Category Archives: Science

Science

Still

I had both of my babies at home, the first in a small two up two down terraced house, the second in the slightly larger house that we still live in, just a couple of streets away. Both are within 5 minutes drive of a major teaching hospital.

My girls were born safe and healthy, with no problems or complications. I was lucky.

Bad things happen.

In my first delivery, the midwife arrived early, which is to say, she set out after the second phone call because, she’d had a bad experience the night before (the cord caught around the baby’s neck as it was being pushed out, and she had struggled to keep the baby alive). Since it turns out that I’m the kind of woman who has 3 hour labours (the average is closer to 12 hours)  if she’d left it much later she’d have arrived too late.

The second midwife (one attends for the mother, one attends for the baby) failed to arrive in time. Since she’s the one who brings the pain relief (air and gas) it was a short but painful birth, with a first degree tear (not stitched – should have been stitched, never rely on nature to fix a raggedy labial tear).

But in conversation about the Vicky Foxcroft article afterwords, I took exception with one commentator who suggested that planned home births were the reason for the high still birth rate in the UK. It’s just not factually correct.
Babies are classed as stillborn if they die at any point after 28 weeks of pregnancy, up to the birthing process itself which is when half occur. Over 98% of stillbirths happen in low and middle-income countries. Pakistan has a rate of 43.1 for every 1,000 children born – that’s one in every 23 mothers finding out their baby is dead.

But bad things happen everywhere.

For every 1,000 babies born in Britain, 2.9 are stillborn (based on at least 28 weeks of gestation) – more than twice the rate of 1.4 in Iceland. Britain is now 21 out of 35 of the world’s wealthy countries according to the Lancet Stillbirth Series (2016). Croatia, Poland and Czech Republic have better stillbirth rates than the UK.

Equally worrying is the UK’s annual rate of reduction, which is now just 1.4% – placing us 114th globally for progress on stillbirths.

So what aren’t we doing as well as we might?

The Netherlands, which has cut its rates by almost 7%, hasn’t just improved care during the birth, but focused on women’s health while they are pregnant and even before that too. In particular, it has had a huge programme to reduce maternal smoking, as well as structured investment in analysis and understanding of each stillbirth.

Here in the UK, underlying the overall rate of 2.9 per 1000, the survey found mothers in the most deprived areas were up to twice as likely to experience a stillbirth as the country’s most affluent mums – although that research only covered the years up to 2005. Poorer mothers are more likely to smoke and more likely to be either significantly overweight or underweight, all risk factors for stillbirth.

And this is why I think I was so offended by the references to home birth in the context of still birth. In order to reduce the rate of stillbirth in the UK, it’s important to understand the risks, where they arise and what can be done to mitigate them.

Both the UK and Iceland have tiny levels of home births, both around 2% of annual births. Stillbirth, like most birth, is a hospital phenomena in the main (98%) of cases. If we want to improve our rates of stillbirth, we need to tackle the real causes.

  • 10 babies are stillborn every day in the UK.
  • In women with a BMI over 30, the risk rises to 1 in 100 (from 2.9 per thousand). An increasing BMI is associated with an increased incidence of pre-eclampsia, gestational hypertension, macrosomia, induction of labour and caesarean deliveries.
  • Underweight mothers also have an enhanced risk of stillbirth where being underweight (a BMI of < 19.9 kg / m2) has been shown to be associated with an increased risk of preterm deliveries, low birth weight and anaemia and a decreased risk of pre-eclampsia, gestational diabetes, obstetric intervention and post-partum haemorrhage
  • Women who smoke have an enhanced risk of stillbirth. In meta-analysis research carried out by BMC Public Health smoking during pregnancy was significantly associated with a 47% increase in the odds of stillbirth.
  • Around half of all stillbirths are linked to placental complications.
  • Other causes include bleeding before or during labour, placental abruption, pre-eclampsia, a problem with the umbilical cord, obstetric cholestasis, a genetic physical defect in the baby, pre-existing diabetes, and infection in the mother that also affects the baby.
  • Reduced fetal movement is a good indicator of stillbirth, with slowing down of movement noticed by the mother in two out of three stillbirths.

Still, Dr David Richmond, consultant gynaecologist and president of the Royal College of Obstetricians and Gynaecologists, describes the survey as a “wake-up call”.

In the UK, there is still much to be done to ensure our rate of progress is as good as the best in Europe.

Through the Each Baby Counts initiative, we are this year beginning to undertake a structured review of each and every stillbirth that occurs during labour in term pregnancies to help identify common risk factors, learn from what went wrong and apply the lessons in maternity units across the country.

– DR DAVID RICHMOND
A recent report by the NHS Saving Babies’ Lives – NHS England gives recommendations that aim to reduce the rates of stillbirth by half by 2030.

One of the most striking observations is how often poor fetal growth corresponds with stillbirth, consistent with a recent Panorama programme that suggested regular scans could halve the UK rate of still birth by tracking growth and highlighting failure to thrive. The latter can often be addressed by inducing early births.

The four key recommendations are based on extending best practice around the country and include:
  • Reducing smoking in pregnancy
  • Risk assessment and surveillance for fetal growth restriction
  • Raising awareness of reduced fetal movement
  • Effective fetal monitoring during labour

None of these relate to home births. All of the recommendations require joined up, consistent maternal care with time to be spent monitoring, managing, helping women to manage their lives and their pregnancies.

Rants&Rambles, Science

Genie

Scientists have, for the first time, corrected a disease-causing mutation in early stage human embryos with gene editing. The technique, which uses the CRISPR-Cas9 system, corrected the mutation for a heart condition at the earliest stage of embryonic development so that the defect would not be passed on to future generations.

The work, which is described in Nature on August 2, 2017, is a collaboration between the Salk Institute, Oregon Health and Science University (OHSU) and Korea’s Institute for Basic Science and could pave the way for improved in vitro fertilization (IVF) outcomes as well as eventual cures for some of the thousands of diseases caused by mutations in single genes.

Though gene-editing tools have the power to potentially cure a number of diseases, scientists have proceeded cautiously, in part to avoid introducing unintended mutations into the germ line (cells that become eggs or sperm). The research in the current study adheres closely to guidelines established by OHSU’s Institutional Review Board and additional ad-hoc committees set up for scientific and ethical review.

Hypertrophic cardiomyopathy (HCM) is the most common cause of sudden death in otherwise healthy young athletes, and affects approximately 1 in 500 people overall. It is caused by a dominant mutation in the MYBPC3 gene, but often goes undetected until it is too late. Since people with a mutant copy of the MYBPC3 gene have a 50 percent chance of passing it on to their own children, having two genetic strands one faulty one not, being able to correct the mutation in embryos would prevent the disease not only in affected children, but also in their descendants.

The researchers generated induced pluripotent stem cells from a skin biopsy donated by a male with HCM and developed a gene-editing strategy based on CRISPR-Cas9 that would specifically target the mutated copy of the MYBPC3 gene for repair. The targeted mutated MYBPC3 gene was cut by the Cas9 enzyme, allowing the donor’s cells’ own DNA-repair mechanisms to fix the mutation during the next round of cell division by using either a synthetic DNA sequence or the non-mutated copy of MYBPC3 gene as a template.

Using IVF techniques, the researchers injected the best-performing gene-editing components into healthy donor eggs newly fertilized with the donor’s sperm. They also tried a second method, introducing the gene editing components along with sperm into the egg prior to fertilisation.Then they analyzed all the cells in the early embryos at single-cell resolution to see how effectively the mutation was repaired.

The scientists were surprised by just how safe and efficient the method was using the second method ie. introducing the gene editor and the sperm prior to fertilisation and allowing the embryonic repair and replication process to identify the faulty gene as early as possible.

Not only did a high percentage of embryonic cells get repaired, but also gene correction didn’t induce any detectable off-target mutations and genome instability — major concerns for gene editing. In addition, the researchers developed a robust strategy to ensure the repair occurred consistently in all the cells of the embryo. (Spotty repairs can lead to some cells continuing to carry the mutation.)

“Even though the success rate in patient cells cultured in a dish was low, we saw that the gene correction seems to be very robust in embryos of which one copy of the MYBPC3 gene is mutated,” says Jun Wu, a Salk staff scientist and one of the paper’s first authors. This was in part because, after CRISPR-Cas9 mediated enzymatic cutting of the mutated gene copy, the embryo initiated its own repairs. Instead of using the provided synthetic DNA template, the team found, surprisingly, that the embryo preferentially used the available healthy copy of the gene to repair the mutated part. “Our technology successfully repairs the disease-causing gene mutation by taking advantage of a DNA repair response unique to early embryos” says Wu.

Izpisua Belmonte and Wu emphasize that, although promising, these are very preliminary results and more research will need to be done to ensure no unintended effects occur.

“Our results demonstrate the great potential of embryonic gene editing, but we must continue to realistically assess the risks as well as the benefits,” adds Izpisua Belmonte.

Future work will continue to assess the safety and effectiveness of the procedure and efficacy of the technique with other mutations.

And reactions to the story in various newspaper seem to split into two basic camps: “this is brilliant, science at it’s best, leading us towards a glorious future that only primitives could disagree with” versus “this is satan’s work”.

It seems to me that the people so quick to condemn the doubters, are actually a bit naive about science and its often flawed nature. We are a long way away from any tangible good coming from this experiment and the ethical and moral questions it raises are considerable; something pointedly acknowledged by the scientists involved. An easier and quicker way to screen for this genetic disease would be to scan the sperm and filter out the faulty before using the healthy sperm to fertilise healthy eggs. Being able to cut and paste sperm in a petri dish, as opposed to sifting them to exclude the damaged,is an interesting intellectual exercise rather than a practical one.

The success rate when editing the faulty sperm prior to fertilisation was low. The scientists involved do not understand why or how the embryonic repair function works the way it does or indeed why it was so successful in choosing a healthy non-mutated copy of the gene as a template in replication.It may simply be that the genetic scissors attaches itself to the faulty gene and renders it somehow visible (and undesirable) to the embryonic replication system ie. the process was identifying and rejecting artificial intervention anywhere rather than anything more positive.

A surprising number of positive comments failed to distinguish between normal medical intervention, antibiotics, surgery, vaccination etc and genetic alteration that changes subsequent generations. A number seemed entirely content to compare gene editing with dog breeding, seemingly unaware of the obvious unintended yet damaging health implications in any number of dog breeds. The most fervent of supporters for the new research seemed surprisingly religious in their beliefs, with really a minimum of understanding and an awful lot of faith on display.

I have no patience with the idea that new scientific research is the work of the devil but I feel a bit uneasy about this messing about with our genetic heritage. We still know so very very little about how our genetic material interacts and operates that it seems inevitable that there will be some unintended consequences once we start messing about. I’m not so much fearful of deliberate malicious intervention, as I am of accidents where a scientist manages to fix problem (A) and three generations later we find that the IQ of a population drops 10 points, or that problem (A) also switched on some reaction in the immune system that would have allowed us to live an extra ten years without dementia.

It’s the unintended accident that worries me rather than the happy accident that this experiment seems to have discovered.

Rants&Rambles, Science

STOP

Throughout history, humanity has been blighted by epidemics of communicable diseases that medical science and public policy have, to varying degrees, been able to control. Sanitation, immunisation, mosquito nets, and antimicrobial agents are examples of developments that have helped to generate substantial reductions in cholera, dysentery, smallpox, measles, HIV, tuberculosis, and many other infectious diseases.

More people die in the developing world from non-communicable disease than communicable, though it can be tricky to raise funds for heart attacks over diphtheria. Non-communicable diseases are now emerging as major burdens in low-income and middle-income countries. This is especially true of the epidemics of lung cancer, chronic obstructive pulmonary disease (COPD), cardiovascular disease, and other disorders that are caused by tobacco smoking.

We know it’s bad for us to smoke, but maybe not quite ho bad.

A new report in The Lancet using data from the Global Burden of Disease Study provide comprehensive estimates of death and disability caused by smoking at the country level. The findings are sobering. In 2015, smoking caused more than one in ten deaths worldwide, killing more than 6 million people with a global loss of nearly 150 million disability-adjusted life-years.

Smoking prevalence and consequent morbidity and mortality are now falling in most (but not all) rich countries, but future mortality in low-income and middle-income countries is likely to be huge.

Worldwide, one in four men, and a total of 933 million people, are estimated to be current daily smokers, and 80% of these smokers live in low-income and middle-income countries. Half of these, or half a billion people alive today, can be expected to be killed prematurely by their smoking unless they quit.

At present, smoking prevalence is still low in countries with a low socio-demographic index, but, on past experience in richer countries, it is only a matter of time before men and then women in all countries take up smoking, and in due course die from lung cancer, COPD, and other diseases caused by smoking, as has happened in the richer world. Even though the prevalence of smoking is decreasing in many low-income and middle-income countries, including many of those with the most smokers (eg, China and India), population growth means that the number of smokers, and hence the burden of harm from smoking, continues to rise.

Responsibility for this global health disaster lies mainly with the transnational tobacco companies, which clearly hold the value of human life in very different regard to most of the rest of humanity.

For example, the latest annual report from British American Tobacco (BAT), historically the most global of today’s five transnational companies, details with apparent pride their geographical diversity, strong earnings and market share growth, market leadership in more than 55 countries, and manufacturing facilities in 42 of them.

In 2016, BAT sold 665 billion cigarettes, making £5·2 billion in profit; and recorded rising profits across most of the world. Countering the heft and influence of commercial behemoths such as this demands human resources, governance, expertise, and financial backing that few rich countries have yet to fully establish, let alone those countries at the lower end of the development spectrum.

The WHO Framework Convention Alliance provides detailed guidance to support implementation of a growing range of effective tobacco control policies, including taxation, advertising bans, smoke-free policies, and protection against the vested interests of the tobacco industry, but, in most parts of the world, translating this guidance into effective legislation has a long way to go.

Like in many rich countries, tobacco control legislation too often becomes mired in procedure and delayed or otherwise undermined by tobacco industry misrepresentation of science, fearmongering over tax revenue and illicit supply, corporate social responsibility activities, offers of help drafting tobacco laws, threatened or real legal action, and, in some countries, economic dependence on tobacco growing, and conflicts of interest.

The persistence of smoking in the countries first affected by the tobacco epidemic reflects decades of failure first to recognise smoking as a health problem, and second to take decisive action to implement the policies currently promoted by the WHO Framework Convention on Tobacco Control, but articulated long ago in the Royal College of Physicians’ report of 1962

Today, the smoking epidemic is being exported from the rich world to low-income and middle-income countries, slipping under the radar while apparently more immediate priorities occupy and absorb scarce available human and financial resources. The epidemic of tobacco deaths will progress inexorably throughout the world until and unless tobacco control is recognised as an immediate priority for development, investment, and research.

Rich-world experience also teaches that where the tobacco industry leads and succeeds today, so the alcohol and food industries follow tomorrow

Rants&Rambles, Science

Who wants to live forever?

People are very afraid of cancer, with good reason. Unlike other things that kill us, it often seems to come out of nowhere.

But evidence suggests that cancer may be preventable, too. Unfortunately, this has inflamed as much as it has assuaged people’s fears.

As a physician, I have encountered many people who believe that heart disease, which is the single biggest cause of death among Americans, is largely controllable. After all, if people ate better, were physically active and stopped smoking, then lots of them would get better. This ignores the fact that people can’t change many risk factors of heart disease like age, race and family genetics.

People don’t often seem to feel the same way about cancer. They think it’s out of their control. A study published in Science in January 2015 seemed to support that view. It tried to explain why some tissues lead to cancer more often than others. It found a strong correlation between the number of times a cell divides in the course of a lifetime and the risk of developing cancer.

In other words, this study argued that the more times DNA replicates, the more often something can go wrong. Some took this to mean  that cancer is much more because of “bad luck” than because of other factors that people could control.

But this is not really what the study showed. Lung cells, for instance, divide quite rarely, and still account for a significant amount of cancer. Cells in the gastrointestinal tract divide all the time and account for many fewer cancers. Some cancers, like melanoma, were found to be in the group of cancers influenced more by intrinsic factors (or those we can’t control), when we clearly know that extrinsic factors, like sun exposure, are a major cause.

Further, this study was focused more on the relative risks of cancer in one type of tissue versus another. What we really care about is how much we can reduce our own risk of cancer by changing our behavior.

A more recent study published in Nature argues that there is quite a lot we can do to prevent cancer. Many studies have shown that environmental risk factors and exposures contribute greatly to many cancers. Diet is related to colorectal cancer. Alcohol and tobacco are related to oesophageal cancer. HPV is related to  cervical cancer, and hep C is related to liver cancer.

And you’d have to be living under a rock not to know that smoking causes lung cancer and that too much sun can lead to skin cancer.

Using sophisticated modeling techniques, the researchers argued that less than 30% of the lifetime risk of getting many common cancers was because of intrinsic risk factors, or the “bad luck.” The rest were things you can change.

Most recently, in JAMA Oncology, researchers sought to quantify how a healthful lifestyle might actually alter the risk of cancer. They identified four domains that are often noted to be related to disease prevention: smoking, drinking, obesity and exercise.

They defined people who engaged in healthy levels of all of these activities as a “low risk” group. Then they compared their risk of getting cancer with people who weren’t in this group. They included two groups of people who have been followed and studied a long time, the Nurses’ Health Study and the Health Professionals Follow-up Study, as well as national cancer statistics.

Of the nearly 90,000 women and more than 46,000 men, 16,531 women and 11,731 men fell into the low-risk group. For each type of cancer, researchers calculated a population-attributable risk, which is the percentage of people who develop cancer who might have avoided it had they adopted low-risk behaviors.

About 82% of women and 78% of men who got lung cancer might have prevented it through healthy behaviors. About 29% of women and 20%t of men might have prevented colon and rectal cancer. About 30%t of both might have prevented pancreatic cancer. Breast cancer was much less preventable: 4 percent.

Over all, though, about 25% of cancer in women and 33% in men was potentially preventable. Close to half of all cancer deaths might be prevented as well.

No study is perfect, and this is no exception. These cohorts are overwhelmingly white and consist of health professionals, who are not necessarily like the population at large. But the checks against the national data showed that if anything, these results might be underestimating how much cancer is preventable by healthy behaviors.

This also isn’t a randomized controlled trial, and we can certainly argue that it doesn’t prove causation.

A bigger concern to me is that people might interpret these findings as assigning fault to people who get cancer. You don’t want to get into situations where you feel as if people don’t deserve help because they didn’t try hard enough to stay healthy. Much of cancer is still out of people’s control.

In this study, “low risk” status required all four healthy lifestyles. Failing in any one domain put you in the high-risk category, and that seemed like a lot to ask of people.

On further reading, though, it’s clear that the requirements weren’t overly burdensome. Not smoking was defined as never having smoked or having quit at least five years ago. That’s clearly good for health. Moderate alcohol consumption was defined as no more than one drink a day on average for women, and no more than two for men. It in no way requires abstinence.

Adequate weight was defined as a B.M.I. of at least 18.5 and no more than 27.5. The cutoff for “overweight” is 25, meaning that you don’t have to be thin; you just have to be less than obese (B.M.I. 30). Finally, exercise was defined as 150 minutes a week of moderate-intensity activity or 75 minutes of vigorous-intensity activity. That’s a reasonable and quite achievable goal.

I was surprised to realize that I’m already “low risk.” I bet many people reading this are “low risk,” too.

As we talk about cancer “moonshots” that will most likely cost billions of dollars and might not achieve results, it’s worth considering that — as in many cases — prevention is not only the cheapest course, but also the most effective.

Simple changes to people’s behaviors have the potential to make sure many cancers never occur. They have a side benefit of preventing health problems in many other areas, too. Investment in these efforts may not be as exciting, but it may yield greater results.