Nanomedicine - Tiny is the Next Big Thing

Your mother was right; good things do come in small packages, sometimes so small that a conventional lab microscope cannot see them. Nanotechnology, the science of the extremely tiny, has become the new high-tech frontier and an important emerging industry with a projected annual market of around one trillion US dollars by 2015.

Although serious work on this infinitesimally small order of magnitude only commenced in laboratories about ten years ago, scientists now project revolutionary advances in the medical, pharmaceutical, diagnostics and imaging sectors arising from the application of nanotechnology to health.

By all accounts, nanomedicine will constitute one of the most exciting fields of study in medicine in the coming decades. This fast-developing and increasingly lucrative field, which involves manipulating atoms and molecules to create tiny devices, smaller than one-thousandth the diameter of a human hair, holds extraordinary promise for the diagnosis, prevention and treatment of disease.

A nanometre is one-billionth of a meter, and it is at this size scale – about 100 nanometres or less – that biological molecules and structures inside living cells operate. More than just an extension of "molecular medicine," nanomedicine aims to employ nanoscale machine systems to address medical problems, and to maintain and improve human health at the molecular scale.

The European Science Foundation believes that nanomedicine is about to deliver “a healthcare paradigm shift” in which it will be possible to monitor people on the basis of known genetic predispositions, diagnose disease before there are any symptoms, administer drugs that are precisely targeted, and use non invasive imaging tools to demonstrate that the treatment was effective.

A recent ESF report notes that Europe is particularly strong in many areas of nanotechnology needed for advances in nanomedicine and that several European companies are at the cutting-edge of research in this area.

Bringing together experts from all over Europe and further afield, a new EU NANOMED project was launched in February this year to examine all aspects of nanomedicine and provide an objective answer to claims that this rapidly evolving field will change the face of healthcare forever.

The panel will for the first time look at all aspects - Economic, Patient Attitudes, Regulatory, Ethics and Communication - and enable EU policy makers to properly direct what has already been identified a major area for strategic investment in the new Framework V11 programme. The final report will be presented at the end of the year.

“Working at the nanoscale is already leading to new highly targeted medicines, improved imaging and diagnostics of disease and even a new generation of implantable sensors for monitoring your health,” surmises Professor Sir John Beringer, who is chairing the project.

Drug delivery:

In terms of therapy, one of the most significant impacts of nanomedicine will mostly likely be realised in drug delivery. Nanoparticles can enable doctors to target drugs at the source of the disease, which increases efficiency and minimises side effects. The first nanotechnology-based targeted drug delivery systems are already on the market, with numerous others in clinical trials or under development. Drug delivery accounts for approximately 80 percent of global sales in nanomedicine and 58 percent of patent filings worldwide. In April 2006, the journal Nature Materials estimated that 130 nanotech-based drugs and delivery systems were being developed worldwide.

Some recent advances in this area include a potential new arsenal for meningitis treatment and the war on drug-resistant bacteria and fungal infections with the development of novel peptide nanoparticles by scientists at the Institute of Bioengineering and Nanotechnology (IBN) of Singapore.

The unique chemical structure of these stable bioengineered nanoparticles provides for the first time membrane-penetrating components on their surface, which allows them to traverse the blood brain barrier, offering a superior alternative to existing treatments for brain infections.

Pre-clinical tests, reported recently in Nature Nanotechnology, have shown that IBN's peptide nanoparticles are also biocompatible and cause no damage to the liver or kidneys at tested doses.

In the battle against cardiovascular disease, researchers and engineers in California have developed a nanoparticle that specifically detect and attack atherosclerotic plaques. The new development is described in a recent issue of the Proceedings of the National Academy of Sciences.

The nanoparticles in this study are lipid-based collections of molecules that form a sphere called a micelle. The micelle has a peptide, a piece of protein, on its surface, and that peptide binds to the surface of the plaque.

Cancer:

This tiny technology is also taking on cancer, in a very big way. Much of this pioneering research in recent months is focusing on targeting cancer with 'smart bombs'. Scientists at the University of Central Florida (UCF) have just released details about their newly engineered nanoparticles with a dual role, as diagnostic and therapeutic agents, that could someday target and destroy tumours, sparing patients from toxic, whole-body chemotherapies.

The researchers used Taxol - one of the most widely used chemotherapeutic drugs - for their cell culture studies, just published in the journal Small. Taxol normally causes many negative side effects because it travels throughout the body and damages healthy tissue as well as cancer cells. However, the Taxol-carrying nanoparticles engineered in the UCF laboratory are modified so they carry the drug only to the cancer cells, allowing targeted cancer treatment without harming healthy cells. This is achieved by attaching a vitamin (folic acid) derivative that cancer cells like to consume in high amounts.

In addition, the nanoparticles carry a fluorescent dye and an iron oxide magnetic core so that their locations within the cells and the body can be seen by optical imaging and magnetic resonance imaging (MRI). That allows a doctor to see how the tumour is responding to the treatment.

The nanoparticles also can be engineered without the drug and used as imaging (contrast) agents for cancer. If there is no cancer, the biodegradable nanoparticles will not bind to the tissue and will be eliminated by the liver. The iron oxide core will be utilised as regular iron in the body.

In a feat of trickery, immunologists at Dartmouth Medical School in New Hampshire, USA, recently devised a Trojan horse to help overcome ovarian cancer, unleashing a surprise killer in the surroundings of a hard-to-treat tumour.

Using nanoparticles, the team has reprogrammed a protective cell - the dendritic cells - that ovarian cancers have corrupted to feed their growth, turning the cells back from tumour friend to foe.

Their research, published online July 13 for the August Journal of Clinical Investigation, offers a promising approach to orchestrate an attack against a cancer whose survival rates have barely budged over the last three decades.

The National Cancer Institute – the US Government’s principle agency for cancer research – fully recognises nanomedicine’s massive potential, creating the Alliance for Nanotechnology in Cancer in the hope that its multi-million dollar investment in this branch of nanomedicine could lead to breakthroughs in terms of detecting, diagnosing, and treating various forms of cancer.

This enterprise is already producing results; in recent weeks researchers involved in a MIT/Harvard collaboration announced the development of an implantable diagnostic device offering continuous cancer monitoring, while scientists at the University of Massachusetts have devised a “chemical nose” array of nanoparticles and polymers to differentiate not only between healthy and cancerous cells but also between metastatic and non-metastatic cancer cells.

And there is progress towards drug-free cancer treatment as nanoparticle-based photothermal ablation is showing extraordinary promise as an unusually effective and potentially revolutionary cancer therapy.

This approach uses light at near-infrared wavelengths that pass through tissue, in combination with gold-based nanoparticles specifically engineered to absorb that light and convert it to heat.

The light-absorbing nanoparticles serve as highly localised heat sources that destroy cells in their immediate vicinity by hyperthermia. This method has been shown to be highly effective in extensive animal studies, with tumour remission rates above 90 per cent.

The US FDA recently granted approval for initial human trials of this therapy for head and neck cancer.

Researchers at the University of California recently presented their pioneering work in this area to the American Chemical Society's 237th National Meeting in March this year. They have developed the first hollow gold nanospheres - smaller than the finest flecks of dust - that search out and "cook" cancer cells far more effectively than their sold gold counterparts.

These new cancer-destroying nanospheres show particular promise as a minimally invasive future treatment for malignant melanoma, the most serious form of skin cancer, the researchers say.

The hollow gold nanospheres are equipped with a special "peptide." That protein fragment draws the nanospheres directly to melanoma cells, while avoiding healthy skin cells. After collecting inside the cancer, the nanospheres heat up when exposed to near-infrared light, which penetrates deeply through the surface of the skin. In recent studies in mice, the hollow gold nanospheres did eight times more damage to skin tumours than the same nanospheres without the targeting peptides.

The next step is to try the nanospheres in humans. This requires extensive preclinical toxicity studies. The mice study is the first step, but the researchers acknowledge there is a long way to go before it can be put into clinical practice.

However, the first human trials of nanoparticle-delivered 'suicide' genes that can slow and even halt ovarian tumour growth are expected to commence within 18 to 24 months according to a report in Cancer Research, a journal of the American Association for Cancer Research. US researchers revealed that nanoparticle delivery of diphtheria toxin-encoding DNA selectively expressed in ovarian cancer cells reduced the burden of ovarian tumours in mice. A number of the treated tumours failed to grow at all.

"This report is definitely a reason to hope. We now have a potential new therapy for the treatment of advanced ovarian cancer that has promise for targeting tumour cells and leaving healthy cells healthy," said lead researcher Prof Janet Sawicki from the Lankenau Institute for Medical Research in Pennsylvania.

Diagnostics:

Another highly attractive area of nanomedicine is diagnostics at nanoscale. The aim is to identify a disease at the earliest possible stage. Ideally, a single cell with ill behaviour would be detected and cured or eliminated.

Making enormous strikes in this area is a research team at the University of Nottingham who are developing revolutionary ultrasonic nanotechnology that could allow scientists to see inside a patient’s individual cells to help diagnose serious illnesses.

The components of this new technology would be many thousand times smaller than current systems. Ultrasound refers to sound waves that are at a frequency too high to be detected by the human ear, typically 20 kHz and above. Medical ultrasound uses an electrical transducer the size of a matchbox to produce sound waves at much higher frequencies, typically around 100 to 1000 times higher to probe bodies.

The Nottingham researchers are aiming to produce a miniaturised version of this technology, with transducers so tiny that you could fit 500 across the width of one human hair, which would produce sound waves at frequencies a thousand times higher again, in the GHz range.

Dr Matt Clark of the Ultrasonics Group in the university’s Division of Electrical Systems and Optics explains: “To produce nano-ultrasonics you have to produce a nano-transducers, which essentially means taking a device that is currently the size of a matchbox and scaling it down to the nanoscale. How do you attach a wire to something so small?

“Our answer to some of these challenges is to create a device that works optically — using pulses of laser light to produce ultrasound rather than an electrical current. This allows us to talk to these tiny devices.”

Tissue engineering and nano-scaffolding:

New concepts for nanotechnology in regenerative medicine give hope to many patients with organ failure or severe injuries. An extraordinary revelation by American military researchers in December last year took many by surprise when they claimed to have unlocked the secret to regrowing limbs and recreating organs in humans who have suffered major injuries.

Using "nanoscaffolding", Army researchers said they had regrown a man's fingertip and the internal organs of several test subjects. Their pioneering work was revealed officially at the 26th Army Science Conference in Florida in December 2008.

A very fine apparatus, a scaffold, made of polymer fibers hundreds of times finer than a human hair, are put in place of a missing limb or damaged organ. The nanoscaffold guides cells to grab onto it so they can begin to rebuild missing bones and tissue. Over time, the scaffold breaks down and is naturally passed from the body.

Dr John Parmentola, director of research and laboratory management for the US army, explained that by using nanoscaffolding the military was able to regrow a man's fingertip, restoring everything he had lost - the nail, the bone, the tissue.

Dr Parmentola added the military has been able to regrow "whole bladders" in people who have had bladder damage. The technology has also been used to repair the wall of a woman's uterus.

Several breakthroughs with nanoscaffolding preceded the US army's stunning announcement. Back in June 2006, researchers from the University of Sheffield in England used nanoscaffolding to repair skin damage in people with third-degree burns and they discovered that skin cells will “sort themselves” into the right arrangement if given a proper foothold.

In February 2008, a PhD student from Monash University in Melbourne, Australia, unveiled research into how nanoscaffolding could repair nerve damage. And later that year, researchers at the City University of Hong Kong, reported claims that nanoscaffolding would soon revolutionise bone grafts and implants.

The downside:

While it is difficult to find fault with a technology that promises to cure cancer almost before it starts and prevent the spread of deadly infectious diseases, there are toxicological concerns and ethical issues that come with nanomedicine and they have to be addressed alongside the benefits.

Nanomedicine, and nanotechnology in general, is new and little experimental data about unintended and adverse effects exists. The lack of knowledge about how nanoparticles might affect or interfere with the biochemical pathways and processes of the human body is particularly troublesome.

Although nanoparticles have been linked to lung damage, for example, it has not been clear how they cause it. However, this summer Chinese researchers discovered that a class of nanoparticles being widely developed in medicine - ployamidoamine dendrimers (PAMAMs) – can cause lung damage by triggering a type of programmed cell death known as autophagic cell death.

Also, they were able to block the process by using an autophagy inhibitor to prevent the cell death and counteracted nanoparticle-induced lung damage in mice. Their study is published in the newly launched Journal of Molecular Cell Biology.

A group of academics and industrialists in the US recently collaborated on a unique blueprint that will serve to educate the first generation of nanobiologists on the known physical and chemical properties of nanomaterials as well as particulars on the nano-bio interface. The authors’ analysis, published in the July issue of the journal Nature Materials, should help identify the potential risks of engineered nanomaterials and to explore design methods that will lead to safer and more effective nanoparticles for use in a variety of treatments and products.

Conclusion:

The high-risk, high-payoff global nanotechnology phenomenon is in full swing. There is enormous excitement and expectation regarding nanotechnology’s potential impact on every aspect of society – even space travel. At NASA’s Ames Research Center, for instance, researchers are developing nano-based medical technologies that could be injected into astronauts to detect and kill cancers caused by the massive cosmic radiation exposure expected during a years-long manned Mars mission (proposed for launch in 2020).

The creation of nanodevices, such as nanobots capable of performing real-time therapeutic functions in vivo, is one eventual goal. Already this year researchers at Harvard University have created the smallest-yet nanodevice propulsion system. The corkscrew flagella nanoscale device mimics the way that some bacteria swim and overcomes some of the limitations of other proposed propulsion systems for nanoscale devices.

A mere 5,500 years took us from the wheel to the double helix. Then 50 years to the human genome. In the coming years significant research will be undertaken in various areas of nanomedicine – generating both evolutionary and revolutionary products. These efforts will traverse new frontiers to the understanding and practice of medicine. Even if we don't see the nanorobots of Fantastic Voyage fame for a few years, nanomedicine still has immense potential to impact all of our lives.

Ameisen's Miracle Molecule

Applauded by many for his personal courage and slated by some for his controversial claims, Dr Olivier Ameisen bared his darkest secret to the world in his recently published memoirs and triggered an impassioned debate over his claim to have discovered a cure for alcoholism.

The Paris-born cardiologist had a brilliant career at one of America’s top teaching hospitals when he developed a profound addiction to alcohol. His binges would last several days until the damage he inflicted on his body would compel him to admit himself to hospital with serious, and at times, life-threatening injuries.

He broke bones with no memory of falling; he nearly lost his kidneys; he almost died from massive seizures during acute withdrawal. For him, “alcoholism was a biological prison and there was no way to break down the walls”.

When Olivier feared his addiction could put his patients at risk, he abandoned his flourishing practice in New York City, and then, fearing for his own life, immersed himself for three years in Alcoholics Anonymous, various therapies, rehab – eight times – and a plethora of medications. Nothing worked.

During this struggle, he repeatedly complained to his doctors that if they could treat his chronic anxiety disorder, his alcoholism would be cured. Then he happened upon an article in the New York Times in 2000 about a researcher studying the effect of a muscle relaxant called baclofen on a drug addict’s addiction to cocaine.

Baclofen has been used safely for years as a treatment for various types of muscle spasticity, but has more recently shown promising results in studies with laboratory animals addicted to a wide variety of substances.

Olivier self-prescribed the drug and experimented with increasingly higher doses until he finally reached a level high enough to leave him free of any craving for alcohol. That was more than five years ago.

"After years of battling uncontrollable addiction, I have achieved the supposedly impossible: complete freedom from craving," he says with a forthright sincerity that is characteristic of his writing in his book “The End of My Addiction”.

Olivier theorises that baclofen relaxed his chronic muscular and nervous tension, kept it from intensifying into chronic anxiety and panic, and thereby short-circuited the craving for alcohol to resolve that extreme distress.

The results for him were truly remarkable, and his self-case report published by the journal Alcohol and Alcoholism in 2005 gathered slow but intensive interest.

His findings presented a new concept: medication-induced complete and prolonged suppression of substance-dependence symptoms with alleviation of co-morbid anxiety.

But this thesis was largely met with resistance from the some members of the medical community - though his work was later supported by the findings of other researchers - and in response, he says, he wrote this book.

‘The End of My Addiction’ (Piatkus 2009) is both an autobiography and a groundbreaking call to action – “an urgent plea for research that can rescue millions from the scourge of addiction and spare their loved ones the collateral damage of the disease”.

When it was first published in France in late 2008, it became an instant bestseller. With its eye-catching message, ‘Le Dernier Verre’ (‘The Last Glass’) prompted thousands of recovering alcoholics to ask their doctors for baclofen. The English translation, which was published in March this year, sparked a predictable worldwide escalation of interest in this cheap and once inconspicuous drug.

In sharing the story of this discovery and his recovery, and with unsparing honesty, Olivier also bravely recounts every explicit and painful detail of his fall from grace, from reason, and from the lofty heights of a specialist medical practice among America’s elite.

Born and raised in Paris, Olivier says he was a lifelong sufferer from chronic anxiety and panic attacks. The son of Holocaust survivors, he was a prodigiously gifted pianist, but opted ultimately for a career in medicine, which he thought would give him the security he craved. In 1983 the young doctor moved to New York to join the prestigious cardiology team at New York Hospital and Cornell University Medical College (now New York-Presbyterian Hospital and Weill Cornell Medical College), where he became respectively an associate attending physician and associate professor of clinical medicine. In addition, he opened a successful private cardiology practice in Manhattan in 1994.

As an active participant in cardiology research at New York Hospital/Cornell, Olivier co-authored 16 papers in peer-reviewed medical journals on the evaluation of coronary artery disease and related topics.

Yet, he was still plagued by feelings of self-doubt and imminent failure. “Throughout my life I had been plagued by anxious feelings of inadequacy, of being an impostor on the brink of being unmasked constant anxiety,” Olivier writes.

He was unable to quell the anxiety he constantly felt until, in his 30s, he turned to alcohol as a form of self-medication. He recalls: “I hated the taste. I would drink whisky and hold my nose as I drank.” And from a social drinker, he became a hopeless alcoholic.

“As my drinking had increased, I had scrupulously honoured my first duty as a doctor - to do no harm. I stopped driving. And I never set foot in my office or the hospital when I was not completely sober.

“But the fact is, I was terrified of living without alcohol. Without it, I would be an anxious wreck. Despite the outward successes - at the very nadir of my alcoholism I was awarded the French Legion of Honour for services to medicine - I struggled with a deep sense of failure, and feared that the world would see that my accomplishments were nothing but a sham,” he confesses.

Occasionally, in a veiled appeal for help, Olivier would discreetly ask his medical colleagues about how to help ‘someone’ with a drinking problem. They’d ask, “Is the person close to you?” If he said no, they’d say, “You don’t want to get involved, it’s a minefield.” If yes, “Well I really don’t know what to say. It’s very complex…”

Recent studies have shown that, at least among doctors who are not specialists in the field, missed or delayed diagnosis is the rule, rather than the exception, in cases of addiction. One study videotaped doctors and patients and found that when patients mentioned addiction issues, doctors tend to change the subject as quickly as possible.

“I didn’t know what to make of this phenomenon when I first encountered it. But it dawned on me that doctors are uncomfortable with the subject because they don’t have a reliable treatment to deliver or recommend,” Olivier suggests.

The lack of a reliable treatment also explains the moral assumptions attached to addiction, he continues. “Admitting my problem drinking to most of my friends and my colleagues terrified me, too. I feared being ostracised, and since I felt that drinking should be under my control I felt ostracism would be justified.”

Naively, he assumed that very few doctors had a drinking problem, when in fact research has shown that ten percent of doctors will become dependent on alcohol at some point in their lives. And, according to the British Medical Association, doctors are three times more likely than the general population to have liver cirrhosis from alcohol abuse.

Between binges, Olivier clung to abstinence, called his AA sponsor regularly, visited his therapist and worked overtime in his practice so that he had no free time for drinking. But inevitably the cravings would consume him again and he would drink for days.

“Through my drinking I broke my shoulder, my wrist and three ribs. I often considered taking my own life. I had a feeling that I could easily have a bad accident that would result in me breaking my back and living the rest of my life as a paraplegic. But something held me back. It was this feeling that if I died, I was sure that someone would discover the cure for this disease the day after.”

As his need for alcohol increased, he began to ease himself out of his practice. He told all his doctors: “I use alcohol as a tranquilliser. If you rid me of anxiety, I'll stop drinking.” His doctors all told him: “You're anxious because you drink. Stop drinking and your anxiety will subside.”

Olivier’s suspicion was that his chronic physical uneasiness was triggering addictive behaviour, which was then exacerbated by this self-medication gone wrong.

He began to have paralysing panic attacks. These began innocuously enough with a twitching in his calf muscles. The next symptoms were tightness in his chest; he felt he couldn't breathe. And then unstoppable panic took over his whole being.

“I began increasing my intake of the drug that brought relief: alcohol. Talk about a slippery slope. The more I drank to ease my anxiety, stave off panic and counter insomnia, the more I had to drink for the same effect.

“I was an accident waiting to happen. When, in August 1997, I wound up in New York Hospital with acute withdrawal seizures that nearly killed me, it was devastating - and a great relief. I thought: 'I am no longer hiding my drinking from anyone. Now I will get proper treatment and recover’,” he admits.

Fearing for his own patients, he gave up his practice and returned to Paris. Over the next three years Olivier tried everything from rehab to prescriptions for tranquillisers and anti-depressants. He also tried acupuncture and hypnotherapy, both of which had zero effect. He consulted a highly recommended specialist in cognitive behavioural therapy to try to resolve the emotional experiences that triggered drinking, but this therapist seemed more interested in turning Olivier from a binge spirits drinker into a moderate wine drinker.

“I told every doctor and therapist I saw that my fundamental problem was anxiety. None took this seriously.”

One day in November 2000, a former girlfriend sent him an article she came across in the New York Times about a researcher studying the effect of a muscle relaxant called baclofen on a drug addict's craving for cocaine.

“I read with fascination about how scans conducted by the psychologist Dr Anna Rose Childress, an addiction researcher at the University of Pennsylvania, showed a remarkable quieting of brain activity in a cocaine addict who was taking baclofen to control spasms. The addict said this medication reduced his craving substantially.

“I did not want to get my hopes up too much, but I did wonder: Could baclofen help me stop drinking?”

Over the next couple of months, he started taking baclofen, steadily increasing his dose to 180 milligrams a day. The short-term results were remarkable. It relaxed his muscles completely and gave him a peaceful sleep - both things he had never experienced before.

“It reduced my craving for alcohol and enabled me to remain abstinent for longer periods between binges. But I still had binges - and with them came the blackouts and accidents.

“In order to reach a point where I would lose the motivation to consume alcohol at all, it seemed I'd have to increase the baclofen dose. But I was in unknown territory, already taking six times the dose used in previous brief experiments with alcoholics.”

But in January 2004, he decided it was now or never: if he continued to follow his doctors' advice, he felt he would keep lapsing into binges and eventually die from drinking. He had to take my treatment into his own hands.

Based on animal studies, he decided that by increasing the dose gradually he could tolerate up to 300 mg. At 270 milligrams he went out with friends for tea. “I saw a man to my right drinking whisky - and I felt neutral. I looked at him again. Again I felt neutral. Since the onset of my alcoholism, this had never happened - I'd have wanted a drink, too. Within five weeks of taking the higher does, baclofen had made this change in me happen. I dared to look at the bar with its gleaming bottles. No alcohol thoughts came to mind; no craving for alcohol troubled me. I thought: 'I am in a fairy tale or a dream. In a moment the spell will break, and I will wake up to the horror of needing a drink.' But I didn't,” he says.

Olivier gradually reduced his intake of baclofen over the next two weeks to 120mg; it appears that going up to 270 mg had apparently triggered a threshold response, which could now be maintained at the lower dosage.

Five years later, Olivier is still taking Baclofen, and he remains free from cravings and liberated from the curse of alcoholism that had plagued him for almost two decades.

“By completely suppressing my addiction, baclofen saved my life. I believe it can save and improve the lives of many others by completely suppressing their addictions, and I have written his book to that end”.

Olivier currently is Visiting Professor of Medicine at State University of New York Downstate Medical Centre, and divides his time between New York and Paris.

What his colleagues say:

Some doctors have decided to overlook the fact that baclofen is not authorised for treating alcoholism, and are reporting exciting results.

"I prescribed it to two alcoholics who were really at the end of the road. To be honest, it was pretty miraculous," says Dr Renaud de Beaurepaire of the Paul-Guiraud hospital at Villejuif near Paris. "Ameisen has made an extraordinary discovery," he adds. "The whole world will thank him for it."

Dr Pascal Garche of the Geneva University Hospital alcoholism unit has also conducted a limited experiment. He gave 12 patients a course of baclofen. Seven showed remarkable signs of recovery. "I have never had reactions like this before," he comments. "We cannot ignore findings such as this - The book is going to set the cat among the pigeons." Dr Garche admits that some patients withstand large doses of baclofen better than others. He has sought permission to extend his programme.

Other medical specialists are sceptical and even angry that Dr Olivier Ameisen should claim there is a simple pharmaceutical solution to what they insist is a complex physical, mental and social disease.

"Encouraging people to think that there is a miracle molecule is to completely misunderstand the nature of alcoholism, and is extremely irresponsible," says Dr Michel Reynaud of Paul-Brousse hospital in Paris.

"We need comprehensive tests to determine how this drug acts, if it is effective and at what dosage, and if it is genuinely harmless in the longer term," says Alain Rigaud, President of France’s National Association for the Prevention of Alcoholism and Addiction. "But even if it turns out to work, that does not mean a drug alone is the solution."

Since the publication of Olivier’s book, a spokesperson for the French government agency, which tests and approves drugs, L'Agence française de securité sanitaire des produits de santé (Afssaps), has cautioned that baclofen is "not an anodyne drug" and can have adverse side effects. However, he said the agency is considering "how to organise clinical trials" which would put Dr Ameisen's claims to the test.

It has been remarked in the media that no pharmaceutical company would sponsor such trials because baclofen has been out of copyright since 1997.

Dr Olivier Ameisen issues a heart-felt appeal to medical colleagues in his book: “Until a randomised clinical trial of dose-dependent baclofen is mounted, I ask all doctors who treat addiction to consider prescribing baclofen off-label for case of those patients who remain ill despite exhausting therapies and have no alternative treatment for a devastating and often deadly disease.”

He also calls on Government health agencies and officials, politicians, non-governmental health organisations, and citizens to support full-scale randomised clinical trials of high-dose baclofen.

How does it work?

Exactly how baclofen produces craving suppression and alleviates underlying dysphoria must still be explained by further research. But important parts of the answer have been established. Baclofen affects the neurotransmitters dopamine, GABA, and glutamate. It enhances GABA activity, reduces glutamate, and through these effects reduces dopamine. In so doing it seems to play a role in balancing the brain’s reward mechanism.

In addition to the fact the baclofen has been shown to does-dependently suppress motivation to consume alcohol, cocaine, heroin, nicotine, and amphetamine in animals, low-dose baclofen has been shown in randomised trials with dependent patients to reduce craving for cocaine and opiates as well as alcohol, and in an open trial, craving for food binge eating and bulimia.

While Dr Olivier Ameisen has reported no side effects after five years of using baclofen, hallucinations and seizures have occurred from abrupt withdrawal of Baclofen. Side effects have included: somnolence, dizziness, paresthesia, nausea, vomiting, headache and constipation. There is a report of a Baclofen overdose (300 mg with alcohol), which led to severe respiratory depression requiring airway and respiratory support.

A 2007 study published in the Lancet concluded that baclofen is effective at promoting alcohol abstinence in alcohol-dependent patients with liver cirrhosis, and could have an important role in treatment of these individuals.

Dr Giovanni Addolorato, Institute of Internal Medicine, Catholic University of Rome, Italy, and colleagues did a trial of 148 alcohol-dependent patients with liver cirrhosis that had been referred to their institute.

The researchers found that 71 percent of the baclofen patients (30/42) achieved and maintained alcohol abstinence, compared to 29 percent (12/42) of those receiving placebo. Patients taking baclofen also abstained from alcohol for more than twice as long as patients given placebo (62.8 days versus 30.8 days).

Alcoholism –

Worldwide, about ten percent of the population is vulnerable to becoming dependent on alcohol, and significant percentages are vulnerable to developing dependence.

A report published by the Health Research Board (HRB) in 2007 shows that alcohol consumption in the Irish population has increased by 17 percent over the past 11 years, from 11.5 litres per adult in 1995 to 13.4 litres in 2006.

This rise in consumption has led to increases in alcohol-related harm and disease, and has resulted in more than 1,775 deaths.

According to an EU survey on alcohol consumption published in 2007, Ireland topped the poll, with 34 percent of Irish people questioned saying they "usually" binge drink,

The X Factor

^{There’s a revolution coming. A sea change in clinical care is just over the horizon and it promises a life-saving opportunity for millions of people worldwide, so says one of the most internationally respected experts on anticoagulant therapy, Professor Alexander Turpie.}

And he should know. The Professor of Medicine at McMaster University in Ontario, Canada, has been at the forefront of evaluating anti-thrombotic agents for more than forty years, from his 1965 study in East Africa on the anticoagulation action of Puff Adder venom to Principal Investigator in the groundbreaking RECORD programme - the largest clinical investigation ever conducted of an oral anticoagulant in the prevention of venous thromboembolism (VTE) after knee or hip replacement surgeries.

On a whistle-stop visit to Ireland Prof Turpie spoke to Scope of his excitement in the wake of huge strides now being made in anticoagulant therapy for the first time in decades. “We really are on the verge of something new in anticoagulants, and all the data that we’re seeing is extremely promising. I suspect that by two or three years from now we will have a complete change in anticoagulant management,” he predicts.

And not before time, when you consider that for 65 years, in terms of oral anticoagulants, all we've had are the vitamin K antagonists, the most commonly used being Warfarin. Although these drugs are effective, they have numerous limitations. They have a slow onset of action, which requires them to be over-lapped with parenteral agents for an immediate anticoagulant response when treating someone with established thrombosis.

Another difficulty is the variable dose requirement, and this variability reflects genetic polymorphisms in Warfarin metabolism that are quite common. It also reflects the effects of food and multiple drugs on the dosage requirements. This varying anticoagulant response to the vitamin K antagonists requires monitoring, which is inconvenient for patients, inconvenient for doctors, and often leads to an under use of these drugs in situations where patients should be on them.

But Prof Turpie is optimistic for the future: “There has been enormous developments in anti-thrombotic therapy over the past twenty years and it’s largely because we have been able to demonstrate that anticoagulant drugs work in many situations, Heparin and Warfarin, but there has been a whole new series of anti-coagulant drugs which have the potential to change how we practice.

“There are many areas where anti-coagulant drugs or blood thinners have been effective, one is the prevention of deep vein thrombosis and pulmonary embolism - in patients who have orthopaedic procedures for example - they are effective in the treatment of thrombosis, they are effective in preventing stroke in patients who have atrial fibrillation and they are also effective in the management of some patients who have acute coronary syndrome, so it’s a very broad spectrum of clinical uses.

“Many are given by injection and the only ones that are given by mouth currently are the vitamin K antagonists, one of which is Warfarin, but when one looks at the clinical needs of anti-coagulant therapy we really need a new drug that is given by mouth that doesn’t have the limitations of Warfarin, which are the requirement to monitor, interactions with drugs and food etc, and not least the varying response among individuals.”

The development of new drugs in this area is based on a greater understanding of coagulation. Most of the promising new agents are targeting single coagulation factors where as, in the past, the drugs have targeted multiple coagulation factors.

Parenteral agents, such as heparin and low-molecular-weight heparin, target multiple enzymes in the clotting cascade, predominantly thrombin and Factor Xa, but also clotting enzymes higher up in the coagulation cascade, and it is not possible to control how they target one over the other.

Vitamin K antagonists are even more problematic because they lower the functional levels of the vitamin K-dependent clotting factors - prothrombin, Factor VII, Factor IX, and Factor X - but the rates at which they do that are variable.

“It really makes sense to focus in on one or the other of the key clotting enzymes in coagulation,” explains Prof Turpie. “Most of the attention right now is focused on either thrombin (Factor IIa) or Factor Xa and there is some exciting results with some of these new oral agents.”

Research that is complete and has resulted in approval by the European Commission in 2008 of two new oral anticoagulant - dabigatran etexilate (Pradaxa), a direct thrombin inhibitor, and rivaroxaban (Xarelto), a direct inhibitor of coagulation Factor Xa - is prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients who have hip replacement and knee replacement surgery.

“This is a very important area because more and more people are getting old and more people are getting degenerative joint disease, and require surgery to correct what are effectively ‘mechanical disorders’, which are preventing them from any normal lifestyle,” says Prof Turpie. “The problem is that these operations are major and are associated with a risk of thrombosis, and as a result there are recommendations to give these patients anti-coagulant drugs.”

Venous blood clots occur in 40 to 60 percent of patients undergoing major orthopaedic surgery who do not receive preventive care.

“Now we have new drugs that target single coagulation factors and have lots of practical advantages over the current drugs. They are given by mouth - rivaroxaban is once a day, the others are twice a day - without the requirements of monitoring. So you can see the big advantage practically.

“The big question is do they work? Well, we can look at the clinical trials to see that they do. Both of them are approved for use in Ireland. Dabigatran has not got as strong data as rivaroxaban. It has been tested in three phase III clinical trials against low molecular weight heparin, two of them show non inferiority with LMWH and the other one failed to show non-inferiority, so there is mixed data with dabigatran. Despite that, the overall data set indicates probable clinical equivalence.

“Rivaroxaban, on the other hand, has had four clinical trials – this is the RECORD programme that I’m involved in – and showed superiority over LMWH. So not only was it equivalent, it was better. Further more, when one looks at the totality of the Rivaroxaban data there is a reduction of symptomatic thrombosis and mortality. So this is a new finding. Now we have hard evidence that we can reduce symptomatic thrombosis and mortality and that’s a big advantage.”

The soft-spoken Scotsman is eager to address a key issue raised by many who have been awaiting these research findings: is this benefit associated with more bleeding?

“In clinical trials statistically there was no difference with bleeding but when you do the composite of all of them there is a trend towards more bleeding, and that doesn’t surprise me if you’ve got a very potent anti-coagulant given early that there will be a little more bleeding. But overall the net clinical benefit is quite dramatic and I think that out weights any possible adverse effect,” he explains.

Indeed, an Advisory Committee of the US Food and Drug Administration (FDA) issued a favourable review of rivaroxaban on 19th March after examining a number of scientific and clinical questions in relation to the new drug application. At the time of going to press, the FDA was expected to announce its final decision in relation to rivaroxaban’s application in the USA for the prophylaxis of DVT and PE in patients undergoing hip or knee replacement surgery. Again, Prof Turpie voices his optimism: “Based on the recommendation by the expert panel, they should give it approval.”

He is quick to add that these new oral anti-coagulants are also being tested across the spectrum of thrombobolic disease with initial indications pointing to very positive outcomes.

“Dabigatran, for example: data on its application in atrial fibrillation will be available in the Fall of this year when it is presented at the European Society of Cardiology. That’s a study called RE-LY,” he notes.

The Phase III Randomised Evaluation of Long term Anticoagulant therapy (RE-LY) study enrolled more than 18,000 patients in over 900 centres in 44 countries worldwide between December 2005 and December 2007. Investigators compared the efficacy and safety of two blinded doses of dabigatran etexilate with open label Warfarin for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation.

“The study with rivaroxaban - called ROCKET AF: Stroke prevention in patients with atrial fibrillation (Phase III) - is almost finished it’s enrolment but will not be completed until next year.

“There are differences in the clinical trials so there will be slightly different outcomes I believe, we’ll have to wait to see the data, but suffice it to say I think both of them will work in atrial fibrillation,” Prof Turpie adds enthusiastically. “They will make a treatment for the prevention of stroke much simpler in atrial fibrillation and that has the potential to abolish a million strokes a year worldwide. That’s big thing: a massive step forward.

“About one-fifth of all strokes are related to atrial fibrillation, and we know that we can reduce that risk by about 70 percent with anticoagulation therapy, perhaps even more with these new agents. You can imagine the advantage to all of us physicians and health professionals and patients alike if we have a simple way of administering anticoagulants.”

He stresses that there is an enormous unmet clinical need in this area. More than 6 million worldwide have atrial fibrillation and 15 percent to 20 percent of strokes occur in people with this disorder, he remarks.

In addition, the likelihood of developing atrial fibrillation increases with age – 3 to 5 percent of people over 65 have AF. The elderly are also more likely to be taking multiple medications and may have dietary problems.

“So the whole issue of being able to give a fixed dose regimen and a drug that has very few drug interactions or food interactions could be a huge advantage.

“These are all very exciting developments, particularly when you think that for decades we’ve only had Warfarin, but now there is this exciting new potential for choice.”

Each milestone in the evolution of anti-coagulation therapies are landmarks in a personal journey for Prof Turpie, who has committed himself to ongoing investigations in this area for more than four decades, publishing more than 700 articles, abstracts, book chapters, and books.

He holds a medical degree from the University of Glasgow, Scotland, and after completing residencies at the Royal Infirmary and Stobhill General Hospital, Glasgow, where he was also a clinical research fellow, he served as a clinic lecturer for the University of East Africa Medical School in Nairobi, Kenya. During this time he served as a flying doctor with the East African Flying Doctor Service.

“We started doing experiments with snake venom and we found that some of them had anti-coagulant properties and some of them had pro-coagulant properties. Now it was very unsophisticated in those days but it was a very interesting observation, you know, the way that some of these snakes abolished their pray by making them bleed to death and others made them clot. I am pretty certain that a lot of the advances and understanding of coagulation is based on what these venoms used to do to coagulation, and some of them have resulted in therapeutic advances,” he reflects.

After returning to the University of Glasgow for additional training in haemostasis and thrombosis, he was appointed an MRC fellow at McMaster University in Ontario, Canada, where he was also appointed to the full-time faculty in the Department of Medicine. He is now professor of medicine and also an internist on the staff of Hamilton Health Sciences in Ontario.

“I’ve been around for a while and I’ve been lucky enough to see a lot of interesting advances, but I do believe that one of the most important things in anticoagulant therapy will be a revolution in oral anticoagulants, and that will be with a replacement for Warfarin,” Prof Turpie says. “Patients and healthcare providers alike have all been anxiously awaiting something that will take over from Warfarin. Make no mistake, Warfarin is a good drug; it’s an effective drug but it has major problems from a practical point of view.

“If we can have a drug that is as good as Warfarin in terms of it’s effectiveness and is safe and simple to take then there is going to be a revolution.”

VENUS THROMBOEMBOLISM (VTE)

• The estimated total number of symptomatic VTE events in the European Union (EU) is in excess of one million each year
• VTE is the third most common type of cardiovascular disease
• VTE causes over 500,000 deaths in Europe every year.
• Deaths attributable to VTE are estimated to exceed the total combined number of deaths from breast cancer, prostate cancer, AIDS, and traffic accidents annually.
• About one in eight patients will die as a result of a venous blood clot that develops while in the hospital.
• The number of in-hospital deaths due to VTE is five times the total number of deaths from all hospital-acquired infections.
• Hospitalised patients and residents of nursing homes account for about 60% of all cases of VTE.
• 
  

Atrial fibrillation (AF)

• An estimated 2.2 million people in the US and 4.5 million in the EU have atrial fibrillation.
• The risk for stroke (for patients with AF) is age-dependent. In the Framingham study, the annual risk was 1.5 percent in those 50 to 59 years old and 23.5 percent in those 80 to 89 years old.
• Atrial fibrillation is the most common arrhythmia seen in clinical practice.
• For men 55 years of age, the lifetime risk for developing atrial fibrillation is 25 percent: for women 55 years old, the risk is 22 percent
• An estimated one in every six strokes occurs in a patient with atrial fibrillation.

The quest to conquer pre-eclampsia

The act of giving life can be a perilous one for thousands of women worldwide. Globally, pre-eclampsia is a leading cause of maternal and infant illness and death, claiming the lives of more than 100,000 women and at least 500,000 infants every year. Experts agree that this potentially deadly disorder could be prevented with the development of a test that identified women who are at greatest risk, but a screening tool for pre-eclampsia in early pregnancy remains as elusive, thus far, as the Arthurian Holy Grail.

This quest to conquer pre-eclampsia, however, has acquired renewed momentum lately with the arrival on the field of an Irish research team based in University College Cork, who have embraced this challenge with crusade-like vigour and are backed by the world’s largest medical research charity. Developing a predictive test for pre-eclampsia will, of course, secure a place in the annals of medical history for the successful team, but that is not the driving force behind this concerted push to identify a simple, clinically accurate and affordable assay. Research leader Professor Louise Kenny – an obstetrician in Cork University Maternity Hospital – puts it simply: “it’s about saving the lives of young mothers and their babies, that’s why we get up every morning, that’s why this is so important.”

Louise is a dark-haired poster girl for obstetrics research; a PhD graduate - her study of abnormal vascular responses in pre-eclampsia is award winning – most days Louise can be found in the laboratory with her research team and, later, by the bedside delivering babies, and in both worlds she radiates youthful energy, positivism and acumen.

These qualities, coupled with a promising research proposal, were pivotal in convincing the prestigious Wellcome Trust to invest close to a million Euro in her search for an early pregnancy pre-eclampsia test. Despite an attack of nerves while awaiting to deliver her pitch for funding at the Trust’s London office, Louise and her co-principle investigator Professor Phil Baker, Director of the Manchester Biomedical Research Centre, UK, must have presented a very convincing case as their study was awarded a massive grant of €800,000 earlier this year.

This landmark study is being carried out by Louise’s team at the Anu Research Centre of the Department of Obstetrics and Gynaecology, UCC, in collaboration with Baker, her former professor, and his group at the Maternal and Foetal Research Centre.

Louise is acutely aware that the task ahead is a daunting one: there is a lot of money and expectation riding on them to develop the world’s first effective and affordable screening tool for pre-eclampsia, which would undoubtedly transform the future of antenatal care worldwide.

“The Welcome Trust Translational Award is really quiet prestigious award, they’re difficult to get, because what they’re focused on is taking good quality science that is worked up to a certain level and then trying to translate it into something that’s clinically useful; Bench to bedside. We had to physically go to the Wellcome Trust in London and basically convince them that the science we had is good enough and they could take a risk and give us their money: A lot of money. Winning one of these awards is a bit like going into the Dragon’s Den actually because the pressure is now on to produce results,” she adds.

This Wellcome Trust award is built on the Health Research Board (HRB) funded Screening for Pregnancy Endpoints (SCOPE) Project, currently based at Cork University Maternity Hospital and also led by Louise. Essentially, this project is a unique, international collaboration to create a pregnancy biobank that can be used to discover new ways to predict and prevent health problems in late pregnancy, including pre-eclampsia, fetal growth restriction and spontaneous preterm birth.

Ireland’s involvement in this eight-centre international initiative commenced in 2007 with a HRB grant of €1.7 million - the largest award ever made to a single project in Ireland for obstetrics and gynaecological research. SCOPE Ireland is the largest single contributor to the project biobank with samples from more than 3,000 women.

A key ambition of SCOPE is to develop predictive tests that offer first time mothers an accurate, personalised risk rating for each disease. Louise’s focus is pre-eclampsia. And already Louise and her team have identified biomarkers in the blood of women in early pregnancy that they then used to predict the subsequent development of pregnancy complications, particularly pre-eclampsia. It was this exciting finding that clinched the Wellcome Trust award.

“We found the biomarkers by identifying particular metabolites in the blood – these are small molecules which are involved in normal growth, development, and reproduction. We have been collaborating with Manchester - one of the leading centres of metabolomic discovery in Europe for several years - and this award will enable UCC to establish a key role in taking this research forward.”

The work ahead involves confirming that the metabolites they’ve identified can be used to reliably screen for the development of pre-eclampsia. To do this, they will carry out a targeted screening of 3,000 low-risk women.

“The next phase will be to combine clinical information and metabolites to develop the most effective system for predicting problems in pregnancy. The final step is to turn this into a prototype blood test which is suitable for commercial use,” says Louise, her tenor infectiously optimistic. “The award will make a tremendous difference to our work, and hopefully mothers and babies should benefit from the new screening test within the next five to ten years.”



There is currently no clinically useful test for pre-eclampsia, which affects 5 percent of first time mothers. Each year, the number of maternal deaths from pre-eclampsia is equivalent to the loss of 170 jumbo jets of pregnant women. Compounding this tragic statistic is the fact that a quarter of the babies born to mothers with pre-eclampsia are growth restricted and a third are premature. A recent report of the Confidential Enquiry into Stillbirth and Death in Infancy (CESDI) revealed that one in six stillbirths and one in six sudden infant deaths occurred in pregnancies complicated by maternal hypertension.

“Developing a test for pre-eclampsia would make an enormous difference to women and their unborn babies all over the world,” Louise explains. “What we currently use is a combination of clinical risk factors such as personal history, but the vast majority of women who get pre-eclampsia, however, don’t have any history and they certainly don’t have it in their first pregnancy – and 55 per cent of the antenatal population is in their first pregnancy.”

She outlines several decisive criteria governing the success of a predictive test; firstly it has got be effective in early pregnancy; “developing a screening test in late pregnancy is useless, we really have to know at the start of the pregnancy or as early as possible what someone’s risk factor is”.

“There are two reasons for that,” she continues, “firstly it’s because there are some interventions that we can institute that may actually reduce risk and, even if there aren’t many now, given the pace of medical discovery we’d hope that there would be more coming along very shortly.

“But everything we know about this condition tells us that in order for any intervention to work it has to be started early prior to the disease, and preferably as early in pregnancy as possible. So we need a test to tell us who’s at risk because obviously we don’t want to expose every pregnant woman to drugs that she doesn’t need.

“Even in the absence of a very good intervention, the second reason for such a test is because we are then able to tailor antenatal care to women depending on their risk assessment. In this age where we very much try to offer holistic and patient-focused care to women in pregnancy – and one shoe does not fit all - knowing if someone is actually low risk is almost as valuable as knowing that they’re high risk because it mean they can avail of a different package of antenatal care. They could predominantly have their antenatal care based in the community so they don’t have to come into our already overcrowded and under resourced hospitals. There are both patient and health economic benefits all round for the development of this test," she emphasises.

Of course, critically, the screening tool has to be clinically accurate – there are lots of tests out there that have been proposed and have been binned because clinicians found that they’re next to useless.

“So it has to be early pregnancy, it has to be good and, ultimately, it does have to be affordable because the majority of women who die from this condition do so in the developing world,” Louise points out. “And in the developing world more than anywhere else it will probably have the biggest impact. We, in Ireland are a very resource strapped nation anyway and we struggle to offer adequate antenatal care to all the women in our country, as in other European countries, and we are essentially the developed world. Imagine the widespread benefit if we had a cheap simple test that could predict risk in early pregnancy? And in the developing world, you could be sure it would have a massive impact on how they distribute their very limited resources.”

Certainly the kudos for whoever develops a screening tool for pre-eclampsia would be immense and the commercial potential could prove stratospheric. Screening for cervical cancer using the Pap test, for example, is one of the greatest successes of screening and has immortalised its inventor Dr George Nicholas Papanicolaou. Louise graciously tolerates probing questions about her interest in such fringe benefits, even confiding that her thoughts have occasionally drifted down that alluring path of accolade and profit, but it is quite apparent that these are not motivating factors for her work.

“The commercial potential is quite interesting and you can get carried away with being first with this great test but I always try to not forget is that a pregnant woman dies of pre-eclampsia somewhere in the world every third minute. So in the time that we’ve been chatting a handful of young, previously healthy women at the start of their adult life, usually in their first pregnancy, will have died of a disease. But we still don’t have a screening test for it or an effective treatment,” she emotes.

Louise has been researching this disease since the mid ‘90s, soon after her graduation from Liverpool Medical School in the UK. In 2001, while based at the University of Manchester’s Maternal and Fetal Health Research Centre, she embarked on an innovative collaboration with the University’s School of Chemistry to investigate the use of metabolomic technology in the development of a pre-eclampsia screening test.

“These are two disciplines that normally wouldn’t collide through the system, and we’ve been working on that collaboration ever since. The link with SCOPE is that in order to actually identify biomarkers, yes you need quite complex discovery programmes, but they are absolutely crucially dependent on access to patients or samples. That’s where the SCOPE study comes in.”

There are several big research groups internationally working on developing a predictive test for pre-eclampsia, but in recent years some of these teams have joined forces and are now working together in SCOPE to progress this goal.

“The principal investigators in SCOPE, and there are five or six of us, basically just put down the weapons, as it were, over the past decade and decided to join forces and not work in competition. Most of us have been friends and colleagues for many years and we all met through our common interest in pre-eclampsia. I think it’s fair to say that we are all working together now and not in competition, and we found that it has speeded up the rate of discovery massively. A problem shared in a problem halved, and sharing knowledge is everything, we’re not really that bothered about protecting what we know or publishing results first.”

In fact, Louis discloses that they are in the process of assembling data for their first major publication that will detail the 75 biomarkers of interest they have identified, of which 15 potentially hold the key to a screening test. This groundbreaking study will be published before the end of the year.

“Inevitably with anything that is commercially as lucrative as a potential screening test there are other interests, as it were, but the primary focus of both the Wellcome Trust and the SCOPE consortium is in getting a test to the bedside that can actually make a difference.

“Most of us have direct contact with patients. I have a PhD and I work as a scientist but I’m also clinically trained and I work as a doctor. I spend half my time with patients, and that’s really what gets me out of bed in the morning, it’s the idea of developing a test that will make a difference in that portion of our working day.

“In the 21st century, when we’ve made so many breakthroughs in other branches of medicine - and we really have made tremendous medical progress in so many different areas in the last two decades or so - things have stood still in obstetrics research. But with so many people now working together towards a common goal, I think that is about to change.”

The Baseline Study:

One aspect of obstetric research that has always frustrated Prof Louise Kenny is that it usually finished with the baby. The minute the baby was out, obstetrics dissevered interest.

“But we now know that the nine months in utero have a profound effect on how babies grow and develop, not just in infancy but into adult life. It’s a whole concept called foetal programming, and we know, for example, that babies who are born small as a result of pre eclamptic pregnancies are much more likely to grow into adults who develop diabetes and heart disease and hypertension,” she explains.

In 2006, Louise moved from Manchester to Cork to take up key role in the development of the new Anu Research Centre at Cork University Maternity Hospital. “I was lucky that when I arrived in UCC and was setting up the SCOPE study, Deirdre Murray, who was a newly appointed paediatric colleague, and Jonathon Hourihan, who is the head of the Department of Paediatrics, were incredibly enthusiastic about establishing a study on the back of SCOPE that would follow the progress of these babies into childhood, so we set about writing grant applications.”

Funding of €800,000 was secured from the Children’s Research Centre, Our Lady’s Children’s Hospital, Crumlin, enabling the BASELINE (Babies After Scope: Evaluating the Longitudinal Impact Using neurological and Nutritional Endpoints) study to commence.

BASELINE is the first Irish birth cohort study, which will look at why some children develop common childhood diseases while others remain healthy. In August 2008 the first mothers recruited to the SCOPE pregnancy study in Cork began to deliver, and the first BASELINE baby arrived at the clinic in November last year.

“Initially the research will concentrate on the effects of poor growth in the womb, the incidence and prevalence of food allergy and eczema in early childhood and the incidence and effects of maternal and infant vitamin D status on the growth and health of Irish children.

“We have funding to follow the babies up for the first two years, and obviously we’re very much hoping that that funding will be extended, or will attract funding from other agencies, that will allow us to follow these babies through their childhood and into adult life,” says Louise.