Orphan diseases, affect not more than 5 in 10000 people, With some 29 million sufferers in the EU;

The EU offers the pharmaceutical industry some incentives to investigate rare illnesses. According to the General Director of LEEM, Philippe Lamoureux, European-backed research into drugs for the treatment of orphan diseases has led to 68 new medicines approved between 2000 and 2011. But there are between 6,000 and 7000 different rare diseases, so these drugs help just a fraction of sufferers.

Where does animal testing fit into the orphan drug equation? It is present in preclinical trials – as is the case with all drugs – but would it be right to ban the use of animals in research when patients have so few treatments to choose from in the first place? The Journal of Animal Ethics proposes that doctors tell patients, or their carers, the role that animals played in the development of their medicines. If sufferers of rare illnesses had access to this information, would they refuse treatment?

Stopping experimentation on animals in the EU probably wouldn’t stop European patients using drugs that have been tested on animals. The problem would simply be relocated, with testing taking place further away, in countries with less stringent regulations. Banning animal testing could also lead to a slowdown in research, as scientists consider alternative means of testing. The question remains: would sufferers of rare diseases be able to wait?

Some believe that not enough is being done to develop orphan drugs. According to work published by three Italian pharmaceutical researchers, a lack of testing on recommended animal species may have affected the investigations of 24 molecules, candidates for treatment of rare diseases. So when it comes to orphan drugs, should there be more, rather than less, research?

Sufferers of orphan diseases already face limited treatment options. Take animal experimentation out of the equation, and drug development options shrink even further.

The goal is to find ways of alleviating the symptoms of these conditions. We look at how trisomy changes neurological mechanisms and how it influences embryonic development, stem cells, and the programming and function of cells. We identify and target these mechanisms and hope to treat them through therapeutic drugs. These mechanisms are often similar to those affecting humans with comparable conditions.

We can hope to heal humans thanks to the mouse model. Ten years ago there were no real prospects for treating Down syndrome. Today, Roche is testing a new drug to reduce its symptoms, including problems with learning, memory and speech. Other drugs are on their way. Ten years of research mean that we now have several promising leads for treating Down syndrome.

The animals we use also allow us to do research on rare and very rare genetic conditions, those affecting as little as 1 in every 10,000 people. These include 17q21.31 and 16p11.2, two syndromes where a part of a chromosome is “deleted,” and ring chromosome 14, which results in difficult-to-treat epilepsy. The rarity of these conditions means that it can be difficult for doctors to know even what the typical symptoms and their intensity are. The animal experiments can help us determine what is representative and how these symptoms can be treated.

The Three R’s

We take very seriously our efforts to reduce as much as possible the degree of suffering and loss of life among our animals. We have mandatory training on animal handling and well-being before being allowed to work with them and this continues with “on the ground” training as we specialise.

In our work we follow the principles of reduction, refinement, and replacement. By reduction we mean that we follow tightly optimised procedures to reduce the number of animals we need to use. For example, we know exactly how many animals we need to detect a 20% difference between a test population and a “normal” reference population.

By refine we mean making the animals’ lives as positive as possible. This means we emphasise non-invasive methods of experimentation and, when needed, we use anaesthetics and analgesics to reduce any pain felt. In terms of mutations, our animals do not undergo anything that doesn’t occur in nature. Human children with these genetic features are born naturally. If ever there are animals with very serious problems we can put them down (which I have not yet had to do).

Finally we try to replace animals where possible with other means, such as growing and experimenting with cells in Petri dishes. However, this is typically not useful for studying mental disabilities due to Down syndrome, such as long-term memorisation, interaction with space and objects, social recognition, thinking, and senses. For this cell cultures are no substitute. But we are “thrifty,” so to speak, in all we do, including our use of animals. We have to be very careful in how we keep and treat them. In Europe, and certainly in France where I work, the use of animals is very well regulated [hyperlink to French regulation].

There are some who say we don’t need animal testing anymore. But for the kind of research we do, there’s very little that can be achieved with cells in Petri dishes. We do it knowing that people will benefit. In the 1920s, research using dogs and bovines led to knowledge of insulin’s role in diabetes and to the creation of medical treatments (including for animals with diabetes). Today there are still countless diseases which we could treat better. We work knowing that in the end our research will help heal people and improve their lives.

The people who work with laboratory animals are a compassionate bunch who would gladly use alternative methods if they could deliver the same results.

Like many people who do what I do, I’d quite like to become redundant. That is, I’d be content if my current job were made obsolete by advances in science.

As a vet in charge of laboratory animal science at a large research-based pharmaceutical company, I would be delighted if other mechanisms were available that could answer the questions we need to answer.

Nobody becomes a vet without first having a love for animals. For those of us who work with laboratories, we are the ones who guarantee round-the-clock care for the animals and safeguard their welfare.

Some people wonder how one can describe themselves as an animal lover yet do this kind of work. I give the example of my own wife who is a heart fibrillation survivor. Thankfully she leads a normal life, having taken a drug for 20 years now, and she is in great shape.

However, the reality is that the drug that has helped her stay healthy was developed through research on animals. We love cats in our house and I have to explain to my kids that a lot of the basic research that led to better treatments for their mother’s disease was actually done on cats and dogs.

The promise of unimaginable

As things stand today, it’s hard to imagine a world where animal research has been replaced with alternative methods. To be frank, I don’t foresee this happening any time soon, but such is the beauty of science that it tends to throw up all manner of unforeseen – even unforeseeable – advances.

Using animals is complicated but for much of our research, they are the best we have.

Advances in cell culture have taken us a long way but there are times when we need to see how a potential therapy responds to hormones and biochemicals from several organs of the body. The only option is to test the drug in a whole animal.

Of course, the research methods of the past are not as good as those available today. Perhaps in the future we’ll look back and think today’s methods to be primitive.

As I said in my last post, the beauty of science is its uncertainty.

That’s how Usher Syndrome, a rare untreatable genetic disease leading to deaf blindness, first became a part of our lives. You can imagine the emotional rollercoaster, taking us from feeling a sense of shock and injustice to the struggle of dealing with an ‘unacceptable’ situation.

We felt like we had a mandate to fight for a change on behalf of our sons; to fight for a cure or a therapy. Because Usher is also a family affair we combined our efforts with families who had the same or a similar situation. It was then that we realised that we were not alone. Other people – other families – were facing the same challenges.

It’s been a long and winding road through uncharted and unfamiliar territory. Along the way, we received inspiring support from patient-focused researchers and highly-motivated scientists working on a tissue engineering approach to tackling Usher Syndrome.

Their work involves exploration of techniques such as gene therapy or cell therapy. Unlike amphibians and birds, the regeneration of a missing or dysfunctional cells does not take place in humans. Therefore the molecular genetic approach requires an appropriate animal model to understand the disease biology in humans.

Years ago, we could see from a role model, Lanzelot, a Briard Dog with a natural retinal degenerative disease, that gene replacement therapy using a viral vector does work: Lanzelot was treated and cured with this technique, he could run and play with all the other dogs after his treatment. It was the first time of the proof of a principle we all had dreamed about: It’s ironic that our hope for a cure came from an animal with a disease, Lanzelot – and meanwhile more than 50 dogs were involved in the research which gave us the promise to find a solution for our children.

After initial tests with lower species like zebrafish, the test results with a mouse mutant animal model could not be translated into humans, confirming the skepticism of researchers that “…mice tell lies…”.

Those were difficult days and we had to look for further, properly regulated, animal research as no non-animal alternatives or other second-best options are available.

After having tried out all other options with in vitro experiments on cell tissue, computer-animated models and so on, in the end an appropriate animal model cannot be excluded as a last resort, before you start clinical trials with human patients.

Living with a severe disability in these days of expectation and hope for a cure for an untreatable condition like Usher also sharpens our view and perspective on the animal research debate. First it is worth mentioning, that none of us are in a position to define what’s ethical what’s not. Furthermore, when weighing the merits of animal research, it’s important to take account of its purpose. One has to clearly differentiate between testing new cosmetics and efforts to heal patients suffering from severe disabilities.

I can see a social and emotional tendency to pit “animal welfare” against “human welfare”. An illness with the gravity of Ushers stands for the dark side of life. And, if Paul Ehrlich was right to refer to life as chemical incident, in our case it’s more like a chemical accident.

In line with the WHO, the “Constitution Of The World Health Organisation” health is defined as follows: “Health is the state of complete physical, mental and social wellbeing. The enjoyment of the highest attainable standards of health is one of the fundamental rights of every human being“. Further on, the “Convention On The Rights Of Persons With Disabilities” states that all people “…have equal rights to education, employment and cultural life…”.

While we would all prefer to live with a good genetic passport, some of us are living in the kingdom of the sick. Therefore, and from the above-mentioned social contract, our society owes it to people with disabilities to provide the necessary “facilitators” including research in cases like Usher.

I can see no dilemma between different ethical positions if one can agree to respect the scientific rationale for research in severe diseases, if there are no non-animal alternatives!

I ask for respect within the animal welfare debate for all who take a diverging opinion. Caretakers, research scientists and doctors are fighting for a better future life of our patients to end the drama of Usher. I stand for the mandate of my sons like all the others in the medical arena and believe in the basic ethical fundament of our Christian civilisation – called “humanity”.

In the past, researchers were celebrated as the catalysts of a better future.  Today they are portrayed as cynical sinister characters “from Einstein to Frankenstein”.

In the stem cell debate the rivalry for ethical supremacy has taken an absurd focus: if the desire to cure very sick people is defamed as utilitarian thinking, a fair discussion is no longer possible. It is all a matter of weighing up ethics, humanity and confidence in treating suffering human beings who can only hope for a cure.

PHOTO CREDIT: NIDCD

Science is rarely as certain or a simple as some expect. It is never possible to know for sure how new knowledge will be used.

Nor is it reasonable to promise that a series of experiments will deliver a particular benefit. If the results were known in advance, the experiment would not be needed.
So the idea that the use of animals in research should be limited exclusively to cases where the investigator can say with confidence that the outcome will produce tangible results is to misunderstand scientific endeavour.

It also stifles scientists’ curiosity; curtailing the quest for knowledge that has taken us to where we are today.

Small steps lead to giant leaps
For example, researchers studying octopuses’ nervous systems decades ago hardly realised their work would be critical to understanding multiple sclerosis in humans. The octopus experts were deepening our understanding of how animals work because they were fascinated by the question.

Science is incremental. Breakthroughs often look from afar like giant leaps but they are in fact just the latest in a series of small steps.

The same goes for the people whose work on the brains of song birds gave us much of our current understanding of the pre-frontal cortex – an area associated with personality and behaviour but also with addiction and psychological disorders.

All of that basic science, conducted 30 years ago, was the first step on the long road that gave us medicines for people with schizophrenia and depression.

Those researchers didn’t know precisely how their work would be used, just like the electronics experts and computer scientists who helped us understand sound had no clue that one day someone from another branch of science would use that information to design a cochlear implant for deaf children.

Guaranteed uncertainty
Most of the animals used in labs right now are for basic research. Guaranteeing a direct human benefit in the short term is impossible.

Some experiments, of course, will not yield results even in the long term. That too is part of how science works.

Just as most successful entrepreneurs have failed ventures behind them, there are few scientists who can’t think back to a wasted weekend in the lab where a promising line of inquiry came to naught.

Science is imperfect and unpredictable. Long may it remain so.

Ever since Edward Jenner inoculated an eight-year-old boy against smallpox using the pus from a milkmaid’s cowpox blister, animals have been central to vaccination.

That was 1796. More than 200 years later smallpox has been eradicated and deaths caused by infectious diseases like diphtheria, tetanus and polio have been slashed. The benefits for humans have been immense but this progress has come at the cost of literally millions of animals.

We can now be vaccinated against dozens of lethal illnesses but each of these has been developed thanks to animal research and testing. What’s more, guaranteeing the safety and quality of vaccines currently involves testing every batch of vaccines produced on animals.

The upshot is that vaccine quality control accounts for between 10% and 15% of the 100 million or more animals used in laboratories every year. Obviously, this is a very large number so the appetite for alternatives is high.

As well as reducing the number of animals required in line with the 3Rs, finding new ways to make sure vaccines work and are safe could save money and time. Vaccines have relatively short shelf-lives so getting them to doctors and patients without undue delay is essential. The trick is to find non-animal tests without compromising on safety.

At the recent EPAA conference in Brussels, Coenraad Hendriksen of the Netherlands Vaccines Institute, outlined a radical solution which could dramatically change the way vaccines are quality tested. At present, each individual batch of vaccine – produced by manufacturers is tested on animals.

In his presentation, he explained the potential of the ‘consistency approach’ to quality control. In essence, this means moving away from testing every batch. Instead, scientists would test a few batches of vaccine on animals and then apply non-animal tests to batches made with the same starting material.

The aim would simply be to test that the subsequent batches were ‘consistent’ with the original batches which were tested on animals. Some animals would still be needed at the start of the process but the impact of moving to this method could be huge.

So why hasn’t it already been done? Well, partly the answer is normal human inertia: we’ve done it this way for ages and change is never easy. Another reason is that regulators would need to accept this ‘consistency’ testing instead of the current animal-intensive methods. That’s why, as Susanna Louhimies of the European Commission’s environment directorate said at the EPAA event, it’s essential that industry and global regulators work together on this.

Work on the consistency approach is already well under way through the EPAA, although there is still much to be done and Hendriksen acknowledged that a “paradigm shift” would be required if this new approach is to become the norm.

Still, if it means using fewer animals while still producing high-quality vaccines it will be worth the effort.

What if I told you that these technologies already exist and the trick now is to pull them together, apply them and have them accepted by authorities? Well, it’s true.

Some of these tools can be used by themselves, others can be combined to find innovative approaches to research and testing.

By using so-called Integrated Testing Strategies (ITS), major progress could be made in moving towards the 3Rs.  This approach means using tailor-made combinations of animal and non-animal research methods in developing and testing new medicines, although hurdles remain before Europe makes the leap into this new era.

As we mentioned recently, the European Partnership for Alternative Approaches to Animal Testing (EPAA) – a joint effort by policymakers and industry – devoted its annual conference in Brussels to ITS.

The beauty of so-called Integrated Testing Strategies (ITS) is that it can mean using fewer animals which also generally means lower costs. As Dr Thomas Foerster of Henkel put it, this appeals “not just for ethical reasons but also for budget reasons”.

Ready for total replacement?

So why are some of the non-animal methods which are part of ITS not used universally instead of animals? Why can’t we replace animals altogether? Well, right now, even the best available non-animal methods are imperfect.

In some cases, testing how a group of cells in a dish respond to a new drug can be very useful but scientists also need to know how whole organs interact in the presence of the new substance.

Translation: dropping a new medicine on a few brain cells tells you lots of things about how the brain will respond. Testing this drug on some liver cells also tells you something about how the body will deal with this drug. But it’s not quite the same as seeing how the whole brain, liver, kidneys, heart and so on will respond as a whole.

For now then, it seems ITS can be used to reduce the reliance on animal models, but some animals will still be required.

Show me the data!

More research is certainly needed. The other big hurdle to clear is convincing regulators to accept these new kinds of experiment instead of traditional animal-based testing. According to several speakers at the EPAA event, the industry is reluctant to invest heavily in developing these kinds of non-animal methods unless regulators can guarantee that they will accept them.

For their part, regulators have been slow to make such a commitment until they’ve seen data proving that the new non-animal methods are as good as existing tests.  It’s a classical catch-22. Perhaps the only option is to jump together.

Human nature is also a drag on progress. Scientists working in industry and toxicologists in regulatory bodies are used to current animal-based methods. They understand the techniques; they trust the results.

If ITS are to be embraced, experts who are familiar with them will need to be trained or recruited – which is no easy feat. There is also the global aspect. If new ITS were acceptable in Europe but regulators in the US, China and elsewhere would only accept traditional animal-based testing then new medicines would have to be tested twice – which would increase costs rather than reducing them.

Europe can take the lead in this innovative area but there’s no point running too far ahead of the pack.

The take-home from this year’s EPAA annual event was that ITS offer real promise for reducing the use of animals but making this kind of quantum leap is never easy. It looks like we’re at the beginning of a long but exciting story.

We caught up with Nick Meade, from the Genetic Alliance UK, while he was in Brussels. We asked Nick why expensive research is carried out to develop cures for rare diseases affecting only a very small proportion of society.

Listen to his position and please comment.

Given my interest in issues around animal testing, these timely reminders of the burden of disease got me thinking about the contribution that research has made to human health.

Survival rates from breast cancer have been improving for 30 years due in no small part to basic research using animals. Cancer is still to be dreaded however outcomes are much more promising than in the past and anti-cancer treatments are becoming more targeted (and so have fewer side effects).

These days it’s not uncommon to find cancer patients who want to be enrolled in phase III clinical trials so they have a chance of benefitting from the latest innovation medical science has to offer.

They believe new anti-cancer treatments, like chemotherapy, are safe – because they’ve been tested on animals – and they hope the drug will help prolong their lives.

What about non-fatal diseases?

Okay, so cancer is often put forward as a case where the deaths of animals in the lab ultimately helped prevent the deaths of people on oncology wards, albeit not in equal number.

But what about diseases like rheumatoid arthritis (RA)? This is a disease which too often strikes women in their prime. Statistics of woman effected vary slightly but stand at about 75%, compared to 25% of men. Unlike cancer, diagnosis of RA is not received as a death sentence – but it is a prescription for misery, pain, and a dramatic decline in quality of life.

Here we’re talking about a disease which is not immediately life threatening but which can prevent a young mother from playing with her children or heap severe strain on entire families.

Less than a decade ago, a new class of so-called ‘biologic’ drugs – monoclonal antibodies – arrived in doctors’ arsenals. Early work in this field was done using antibodies from mice and rats, and even now some of the human antibodies used in these therapies are produced using transgenic mice.

These drugs changed people’s lives almost overnight. Men and women with RA who could barely move – who couldn’t make a fist let alone drive to work – were given back a large portion of their independence.

‘Something must be done’

When we hear patient stories during awareness days/weeks/months, the visceral reaction is often to say “something should be done about this”.

Indeed it should. But what do we mean when we demand action? That science should find a cure or a treatment to end the suffering? Do we presume that this will involve animal research and, if so, are we okay with that?

So, dear reader, the question to you is:

How do we weigh animal suffering against the burden of human disease?

Is it okay to sacrifice animals to cure cancer? What about arthritis? Or depression? Or restless leg syndrome?

There’s no easy answers – but what’s yours?

The EPAA is an independent platform which brings together the European Commission and industry groups to collaborate on implementing the 3 Rs Declaration. It has been running since 2005 and has done a lot to bring together people who don’t talk as much as they should – like companies and regulators, or scientists and EU officials.

Last year’s event put the focus on ‘reduction and refinement’ while this time around the spotlight is on Integrated Testing Strategies (ITS) in animal research.

ITS can be tricky to define but is essentially a way to connect animal research methods, non-animal testing techniques and computer-based modelling to advance the cause of our old friends, the 3Rs.

Last month the EPAA ran a workshop on ITS so the annual conference is a natural follow-on from that.

The discussion will look at how ITS can be applied in a way that delivers efficient science-based results while reducing the use of animals, but at the same time meeting the growing demands of authorities and legal risk assessors.

Given Europe’s current obsession with innovation and competitiveness, it will be interesting to see whether ITS can really be the silver bullet that delivers all the information scientists need without compromising on speed, cost, or product safety. Plus, given that we’re in Brussels, one wonders what the EU can do to promote the use of appropriate ITS?

Can public and private stakeholders work together on non-competitive projects that will ultimately benefit all, perhaps along the lines of the Innovation Medicines Initiative?

The conference programme looks busy so hopefully we’ll get some answers on 9 November. We’ll be attending with a video to capture feedback from the day.