Redefining rare disease

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Rare disease is commonly defined strictly by its prevalence in a given population. For instance, a disease is considered rare if it affects less than one in 1,500 individuals in the United States or one in 2,000 in Europe. However, the current definition of disease rarity is not only overly simplistic, but also an obstacle to understanding uncommon health conditions. A closer look at just one rare disease reveals a need to question the definition of disease rarity and be mindful of its limitations.

Infection versus disease

Perhaps no other rare disease has been as oversimplified as toxoplasmosis. Toxoplasmosis is a disease caused by a parasite called Toxoplasma gondii. When a pregnant woman acquires this parasite for the first time during pregnancy, it can be transmitted to her foetus congenitally. This mode of transmission results in severe defects in the eyes and brains. Because congenital toxoplasmosis only affects one in 5,000 newborns in the US by some estimates, it is considered a rare disease.

Although toxoplasmosis may be rare, its disease-causing agent is not. In fact, over two billion people worldwide, including a quarter of the American population, harbour the parasite. What becomes apparent is that the current definition of rare disease makes an implicit distinction between infection and disease since infection by a disease-causing microbe does not automatically engender disease. However, while largely dormant, innocuous and asymptomatic in healthy adults, the T. gondii parasite may take advantage of a weakened immune system, emerge from quiescence and cause opportunistic infections, which ultimately result in full-blown toxoplasmosis. Even though the majority of the two billion infected individuals are healthy, they remain susceptible to T. gondii infections. It turns out that the T. gondii parasite may also affect infected individuals’ behaviour and personality. Recent studies suggest a causal relationship between dormant T. gondii parasite and psychological disorders, including schizophrenia.

By neglecting all of this, current ideas of what it means for a disease to be rare impedes our appreciation of the complexity and magnitude of the disease.

Limitations of the current understanding of rare disease

Moreover, basing decisions about the prevalence of a disease solely on how it affects the human population may downplay the problems it causes by failing to take into account its pervasiveness in other species and understating its true economic cost to society.

Toxoplasmosis, for example, affects nearly every warm-blooded animals, including all commercial livestock. It is the leading cause of abortion in sheep and goats. In 1996, toxoplasmosis alone cost the American agricultural industry $7.7 billion, an amount representing 10% of the country’s agricultural Growth Domestic Product at that time.

There may be more to a rare disease than meets the eye so it is imperative not to confine our perception of an uncommon health condition solely to the number of patients who have the disease and be aware of the complexity, magnitude and the true economic cost of that disease.

*Bo Shiun Lai [2013] is a Gates Cambridge Scholar pursuing a PhD in Pathology at the University of Cambridge. He helped develop a new paradigm that can deliver antiparasitic agents across multiple membrane barriers and published his findings on the Proceedings of the National Academy of Sciences USA. Picture of cerebral toxoplasmosis courtesy of Jensflorian and Wiki Commons.

 

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The public and private Isaac Newton

 

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In November of 1690, Isaac Newton sent a long essay to his friend, the philosopher and radical thinker John Locke. In it, Newton set forth the reasons he thought scripture had been corrupted over the centuries – and for his own disbelief in the Trinity, a key tenet of Anglicanism. He asked Locke to see about translating the work into French and having it published – anonymously – on the Continent. The contents of the essay were so controversial that Newton dared not attach his name to it.

The episode was unique. Never again would Newton come as close to publishing such sensitive material about his dramatically unorthodox religious beliefs. But the episode was also indicative of Isaac Newton’s lifelong relationship with publication. Never able merely to reject print culture outright – the rewards of priority, communication and prestige were too great for that – Newton was nevertheless intensely averse to the lack of control that accompanied publication.

Through a long and surprising series of events, Newton’s private papers, (including the original draft of the essay he sent to Locke) have survived to the present day. In The Newton Papers: The Strange and True Odyssey of Isaac Newton’s Manuscripts, I tell their story for the first time. Throughout the course of the nearly three centuries since Newton’s death, the papers have been examined only briefly and intermittently by a handful of people. Through a combination of suppression, neglect, and confusion, the complex, disordered papers were cloaked in mystery until very recently. Now the Newton Project has transcribed nearly 6.5 million words of the writing, including nearly all of his most private religious works. What was once private has become radically public.

The private Newton

What are we to make of the availability of this new material? Since these writings were largely inaccessible until now, how can we relate them to the much more public image of Newton, created in part by his two great publications, the Principia and the Opticks?

These questions have challenged scholars since the papers started to become available in the 1960s. Some have sought to unify the archive, seeking to make connections between the science and the non-science. Others have opted for a Newton of many parts, each free to pursue distinct projects. Such differences of analysis are partly due to changing historical tastes. In this sense, each generation gets the Newton it requires – or deserves. As further research is done on the papers, new arguments will undoubtedly be made about how to understand their contents. The drive to understand the inner world of a man as creative and intellectually important as Newton remains strong.

Newton’s attitude towards publication is one thread that can be used to stitch the archive together, should we wish to do so. Newton despised dispute. Once he had convinced himself that his answers to a question – whether of scientific, mathematical, or theological nature – were correct, he was loath to enter into a debate in order to prove it to others. Once his words were published, there was little he could do about how they were interpreted. Consequently, he was often very reluctant to make anything public.

Suppression

The treatise that Newton sent to Locke was never published during his lifetime. A few months after he sent it, Newton had an abrupt change of heart. ‘I design to suppress them,’ he explained, begging Locke to stop the translation and printing of his words. He had decided that the contents of the essay were too heretical to risk making public in any form.

Newton was right to be wary. Though Locke returned Newton’s own copy of the essay, the translator retained a copy from which several subsequent copies were made. These circulated throughout the 18th century, and Newton’s own name was attached to an unauthorised and inaccurate publication of the entire essay in 1754.

Newton’s reluctance to publish did not only apply to heretical religious beliefs. He published very little of his mathematics during his lifetime. Had he been quicker to do so, he would have avoided the contentious priority dispute with Gottfried Liebniz over the discovery of the calculus. With his natural philosophy and his optics, Newton was more open, but only when friends and supporters convinced him it was in his interest to be so. If Newton had his own way, he would most likely have communicated his scientific discoveries sparingly, in manuscript rather than print, and only to those he deemed friends.

Would Newton be horrified to know that his most private thoughts are now accessible to anyone online? Probably. But he had himself taken care to save these papers throughout his long life. He believed that the day would come when his version of Christianity would be revealed to the masses as the true religion. Perhaps he hoped that then his papers would be able to be freely read and distributed. Theologically speaking, that day has not come, but what has arrived is the moment when Newton’s private beliefs – though still vexing and difficult to understand – are a part of his public image.

*Sarah Dry [2003] did a PhD in the History and Philosophy of Science. Her book The Newton Papers: The Strange and True Odyssey of Isaac Newton’s Manuscripts is published this month by Oxford University Press. Sarah Dry blogs at sarahdry.wordpress.com.

 

Obesity in Africa

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Obesity is rapidly becoming a growing problem across low- and middle-income countries, including those in sub-Saharan Africa. In many African countries, the prevalence of overweight is even estimated to be higher than the prevalence of underweight. With on-going changes in diet, urbanisation, and an increasingly sedentary lifestyle, the prevalence of obesity is predicted to continue to grow.

But what does it mean to be obese? You may have heard from your doctor or from public health campaigns that if your BMI is over 25 then you are overweight, if it’s over 30 then you are obese, and if your waist circumference is more than 94 cm as a man or 80 cm as a women then you have central obesity.

These numbers were chosen because, above these thresholds, you are considered to be at substantially increased risk of diseases like diabetes and cardiovascular diseases. Globally, 44% of the burden of diabetes and 23% of ischaemic heart disease are attributable to overweight and obesity. However, this risk of developing disease at certain levels of body fat and size has been shown to differ between ethnic groups and population.

Although such ethnic variation exists, most of what we know about obesity is based on studies conducted in populations of European descent. By contrast, the relationship between obesity and disease in sub-Saharan African populations is poorly understood.

Redefining obesity 
In collaboration with colleagues at the Medical Research Council/Uganda Virus Research Institute, Uganda, we conducted a study of approximately 6,000 rural Ugandan adults in 2011. In this population, we found that waist circumference and BMI may be useful tools for identifying people who had diabetes, hypertension or dyslipidaemia.
However, the currently recommended cut-offs or waist circumference and BMI may not be appropriate for African populations.

Instead, we suggest that a substantially lower cut-off for waist circumference (≥78 cm) should be considered for men. A slightly higher cut-off (≥82 cm) should be considered for women. We also recommend that, for screening purposes, a BMI cut-off lower than the current recommendation of 25 kg/m2 should be considered.

This was the first study of BMI cut-offs and the largest study of waist circumference cut-offs in sub-Saharan Africa. Much more work still needs to be done to decide on what the best cut-offs should be for African populations. This work is now, therefore, being expanded by the African Partnership for Chronic Disease Research (APCDR) into a large-scale collaborative project across sub-Saharan Africa. We have, so far, collated data on 56,000 individuals from 11 countries across the region.

Public health importance
A clearer understanding of the relationship between anthropometric measures (body size and shape) and risk of disease may be particularly important for sub-Saharan African populations for a number of reasons.

Firstly, the prevalence of obesity and cardiometabolic disease (such as diabetes and heart disease) is increasing across sub-Saharan Africa. Thus, the need for clinical guidelines and prevention programmes related to adiposity (body fat) is growing.

Secondly, resource-limited settings may benefit greatly from low-cost, easy-to-implement indicators of cardiometabolic risk, such as anthropometric measures.

Lastly, sub-Saharan Africa is struggling under a double burden of under- and over-nutrition. It is, therefore, important that clinical guidelines and public health messages are designed to communicate an optimal healthy, rather than simply reduced, body size.

Overall, a better understanding of obesity within sub-Saharan populations will be important for the design and implementation of public healthcare policy and population prevention programmes in an effort to address the growing burden of cardiometabolic diseases.

*Georgina Murphy [2009] did a PhD in Public Health and Primary Healthcare. This work was done as part of a collaboration between the University of Cambridge, Wellcome Trust Sanger Institute, and Medical Research Council/Uganda Virus Research Institute, Uganda. Georgina has now moved to the University of Oxford, Nuffield Department of Medicine (georgina.murphy@ndm.ox.ac.uk). Picture credit: zirconicusso and http://www.freedigitalphotos.net.

The other mass mobilisation on D-Day

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Seventy years ago today, the world witnessed two unprecedented mobilisations.

Remembering both offers insights for our time.

On the shores of Normandy, leaders gather today to remember the pivotal Allied invasion that re-drew the battle lines of World War II. Nearly 160,000 troops crossed the English Channel on June 6, 1944, making it the largest seaborne invasion in history. Yet another deployment had also occurred in tandem: the first mass production of penicillin. Between 1942 and 1944, the US went from possessing enough penicillin for only 10 patients to producing over 400 million doses in time for D-Day.

The tale of penicillin

While Alexander Fleming is remembered as the discoverer of penicillin, many actors – from scientists, government employees, engineers, to drug companies – played midwife to this new drug. Three highlights emerge from penicillin’s journey from chemical compound to mass delivery.

  • First, the discovery process happened in fits and starts: after Fleming’s accidental discovery of the penicillin compound in September of 1928, further development of the compound did not occur until a decade later, when British scientists at Oxford came upon Fleming’s original paper.
  • Second, collaborations amidst the cornfields of Illinois were crucial: the Northern Regional Laboratory in Peoria, Illinois was the initial setting for mass production. A by-product of corn production – lactose – made commercial production of penicillin possible. Strategic partnerships between those Oxford scientists, the US government’s War Production Board, and the Lab’s fermentation division created this opportunity.
  • Lastly, check the groceries! A lab assistant, Mary Hunt, found that a cantaloupe she had bought at market had a “pretty, golden mould” which turned out to be Penicillium chrysogenum. This accidental purchase led to a form of penicillin with 1,000 times the yield over the first batches discovered by Fleming (which were being used in the initial production in Peoria).

By June 1945, American pharmaceutical companies were producing 650 billion units of penicillin monthly. While the major killer in prior wars had been infection rather than battle injuries, World War II would prove different because of penicillin. For example, the death rate from bacterial pneumonia fell from 18% percent in World War I to 1% in World War II.

Today’s challenges of discovery and delivery

Since the time of penicillin’s tale, one composed of a strange alchemy of serendipity and strategy, the innovation enterprise has benefited from significant advances. Fleming’s colleagues did not have PubMed or tens of other tools to share knowledge widely and quickly. Governments did not yet invest billions in fundamental research to develop promising compounds. Today’s manufacturing and distribution systems were still decades away.

Yet even with this scientific and technological prowess, important questions persist. Here are two: In a time when penicillin and its antibiotic offspring are falling to increasing resistance, what might be paradigms of innovation against bacteria? One strategy is to re-stock the pipeline of antibiotics, an area of long-neglected research and development. For example, the recent development of the first anti-tuberculosis drug in 40 years, bedaquiline, will hopefully not be a lone discovery.

Another strategy is to re-imagine the scientific paradigm: explorations into “nano-antibiotics” or targeting virulence factors for vaccine development present ways of conceiving of the pharmaceutical armament in a fundamentally different way. Developing such possibilities will require considerable high-risk investment. A dose of serendipity wouldn’t hurt, either.

A more immediate question confronts millions of patients, including American veterans: when new discoveries are made, how will those fruits be priced, produced, and distributed? The current case of sofosbuvir, a game-changing antiviral for patients with Hepatitis C, has made headlines.

Developed by Gilead Sciences, the drug is priced at $84,000 in the US for a three-month regimen – nearly $1,000 per pill. The choices made by various stakeholders – from Gilead, pharmaceutical companies with competing drugs in development, public and private systems of health delivery, to treatment activists around the world – will shape the trajectory of the drug and the life chances of millions.

It may also catalyse the agenda around pharmaceutical innovation and public policy: in the US, a large proportion of those with Hepatitis C are veterans whose health care is delivered through the Veteran Affairs (VA), a taxpayer funded health system. Whether the medication will be made widely available through public systems such as the VA remains a pressing question.

As we remember D-Day, we might also reflect on the mass deployments required in our time: to meet the twin challenges of creating new innovations and making them broadly accessible.

*Victor Roy [2009] is a Gates Cambridge scholar as a PhD student in sociology and political economy at the University of Cambridge focusing on innovation policy. He is also an MD candidate at Northwestern’s Feinberg School of Medicine and is a Paul and Daisy Soros Fellow for New Americans. Follow him on Twitter: @victorroy. Picture credit: Photokanok and http://www.freedigitalphotos.com.