguments on both sides are convincing. (Note that I am referring to the value of the patenting tools of scientific research per se, not any morality issues relating the use of transgenic mice or stem cells.) Arguably, these patents do the job they are intended for – that is to promote scientific advancement by encouraging investment in research. The potential loss of this investment is driving the scientific outrage at the Advocate General’s opinion on stem cells in Europe. However, any exclusive rights to a technology are bound also to produce some blocking effects, especially if the owner of those rights sets a high price to use the technology, as AIA has presumably done.* Personally, I have my own opinion on whether the current patent system is a Good or a Bad thing with regards to medical research, but this would be a much longer (and much rantier) post. However, which side of the fence you are on as a scientist, seems to depend on where you are with your research – i.e. at a patenting stage or an exploiting stage. I just wonder if the laboratories that purchased Jackson Lab’s mice are planning on patenting any of the cures they develop. I would bet that they probably are.

*Outside of medicine, the case may be more clear-cut. For example, in engineering, patents are probably a good thing. In other fields, such as computer programming, the blocking effect seems to dominate (as discussed in This American Life’s brilliant episode “When Patents Attack!”).

To Salt or Not to Salt

I have always been strangely suspicious of the highly publicized assertion that eating salt is a cause cardiovascular disease (CVD). Maybe as a chemistry student, I disliked seeing this vital electrolyte and perfect cuboid crystal receive continuous bad press. Or maybe its because for some inexplicable reason at school we had a whole double period based entirely around the Salt Manufacturers Association website.

Whatever the reason, according to a new meta-analysis, the Salt Manufacturers of GB (and my innocent brainwashed mind) may not be so wrong. As reported at Nature.com, the meta-analysis (a study of studies), published in the American Journal of Hypertension, has concluded that there was no significant benefit to reducing salt intake.  Now, to be fair, this is one of literally thousands of studies on the relationship between salt and CVD, many which have found the opposite result. For example, as is mentioned in the Nature article, another meta-analysis from 2009 found that a high sodium diet increased risk of stroke by up to 23%. So what does this mean – is salt a problem or isn’t it?

Sodium chloride is the major salt in our bodies and food  Rob Lavinsky 

The reality, is that the answer to the salt question remains unknown. Physiologically, it makes sense that continuous high salt intake could lead to increased blood pressure -  if our kidneys have to retain extra water to maintain the correct salt concentration in our blood. But in actual fact our kidneys are very good at getting rid of salt we don’t need in our urine, and so are able to keep salt levels well in check, as long as we don’t literally drink brine.

The problem with studies examining the link between salt and cardiovascular diseases is that it incredibly hard to measure salt intake accurately over an extended period of time. And it is even harder to control for other factors which have a proven influence in cardiovascular disease, namely the intake of sugars and fats, exertion and smoking rate. More often than not, measuring salt can just act as a substitute for measuring calorific intake.  Thus results between different studies vary widely, and we are left not really knowing if excess salt is harmful or not.

What we do know is that Japanese people eat more salt than British people, but have lower rates of CVD related death. In the 1996-99 INTERMAP Study, daily salt intake was estimated to be around 210 mMol (around 12g) for Japanese men, compared to around 170 mMol (around 10g) for UK men. The WHO recommended daily limit is 5g. And yet 24.7% of Japanese men die of CVD, compared with 37.6% of UK men. Like all statistics these should of course be treated with, my apologies, a pinch of salt (as pointed out on the Radio 4’s More or Less, fewer people France die of CVD then in the UK simply because in the UK unexplained deaths are more often attributed to CVD).  However there is a strong suggestion here that salt cannot be a major contributing factor to CVD risk.

I am not advocating a mass increase in salt intake. It is quite probable that there is some link between salt  and CVD, especially with for those with exceptionally high salt intakes or those who are already at risk of CVD events. However for most people on a normal western diet this link is unclear or marginal. The link between intake of saturated fat and CVD is not. Obese people get strokes, heart attacks, and diabetes at a much higher rate then normal weight people do.  WHO estimates that 2.8 million people die every year as a direct consequence of being obese. Not only this, but obesity is extremely impactful on a person’s quality of life and on a healthcare system's budget. I can’t help but feel that all the efforts by the government and industry to reduce “hidden salt” could be better-spent promoting low calorie lifestyles and subsidising fruit and vegetables.

Of course, the more pressing problem is the way foods are marked and marketed, and how the issue of salt is communicated to the public. Eating salt and overeating are often presented as equivalent sins, when it is clear this is not the case. How easy is it to equate one of the little green segments of the wheel of health smugness on Sainsbury’s packaging for another? The selection of a high fat, but low salt product is marketed as a health compromise.

Green cancels Red?

Only 29.8% of Japanese males over the age of 15 are overweight or obese (BMI of >25) whereas a truly shocking 67.8% of UK males meet the qualification.  It seems clear to me that body fat is a dominant effect, whereas salt intake should only ever be a secondary consideration. Heath guidance to the public needs to be clear and unambiguous, and presenting salt intake as an equal evil to fat and refined sugar intake, will inevitably effect peoples’ eating choices. Research into the effects of salt and CVD should and obviously will continue - however the current message that reducing salt is as important as reducing fat is misleading, and gives people an easier healthy alterative. Having no salt on your daily chips will not stop you getting cardiovascular disease. Not having your daily chips may just do. 

A 21st Century Wager

Escherichia coli cells, if left to grow in a beaker of nutrient solution, will grow and grow and grow until they produce so much toxic waste that all the cells die.

Implying that mankind is not dissimilar to these bugs is not a particularly sophisticated analogy, but perhaps we are not such a sophisticated breed. When it comes managing our consumption and growth, and thus inevitably our own downfall, at the moment we appear to be employing little more forward planning than a beaker of insentient cells.

Today, the Confederation of British Industry (CBI) reported that the UK government is failing to meet 12 out of the 13 emissions targets it set itself, one year after pledging to be the “greenest government ever”. Check out their climate change tracker, which shows just how well the David Cameron’s government is doing at discouraging investment in green tech in the UK. Across the North Sea, Germany has confirmed it is phasing out nuclear power by 2022, in response to the Fukushima incident, despite only currently generating 17% of its energy requirements through renewables. This seems an odd response when, as of yet, no people have died of radiation poisoning in Japan (as far as I know). Especially when you consider that 11 people were killed directly in the Deepwater Horizon disaster, and that vast numbers of people of people are killed every year by cardiopulmonary diseases caused by air pollution. No one seems to be making any similar endeavors to ban oil or coal combustion by 2022.

You can demonstrate with simple maths that if you put more greenhouse gases into the atmosphere (CO₂, methane) the Earth has to get warmer.

This is of course a hugely simplified model, but it illustrates the point. If you increase greenhouse gases in the atmosphere, you must increase the Earth’s temperature. This is unless you simultaneously increase the Earth’s reflectivity ( “albedo”), a large source of which is the shiny white ice caps. Which are, um, melting.

Yet we keep burning fossil fuels and pumping CO₂ into the atmosphere. Just like E.Coli pumping toxic waste products into their little beaker-based worlds. This downright puzzling journey of self-destruction we are all embarking on brings to mind philosophical wager penned by the French scholar Blaise Pascal in 17^th Century. Pascal examines the rational course to take with regard to belief in God:

God is, or He is not

A Game is being played... where heads or tails will turn up.

You must wager. It is not optional.

Let us weigh the gain and the loss in wagering that God is. Let us estimate these two chances. If you gain, you gain all; if you lose, you lose nothing.

You could replace the word “God” with the word “climate change” in this wager and come out with the same result.

In acting to prevent climate change, properly, and full-heartedly, we have nothing to lose. Fossil fuels are running out, and are becoming increasingly expensive and dangerous to obtain. Increased CO₂ in the atmosphere is acidifying the seas, leading to coral bleaching and collapse of fish stocks. Air pollution produced by burning fossil fuels kills an estimated 2 million people every year. Even if the devastating temperature increase predicted by the little equation above, and the world’s leading climate scientists, turns not to pan out, by reducing CO₂ emissions we have nothing to lose. On the other hand, if the scientific consensus is indeed right, we gain all. We gain the Earth.

The 2010 meeting of the United Nations Climate Change Conference, in Cancún, Mexico, failed once again to produce any international legal agreement on CO₂ emissions. All eyes should be on the 2011 United Nations Climate Change Conference (November to 9 December 2011, Durban, South Africa) – the last chance to secure an agreement before the Kyoto Protocol, and its tiny pledged reductions in CO₂ output, expires in 2012.

Patent Pain for Stem Cell Research

Confused how Greenpeace managed to call out Europe’s highest court to break-up the stem-cell party? 

These beautiful dancing fronds are a bundle of human neurons. These cells have not been taken from a brain; instead they have been grown from human embryonic stem-cells. With the capability to turn into any type of cell, human embryonic stem-cells (hESC) have the potential to cure the incurable, from the degenerative diseases of old age, to broken spinal chords. But research into hESC has provoked ethical debate, with religious groups, and organisations such as Greenpeace, being longstanding opponents of their use. Image: Nissim Benvenisty

Way back in 1997, the German Patent Office received an application for a patent from a Dr. Oliver Brüstle. The application was for neural precursor cells that could be used in the treatment of neural defects, and a method for making these cells from pluripotent stem-cells. Dr (now Professor) Brüstle was granted his patent, and he duly put his invention to work developing a new treatment for Parkinson’s Disease.  But now, 14 years after he originally filed his application, the subject matter of Professor Brüstle’s patent is being scrutinized by Europe’s highest court, with implications for the whole stem-cell research field in Europe.

As reported last week in the Guardian, the European Court of Justice (ECJ) will soon rule on whether inventions that use human embryonic stem cells (hESC) in any capacity can be patented under European Law. The Advocate General (a sort of Yoda-of-the-court figure, who provides a legal assessment of the problem before the court makes its judgement) has already given his opinion, and to the dismay of the stem-cell research community, has come out against allowing inventions such as Prof. Brüstle’s, to be patented. But why has this issue arisen now? And if the court does follow it’s Advocate General, will it really lead to the devastation of stem-cell therapies, as supporters of the technology claim?

Following the grant of Brüstle’s original patent, Greenpeace (as it frequently does when it unearths a patent that is not to it’s tastes) took proceedings to the German patents court, alleging that under both German and European Law the patent was invalid. The significant piece of European legislation can be found in the 1998 Biotechnology Directive: 

Article 6

(1)Inventions shall be considered unpatentable where their commercial exploitation would be contrary to ordre public or morality; …

(2) On the basis of paragraph 1, the following, in particular, shall be considered unpatentable:

 …

(c) uses of human embryos for industrial or commercial purposes

Greenpeace argued that because Brüstle relied on pluripotent stem-cells (a type of hESC) to make his neural precursor cells, the invention involved the commercial use of embryos, and was therefore unpatentable according to the Biotechnology Directive. Brüstle obviously disagreed, and the case worked its way up to a higher court, the Bundesgerichtshof. On examining the facts, the Bundesgerichtshof felt a legal brick wall had been reached, and so referred three questions pursuant to hESC and European Law to the ECJ for clarification.

The most pertinent of these questions, currently under deliberation at the ECJ, is the third one. If an invention, which doesn’t actually involve the destruction of embryos per se, but none-the-less specifies ingredients (e.g. pluripotent stem-cells) that can only be obtained through the destruction of embryos, does the invention fall within the scope of Art 6(2)(c) of the Biotechnology Directive? The Advocate General, Judge Yves Bot, was of the opinion that such inventions do use “human embryos for industrial or commercial purposes”, and thus, being contrary to ordre public and morality, cannot be patented.

Despite the dramatic language, a declaration of being “contrary to morality” does not mean such technology is rendered illegal.  A patent does not give you permission to use a particular invention; instead it gives you the right to exclude others from using it. So, if this judgement introduces no legal barrier to using stem-cell technology (in fact, it does quite the opposite, as patents are exclusionary in nature), what is all the fuss about?

Predictably, it is about money. The thirteen stem-cell academics, who wrote to Nature to protest at the Advocate General’s opinion, put the problem as such.  Without the promise of patent protection for stem-cell inventions, who will invest in the development of stem-cell therapies? Universities do not possess the resources to take treatments from the lab to the market, and so rely on assigning or licensing their inventions to big pharmaceutical companies. In the absence of legally guaranteed monopolies, what motivation will these companies have for sponsoring university research or funding expensive clinical trials to allow European stem-cell therapies to reach the marketplace? Instead Pharma companies will take their investments and research grants overseas – the US, for example, following the departure of George W., is as a much more stem-cell research friendly place. In contrast to what the Guardian reports, this is not so much a problem of stem-cell treatments being threatened, but a problem of stem-cell research moving elsewhere.

In their letter, the academics argue that an in vitro fertilised egg is not an embryo, a position which was neatly contradicted by Judge Yves Bot, at least from a legal perspective. But the academics also make a rather more compelling point; in actual fact, sourcing pluripotent hESC no longer requires the routine destruction of embryos. Cell lines (cells that are propagated in a Petri dish ad infinitum) are well established, and as a result, pluripotent stem-cells are available through international cell banks. They can be ordered online. This facet of the stem-cell conundrum does not appear to have been touched upon by the Advocate General. In fact, in paragraph 114 of his judgement (case C-34/10), Bot states the opposite, reasoning that for every additional number of cases of disease treated with stem-cell therapies, a proportional number of embryos would have to be created and destroyed. This, it appears, is simply not the case.

It is unusual for the ECJ not to follow the advice of its Advocate General, but not impossible. It will be interesting to see whether the outrage of the scientific community, and the concerns that have been raised regarding European research interests, have any impact. It will be particularly interesting to see whether the matter of established cell-lines, which seems to have been overlooked in the Advocate General’s statement, will be addressed at all. Can the ECJ come to a judgement that is more lenient on stem-cell inventions than that advised by Judge Yves Bot? 

Watch this vacuole.

(A postscript. Greenpeace has been fighting Mr Brüstle’s patent for many years now, and this case will now return to German courts. Lawyers are expensive. If you love the planet and want to donate to an organisation that fights Earth’s corner, please, please reconsider before donating to Greenpeace. There are many other groups that do a marvellous job of caring for the planet, campaigning against climate change and preserving endangered species, without wasting your hard-earned cash on lengthy lawsuits.)

Great Expectations - Or why I would rather read about Kate n’ Wills than Medical Miracles

JAB TO REVERSE ALZHIEMER’S - Breakthrough vaccine could be available within two years” announced the headline of last Saturday's Daily Mail A slow news day, one might conclude, if TDM was driven to fall back on such an up-beat, non-hysteria inducing headline.

Yet for anyone who has watched a loved one succumb to this brutal, incurable disease, this headline highjacks your attention. Alzheimer’s is a degenerative brain disease that progressively robs sufferers of their personality, their speech and finally their basic functions. It affects around half a million people in the UK alone. There are no effective treatments. An actual cure within two years is an unbelievable result - a proper old-fashioned miracle.

The hero jab of the article is bapineuzumab¹. As the Mail reports, its development is being funded by three of the biggest players on the Pharma scene - Pfizer, Johnson & Johnson and Elan Corporation - which is interpreted as indicative of bapineuzumab's impending blockbuster status.

TDM explains that bapineuzumab is currently in the phase III stage of testing, meaning that “it has passed initial safety hurdles and been shown to be effective”.² Hmm… no phase III data – was the phase II data really good enough to warrant such a proclamatory headline? A quick search on Google scholar reveals that the outcomes of phase II testing were inconclusive (see this phase II trial abstract and this review). In fact there is no requirement for a drug to have been shown to be definitively efficacious at phase II in order for it to enter phase III. If the backers (Pfizer etc) think there is a big enough market for the treatment, it may be worth the gamble taking the treatment to phase III, with the hope that with a larger sample size (1000s of patients as opposed to merely 100s), a statistically significant result will arise. In fact, this article is nothing more than speculation made on the basis that the bapineuzumab has made it into phase III and a quote from one doctor, Dr David Wilkinson, who, in fairness to him, talks only in maybes. As yet there is no data showing a positive effect of bapineuzumab on Alzheimer’s symptoms, never mind any evidence that it reverses the effects of the disease. Dr Ridley of the Alzheimer’s Society, also quoted in the article, puts it succinctly, "it’s too early to tell whether bapineuzumab could benefit people until the results of this trial are known". There is nothing in this article to justify the headline. 

While it is always relatively easy to Mail-bash on science articles, this does raise a wider point. How much of a disservice is done to science by “bigging it up”? i.e. predicting deliverables in 2, 4, 10 years time. Surely this doesn’t sit very well with the very reason research is carried out in the first place – to obtain an answer to an unknown. Furthermore, wrong predictions can only serve to undermine public and financial confidence in evidence based research. And who is really responsible? Is it the big bad media, who don’t know any better (although I suspect everyone who works at the DM did know better re: Saturday’s front page) or is it scientists themselves?

A key example of science “bigged-up” that leaps to mind is The Human Genome Project. Back in 2000, Bill Clinton made a speech announcing to the world that the first draft of the Human Genome was complete. Clinton proclaimed that this achievement would revolutionize medicine, yet last year, on the 10 year anniversary of the speech, the media was full of articles, such as this one from the New York Times, asking why had the HGP failed to live up to its promise. I find this an illogical conclusion - 10 years simply isn’t long enough time for treatments to appear. It typically takes around 15 years for a drug to move from the lab to the market, and that is after you have identified the appropriate target. Genetic diseases are complex, with many, for example cystic fibrosis, involving a myriad of contributory genes, all of which take time to identify. Yet before HGP, finding a human gene took months and was prohibitively expensive. Now a curious researcher can search for any sequence on a database. For free. Far from being a biological curio, the HGP has vastly accelerated and reduced the cost of research into the genetic causes of disease. This will translate it into tests and cures, but it will take more then 10 or 15 years, something that must have been known in 2000, even without the benefit of hindsight.

Regarding the HGP, it is clear that scientists themselves were complicit in the over-sell. Dr Francis S Collins, who predicted genetic tests within 10 years and cures within 15 years, is certainly a scientist. What was his motivation? Perhaps to try and justify the cost, or to ensure future grants? Or perhaps, simply because he was caught up in the moment. Obviously he never predicted the media’s reaction to the disappointment of the HGP a decade down the line. Either way it is a shame, because HGP is a substantial achievement of science and international cooperation, but this has been overshadowed by the initial over-sell.

Back to the Alzheimer’s story. I have little doubt that someday antibodies, or more likely cocktails of antibodies, are going to be invaluable in slowing or even quelling the rampaging effects of Alzheimer’s on the human brain.³ But within 2 years? It is impossible to know, but based on the phase II data for bapineuzumab, I would bet against it. This sort of reporting does nobody any favours. For the Daily Mail, it is after all, a reasonably boring headline – unless Alzheimer’s has directly effected a close family member, you are unlikely to care that much. Short of a “Vajazzling Gives You Cancer” headline, health stories just aren’t likely to compete with yet another headline about the impending bit of out-breeding the royal family is about to do. But importantly, it does science a huge disservice. By creating unjustified expectations, science and medicine can only fail, and thus public confidence in (and enthusiasm for spending on) vital evidence based research is reduced even further. Both scientists and the media have a duty to ensure that science is communicated responsibly, and that predictions, where they are made, are thoughtful and evidence based. Less punchy headlines are an inevitable result, but perhaps, until scientists can make p numbers sexy, science will just have to consent to being left off the front page.

A final comment, this one is directed just at the dirty feet of the Daily Mail. Above everything else, Saturday’s article struck me as an exceptionally exercise in cruelty. For someone who has just received a diagnosis of Alzheimer’s, whether critical enough to read on and understand, or not, that headline would have made their heart leap, and for no real reason.

1. For those who are interested, bapineuzumab is a monoclonal antibody, similar to the antibodies already produced by our bodies, except grown in industrial amounts using mouse cells. Antibodies are like hazard warning labels. They stick to anything in the body that shouldn’t be there, for example a virus or a cancer cell, signalling to the body’s immune cells to attack and dispose of the offending article. Bapineuzumab is an antibody that sticks to amyloid beta, the protein that forms tangled masses in the Alzheimer’s brain called plaques, presence of which during autopsy is the final definitive diagnosis of the disease. The theory behind the vaccine is this: bapineuzumab will stick to the amyloid beta plaques, causing to immune system to clear the amyloid deposits out of the brain, thus undoing the symptoms Alzheimer’s.  However, as explained in this excellent article, it is disputed whether amyloid tangles or plaques are a cause or a symptom of the disease. There are other candidates, including the tau protein, as well as smaller, soluble forms of amyloid beta, which theoretically bapineuzumab could work against as well.

2. Initial safety hurdles are phase I of testing, normally in healthy volunteers (although, with certain drugs that have the potential to cause harm, e.g. chemotherapies and certain Alzheimer drugs, such as bapineuzumab, phase I trial take place in disease sufferers). Phase II trials are small scale testing in people with the actual disease. Drugs that fail phase II often will not progress to phase III, the large scale trials required to get marketing authorization for a drug. 

3. Why? At university, I was lucky enough to be taught by a group researching Alzheimer’s and antibodies, and saw some brilliant data. Unfortunately the unlucky subjects of the experiments were fruit flies engineered to have Alzheimer’s-like symptoms, but none the less, it was enough to make me a believer in the potential of this stuff.