Doing the twist on damaged DNA – Simon Boulton wins the Paul Marks cancer research prize

Dr Simon Boulton in his lab at our London Research Institute

We’re happy to announce that our scientist Dr Simon Boulton has won the prestigious Paul Marks cancer research prize. It’s awarded by the Memorial Sloan Kettering Cancer Center in New York every two years to the brightest and best young scientists in the world, and he’s sharing it with Levi Garraway and DJ Pan.

We’ve funded Dr Boulton throughout his scientific career – except his post-doctoral work in the US – and he heads the DNA Damage Response lab at our London Research Institute Clare Hall Laboratory. We caught up with him for a chat to find out more about his life and work, and – perhaps surprisingly – discovered that his early brushes with science weren’t quite as successful as they are today.

Dr Boulton explains: “When I was at middle school, my science teacher told my parents ‘Make sure he doesn’t go into science because he’s no good at it’. Luckily, I then had a biology teacher who was passionate about the subject, and inspired me to pursue it for my degree.

“When I was a student at the University of Edinburgh, I discovered molecular biology. It was all quite new – this was the mid-nineties – and there were exciting papers coming out every week about genetic engineering and things like that. I became really fixated on it, and decided to go on to do a PhD.”

Luckily for Dr Boulton – just plain Simon back then – he was put in touch with an up-and-coming researcher called Dr Steve Jackson (now Professor) who’d just come back from working in the US at the University of California, Berkeley.

Dr Jackson set up a new lab in Cambridge at the Gurdon Institute, which is jointly funded by Cancer Research UK and the Wellcome Trust, focusing on how cells repair damage to their DNA. Unchecked DNA damage can lead to cancer, so understanding how it works – and what happens when it doesn’t – is vital if we’re to tackle the disease effectively.

Working in Professor Jackson’s lab sparked Dr Boulton’s interest in DNA damage and repair, which is still the area he focuses on with his own team. But after completing his PhD, he needed a change. The next destination was Harvard Medical School, where he worked on the cell cycle – the fundamental biological ‘engine’ in all living cells that makes them multiply. Yet he drifted back towards his earlier passion for DNA repair.

While at Harvard, Dr Boulton joined forces with another researcher, Marc Vidal, who was carrying out large-scale genetic experiments on tiny nematode worms called C. elegans. Together, they carried out a huge study to identify DNA damage genes in the worms, many of which turned out to be related to human genes involved in cancer.

The next step was to find out how they worked and what they were doing.

In 2002, Dr Boulton returned to the UK, where he had been offered the chance to set up his own lab at our Clare Hall campus, part of the prestigious Cancer Research UK London Research Institute.

“It was a great opportunity to come to Clare Hall. I’ve always been open to approaching a problem from a new perspective, and not being afraid to try something new. When I set up the lab, I wanted to go across different model organisms to answer questions about DNA repair, using worms, yeast and mammalian cells. We also use mouse models for the things you simply can’t do with worms, such as the impact of DNA damage on tumorigenesis – the process that leads to cancer.”

Over the past decade, Dr Boulton and his team have made a number of significant discoveries about some of the genes and molecules involved in repairing damage to DNA. In particular, his work has focused on a type of damage known as double-strand breaks, where the DNA ‘ladder’ is completely severed.

Double-strand breaks can be caused by a range of things, such as ionising radiation (e.g. X-rays), or simply stuff going wrong as a cell copies its DNA when it divides. But the breaks are extremely dangerous, as they can lead to the wrong bits of DNA getting stuck back together again when they’re repaired. This wreaks havoc within a cell, with important genes ending up in the wrong place where they can’t be controlled correctly.

Perhaps Dr Boulton’s biggest contribution to the field of cancer research has been uncovering and understanding the role of a molecule called RTEL1. This protein plays a vital role in controlling double-strand break repair.

He explains: “It acts a bit like a ‘reverse gear’ for the repair machinery – it allows cells to undo situations where they’re about to repair damage incorrectly. But there has to be a balance, as if there’s too much RTEL1, then it takes apart productive repair events and cells can’t repair their DNA properly. But if there’s not enough then the wrong DNA ends get ‘glued’ together, which is also very serious.”

But there have been many other discoveries too – Dr Boulton also studies molecules called helicases, which untwist and ‘unzip’ DNA so it can be copied and repaired, and has made significant findings about several of them.

He and his team are now starting to make chemicals that can block some of the molecules they’ve found, with the hope of developing new drugs for cancer. But it’s taken eight or nine years of painstaking hard work to get to this point.

It’s undeniable that the environment of the London Research Institute has been important for Dr Boulton’s success. He says: “Cancer Research UK has brought together some of the top people in the world here at Clare Hall. We can do science that’s very difficult to do anywhere else, underpinned by core funding from the charity.

“Even in the US, researchers are struggling. I think Cancer Research UK has done a remarkable job of continuing to fundraise and fund research, despite the economic crisis. And it’s the charity’s supporters that have been essential for this.”

Like most scientific research today, his work is highly collaborative – something that’s been helped along the way by his friends and colleagues. “Steve West has been like my scientific ‘father’ – a friend, mentor and colleague. The thing that keeps me motivated is the people I work with. I’m privileged to have a lab full of 14 smart people – scary smart! – and they’re fantastic.

“It doesn’t feel like work – it feels more like a hobby and I love it, although one problem is that I don’t switch off. Now I have kids they demand my full attention when I go home, but I’ll still wake up in the middle of the night with an idea for an experiment.”

As for the future, Dr Boulton’s appetite for research and finding new ways to tackle cancer shows no signs of diminishing. He says: “What motivates me and keeps me going with science is that you think you know something, and then you start digging and realise you don’t know anything. Things change very rapidly, which is what makes it so fun. Being in a great environment like the London Research Institute, or the Francis Crick Institute – where we’re moving to in 2015 – is really important.

Dr Boulton will be moving into the new Francis Crick Institute

“I’m excited by the potential for closer interactions with other Cancer Research UK scientists who will be moving there, as well as the people coming from other organisations. You can learn so much talking to developmental biologists, neurobiologists, immunologists and so on – people working in other fields that help to shed light on your own work.”

By winning the Paul Marks prize, Dr Boulton joins the ranks of the brightest young cancer researchers in the world, including fellow Clare Hall resident Dr John Diffley.  We’re immensely proud to have supported him for much of his scientific journey so far, and pleased he didn’t listen to his first science teacher. We look forward to seeing what he discovers in the future.

Kat

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Lawyer: Bradley Manning is doing well in prison

BALTIMORE A lawyer for Army Pvt. Bradley Manning, who now goes by the name of Chelsea Manning, said in a blog post on Thursday the soldier is doing well as he goes through processing at the military prison at Fort Leavenworth.

David Coombs wrote that he spoke on Wednesday with Manning while he goes through the three-to-four-week period known as indoctrination at the Kansas prison. Coombs, who lives in Rhode Island, also said he plans to travel there in the coming weeks to meet with medical staff and the leadership in the quest to allow Manning to receive hormone therapy and other treatment for his gender dysphoria -- the sense of being a woman trapped in a man's body.

Coombs went on the "Today" show last week, a day after Manning was sentenced to 35 years in prison for giving government secrets to WikiLeaks, to announce that Manning wants to live as a woman named Chelsea and begin hormone treatment as soon as possible.

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"These requests address a serious medical need of Chelsea and are consistent with the general medical community's practice of adequate medical care for those with gender dysphoria," Coombs wrote.

It is Army policy not to provide such treatment; soldiers diagnosed with gender dysphoria are administratively discharged. But Manning cannot be discharged until he completes his prison sentence and exhausts all appeals of his court-martial findings.

When asked by The Associated Press on Thursday whether Manning has yet requested treatment, Coombs said in an email it was too soon to provide additional information. He told the AP earlier in the week that if the Army refuses to pay for it, Manning would pay, but it is not clear whether the prison will allow that.

Army Medical Command spokeswoman Maria Tolleson said soldiers are allowed on a case-by-case basis to pay for procedures not covered by the military's medical insurance program, such as elective cosmetic surgery. Manning was diagnosed with gender dysphoria by two Army behavioral health specialists before his trial, but Tolleson said in an email that patient medical records are reviewed and prisoners are re-evaluated when they move to a new facility. She said Army providers use nationally recognized standards found in the current edition of the Diagnostic and Statistical Manual.

Play Video

Coombs wrote on his blog that he told Manning during their conversation Wednesday of the public's response to the "Today" show announcement, and of the decision by several news organizations, including AP, to refer to him by his new name.

"Chelsea was very happy to hear of these developments. She requested that I relay how grateful that she is for everyone's understanding and continued support," Coombs wrote.

Coombs also said Manning has already made some new friends at the prison "who accept her for who she is."

View the original article here

401(k) honchos could do better by doing less

(MoneyWatch) The 401(k) plan was introduced in 1981. By 2006, the total assets in these defined contribution plans had grown to over $1 trillion. The explosive growth has been fueled not only by the tax benefits they provide, but also by the demise of defined benefit plans -- the kind that many corporations had historically provided. Given the amount of assets in these plans, as well as the fact that for over 60 percent of participants their 401(k) plan represents their sole financial asset outside of bank accounts, the actions of plan administrators are vitally important.

Given the importance of these plans (and similar plans such as profit sharing plans), investors should be aware of how well plan administrators select mutual funds. The study "Participant Reaction and the Performance of Funds Offered by 401(k) Plans" provides us with insight to mutual fund selection and other questions to ponder.

The authors examined the performance of all 401(k) plans that filed 11-K reports in 1994 and used publicly available mutual funds as choices offered to participants. They traced the sample through 1999. This database provided a sample of 289 plan years, representing 43 plans, most of which had seven years of data. Over these 289 plan years, 215 funds were added and 45 were dropped. The following is a review of their findings.

Fund Selection Skills

On average, administrators select funds that outperform randomly selected funds of the same type. That provides an appearance of skill. However, because the alphas (performance versus benchmark) for the average plan were negative, performance would have improved if passive funds (such as index funds) had been substituted for the active funds that were selected. The outperformance versus the random sample is likely the result of the fact that plans generally choose only funds from well-known fund families with significant amount of assets under management. Mutual funds have economies of scale. Thus, funds with more assets can charge lower fees.

Please don't do something, stand still

It seems that plan administrators ignore the SEC disclaimer about past performance not being a predictor of future performance. As one would expect, when administrators change offerings, they choose funds that did well in the past. After all, who would choose a fund that had performed poorly? Funds that were added to plans had positive alphas for both one- and three-year periods prior to the change. And, unsurprisingly, managers fire poorly performing funds.

Funds that were dropped had negative alphas for both one- and three-year periods before they were dropped. The funds that were added had an alpha above those that were dropped of 2.8 percent per year for three years before the change and 2.3 percent in the year before the change (note the declining alpha). Unfortunately for investors, when a plan deleted a fund and replaced it with a fund with identical objectives, the deleted funds outperformed the ones they replaced by about 2.5 percent per annum over the next three years.

The authors also examined what happened when a plan replaced all of their offerings from one fund family and added funds from a new fund family. Not surprisingly, they found that the past Sharpe Ratios (a measure of return relative to risk) were higher for the portfolio of added funds than for the portfolio of dropped funds. After replacement, the future Sharpe Ratios were higher for the portfolio of dropped funds than for the funds that replaced them. Once again, inaction would have proved better for investors than action.

Do individual investors make rational decisions?

The authors found that investors in 401(k) plans were "returns chasers." Exhibiting a herd mentality, they increase cash flows to prior period top performers and decrease them to prior period underperformers. Instead of maintaining their portfolio allocations (by rebalancing their portfolios), they change their allocation decisions in a way that exacerbates the changes in allocation caused by returns.

Before concluding, it is worth noting that the findings of the study on the performance of 401(k) plans are very similar to the findings of studies on the performance of pension plans.

The performance of pension plans

The 2007 study, "The Performance of U.S. Pension Plans," covered 716 defined benefit plans (1992-2004) and 238 defined contribution plans (1997-2004). The authors found that their returns relative to benchmarks were close to zero. They also found that there was no persistence in pension plan performance. And they also concluded that "the striking similarities in performance patterns over time makes skill differences highly unlikely."

Another 2005 study, "The Selection and Termination of Investment Management Firms by Plan Sponsors," examined the selection and termination of investment management firms by plan sponsors (public and corporate pension plans, unions, foundations, and endowments). The authors, Amit Goyal and Sunil Wahal, built a dataset of the hiring and firing decisions by approximately 3,700 plan sponsors from 1994 to 2003. The following is a summary of their findings:2

Plan sponsors hire investment managers after large positive excess returns up to three years prior to hiring. The return chasing behavior does not deliver positive excess returns thereafter.Post-hiring excess returns are indistinguishable from zero.Plan sponsors terminate investment managers after underperformance, but the excess returns of these managers after being fired are frequently positive.If plan sponsors had stayed with the fired investment managers, their returns would have been larger than those actually delivered by the newly hired managers.

It is important to note that the above results did not include any of the trading costs that would have accompanied transitioning a portfolio from one manager's holdings to the holdings preferred by the new manager. As we saw was the case with 401(k) plans, all of the activity was counterproductive.

It is also important to keep in mind that these pension plans, because of their size, are generally able to negotiate significantly lower management fees than the fees paid by investors inside of 401(k) plans. Yet, even with the benefit of lower costs, the pension plans were unable to generate above market returns.

Conclusions

The study on 401(k) plans, the first of its kind, found that, in general, plan administrators are doing a very poor job of serving their clients. They make poor selection choices in the first place. Then they compound their mistakes when hiring and firing--the investors would have been better served if the plan administrators were "Rip Van Winkles," asleep and unable to make changes in plan offerings. And, investors in the plans compound the problems by chasing returns.

These findings demonstrate that investors would be better served if plan administrators limited their offerings to low-cost index funds and if investors put their portfolios on autopilot--setting the portfolio to rebalance on a regular (e.g., quarterly or annual) basis. As Pogo said: "We have met the enemy and he is us."

Image courtesy of Flickr user 401(K) 2013.

View the original article here

401(k) honchos could do better by doing less

(MoneyWatch) The 401(k) plan was introduced in 1981. By 2006, the total assets in these defined contribution plans had grown to over $1 trillion. The explosive growth has been fueled not only by the tax benefits they provide, but also by the demise of defined benefit plans -- the kind that many corporations had historically provided. Given the amount of assets in these plans, as well as the fact that for over 60 percent of participants their 401(k) plan represents their sole financial asset outside of bank accounts, the actions of plan administrators are vitally important.

Given the importance of these plans (and similar plans such as profit sharing plans), investors should be aware of how well plan administrators select mutual funds. The study "Participant Reaction and the Performance of Funds Offered by 401(k) Plans" provides us with insight to mutual fund selection and other questions to ponder.

The authors examined the performance of all 401(k) plans that filed 11-K reports in 1994 and used publicly available mutual funds as choices offered to participants. They traced the sample through 1999. This database provided a sample of 289 plan years, representing 43 plans, most of which had seven years of data. Over these 289 plan years, 215 funds were added and 45 were dropped. The following is a review of their findings.

Fund Selection Skills

On average, administrators select funds that outperform randomly selected funds of the same type. That provides an appearance of skill. However, because the alphas (performance versus benchmark) for the average plan were negative, performance would have improved if passive funds (such as index funds) had been substituted for the active funds that were selected. The outperformance versus the random sample is likely the result of the fact that plans generally choose only funds from well-known fund families with significant amount of assets under management. Mutual funds have economies of scale. Thus, funds with more assets can charge lower fees.

Please don't do something, stand still

It seems that plan administrators ignore the SEC disclaimer about past performance not being a predictor of future performance. As one would expect, when administrators change offerings, they choose funds that did well in the past. After all, who would choose a fund that had performed poorly? Funds that were added to plans had positive alphas for both one- and three-year periods prior to the change. And, unsurprisingly, managers fire poorly performing funds.

Funds that were dropped had negative alphas for both one- and three-year periods before they were dropped. The funds that were added had an alpha above those that were dropped of 2.8 percent per year for three years before the change and 2.3 percent in the year before the change (note the declining alpha). Unfortunately for investors, when a plan deleted a fund and replaced it with a fund with identical objectives, the deleted funds outperformed the ones they replaced by about 2.5 percent per annum over the next three years.

The authors also examined what happened when a plan replaced all of their offerings from one fund family and added funds from a new fund family. Not surprisingly, they found that the past Sharpe Ratios (a measure of return relative to risk) were higher for the portfolio of added funds than for the portfolio of dropped funds. After replacement, the future Sharpe Ratios were higher for the portfolio of dropped funds than for the funds that replaced them. Once again, inaction would have proved better for investors than action.

Do individual investors make rational decisions?

The authors found that investors in 401(k) plans were "returns chasers." Exhibiting a herd mentality, they increase cash flows to prior period top performers and decrease them to prior period underperformers. Instead of maintaining their portfolio allocations (by rebalancing their portfolios), they change their allocation decisions in a way that exacerbates the changes in allocation caused by returns.

Before concluding, it is worth noting that the findings of the study on the performance of 401(k) plans are very similar to the findings of studies on the performance of pension plans.

The performance of pension plans

The 2007 study, "The Performance of U.S. Pension Plans," covered 716 defined benefit plans (1992-2004) and 238 defined contribution plans (1997-2004). The authors found that their returns relative to benchmarks were close to zero. They also found that there was no persistence in pension plan performance. And they also concluded that "the striking similarities in performance patterns over time makes skill differences highly unlikely."

Another 2005 study, "The Selection and Termination of Investment Management Firms by Plan Sponsors," examined the selection and termination of investment management firms by plan sponsors (public and corporate pension plans, unions, foundations, and endowments). The authors, Amit Goyal and Sunil Wahal, built a dataset of the hiring and firing decisions by approximately 3,700 plan sponsors from 1994 to 2003. The following is a summary of their findings:2

Plan sponsors hire investment managers after large positive excess returns up to three years prior to hiring. The return chasing behavior does not deliver positive excess returns thereafter.Post-hiring excess returns are indistinguishable from zero.Plan sponsors terminate investment managers after underperformance, but the excess returns of these managers after being fired are frequently positive.If plan sponsors had stayed with the fired investment managers, their returns would have been larger than those actually delivered by the newly hired managers.

It is important to note that the above results did not include any of the trading costs that would have accompanied transitioning a portfolio from one manager's holdings to the holdings preferred by the new manager. As we saw was the case with 401(k) plans, all of the activity was counterproductive.

It is also important to keep in mind that these pension plans, because of their size, are generally able to negotiate significantly lower management fees than the fees paid by investors inside of 401(k) plans. Yet, even with the benefit of lower costs, the pension plans were unable to generate above market returns.

Conclusions

The study on 401(k) plans, the first of its kind, found that, in general, plan administrators are doing a very poor job of serving their clients. They make poor selection choices in the first place. Then they compound their mistakes when hiring and firing--the investors would have been better served if the plan administrators were "Rip Van Winkles," asleep and unable to make changes in plan offerings. And, investors in the plans compound the problems by chasing returns.

These findings demonstrate that investors would be better served if plan administrators limited their offerings to low-cost index funds and if investors put their portfolios on autopilot--setting the portfolio to rebalance on a regular (e.g., quarterly or annual) basis. As Pogo said: "We have met the enemy and he is us."

Image courtesy of Flickr user 401(K) 2013.

View the original article here

401(k) honchos could do better by doing less

(MoneyWatch) The 401(k) plan was introduced in 1981. By 2006, the total assets in these defined contribution plans had grown to over $1 trillion. The explosive growth has been fueled not only by the tax benefits they provide, but also by the demise of defined benefit plans -- the kind that many corporations had historically provided. Given the amount of assets in these plans, as well as the fact that for over 60 percent of participants their 401(k) plan represents their sole financial asset outside of bank accounts, the actions of plan administrators are vitally important.

Given the importance of these plans (and similar plans such as profit sharing plans), investors should be aware of how well plan administrators select mutual funds. The study "Participant Reaction and the Performance of Funds Offered by 401(k) Plans" provides us with insight to mutual fund selection and other questions to ponder.

The authors examined the performance of all 401(k) plans that filed 11-K reports in 1994 and used publicly available mutual funds as choices offered to participants. They traced the sample through 1999. This database provided a sample of 289 plan years, representing 43 plans, most of which had seven years of data. Over these 289 plan years, 215 funds were added and 45 were dropped. The following is a review of their findings.

Fund Selection Skills

On average, administrators select funds that outperform randomly selected funds of the same type. That provides an appearance of skill. However, because the alphas (performance versus benchmark) for the average plan were negative, performance would have improved if passive funds (such as index funds) had been substituted for the active funds that were selected. The outperformance versus the random sample is likely the result of the fact that plans generally choose only funds from well-known fund families with significant amount of assets under management. Mutual funds have economies of scale. Thus, funds with more assets can charge lower fees.

Please don't do something, stand still

It seems that plan administrators ignore the SEC disclaimer about past performance not being a predictor of future performance. As one would expect, when administrators change offerings, they choose funds that did well in the past. After all, who would choose a fund that had performed poorly? Funds that were added to plans had positive alphas for both one- and three-year periods prior to the change. And, unsurprisingly, managers fire poorly performing funds.

Funds that were dropped had negative alphas for both one- and three-year periods before they were dropped. The funds that were added had an alpha above those that were dropped of 2.8 percent per year for three years before the change and 2.3 percent in the year before the change (note the declining alpha). Unfortunately for investors, when a plan deleted a fund and replaced it with a fund with identical objectives, the deleted funds outperformed the ones they replaced by about 2.5 percent per annum over the next three years.

The authors also examined what happened when a plan replaced all of their offerings from one fund family and added funds from a new fund family. Not surprisingly, they found that the past Sharpe Ratios (a measure of return relative to risk) were higher for the portfolio of added funds than for the portfolio of dropped funds. After replacement, the future Sharpe Ratios were higher for the portfolio of dropped funds than for the funds that replaced them. Once again, inaction would have proved better for investors than action.

Do individual investors make rational decisions?

The authors found that investors in 401(k) plans were "returns chasers." Exhibiting a herd mentality, they increase cash flows to prior period top performers and decrease them to prior period underperformers. Instead of maintaining their portfolio allocations (by rebalancing their portfolios), they change their allocation decisions in a way that exacerbates the changes in allocation caused by returns.

Before concluding, it is worth noting that the findings of the study on the performance of 401(k) plans are very similar to the findings of studies on the performance of pension plans.

The performance of pension plans

The 2007 study, "The Performance of U.S. Pension Plans," covered 716 defined benefit plans (1992-2004) and 238 defined contribution plans (1997-2004). The authors found that their returns relative to benchmarks were close to zero. They also found that there was no persistence in pension plan performance. And they also concluded that "the striking similarities in performance patterns over time makes skill differences highly unlikely."

Another 2005 study, "The Selection and Termination of Investment Management Firms by Plan Sponsors," examined the selection and termination of investment management firms by plan sponsors (public and corporate pension plans, unions, foundations, and endowments). The authors, Amit Goyal and Sunil Wahal, built a dataset of the hiring and firing decisions by approximately 3,700 plan sponsors from 1994 to 2003. The following is a summary of their findings:2

Plan sponsors hire investment managers after large positive excess returns up to three years prior to hiring. The return chasing behavior does not deliver positive excess returns thereafter.Post-hiring excess returns are indistinguishable from zero.Plan sponsors terminate investment managers after underperformance, but the excess returns of these managers after being fired are frequently positive.If plan sponsors had stayed with the fired investment managers, their returns would have been larger than those actually delivered by the newly hired managers.

It is important to note that the above results did not include any of the trading costs that would have accompanied transitioning a portfolio from one manager's holdings to the holdings preferred by the new manager. As we saw was the case with 401(k) plans, all of the activity was counterproductive.

It is also important to keep in mind that these pension plans, because of their size, are generally able to negotiate significantly lower management fees than the fees paid by investors inside of 401(k) plans. Yet, even with the benefit of lower costs, the pension plans were unable to generate above market returns.

Conclusions

The study on 401(k) plans, the first of its kind, found that, in general, plan administrators are doing a very poor job of serving their clients. They make poor selection choices in the first place. Then they compound their mistakes when hiring and firing--the investors would have been better served if the plan administrators were "Rip Van Winkles," asleep and unable to make changes in plan offerings. And, investors in the plans compound the problems by chasing returns.

These findings demonstrate that investors would be better served if plan administrators limited their offerings to low-cost index funds and if investors put their portfolios on autopilot--setting the portfolio to rebalance on a regular (e.g., quarterly or annual) basis. As Pogo said: "We have met the enemy and he is us."

Image courtesy of Flickr user 401(K) 2013.

View the original article here