Scientists Think They’ve Traced the Very First Mutations in a Human Life

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For the first time, scientists have caught a glimpse of the earliest genetic mutations in human development.

Using whole genome sequencing, they wound back time on cell samples from adults and revealed what took place in the genome when they were still microscopic embryos. It turns out, our first two cells contribute to our development in very different ways.

Mutations come in two forms: the hereditary ones we get from our parents, which can be found in virtually every cell of the body; and the acquired (or somatic) mutations that can occur at any stage of a person’s life, including those very first days when the embryo is just starting to split into multiple cells.

Somatic mutations don’t necessarily cause problems, but they can sometimes lead to cancer and other diseases. They also don’t necessarily live in every cell (that’s called mosaicism).

We have a fairly murky understanding of the somatic mutations that happen during the earliest life stages, because we can’t just watch that stuff happening in real time.

But now researchers have discovered a way to trace these mutations back to their first appearance.

“This is the first time that anyone has seen where mutations arise in the very early human development. It is like finding a needle in a haystack,” says geneticist Young Seok Ju from the Wellcome Trust Sanger Institute in the UK and the Korea Advanced Institute of Science and Technology.

“There are just a handful of these mutations, compared with millions of inherited genetic variations, and finding them allowed us to track what happened during embryogenesis.”

To find these mutations, the team analysed blood and tissue samples from 279 people with breast cancer. Using samples from cancer patients allowed them to test whether mutations were present in both normal blood and tissue, and in surgically removed tumour samples.

Since breast cancer tumours develop from a single cell, a somatic mutation would either be present in every tumour cell, or not at all, which gives a clue to its possible origins.

By tracking and comparing the spread of different mutations in these various tissue samples, the scientists verified a whopping 163 mutations that must have happened within the first few cell divisions of the persons’ embryonic development.

This gave them a unique insight into how early embryonic cells interact.

And that’s not all – a statistical analysis revealed that when a fertilised egg divides for the first time, those two cells actually contribute building material for the rest of the body at different proportions.

It appears that one of the first two cells that make us up gives rise to 70 percent of the body tissue, while the other one chips in for the rest.

“We determined the relative contribution of the first embryonic cells to the adult blood cell pool and found one dominant cell – that led to 70 percent of the blood cells – and one minor cell,” says molecular biologist Inigo Martincorena from the Sanger Institute.

“This opens an unprecedented window into the earliest stages of human development.”

That’s exciting, because having that window will let us discover even more about how humans develop and acquire various mutations from the get-go.

Even though the vast majority of mutations are random and harmless, occasionally they can affect an important gene, causing a developmental disorder or a disease.

“Essentially, the mutations are archaeological traces of embryonic development left in our adult tissues, so if we can find and interpret them, we can understand human embryology better,” says lead researcher Mike Stratton, director of the Wellcome Trust Sanger Institute.

The researchers hope their discovery is just the first of many steps that will help us gain a better understanding of what happens to humans in the earliest days, when we’re all nothing more than just a clump of cells.

The research was published in Nature.

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FDA approves drug to treat Parkinson’s disease

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The U.S. Food and Drug Administration today approved Xadago (safinamide) tablets as an add-on treatment for patients with Parkinson’s disease who are currently taking levodopa/carbidopa and experiencing “off” episodes. An “off” episode is a time when a patient’s medications are not working well, causing an increase in Parkinson’s symptoms, such as tremor and difficulty walking.

“Parkinson’s is a relentless disease without a cure,” said Eric Bastings, M.D., deputy director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research. “We are committed to helping make additional treatments for Parkinson’s disease available to patients.”

An estimated 50,000 Americans are diagnosed with Parkinson’s disease each year, according to the National Institutes of Health, and about one million Americans have the condition. The neurological disorder typically occurs in people over age 60, though it can occur earlier, when cells in the brain that produce a chemical called dopamine become impaired or die. Dopamine helps transmit signals between the areas of the brain that produce smooth, purposeful movement – such as eating, writing, and shaving. Early symptoms of the disease are subtle and occur gradually. In some people, Parkinson’s disease progresses more quickly than in others.

The efficacy of Xadago in treating Parkinson’s disease was shown in a clinical trial of 645 participants who were also taking levodopa and were experiencing “off” time. Those receiving Xadago experienced more beneficial “on” time, a time when Parkinson’s symptoms are reduced, without troublesome uncontrolled involuntary movement (dyskinesia), compared to those receiving a placebo. The increase in “on” time was accompanied by a reduction in “off” time and better scores on a measure of motor function assessed during “on” time than before treatment.

In another clinical trial of 549 participants, the participants adding Xadago to their levodopa treatment had more “on” time without troublesome uncontrolled involuntary movement compared to those taking a placebo, and also had better scores on a measure of motor function assessed during “on” time than before treatment.

Certain patients should not take Xadago. These include patients who have severe liver problems, or who take a medicine used to treat a cough or cold called dextromethorphan. It also should not be taken by patients who take another medicine called a monoamine oxidase inhibitor (MAOI) because it may cause a sudden severe increase in blood pressure, or by those who take an opioid drug, St. John’s wort, certain antidepressants (such as serotonin-norepinephrine reuptake inhibitors, tricyclics, tetracyclics, and triazolopyridines), or cyclobenzaprine, because it may cause a life-threatening reaction called serotonin syndrome.

The most common adverse reactions observed in patients taking Xadago were uncontrolled involuntary movement, falls, nausea, and trouble sleeping or falling asleep (insomnia).

Serious, but less common, risks include the following: exacerbated high blood pressure (hypertension); serotonin syndrome when used with MAOIs, antidepressants, or opioid drugs; falling asleep during activities of daily living; hallucinations and psychotic behavior; problems with impulse control/compulsive behaviors; withdrawal-emergent hyperpyrexia (fever) and confusion; and retinal pathology.

The FDA granted approval of Xadago to Newron Pharmaceuticals.

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Vitamin D Has Been Linked to Autism Prevention in Animal Studies

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Researchers have found that vitamin D treatments during pregnancy appear to prevent the development of autism in mice, and are now planning to investigate if similar effects can be achieved in humans using vitamin D supplements.

The research is still in its very early stages, but it’s thought that vitamin D plays a big role in early brain development, and previous studies have suggested that vitamin D deficiency could influence the increased size and unique shape observed in the brains of people with autism spectrum disorder (ASD).

“Our study used the most widely accepted developmental model of autism, in which affected mice behave abnormally and show deficits in social interaction, basic learning, and stereotyped behaviours,” says one of the team, Darryl Eyles from the University of Queensland in Australia.

“We found that pregnant females treated with active vitamin D (a different form than in supplements) in the equivalent of the first trimester of pregnancy produced offspring that did not develop these deficits.”

For some background into the extensive research that’s been done on vitamin D and autism in the past, for more than a decade, scientists have been trying to figure out the significance of animal studies that have linked severe vitamin D deficiency to increased brain size and enlarged ventricles – characteristics similar to those found in children with ASD.

With ASD being such a complex condition, and thought to be affected by a range of risk factors, including genetics and perhaps even environmental conditions such as air pollutants and viral infections, this has been particularly difficult to study in humans.

But we have seen hints that there could be something to this hypothesis, not least of which is the fact that vitamin D deficiency during pregnancy has been linked to an array of physical and psychological conditions including schizophrenia, asthma, and reduced bone density.

Then there was that 2008 study by Swedish researchers that found the prevalence of autism and related disorders was three to four times higher among Somali immigrants in Stockholm than non-Somalis.

The trend seemed to be occurring in Minnesota too, with a separate group of researchers finding that the rate of ASD in the 60,000 Somali immigrants living in the state was comparable to those who had migrated to Sweden.

And it wasn’t because Somalis are genetically pre-disposed to the condition – in fact, it appeared to the opposite.

“It has shocked the community. We never saw such a disease in Somalia. We do not even have a word for it,” Huda Farah, a Somali-born molecular biologist, told Gabrielle Glaser at Scientific American at the time.

The researchers suspected that in both cases, the unusually high rate of ASD in Somali immigrants was down to the fact that they were getting less sun in their new homes than they were in their native country, which would have lowered their vitamin D levels.

As Glaser explained:

“At northern latitudes in the summertime, light-skinned people produce about 1,000 international units (IUs) of vitamin D per minute, but those with darker skin synthesise it more slowly, says Adit Ginde, an assistant professor at the University of Colorado Denver School of Medicine. Ginde recommends between 1,000 to 2,000 IUs per day.”

Fast-forward to 2016, when an international team of researchers published a paper that also highlighted a link between vitamin d deficiency during pregnancy and autism.

Looking at blood samples from 4,229 pregnant women and their children, the researchers found that those with lower than average vitamin D levels at 20 weeks’ gestation were more likely to have a child with autistic traits by the age of six.

The team reported that pregnant women who were deficient in vitamin D had “significantly higher” scores on established autism scales than those with average vitamin D levels.

“Just as taking folate in pregnancy has reduced the incidence of spina bifida, the results of this study suggest that prenatal vitamin D supplements may reduce the incidence of autism,” lead researcher John McGrath told ABC at the time.

Now, the University of Queensland team has similar results, this time based on mouse models.

They treated pregnant mice in the equivalent of their first trimester with the active hormonal form of vitamin D, and tested the behaviour of their offspring as they developed.

Behavioural studies, maze tests, social interactions, fear conditioning, and marble burying activities were all administered to assess the mouse pups’ anxiety, sociability, stereotyped behaviour (repetitive movements like pacing and rocking) and emotional learning and memory.

They found no signs of behaviours that would be linked to ASD in any of the mice.

“The present study tested the hypothesis that maternal administration of the active vitamin D hormone … would prevent autism-relevant behavioural abnormalities,” the team reports in their paper.

“Our data support this hypothesis by showing that maternal vitamin D co-administration blocked the emergence of the ASD-relevant deficits in social interaction, stereotyped behaviour, and emotional learning and memory.”

The team also disproved a promising hypothesis for why lower vitamin D levels appear to be linked to higher autism risk – they found no evidence that the vitamin had a protective anti-inflammatory effect during brain development in the womb.

Of course, attempting to replicate the results in humans is going to be complicated. For one thing, the active vitamin D hormone used by the team cannot be given to pregnant women, because it could risk the skeletal development of the foetus.

But they suggest that cholecalciferol – the vitamin D supplement form that is safe for pregnant women to take – could have similar preventative effects.

“Recent funding will now allow us to determine how much cholecalciferol … is needed to achieve the same levels of active hormonal vitamin D in the bloodstream,” says one of the team, Wei Luan.

“This new information will allow us to further investigate the ideal dose and timing of vitamin D supplementation for pregnant women.”

To be clear, we’re still way too early on in the research process for anyone to be changing their behaviour during pregnancy based on these results – if you’re worried about your vitamin D levels, go see your doctor for personalised medical advice.

But the study is yet another piece of the puzzle that could help us understand at least one of the potential risk factors for a very complicated condition, and that could make all the difference in the future.

As autism expert Andrew Whitehouse from the Telethon Kids Institute, who was not involved in the 2016 study, told The Guardian:

“There are likely dozens, if not hundreds, of different mechanisms that can lead to autism. Now this study gives us an inkling of one possible mechanism, but before we think about anything, we need to see a replication of this finding.

What we know is that vitamin D during pregnancy is very important for how the baby develops.”

The latest study has been published in Molecular Autism.

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FDA approves first treatment for rare form of skin cancer

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The U.S. Food and Drug Administration granted accelerated approval to Bavencio (avelumab) for the treatment of adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (MCC), including those who have not received prior chemotherapy. This is the first FDA-approved treatment for metastatic MCC, a rare, aggressive form of skin cancer.

“While skin cancer is one of the most common cancers, patients with a rare form called Merkel cell cancer have not had an approved treatment option until now,” said Richard Pazdur, M.D., acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research and director of the FDA’s Oncology Center of Excellence. “The scientific community continues to make advances targeting the body’s immune system mechanisms for the treatment of various types of cancer. These advancements are leading to new therapies—even in rare forms of cancer where treatment options are limited or non-existent.”

According to the National Cancer Institute, approximately 1,600 people in the United States are diagnosed with MCC every year. While the majority of patients present with localized tumors that can be treated with surgical resection, approximately half of all patients will experience recurrence, and more than 30 percent will eventually develop metastatic disease. In patients with metastatic MCC, the cancer has spread beyond the skin into other parts of the body.

Bavencio targets the PD-1/PD-L1 pathway (proteins found on the body’s immune cells and some cancer cells). By blocking these interactions, Bavencio may help the body’s immune system attack cancer cells.

Bavencio received an Accelerated Approval, which enables the FDA to approve drugs for serious conditions to fill an unmet medical need using clinical trial data that is thought to predict a clinical benefit to patients. Further clinical trials are required to confirm Bavencio’s clinical benefit and the sponsor is currently conducting these studies.

Today’s approval of Bavencio was based on data from a single-arm trial of 88 patients with metastatic MCC who had been previously treated with at least one prior chemotherapy regimen. The trial measured the percentage of patients who experienced complete or partial shrinkage of their tumors (overall response rate) and, for patients with a response, the length of time the tumor was controlled (duration of response). Of the 88 patients who received Bavencio in the trial, 33 percent experienced complete or partial shrinkage of their tumors. The response lasted for more than six months in 86 percent of responding patients and more than 12 months in 45 percent of responding patients.

Common side effects of Bavencio include fatigue, musculoskeletal pain, diarrhea, nausea, infusion-related reactions, rash, decreased appetite and swelling of the limbs (peripheral edema). The most common serious risks of Bavencio are immune-mediated, where the body’s immune system attacks healthy cells or organs, such as the lungs (pneumonitis), liver (hepatitis), colon (colitis), hormone-producing glands (endocrinopathies) and kidneys (nephritis). In addition, there is a risk of serious infusion-related reactions. Patients who experience severe or life-threatening infusion-related reactions should stop using Bavencio. Women who are pregnant or breastfeeding should not take Bavencio because it may cause harm to a developing fetus or a newborn baby.

The FDA granted this application Priority Review and Breakthrough Therapy designation. Bavencio also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted accelerated approval of Bavencio to EMD Serono Inc.

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Two-Thirds of Cancer Mutations Are Random and Unavoidable, Scientists Claim

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Almost two-thirds of cancer mutations are caused by random DNA-copying errors during cell division and are impossible for us to avoid, regardless of lifestyle and the genes we inherit from our parents, according to new research.

The findings – which estimate that 66 percent of cancer mutations are effectively bad luck that we can’t do anything about – support the conclusions of a controversial paper released in 2015 by the same researchers, which came under fire for appearing to suggest that there was nothing we could do to prevent various cancers.

This time around, the team from Johns Hopkins University are at pains to emphasise that their findings don’t contradict what we know about cancer prevention – nor detract from the importance of environment and heredity in terms of causing cancer.

“It is well-known that we must avoid environmental factors such as smoking to decrease our risk of getting cancer. But it is not as well-known that each time a normal cell divides and copies its DNA to produce two new cells, it makes multiple mistakes,” says biostatistician Cristian Tomasetti.

“These copying mistakes are a potent source of cancer mutations that historically have been scientifically undervalued, and this new work provides the first estimate of the fraction of mutations caused by these mistakes.”

When Tomasetti and geneticist Bert Vogelstein last examined the role of these random mutations driving cancer growth, they were criticised for only examining US heath data – and for not providing results on breast or prostate cancer.

In the new study, to broaden the scope of their original findings, they examined medical data from 68 countries on 32 types of cancer – including breast and prostate – to find what proportion of mutations that cause cancer are due to random mistakes made during DNA copying.

The team found that the extent to which random mutations contribute to cancer growth differs between each kind of cancer, but it certainly looks to be a significant factor.

In the case of pancreatic cancer, the researchers say that 77 percent of the mutations that cause tumours are due to random DNA copying mistakes, whereas 18 percent are down to environmental factors, with inherited genes accounting for the remaining 5 percent.

In other cancers – including prostate, brain, and bone cancer – the researchers found that 95 percent of cancer mutations are a result of cell division errors.

For some cancers, though, bad luck appears to play a smaller role.

In lung cancer, 65 percent of mutations are due to environment – such as smoking, or living in a polluted area – whereas DNA copying errors account for the other 35 percent, with heredity playing no role.

Overall, the team estimates that 66 percent of cancer mutations are due to random, unavoidable mistakes made during cell division, with 29 percent being attributable to environment, and 5 percent being inherited.

Despite the controversy that greeted their results last time, the authors say their findings actually complement the scientific consensus on cancer: that approximately 40 percent of cases can be prevented.

“We need to continue to encourage people to avoid environmental agents and lifestyles that increase their risk of developing cancer mutations,” says Vogelstein.

“However, many people will still develop cancers due to these random DNA copying errors, and better methods to detect all cancers earlier, while they are still curable, are urgently needed.”

Despite the sweeping nature of the new analysis, not everybody is convinced by the new findings.

Some researchers say it’s too simplistic to arbitrarily conclude that cancer as a whole can be divvied up neatly into three key categories – random mutations, environment, and heredity – arguing that the interplay between these factors could itself be another contributor.

“We’re not saying the only thing that determines the seriousness of the cancer, or its aggressiveness, or its likelihood to cause the patient’s death, are these mutations,” Vogelstein told Richard Harris at NPR.

“We’re simply saying that they are necessary to get the cancer.”

If the findings end up being accepted by other cancer researchers, the idea that randomness – in other words, bad luck – is more significant in causing cancer than other contributing factors could amount to what Tomasetti calls “a complete paradigm shift in how we think about cancer and what causes cancer”.

On one hand, it could make it easier for cancer patients and their families to process their diagnoses – especially in cases where conscious lifestyle choices (to not smoke, or to eat healthily) weren’t rewarded.

“They need to understand that these cancers would have happened no matter what they did,” Vogelstein told media at a press conference on Thursday.

“We don’t need to add guilt to an already tragic situation.”

The findings could also help steer research to investigate the biological processes behind random mutations that we don’t currently understand. While there’s nothing we can do to prevent natural DNA copying mistakes made at the cellular level today, that might not always be the case.

“Something we don’t consider a modifiable risk factor today might look modifiable in the future,” geneticist Paul Meltzer from the US National Cancer Institute’s Centre for Cancer Research, who wasn’t involved with the study, told the Los Angeles Times.

“What we call the ‘bad luck’ in the gene replication, we may have ways to reduce that in the future.”

The findings are reported in Science.

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