May 2016 – The Brain Bank North West

“Accidents will happen” – when serendipity meets drug discovery

May 29, 2016 by The Brain Bank North West

Few would argue that advancements in science require hard work, long hours and intellectual minds. But a few accidents along the way can certainly help as well. Serendipity, the accidental, but very fruitful, discovery of something other than what you were looking for, has played a significant role in drug discovery through the ages. Here are just three examples to whet your appetite…

Warfarin

Screen Shot 2016-05-29 at 21.56.59 Today, warfarin is the main blood thinner (anticoagulant) used in the treatment of blood clotting disorders, heart attacks and strokes. However, its story began on the prairies of North America and Canada during The Great Depression. During the 1920s, financial hardship forced farmers in these areas to feed damp or mouldy hay to their livestock. As a result, many of these seemingly healthy cattle started to die from internal bleeding (haemorrhaging) – an illness later given the name ‘sweet clover disease.’ Although investigators were able to attribute sweet clover disease to the consumption of mouldy hay, the underlying molecule responsible for causing the disease remained a mystery. Consequently, the only potential solutions offered to farmers at the time were to remove the mouldy hay or transfuse the bleeding animals with fresh blood.

It was not until 1939 in the lab of Karl Link that the guilty molecule was isolated – an anticoagulant known as dicoumarol. This is a derivative of the natural molecule coumarin, responsible for the well-recognised smell of freshly cut grass. With the idea of creating a new rat poison designed to kill rodents through internal bleeding, Link’s lab investigated a number of variations of coumarin under the funding of the Wisconsin Alumni Research Foundation (WARF). One of these derivatives was found to be particularly effective. Thus in 1948, the rat poison warfarin was born, named after the Body who funded its discovery.

Despite its clear anticoagulating properties, reservations remained about using warfarin clinically in humans. This was until 1951 when a man who had overdosed on warfarin, in an attempt to commit suicide, was successfully given vitamin K to reverse the anticoagulating effects of the rat poison. Hence, with a way to reverse these, the production of a variation of warfarin for human use was developed under the name ‘Coumadin’. This was later successfully used to treat President Dwight Eisenhower when he suffered a heart attack, giving the drug widespread popularity in the treatment of blood clots, which has continued for the last 60 years.

Penicillin

Screen Shot 2016-05-29 at 21.57.08 No article on serendipity in drug discovery would be complete without at least mentioning the discovery of the antibiotic penicillin by Sir Alexander Fleming. It was 1928 when Fleming returned to his laboratory in the Department of Systematic Bacteriology at St. Mary’s in London after a vacation. The laboratory was in its usual untidy and disordered state. However, while clearing up the used Petri dishes piled above a tray of Lysol, he noticed something odd about some of the Petri dishes which had not come into contact with the cleaning agent. The Petri dishes contained separate colonies of staphylococci, a type of bacteria responsible for a number of infections such as boils, sepsis and pneumonia. There was also a colony of mould near the edge of the dish, around which there were no visible staphylococci or at least only a few small and nearly transparent groups. Following a series of further experiments, Fleming concluded that this mould, which he named ‘penicillin’, was not only able to prevent the growth of staphylococcal bacteria, but also killed this type of bacteria.

Screen Shot 2016-05-29 at 21.57.15 However, while today the value of penicillin is well recognised, there was little interest in Fleming’s discovery in 1929. In fact, in a presentation of his findings at the Medical Research Club in the February of that year, not a single question was asked. It was only when pathologist Howard Florey from Oxford happened across Fleming’s paper on penicillin that the true clinical significance of the drug was acknowledged. In 1939, along with Ernst B. Chain and Norman Heatley, Florey conducted a series of experiments in which they infected mice with various bacterial strains including staphylococcus aureus. They then treated half the mice with penicillin while leaving the others as controls. While the controls died, the researchers found that penicillin was able to protect the mice against these types of infection. These exciting findings appeared in the Lancet in 1940 and eventually led to the commercial production of the drug for use in humans in the early 1940s in the United States. Since then, an estimated 200 million lives have been saved with the help of this drug.

Viagra

Despite today being widely known for its ability to help men with erectile dysfunction, Viagra was not originally designed for this purpose. The drug company Pfizer had initially hoped to develop a new treatment for angina, one that worked to reverse the constriction of blood vessels that occurs in this condition. However, clinical trials of Viagra, known then as compound UK92480, showed poor efficacy of the drug at treating the symptoms of angina. Nonetheless, it was highly effective in causing the male recipients in the trial to develop and maintain erections.

Upon further investigation, it was identified that, rather than acting to relax the blood vessels supplying the heart, Viagra caused the penile blood vessels to relax. This would lead to increased blood flow to this appendage, resulting in the man developing an erection. Following this unexpected discovery, Pfizer rebranded Viagra as an erectile dysfunction drug and launched it as such in 1998. Today, Viagra is one of the 20 most prescribed drugs in the United States and has, I’m sure, left Pfizer thanking their lucky stars they were involved in its serendipitous discovery.

The accidental discoveries of warfarin, penicillin and Viagra are just three instances of serendipity in drug discovery from a long list – one far longer than can fit in this article. Nevertheless, these cases provide excellent examples of how unplanned factors such as mysterious deaths, unexpected side effects during drug trials, and even just plain untidiness, has led to significant advances in the field of drug discovery. Such serendipitous events have given us a range of indispensable medications which we still rely on today, and I’m sure will continue to provide new and exciting breakthroughs in the future.

Post by: Megan Barrett

Palming off unsustainability

May 23, 2016 by The Brain Bank North West

When I first landed in Singapore last October I expected to be greeted by clear skies and sunshine but, in reality, I couldn’t even see the famous skyline in front of me. Welcome to the reality of living in South East Asia during the dry season. While most people will remember the news stories about the ‘haze crisis of 2015’, what many don’t realize is that this was not an isolated event, in fact haze is a persistent problem in this part of the world.

What causes the Haze?
Haze arises from the burning of forest areas for agriculture in the neighboring regions of Indonesia, normally through illegal ‘slash and burn’ practices of land clearing. Although slash and burn is not a new farming technique, increasing requirement of land for the growing of palm oil and paper production now results in larger and often uncontrolled fires. In addition, the land which is cleared is often peatland which, when burnt, leads to denser and longer lasting fires. The resulting ash and debris is carried to neighboring countries leading to dense smog – think of the foggiest day in the UK, then remember that fog is just caused by water whereas the haze in SE Asia is formed of ash and debris.

During the dry season this makes it hard to see and, for some, hard to breath and carry out daily tasks like walking upstairs or going to the shops. Already the PSI (pollutant standard index) here in Singapore is on the rise, reaching moderate levels while I’m writing this article.

6373026485_dc8f75e253_z While here in the city we think mostly of the effect the haze and land burning has on us but it’s not just people that are affected. Indonesia is one of the most bio-diverse countries on the planet, most famously home to Orangutans. Destruction of the forests doesn’t just pollute their air, it also destroys their homes. According to online sources, up to 5000 already endangered Orangutans are killed every year through the destruction of their habitat for palm oil productions

The palm oil problem
Palm oil is a type of vegetable oil and a highly concentrated form of fat found in many household products from cosmetics to junk food. Over 80% of the world’s palm oil is produced in the Indonesian regions of Borneo (Sumatra and Kalimantan), with the majority of this traded through companies right here in Singapore. Many people have not heard of palm oil due to frequent product mislabeling: note that it is often mislabeled as kernel oil or vegetable oil.

However, it is important to recognise that palm oil itself is not technically the problem. The main issue lies with the unsustainability of current palm oil farming practices. Specifically the process of cut and burnt farming, failure to replace felled trees and the over-exploitation of land as the demand for palm oil overtakes tree growth. Even ‘so called’ sustainable methods of palm oil agriculture have come under scrutiny by environmentalists.

The crux of this issue is that, until the demand for palm oil products decreases, or better farming methods are devised the haze will continue in a futile cycle – food for thought as we tuck into ice cream on a hot day.

Post by: Stephanie Macdonald

For more information of products made using sustainable palm oil see here:

Ovarian cancer: early diagnosis is the best treatment

May 17, 2016May 14, 2016 by The Brain Bank North West

The 8th of May was world ovarian cancer day. Ovarian cancer is considered to be the most lethal gynaecological malignancy, being the fourth most common cause of cancer death in women in the developed world (1). Early stage misdiagnosis is common, especially since symptoms (such as feeling bloating, abdominal pain, difficulty eating or constipation) can be incorrectly attributed to common stomach and digestive complaints. Indeed, of the approximately 7000 new cases diagnosed in the UK each year, only a small percentage of diagnoses (around 20%) (2) will be early stage where the survival rate is over 90%. The key to successful early diagnosis lies in the frequency and the number of symptoms a woman suffers.

Risk factors and diagnosis:

Common risk factors include: menopause (this being the most significant risk), mutations in genes associated with DNA repair like BRCA1 and BRCA2 genes, family history, infertility or having fertility treatment, endometriosis or being overweight.

There is unfortunately no accurate screening to diagnose ovarian cancer. Current screening practices rely upon CA125 (a tumor marker that can be detected in the blood) screening, alongside abdominal and transvaginal ultrasound (3). However, CA125 screening lacks both specificity and sensitivity. Specifically, CA125 can be detected in a range of cancers and in benign conditions in premenopausal women like endometriosis, pelvic inflammatory disease or even pregnancy, it is also more accurate for late stage diagnosis.

Treatment:

The standard of care for patients with advanced disease involves surgical tumour debulking followed by chemotherapy but sadly most patients will relapse within 18 months and eventually will die from the disease. Over the years clinical trials have been set up to explore combinations of drugs which could improve the prognosis for ovarian cancer patients. One of these therapies is called targeted cancer therapy or biological therapy and involves stopping tumour growth through interfering with tumour biology. Tumours need to spread out to find oxygen and nutrients, a process called angiogenesis (this being crucial for tumour growth and proliferation). Several anti-angiogenic drugs have been developed and are now being tested in preclinical and clinical settings. The aim is to target not the tumour but the surrounding structures (blood vessels) necessary for tumour growth. VEGF is a molecule which is overexpressed in most solid tumours including ovarian cancer and is crucial in tumour angiogenesis. So this molecule represents a good drug target, the rationale being that inhibition of VEGF may eliminate or delay tumour growth. Bevacizumab (Avastin) is a monoclonal antibody that binds VEGF and sequesters it, causing blood vessels growth to stop, thus making it more difficult for the tumour to grow. It is the only anti-angiogenic drug licenced to be used in women with advanced ovarian cancer alongside chemotherapy. However, despite promising results in initial studies it has so far not proved beneficial to overall survival rates and some people consider it not to be cost-effective (4).

Another targeted cancer therapy used to treat ovarian cancer is inhibition of PARP1 (a molecule involved in DNA repair). This drug is called olaparib and is offered to patients with deficient tumour suppressor proteins BRCA1 and BRCA2 since cells deficient in BRCA1/2 are more sensitive to PARP1 inhibitors. PARP1 and BRCA1/2 are involved in repairing broken DNA, in patients carrying BRCA mutations, inhibition of PARP1 results in cumulative DNA damage and tumor cell death.

There are also a range of antivascular agents (drugs which attacks the blood supply of a tumor) now entering clinical trials (5). We are also making advances in immunologic therapies and in drugs targeting relevant gene mutations but, in some cases, toxic side effects make these treatments unfeasible.

The future:

Despite advances in drug research, early-stage detection is still believed to be the key to improved survival. Therefore continued research into biological markers for early detection and diagnosis is vital. It is hoped that such research, alongside work into finding biomarkers that predict disease progression, drug response and allow us to select patients who benefit the most from a specific treatment option will give us a fighting chance against ovarian cancer.

References

Paik ES, Lee Y-Y, Lee E-J, Choi CH, Kim T-J, Lee J-W, et al. Survival analysis of revised 2013 FIGO staging classification of epithelial ovarian cancer and comparison with previous FIGO staging classification. Obstetrics & Gynecology Science. 2015 ;58(2):124-34.
Hennesy BT, Coleman RL, Markman M. Ovarian cancer. Lancet 2009. 17;374:1371-82
Jayson GC, Khon EC, Kitchener HC, Ledermann JA. Ovarian Cancer. Lancet 2014. 2014;384:1376-88.
Robert H. Carlson. Antiangiogenic Therapy’s Value in Ovarian Cancer Questioned. Oncology Times 12/25/14
Bell-McGuinn K, Konner J, Tew W, Springgs DR. New drugs for ovarian cancer. Ann Oncol. 2011 Dec;22 Suppl 8:viii77-viii82. doi: 10.1093/annonc/mdr531.

Links of interest:

UK CR. Ovarian Cancer incidence by UK region 2015 [cited 2016 07.01]. Available from: http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/ovarian-cancer/incidence#ref-0.
Post By: Cristina Ferreras

Yoga for health: uniting body and mind

May 9, 2016May 8, 2016 by The Brain Bank North West

Yoga is an eastern tradition which is becoming increasingly popular in Western societies. Although the spiritual elements of this ancient Indian practice have partially disappeared in its westernised form, the practice still remains a holistic and multi-dimensional approach to maintaining good health and wellbeing (de Manincor et al., 2015). This is reflected in the meaning of its Sanskrit name: ‘to unite’ or ‘to attain what is previously unattainable’ (Uebelacker et al., 2010). Its main elements include physical postures (asanas), breathing techniques (pranayama) and meditation (dhyana) (Uebelacker et al., 2010). The emphasis on these elements differs between styles, e.g. Iyengar yoga focuses on the alignment of the body in asanas, whilst vinyasa teaches to link breath with movement. In addition, yogis promote positive values and attitudes, as well as lifestyle. Research has shown that it can help with health problems ranging from mental health difficulties to musculoskeletal ailments.

So, is yoga really effective and beneficial for our health and if so, what is its secret?

Meditation is one of the core elements of yoga.

Randomised controlled studies of yoga have shown that it can reduce pain and improve functional outcomes for individuals with physical problems such as lower back pain and fibromyalgia (Ward et al., 2013). Some evidence indicates that yoga can not only manage, but also reduce some musculoskeletal problems such as scoliosis – a condition in which the spine curves laterally (Fishman et al., 2014). Scoliosis patients who performed a pose known as the ‘side plank’ for an average of 90 seconds a day, most days of the week for seven months, showed a decrease in the lateral spine curvature by around 32%. The more conscientiously the patients practiced the side plank, the more their spine improved. The authors of the study emphasise the importance of performing the pose on the convex side of the spine only (do not try this without a consultation with a specialist). Such asymmetry of the exercise might achieve its effect by strengthening the weaker side of the vertebral column. The results of this study are very encouraging, however randomized controlled trials with a longer follow-up period are needed to substantiate these findings.

Although other forms of physical activity, such as stretching, can be equally effective in improving daily functioning, in some cases yoga has been shown to be superior to physical therapy. Specifically, when it come to improving quality of life and reducing depression, which often accompanies physical illness (Ward et al., 2013). Indeed, yoga has been shown to help those with mood disorders, including women with postnatal depression (Buttner et al., 2015).

It can however be difficult to draw clear conclusions from research which examines yoga for health. Specifically because the type of yoga, the intensity and length of practice vary greatly among studies. Is it possible to formulate a ‘prescription’ yoga practice that would provide clear evidence of its effectiveness? Some yoga experts suggest that, in order to help reduce depression and anxiety, yoga practice not only needs to include certain key elements, but also avoid some of other components (de Manincor et al., 2015). For example, both depression and anxiety might be alleviated with breath regulation, however depressed individuals benefit more from the focus on the inhalation, whilst those with anxiety from lengthening the exhale and ‘humming bee’ (bhramari) technique. Anxious yoga students should avoid rapid breathing techniques, as well as heated and crowded yoga rooms. It is suggested that students with mental health problems should practice for 30-40 minutes 5 times a week for 6 weeks. However, frequency of practice is more controversial among teachers of yoga for musculoskeletal conditions, predominantly because unsupervised yoga sessions can be harmful to those with no previous yoga experience (Ward et al., 2014). However, experts in both areas agree that yoga practice that aims to help with specific problems should be integrated, personalized and taught by those with sufficient experience and training, specifically relating to the condition of their students.

The active ingredients of yoga are thought be mindfulness and physical activity (Uebelacker et al., 2010). Both of these elements are important in other approaches to treating health problems. One of the advantages of yoga, however, is its holistic focus on reaching one’s full potential rather than reducing the symptoms of illness, as well as its emphasis on uniting the mind and body and building self acceptance (Uebelacker et al., 2010). Although it can be difficult to meet the exact requirements for yoga as a treatment for physical and mental health problems, i.e. frequency of practice and structured personlised classes, it still remains a promising adjunct therapy. So, let us hope that the growing popularity of ‘attaining what is previously unattainable’ might increase the access and diversity of classes.

Post by: Jadwiga Nazimek

References:

Buttner, M. M., R. L. Brock, M. W. O’Hara, and S. Stuart, 2015, Efficacy of yoga for depressed postpartum women: A randomized controlled trial: Complement Ther Clin Pract, v. 21, p. 94-100.

de Manincor, M., A. Bensoussan, C. Smith, P. Fahey, and S. Bourchier, 2015, Establishing key components of yoga interventions for reducing depression and anxiety, and improving well-being: a Delphi method study: BMC Complement Altern Med, v. 15, p. 85.

Fishman, L. M., E. J. Groessl, and K. J. Sherman, 2014, Serial case reporting yoga for idiopathic and degenerative scoliosis: Glob Adv Health Med, v. 3, p. 16-21.

Uebelacker, L. A., G. Epstein-Lubow, B. A. Gaudiano, G. Tremont, C. L. Battle, and I. W. Miller, 2010, Hatha yoga for depression: critical review of the evidence for efficacy, plausible mechanisms of action, and directions for future research: J Psychiatr Pract, v. 16, p. 22-33.

Ward, L., S. Stebbings, D. Cherkin, and G. D. Baxter, 2013, Yoga for functional ability, pain and psychosocial outcomes in musculoskeletal conditions: a systematic review and meta-analysis: Musculoskeletal Care, v. 11, p. 203-17.

Ward, L., S. Stebbings, K. J. Sherman, D. Cherkin, and G. D. Baxter, 2014, Establishing key components of yoga interventions for musculoskeletal conditions: a Delphi survey: BMC Complement Altern Med, v. 14, p. 196.

Understanding cosmetic testing in the UK.

May 1, 2016 by The Brain Bank North West

If we were to ask you which of the following high street brands use animals to test the cosmetic products they sell in their UK stores (Tesco, Sainsbury’s, Boots, The Body Shop, Lush or none of these); what would your answer be?

Many of us will have seen Lush’s bag which boldly expresses the store’s dedication towards the fight against animal testing but what about the other four?

You may be surprised to learn that none of these high street brands currently use animals to test their cosmetic products. In fact it has been illegal to test cosmetic products or any of their ingredients on animals in the UK since 1998 and an EU-wide ban has been in place since 2013. This means that no cosmetic product sold anywhere in the EU should include new ingredients tested on animals. Although many ingredients will have been tested at some point in the past before these legislations came into play.

If you didn’t already know this don’t feel bad, a recent survey carried out by ‘Understanding Animal Research’ found that only 38% of respondents were aware of these legislations. And, advertising in many stores can perpetuate the belief that some UK cosmetics are still tested on animals. Specifically, products marketed as ‘cruelty free’ or ‘not tested on animals’ may not technically be examples of false advertising but they do perpetuate the incorrect belief that some product sold in UK stores are still tested on animals.

Wendy Jarrett, CEO of Understanding Animal Research, said:

“The proliferation of ‘Not tested on animals’ or ‘Cruelty-Free’ logos has led many to believe that other cosmetic products sold on the UK market are tested on animals – something which has not been the case for 18 years. While animals continue to play a small but key role in medical developments, the UK has successfully eliminated such testing for cosmetics and, more recently, household products.”

This is undoubtedly a huge step forward and we are also heartened to know that the UK government is currently working with a number of non-EU countries supporting them to move away from cosmetic animal testing towards non-animal alternatives.

So, the next time you are out shopping for cosmetics or household products you can shop with the confidence that none of the products you see on the shelves will be tested on animals!

Post by: Sarah Fox