̽��ֱ�� of Cambridge - Academy of Finland

Genome-editing tool could increase cancer risk in cells, say researchers

cjb250 — Mon, 11 Jun 2018 15:00:48 +0000

̽��ֱ��team, led by Professor Jussi Taipale, now at the Department of Biochemistry, Cambridge, found that CRISPR-Cas9 triggers a mechanism designed to protect cells from DNA damage, making gene editing more difficult. Cells which lack this mechanism are easier to edit than normal cells. This can lead to a situation where genome-edited cell populations have increased numbers of cells in which an important mechanism protecting cells against DNA damage is missing.

Discovered in bacteria, the CRISPR-Cas9 system is part of the armoury that bacteria use to protect themselves from the harmful effects of viruses. Today it is being co-opted by scientists worldwide as a way of removing and replacing gene defects.

One part of the CRISPR-Cas9 system acts like a GPS locator that can be programmed to go to an exact place in the genome. ̽��ֱ��other part – the ‘molecular scissors’ – cuts both strands of the faulty DNA so that it can be replaced with DNA that does not have the defect.

However, in a study published today in the journal Nature Medicine, researchers found unexpected consequences from using CRISPR-Cas9.

“We managed to edit cancer cells easily, but when we tried to edit normal, healthy cells, very little happened,” explains Dr Emma Haapaniemi from the Karolinska Institutet, Sweden, the study’s first author.

“When we looked at this further, we found that cutting the genome with CRISPR-Cas9 induced the activation of a protein known as p53, which acts like a cell’s alarm system, signalling that DNA is damaged, and opens the cellular ‘first aid kit’ that repairs damage to the DNA. ̽��ֱ��triggering of this system makes editing much more difficult.”

In fact, this process went further, leading to the strong selection of cells that lacked the p53 pathway. Absence of p53 in cells makes them more likely to become tumorous as damage can no longer be corrected. Around a half of all tumour cells are missing this pathway.

“CRISPR-Cas9 is a very promising biological tool, both for research purposes and for potential life-saving medical treatments, and so has understandably led to great excitement within the scientific community,” says Professor Taipale, who led the work while at the Karolinska Institutet.

“We don’t want to sound alarmist, and are not saying that CRISPR-Cas9 is bad or dangerous. This is clearly going to be a major tool for use in medicine, so it’s important to pay attention to potential safety concerns. Like with any medical treatment, there are always side effects or potential harm and this should be balanced against the benefits of the treatment.”

̽��ֱ��team found that by decreasing activity of p53 in a cell, they could more efficiently edit healthy cells. While this might also decrease the risk of selecting for p53-deficient cells, it could leave cells temporarily vulnerable to mutations that cause cancer.

Professor Taipale says that once they better understand how the DNA response is triggered by the cut, it may be possible to prevent this mechanism kicking in, reducing the selective advantage of cells deficient in p53.

“Although we don’t yet understand the mechanisms behind the activation of p53, we believe that researchers need to be aware of the potential risks when developing new treatments,” he adds. “This is why we decided to publish our findings as soon as we discovered that cells edited with CRISPR-Cas9 can go on to become cancerous.”

̽��ֱ��research was supported by the Knut and Alice Wallenberg Foundation, Cancerfonden, Barncancerfonden and the Academy of Finland.

A second team in Novartis Research Institute in Boston, MA, has independently obtained similar results. They are also published today in the same journal.

Reference
Haapaniemi, E et al. CRISPR/Cas9-genome editing induces a p53-mediated DNA damage response. Nature Medicine; 11 June 2018; DOI: 10.1038/s41591-018-0049-z

More research needs to be done to understand whether CRISPR-Cas9 – molecular ‘scissors’ that make gene editing a possibility – may inadvertently increase cancer risk in cells, according to researchers from the ̽��ֱ�� of Cambridge and the Karolinska Institutet.

We don’t want to sound alarmist, and are not saying that CRISPR-Cas9 is bad or dangerous. This is clearly going to be a major tool for use in medicine, so it’s important to pay attention to potential safety concerns

Jussi Taipale

ulleo

Scissors cut metal

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Tired of London? Maybe it’s time to change postal districts

cjb250 — Mon, 12 Jan 2015 20:00:00 +0000

Between 2009 and 2011, the BBC collected data from almost 590,000 people as part of its Big Personality Test. An international team of researchers has analysed data from the subset of 56,000 Londoners to examine how associations between personality and life satisfaction differed across the 216 postal districts of Greater London. ̽��ֱ��results are published today in the journal Proceedings of the National Academy of Sciences.

“It’s very common for people to talk about where is the best place to live, but most research has tended to look at factors such as income and low crime rates, and only on a very broad geographical scale, failing to consider individual differences in personality,” says Dr Markus Jokela from the ̽��ֱ�� of Helsinki, Finland. “As a result, studies imply that all people would be equally happy in the same places. It’s a one-size-fits-all conclusion that, as we show, is misleading because one’s level of happiness is dependent on whether their environment is suited to their personality.”

̽��ֱ��researchers found geographical differences and clustering in levels of life satisfaction and certain personality traits. For example, people clustered around central and urban areas were the most open – and, to a lesser degree, the most extroverted – with levels decreasing when moving to outer regions. Areas of greater average openness also showed a mixture of neighbourhood characteristics, including higher population density and higher housing prices, higher ethnic and religious diversity, and higher crime rate. ̽��ֱ��findings support previous research showing that openness is associated with broad interests and tolerance for alternative lifestyles and ideas, and that these dispositions are often thought to characterize residents of densely populated urban areas.

Click on the images to expand

̽��ֱ��least agreeable areas were found in western central London, an area that has the highest crime rate, busiest pedestrian traffic, and some of the highest housing prices in the capital. ̽��ֱ��researchers believe this could be interpreted to support the popular notion that residents of big cities tend to be less considerate towards other people.

̽��ֱ��researchers found higher levels of life satisfaction in the most affluent regions of London and pockets of low life satisfaction in northwest, northeast, and south London. As with previous studies, the researchers found that people who were most emotionally stable and/or extroverted tended to have the greatest life satisfaction – and this was not affected by the area in which they lived.

Importantly, the researchers also showed that the strength of associations between personality traits and life satisfaction were dependent on neighbourhood characteristics. For example, in postal districts with higher extraversion, lower agreeableness and lower conscientiousness, people tended to show greater life satisfaction if they were more open to new experiences.

In areas that reported lower levels of life satisfaction, the most agreeable and conscientious tended to fare best – to be the most satisfied – suggesting that these personality traits are more important determinants of life satisfaction for individuals living in less favourable environmental circumstances.

Overall, the analysis of personality–neighbourhood interactions showed that openness to experience, agreeableness, and conscientiousness were differently associated with life satisfaction of individuals depending on their residential location and specific characteristics of those locations. This suggests that finding the best place to live will depend on the match between individual dispositions and neighbourhood characteristics.

“Together, these findings not only add to our understanding of the ways in which features of our personalities relate to our physical environments, but they also provide potentially useful information for choosing a place to live,” says Dr Jason Rentfrow from the Department of Psychology and a Fellow of Fitzwilliam College at the ̽��ֱ�� of Cambridge. “Granted, most people don’t have the luxury of complete control over where they live, but given their budgets, people can decide whether it’s more important to live in the centre of town, where daily life is vibrant and accommodation is small, or further out where daily life is slower but space is more plentiful. Making the decision that fits with your personality could have an effect on your overall life satisfaction.”

This study was funded by the Kone Foundation and the Academy of Finland.

“When a man is tired of London, he is tired of life,” observed the writer Samuel Johnson in the eighteenth century. In fact, research published today suggests such a man may be merely living in the wrong postcode. A study of 56,000 Londoners found that a person’s life satisfaction depends, at least in part, on whether their personality suits the place where they live.

Making the decision [on where to live] that fits with your personality could have an effect on your overall life satisfaction

Jason Rentfrow

Vadim Timoshkin

Way Out (cropped)

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Antipsychotic drugs linked to slight decrease in brain volume

cjb250 — Fri, 18 Jul 2014 18:00:00 +0000

As we age, our brains naturally lose some of their volume – in other words, brain cells and connections. This process, known as atrophy, typically begins in our thirties and continues into old age. Researchers have known for some time that patients with schizophrenia lose brain volume at a faster rate than healthy individuals, though the reason why is unclear.

Now, in a study published in the open access journal PLOS ONE, a team of researchers from the ̽��ֱ�� of Oulu, Finland, and the ̽��ֱ�� of Cambridge has identified the rate of decrease in both healthy individuals and patients with schizophrenia. They also documented where in the brain schizophrenia patients have more atrophy, and have examined links between atrophy and antipsychotic medication.

By comparing brain scans of 33 patients with schizophrenia with 71 control subjects over a period of 9 years – from age 34 to 43 – the researchers were able to show that schizophrenia patients lost brain volume at a rate of 0.7% each year. ̽��ֱ��control participants lost brain volume at a rate of 0.5% per year.

Scientists have previously speculated that antipsychotic medication used to treat schizophrenia may be linked to this decrease in brain volume. Today’s research confirms this association, showing that the rate of decrease in volume was greater when the dose of medication was higher. However, the mechanisms behind this – and whether it was in fact the medication that was causing this greater loss of tissue – are not clear. Some researchers have previously argued that whilst older antipsychotic medications might cause brain volume decreases, newer antipsychotic medications may protect against these decreases. However, today’s research suggests that both classes of antipsychotic medication are associated with similar declines in brain volume.

̽��ֱ��researchers also looked at whether there was any link between the volume of brain lost and the severity of symptoms or loss of cognitive function, but found no effect.

Professor Juha Veijola from the Department of Psychiatry at the ̽��ֱ�� of Oulu, Finland says: “We all lose some brain tissue as we get older, but people with schizophrenia lose it at a faster rate. We’ve shown that this loss seems to be linked to the antipsychotic medication people are taking. Research like this where patients are studied for many years can help to develop guidelines about when clinicians can reduce the dosage of antipsychotic medication in the long term treatment of people with schizophrenia.”

“It’s important to stress that the loss of brain volume doesn’t appear to have any effect on people over the nine year follow-up we conducted, and patients should not stop their medication on the basis of this research, ” adds Dr Graham Murray from the Behavioural and Clinical Neuroscience Institute and the Department of Psychiatry at ̽��ֱ�� of Cambridge. “A key question in future will be to examine whether there is any effect of this loss of brain volume later in life. We need more research in larger studies with longer follow-ups to evaluate the significance of these brain changes.”

̽��ֱ��research was supported by the Academy of Finland, Medical Research Council, Sigrid Jusélius Foundation, and the Brain and Behavior Research Foundation.

A study published today has confirmed a link between antipsychotic medication and a slight, but measureable, decrease in brain volume in patients with schizophrenia. For the first time, researchers have been able to examine whether this decrease is harmful for patients’ cognitive function and symptoms, and noted that over a nine year follow-up, this decrease did not appear to have any effect.

̽��ֱ��loss of brain volume doesn’t appear to have any effect on people, and patients should not stop their medication on the basis of this research

Graham Murray

Adrian Cousins, Wellcome Images

Schizophrenia - hearing voices (Artist's illustration)

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