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Wealth Managers Belie Gloomy Cliches
Wayne Warner hasn't rushed onto retirement.
But the 83-year-old majority owner of Wayne Warner & Associates, a registered investment adviser in Fallbrook, Calif., has long known that his sudden death or incapacitation would disconcert his clients and double the workload of his business partner, Jayne Byrne.
So the man who helps clients fund comfortable retirements has been getting ready for his own, planning for a partial sale of the business he has been building since the mid-1960s.
Warner and others like him can take comfort from a growing sense that the market for independent RIA sales has improved. "We're definitely seeing more activity" as a nascent economic recovery prompts RIAs that kept quiet in dark days of 2008 and 2009 to come looking for buyers, said Lawrence Hughes, head of Bank of New York Mellon's (BK) wealth-management division.
There are those who question the value of an independent advisory business of WWA's small size. It manages around $85 million.
This makes it a "have not" outfit, according to "Back to the Future," a 2005 white paper on the market for registered investment advisers. These small firms compensate their owners well enough, but lack capital to accelerate growth or respond nimbly to changes in the marketplace by investing in new technologies and dealing with more stringent compliance, the paper argued.
And according to a 2010 paper called "Creating, Measuring and Unlocking Enterprise Value in a Wealth Manager" by RIA equity backer Fiduciary Network, only 200 to 400 of the 25,000 RIAs in existence "possess the potential to build material enterprise value."
Warner and Byrne disagree. "The misconception is that small advisory firms are in this for the money," said Byrne. "We make a good living for ourselves and our families–but the other aspect is that this is an exciting business, and people really need our help."
In 2007, the partners started planning in earnest for the founder's departure. WWA had been courted by so-called rollup firms, but it wanted to sell only Warner's piece of the business and have Byrne, 35 years his junior, stay on as lead partner. They also wanted an ownership that still emphasized client service. So they focused on like-sized firms run by independent, experienced principals who emphasize financial planning.
Now, capping a search that was prolonged not by the downturn but the partners' desire to vet as many candidates as possible, WWA is closing on a deal with a pair of local advisers. They are roughly Byrne's age, and would buy Warner's shares in the firm over several years as he transitions out of the business.
BNY Mellon's Hughes said the RIA market is improving not just because retirement-age and recession-weary owners are anxious to cash in on stronger valuations. Many owners would also rather sell than pay for the improvements needed to compete in a marketplace where clients want more services from their advisers and where regulation is getting tighter.
But investment banker Daniel Seivert isn't sure BNY Mellon has an accurate read. BNY Mellon is one of the past decade's busiest wealth-firm acquirers, so it makes sense that it would hear from firms that are feeling shaky and looking for the kind of upgrades it can provide.
The easy profits and growth of the mid-2000s may have disappeared, "but it's unbelievable how many firms grew in 2008 and 2009," said Seivert, CEO of Los Angeles-based Echelon Partners. "A lot are cash cows run by guys in their seventies who love their jobs," he added.
Thomas Coyle is a special writer with Dow Jones who covers the wealth-management industry.


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Chuck White (Super Pro) and Tim Zyla (Pro) Notch Their Second Wins of the Season!
Hot weather has invaded the Southern Tier and Saturday was no exception as a blazing hot sun blistered Rumble Ridge for the Mid-Season Championships held on July 16, 2011 at Skyview Drags. With an entire day filled with double points races on the line, racers filled the pits to take their shot at the top money and to add to their points as the standings in each class tighten up for the second half of the season.
The day started off with the Precision Crankworks Junior Dragster class, where 16 young racers filled the field. In the Second Chance Race, non-winners of Round 1 Eliminations get additional seat time and the chance to continue racing for bragging rights. The finals pitted rookie driver Faith Peckham from Oriskany Falls, NY against 15-year old Kimberly Klein from Livingston Manor, NY. In her first ever final round, Peckham proved her mettle as she cut a .5367 reaction time against Klein's .6080 light. Peckham ran an 8.9932 ET at 70.18 mph on her 8.97 dial to take the win over Klein's 8.9932 ET at 80.84 mph on her 8.97 dial. In Junior Dragster Eliminations, 2 of the youngest racers in the field showed their stuff as they worked their way through the pack and made it to the final round. Twelve year old Ron Klein from Livingston Manor, NY faced 11-year old Morgan Burgess out of Canton, PA who was making her first ever finals appearance. Earlier in the day, Burgess won the iPod Shuffle presented by Dave Connor, who races his 'Slingshot One" front-engine dragster in Pro Class. Connor, who tows in from Camptown, PA generously donate the gift for the Junior Program. Burgess hoped her lucky day would continue as she staged her car against Klein in the finals. But the ever tough Klein would have a nice .5530 reaction time right out of the gate to Burgess' .6630 light. Burgess ran a 10.9311 at 56.87 mph on her 11.10 dial and broke out. Klein ran a 9.2028 at 71.13 mph on his 9.16 dial to take the win light.
In the Super Pro class, the fastest cars take to the lanes to vie for the $900 top prize money. The field started off with 16 racers in their beautiful dragsters, altereds and door slammers. Chuck White, who races out of Ontario, NY had the worst luck in Round 1 Eliminations. He lined up against the altered of Chet Dragon and lost by .0000 at the stripe. "Who loses by .0000?" exclaimed White. Hoping that his bad luck had run its course, White bought back and made it through the Buy Back round to get back into eliminations. Meanwhile, just up pit row, point's leader Kathy Kiekel from Binghamton, NY was struggling to find her rhythm. "I went a .497 red in my first time trial so I rolled 10 in the box and then proceeded to go a .494 red in my second time trial," sighed Kiekel. The lights continued to give Kiekel trouble in eliminations but Lady Luck shined on her and by the quarterfinals Kiekel was one of the 6 cars that were left. "My husband leaned into my truck in the staging lanes and said, 'Now is the time to find it Kathy. You want that Bye run into the finals with only 3 cars left.' Talk about pressure," she laughs. Kiekel was the first pair out and once her win light came on, she had to wait to see if her run was good enough to earn her the bye into the final round. "A race is over in 5-6 seconds, but it seemed like I was waiting an eternity for Don to get back from watching the other two races," said Kiekel. Kiekel's husband, currently tied with her for the point's lead, finally wheeled back into the pits to tell her that she was the bye run in the semi-finals. "My little S10 was doing its job all day," said Kiekel. Now it's time for the driver to work some magic. Chuck White and his Malibu would face the 2010 Miller dragster of Russ Denmark out of Ovid, NY. White took the win out of the right lane and Kiekel took her solo pass down the left lane. The finals were set with White facing Kiekel. "I'm dialed a 6.66 for the finals," said White. "And I'm being chased by an ordained minister with the flames of hell painted on her truck! This is going to be a great race." White's slower dialed Malibu took off first with Kiekel giving chase. White had a .5178 reaction time to Kiekel's best of the day .5037 reaction. Kiekel ran a 6.0591 on her 6.03 dial and White ran a 6.6713 on his 6.66 dial. In the end, the margin of victory was a mere .003 in White's favor as he earned his second win at Skyview this season.
In the Pro class, 32 modified cars filled the field looking for their chance at the $900 top prize money. Current point's leader, rookie Tim Zyla out of Sayre, PA and second place point's racer, 2010 Pro Class Rookie of the Year Steve Cross from Friendsville, PA had their eyes set on the prize money and the double points. "This is the time you want everything working perfectly," said Cross. "I need to focus today and just do my job," added Zyla. Both racers worked their way through the pack and in the end, the final round would feature their dueling Camaros. Zyla had the advantage off the starting line with a .5628 reaction time to Cross' .6219 but both race cars would break out by running under their dial ins. Cross ran a 6.3352 ET on his 6.39 dial while Zyla ran a 6.3191 on his 6.33 dial in to take the win light. This was Zyla's second win of the season. "I tried to stay focused the entire day and do everything I was supposed to," said Zyla. "I had good lights all day and the Manley Houghtalen owned Camaro was doing its job as well. I had just run a 6.36 the prior run so I don't know where that 6.31 came from, but I broke out by less than Steve so Lady Luck played her part in this win as well." Mel Teed from Friendsville, PA was the semi-finalist in her Olds Cutlass 442.
In the Bike/Sled class, 15 motorcycle and snowmobile racers lined the staging lanes at the start of the race. Kenny Dolatowski tows his sled from Camillus, NY and Brent Garcia brings his Buell bike in from Cincinnatus, NY. The long tows for both racers proved to be a good omen as they met in the final round. Garcia, dialed in at a 6.92 would leave first with Dolatowski, dialed in at a 6.24 giving chase. Garcia had a .6327 reaction time but Dolatowski was too eager to chase him down and went red off the starting line, handing the win over to Garcia. Garcia is the 2010 Bike/Sled class defending champion. Boyd McGarry was the semi-finalist.
In the Street Money class, 21 racers were looking to improve their point standings and earn the $200 top prize money. Charlie Fulmer and current point's leader Howie Conklin, from Grahamsville, NY seem to enjoy racing each other in the finals and this race would see them lined up against each other once again. Conklin had a .6648 reaction time and ran an 8.4932 on his 8.47 dial in. Fulmer had a very good .5268 reaction time and ran an 8.9392 on his 8.78 dial in to earn his second win of the season and of his career. Matt Peterson from Spencer, NY and Joe Patelunas from Elmira, NY were semi-finalists.
In the Street Trophy class, 8 racers vied for the trophy and bragging rights for the week. Current point's leader Howie Conklin worked his way through the field and faced Shanon Fenton from Laceyville, PA in the finals. Conklin's Strip Blazer II Malibu would take the win light as he ran an 8.4843 on his 8.47 dial in. The Mustang of Fenton was too fast as it ran a 7.9168 on a 7.98 dial trying to run down Conklin, who had a significant starting line advantage with his reaction time.
In the Teen Championship Racing (TCR) class, open to all 13-17 year olds who take to the track in their family car with a parent/guardian riding in the passenger's seat to help coach them, Brandon Searcy from Waverly, NY faced Teresa Kurtz from Richford, NY. Searcy had a stellar .5147 reaction time to take the win.
Skyview Drags also welcomed back Northeast Open Comp to the track. Kenneth Roberts from Ulster, PA continued to dominate in this class as he drove his USS Nemesis to earn a win over Larry Carasea and his beautiful Camaro from Vestal, NY. Roberts had a .6098 reaction time and ran a 9.6750 on his 9.66 dial. Carasea jumped the gun just a bit when he went red and ended his chances for a win.
The track will be open for Test & Tune on Friday, July 22 but will be closed for racing on Saturday, July 23, 2011. Skyview Drags will reopen for Test & Tune on Friday, July 29 and then will hold a regular point's race on Saturday, July 30, 2011. Visit www.skyviewdrags.com for their complete schedule and racing information.
Pictures taken by Jason Auman. Visit www.jasonauman.smugmug.com to see his complete gallery of Skyview racing pictures available for purchase

subset: commoncrawl


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As a member, regardless of your age or years of service credit, you may apply for disability retirement if you are mentally or physically disabled from the further performance of your duty, and your disability is probably permanent. The TRS Medical Board must certify your disability. To certify a disability, the Medical Board reviews information provided by the member and the member's physician, along with clinical evidence such as medical history, diagnostic tests, and laboratory results.
If you qualify for disability retirement and have at least 10 years of service credit, you are entitled to a monthly annuity that is not reduced due to early age. If you have less than 10 years of service credit, TRS provides a monthly disability retirement benefit of $150 that is payable for the lesser of the number of months you have been covered by TRS, the duration of your disability, or your lifetime.
For additional information, please refer to the TRS Benefits Handbook. To request an estimate and application packet for disability retirement, complete and mail to TRS a Request for Estimate of Retirement Benefits form (TRS 18) (pdf).
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Binomial Nomenclature
This is the way in which organisms have been classified over time, with most organisms being described in either greek or latin. Although latin is now a defunct language, classification of organisms are still being classified with this language. An example of the language used is yucca filamentosa, a plant of the yucca genus and the unique filamentosa species.
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Natural Gas STAR Service Provider Directory
Sulphur Experts Inc.
- Contact:
- Jamie Swallow (email@example.com)
- Address:
- 12 Manning Close N.E
Calgary, Alberta T2E 7N6, Canada
- Tel:
- (281) 229-5054
- Website:
- www.sulphurexperts.com
Sulphur Experts has been providing solutions to sulphur plant problems for more than 30 years under the internationally-recognized name - Western Research. Sulphur Experts Inc. is an independent process engineering company reflecting our focus on the sulphur plant. The company comprises the same engineers and technologists, products and services previously marketed through the process engineering group of BOVAR Western Research, and has continued the tradition of providing quality process engineering consulting and sulphur plant testing to the oil refining and natural gas processing industries.


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Ming-Tzu @ 10:07 pm
Nov 16, 2010
Immortal Technique killed it but best performance of the night goes to Cold Crush Brothers and Big Daddy Kane! Close runner-up goes to the reunion of the Fantastic Romatic Five.
PS: That was an obvious jab at Solar right?
It's not that serious. Or is it?
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Eastern States: Filing of Plat of Survey
Notice Of Filing Of Plat Of Survey; Minnesota.
The Bureau of Land Management (BLM) will file the plat of survey of the lands described below in the BLM-Eastern States, Springfield, Virginia, 30 calender days from the date of publication in the Federal Register.
Table of Contents Back to Top
FOR FURTHER INFORMATION CONTACT: Back to Top
Bureau of Land Management, 7450 Boston Boulevard, Springfield, Virginia 22153. Attn: Cadastral Survey.
SUPPLEMENTARY INFORMATION: Back to Top
This survey was requested by the Bureau of Indian Affairs.
The lands we surveyed are:
Fifth Principal Meridian, Minnesota
The plat of survey represents the dependent resurvey of a portion of the south and west boundaries and a portion of the subdivisional lines; and the survey of the subdivision of sections 2, 4, 11, 13-15, 18-28, and 32-36, Township144 North, Range 39 West, of the Fifth Principal Meridian, Minnesota, and was accepted November 17, 2004. We will place a copy of the plat we described in the open files. It will be available to the public as a matter of information.
If BLM receives a protest against this survey, as shown on the plat, prior to the date of the official filing, we will stay the filing pending our consideration of the protest.
We will not officially file the plat until the day after we have accepted or dismissed all protests and they have become final, including decisions on appeals.
Dated: November 17, 2004.
Stephen D. Douglas,
Chief Cadastral Surveyor.
[FR Doc. 04-26801 Filed 12-6-04; 8:45 am]


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I don't really feel like posting much these days. Maybe it is because I am about to pop out a human and all I can think about is organizing the house or baking cookies? Maybe it is lack of sleep? Sleep is much harder to come by when your organs are pushed into places they shouldn't be and you have a person beating you up from the inside.
Luckily, I figured out the perfect Continue reading


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Former C4 Popworld presenter, host of The Morning After Show and Mardi Gras comedy competition finalist. Simon has won an RTS Award for his work on Never Mind The Buzzcocks as well as a Broadcast Award, two British Comedy Awards and was most recently nominated for a BAFTA.
He left BBC2's Never Mind The Buzzcocks to concentrate on his live stand-up shows across the country, so expect to see a lot more of him in future.
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Open May 1 - October 10
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Arsenal Message Board
Is this a fair reflection on our tranfer activities?
Arsenal: Taking advantage of Malaga's financial struggles once again, Nacho Monreal should be a good replacement for injured Kieran Gibbs but other than that this was a woeful window for the Gunners.
After promising the sun and the moon to the disgruntled fans, it is clear that Arsenal's management has only one thing on its mind: its profit margin. It's understandable that the club wants to remain financially stable as Financial Fair Play kicks into effect in the near future, but there were plenty of bargains to be found in this market.
Ba, one of the elite strikers in the Premier League, was available for under 10 million pounds, and Remy was available at only 8 million pounds. Olivier Giroud might be showing positive signs recently but the club continues to underwhelm with its bench options. To add further insult to injury, Yann M'Villa, a long time target of Arsene Wenger, was available for only 9.6 million pounds and ended up in Russia. For a club that has desperately lacked steel in its midfield, acquiring the French international could have made a huge difference.
With Tottenham looking stronger each game and Liverpool adding big time young players, this might be the season where things unravel and Arsenal could miss the Champions League. If that happens, Wenger could be the unfortunate fall guy.
http://ph.news.yahoo.com/winners-losers-januarys-transfer-window-090000453--mls.htmlSort: Newest | Oldest | Most Replied Expand all replies
Wenger is everything a clubs board would want in a manager, he makes the CL every season, he makes them money, he doesn't bad mouth them, he is very secretive and he takes the flack for them.
I just can't see him being replaced, unless it's his wish!
I think we are all disapointed we didn't bring in more players to help fight for that 3/4th spot and whilst Nacho Man seems like a very good addition we will still see Per Merts in the middle of the park, and on his present form is bloody worrying.
If Arsen doesn't bring in these hi quality players in the summer after giving the word he has the money to spend but just not the right time, then he will be absolutely slaughtered and even the faithful will turn of which I'm sure!
The boundaries are being tested more than ever. We may have to rely on luck (or lack of it for Liverpool & Spurs) in order to even qualify for the CL next year. We simply do not have the depth of quality in the squad to win it, let alone the EPL.
I'm not sure if Wenger will be asked to fall on his sword, but Kroenke should be more vocal in the level of support he is giving to Wenger to improve the team.
- 2 Replies to John
The problem with Kroenke (or one of them at least) is that he's not vocal at all.
We don't hear anything from him about his vision for Arsenal and what the club is tryuing to achieve.
As other posters on here have alluded to, this just seems to reaffirm that whilst the club is making money for him he doesn't give a sh*t.
FABONGRASSS FABONGRASSS Feb 1, 2013 16:49 Flag
'I'm not sure if Wenger will be asked to fall on his sword'
You really are in cloud cuckoo land.
"Arsenal could miss the Champions League. If that happens, Wenger could be the unfortunate fall guy."
.....but only if he doesn't win it. Think Chelsea eg.....No??
There's always the CWCup. Or Europa. Whats the problem. Bums on seats isnt it?
- 1 Reply to JamesB
William Guy William Guy Feb 1, 2013 20:11 Flag
"There's always the CWCup" - huh - didnt that finished in 1998–99


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SKU FRM-65395-C Color Blue Age 12-18 years, 18+ Age Group Adult, Teen Size Chart http://www.toynk.com/forum/ UPC 721773653957 Manufacturer Forum Novelties
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Marching to Our Own Sequences
Imagine being asked to copy a library of books. Doing it yourself would take forever. You'd probably call some friends and come up with a plan to divide and conquer.
That's what a human cell does when faced with the task of replicating six billion letters of DNA each time it divides. Instead of reading each chromosome in one slow pass, DNA replication machinery dives in at many origin points. Some segments get copied earlier or later than others.
A new study from geneticists at Harvard Medical School and the Broad Institute of Harvard and MIT has found that this replication plan—including where the origin points are and in what order DNA segments get copied—varies from person to person.
The study, published online Nov. 13 in Cell, also identifies the first genetic variants that orchestrate replication timing.
"Everyone's cells have a plan for copying the genome. The idea that we don't all have the same plan is surprising and interesting," said Steven McCarroll, assistant professor of genetics at HMS, director of genetics for the Stanley Center for Psychiatric Research at the Broad and senior author of the paper.
"It's a new form of variation in people no one had expected," said first author Amnon Koren, postdoctoral fellow at HMS and the Broad. "That's very exciting."
Hidden orchestrator
DNA replication is one of the most fundamental cellular processes, and any variation among people is likely to affect genetic inheritance, including individual disease risk as well as human evolution, the authors said.
It's been known that replication timing affects mutation rates; DNA segments that are copied late or too early tend to have more errors. The new study indicates that people with different timing programs therefore have different patterns of mutation risk across their genomes.
For example, McCarroll's team found that differences in replication timing could explain why some people are more prone than others to certain blood cancers.
Researchers had previously known that acquired mutations in the gene Janus kinase 2, or JAK2, lead to these cancers. They had also noticed that people with such JAK2 mutations tend to have a distinctive set of inherited genetic variants nearby, but they weren't sure how the inherited variants and the new mutations were connected. McCarroll's team found that the inherited variants are associated with an "unusually early" replication origin point and proposed that JAK2 is more likely to develop mutations in people with that very early origin point.
"Replication timing may be a way that inherited variation contributes to the risk of later mutations and diseases that we usually think of as arising by chance," said McCarroll.
Untapped riches
McCarroll, Koren and colleagues were able to make these discoveries in large part because they invented a new way to obtain DNA replication timing data. Turned out, it was hiding in plain sight.
Until now, to study replication timing, scientists needed to painstakingly "grow cells for a couple of weeks and sort them with a special machine and do a big, complicated, expensive, time-consuming experiment"—all to obtain material from just a few people at a time, said Koren.
The team suspected there was an easier way. They turned to the 1000 Genomes Project, which maintains an online database of sequencing data collected from hundreds of people around the world.
Because much of the DNA in the 1000 Genomes Project had been extracted from actively dividing cells, the team hypothesized that information about replication timing lurked within.
They were right. They counted the number of copies of individual genes in each genome. Because early replication origins had created more segment copies at the time the sample was taken than late replication origins had, they were able to create a personalized replication timing map for each person.
"People had seen these patterns before, but just dismissed them as artifacts of sequencing technology," said McCarroll. After conducting numerous tests to rule out that possibility, "we found that they reflect real biology."
The researchers then compared each person's copy number information with his or her genetic sequence data to see if they could match specific genetic variants to replication timing differences. From 161 samples, they identified 16 variants. The variants were short, and most were common.
"I think this is the first time we can pinpoint genetic influences on replication timing in any organism," said Koren.
The variants were located near replication origin points, leading the team to wonder if they affect replication timing by altering where a person's origin points are. They also suspect that the variants work by altering chromatin structure, exposing local sequences to replication machinery. The team intends to find out. They also want to search for additional variants that control replication timing.
"These 16 variants are almost certainly just the tip of the iceberg," said Koren.
The door is open
As more variants come to light in future studies, researchers will be better able to manipulate replication timing in the lab and learn more about how it works and what its biological significance is.
Such studies should flourish now that the team has shown that "all you need to do to study replication timing is grow cells and sequence their DNA, which everyone is doing these days," said Koren. The new method "is much easier, faster and cheaper, and I think it will transform the field because we can now do experiments in large scale."
"We found that there is biological information in genome sequence data," added McCarroll. "But this was still an accidental biological experiment. Now imagine the results when we and others actually design experiments to study this phenomenon."
This research was funded by the National Human Genome Research Institute (R01 HG 006855), the Integra-Life Seventh Framework Programme (grant #315997), the Stanley Center for Psychiatric Research, the Howard Hughes Medical Institute and the Harvard Stem Cell Institute.
New Branch Added to European Family Tree
The setting: Europe, about 7,500 years ago.
Agriculture was sweeping in from the Near East, bringing early farmers into contact with hunter-gatherers who had already been living in Europe for tens of thousands of years.
Genetic and archaeological research in the last 10 years has revealed that almost all present-day Europeans descend from the mixing of these two ancient populations. But it turns out that's not the full story.
Researchers at Harvard Medical School and the University of Tübingen in Germany have now documented a genetic contribution from a third ancestor: Ancient North Eurasians. This group appears to have contributed DNA to present-day Europeans as well as to the people who travelled across the Bering Strait into the Americas more than 15,000 years ago.
"Prior to this paper, the models we had for European ancestry were two-way mixtures. We show that there are three groups," said David Reich, professor of genetics at HMS and co-senior author of the study.
"This also explains the recently discovered genetic connection between Europeans and Native Americans," Reich added. "The same Ancient North Eurasian group contributed to both of them."
The research team also discovered that ancient Near Eastern farmers and their European descendants can trace much of their ancestry to a previously unknown, even older lineage called the Basal Eurasians.
The study was published online Sept. 17 in Nature.
Peering into the past
To probe the ongoing mystery of Europeans' heritage and their relationships to the rest of the world, the international research team—including co-senior author Johannes Krause, professor of archaeo- and paleogenetics at the University of Tübingen and co-director of the new Max Planck Institute for History and the Sciences in Jena, Germany—collected and sequenced the DNA of more than 2,300 present-day people from around the world and of nine ancient humans from Sweden, Luxembourg and Germany.
The ancient bones came from eight hunter-gatherers who lived about 8,000 years ago, before the arrival of farming, and one farmer from about 7,000 years ago.
The researchers also incorporated into their study genetic sequences previously gathered from ancient humans of the same time period, including early farmers such as Ötzi "the Iceman."
"There was a sharp genetic transition between the hunter-gatherers and the farmers, reflecting a major movement of new people into Europe from the Near East," said Reich.
Ancient North Eurasian DNA wasn't found in either the hunter-gatherers or the early farmers, suggesting the Ancient North Eurasians arrived in the area later, he said.
"Nearly all Europeans have ancestry from all three ancestral groups," said Iosif Lazaridis, a research fellow in genetics in Reich's lab and first author of the paper. "Differences between them are due to the relative proportions of ancestry. Northern Europeans have more hunter-gatherer ancestry—up to about 50 percent in Lithuanians—and Southern Europeans have more farmer ancestry."
Lazaridis added, "The Ancient North Eurasian ancestry is proportionally the smallest component everywhere in Europe, never more than 20 percent, but we find it in nearly every European group we've studied and also in populations from the Caucasus and Near East. A profound transformation must have taken place in West Eurasia" after farming arrived.
When this research was conducted, Ancient North Eurasians were a "ghost population"—an ancient group known only through the traces it left in the DNA of present-day people. Then, in January, a separate group of archaeologists found the physical remains of two Ancient North Eurasians in Siberia. Now, said Reich, "We can study how they're related to other populations."
Room for more
The team was able to go only so far in its analysis because of the limited number of ancient DNA samples. Reich thinks there could easily be more than three ancient groups who contributed to today's European genetic profile.
He and his colleagues found that the three-way model doesn't tell the whole story for certain regions of Europe. Mediterranean groups such as the Maltese, as well as Ashkenazi Jews, had more Near East ancestry than anticipated, while far northeastern Europeans such as Finns and the Saami, as well as some northern Russians, had more East Asian ancestry in the mix.
The most surprising part of the project for Reich, however, was the discovery of the Basal Eurasians.
"This deep lineage of non-African ancestry branched off before all the other non-Africans branched off from one another," he said. "Before Australian Aborigines and New Guineans and South Indians and Native Americans and other indigenous hunter-gatherers split, they split from Basal Eurasians. This reconciled some contradictory pieces of information for us."
Next, the team wants to figure out when the Ancient North Eurasians arrived in Europe and to find ancient DNA from the Basal Eurasians.
"We are only starting to understand the complex genetic relationship of our ancestors," said co-author Krause. "Only more genetic data from ancient human remains will allow us to disentangle our prehistoric past."
"There are important open questions about how the present-day people of the world got to where they are," said Reich, who is a Howard Hughes Medical Investigator. "The traditional way geneticists study this is by analyzing present-day people, but this is very hard because present-day people reflect many layers of mixture and migration.
"Ancient DNA sequencing is a powerful technology that allows you to go back to the places and periods where important demographic events occurred," he said. "It's a great new opportunity to learn about human history."
This project was supported in part by the National Cancer Institute (HHSN26120080001E and NIH/NCI Intramural Research Program), National Institute of General Medical Sciences (GM100233 and GM40282), National Human Genome Research Institute (HG004120 and HG002385), an NIH Pioneer Award (8DP1ES022577-04), National Science Foundation (HOMINID awards BCS-1032255 and BCS-0827436 and grant OCI-1053575), Howard Hughes Medical Institute, German Research Foundation (DFG) (KR 4015/1-1), Carl-Zeiss Foundation, Baden Württemberg Foundation and the Max Planck Society.
Genes and Immunity
Researchers from Harvard Medical School and the Broad Institute of MIT and Harvard have uncovered unexpectedly complex patterns in the T lymphocyte responses that individual people mount, reflecting environmental influences as well as a genetic component. The study lays the groundwork for further explorations into the relative contributions of genes and their environment on immunological processes, the scientists said, which could illuminate autoimmune disease and its genetic underpinnings.
The findings are reported in Science and stem from the ImmVar Project, a wide-ranging analysis of variation in gene expression in the immune system. Christophe Benoist, Morton Grove-Rasmussen Professor of Immunohematology at HMS, and Aviv Regev, a Broad Institute core member, an associate professor at MIT, and Howard Hughes Medical Institute investigator, led the third and final phase, which focused on CD4+ T cells, immune cells that are major players in autoimmune disease.
In this study, after the scientists accounted to the best possible extent for environmental influences and immunological history, they still found that the ancestry of the donor significantly affected T cell responses. "There is a signature of variation in adaptive immune response," Benoist said. "In general, there is stronger activation of some genes in people of African ancestry, in particular for a type of response in T helper 17 (Th17) cells that tend to protect us from microbes that enter airways or the intestinal tract. Those responses are also highly involved in autoimmune disease."
"The combination of careful immunological work, high-throughout assays, and sophisticated analytics essential to dissect such a complex system could only have happened within the partnership of the ImmVar consortium, bringing together the expertise of immunologists and clinicians in the Harvard-affiliated hospitals with genomics and computational experts at the Broad and MIT," Regev said.
In autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease and multiple sclerosis, immune cells mistakenly attack the body's own tissues as if they were invaders. In healthy people, the immune system achieves a state of tolerance, quelling defensive measures after a threat has abated.
Scientists have previously identified genes that are important in controlling the autoimmune response, but this is the first time that differences in T cell activation between population groups have been revealed.
In the current study, the scientists analyzed blood samples collected from 348 healthy volunteers representing African, Asian or European ancestry. After the researchers genotyped the samples and isolated CD4+ T cells, the T cells were activated in cell culture to model their response to antigens. A computational analysis measured which genes were turned on or off in the cells from each person.
Activation of autoimmune-associated genes can vary between individuals in a complicated interplay of genes and environment. Each person's immunological history is written in a constellation of events, from being vaccinated against the measles in childhood to having the flu last winter. Benoist compares it to learning and personality: All the memories you accumulate make you who you are.
In one's immunological history, "environment" also encompasses the microbial world people inhabit. The hygiene hypothesis holds that people who have encountered more challenges to their immune system—harmful microbes—are less likely to have the runaway response that is the hallmark of autoimmune disease. People who grow up exposed to fewer microbes may have difficulty stopping the immune response when it is no longer needed.
There is a strong inherited component to autoimmune disease, but changing one's environments is also important, Benoist noted. People who relocate to a new region tend to acquire the frequency of autoimmune disease of where they are going, observational research has reported. For example, he said, there is little autoimmune disease in India, but people of Indian origin who have lived in the US, from an early age have about the same frequency of autoimmune disease as people of European origin who also live in the US.
One possibility is that at least some of this variation may reflect evolutionary adaptations to the pathogens people encountered during human migrations out of Africa 50,000 years ago. A more robust immune response would have been advantageous in sub-Saharan Africa but deleterious at higher latitudes, with fewer microbial pathogens.
"It's a tantalizing idea, but it's highly speculative," Benoist said.
This work was supported by National Institute of General Medical Sciences grant RC2 GM093080, NIH F32 Fellowship (F32 AG043267), HHMI, and a Harry Weaver Neuroscience Scholar Award from the National Multiple Sclerosis Society (JF2138A1).
Sweet Feat
Everything about hummingbirds is rapid. An iridescent blur to the human eye, their movements can be captured with clarity only by high-speed video.
Slowed down on replay, their wings thrum like helicopter blades as they hover near food. Their hearts beat 20 times a second and their tongues dart 17 times a second to slurp from a feeding station.
It takes only three licks of their forked, tube-like tongues to reject water when they expect nectar. They pull their beaks back, shake their heads and spit out the tasteless liquid. They also are not fooled by the sugar substitute that sweetens most diet cola.
These hummingbirds look mad.
The birds' preference for sweetness is plain, but only now can scientists explain the complex biology behind their taste for sugar. Their discovery required an international team of scientists, fieldwork in the California mountains and at Harvard University's Concord Field Station, plus collaborations from Harvard labs on both sides of the Charles River.
Now, in a paper published in Science, the scientists show how hummingbirds' ability to detect sweetness evolved from an ancestral savory taste receptor that is mostly tuned to flavors in amino acids. Feasting on nectar and the occasional insect, the tiny birds expanded throughout North and South America, numbering more than 300 species over the 40 to 72 million years since they branched off from their closest relative, the swift.
"It's a really nice example of how a species evolved at a molecular level to adopt a very complex phenotype," said Stephen Liberles, HMS associate professor of cell biology. "A change in a single receptor can actually drive a change in behavior and, we propose, can contribute to species diversification."
This sweet discovery all started with the chicken genome. Before scientists sequenced its genes, people assumed that chickens and all birds taste things the same way that mammals do: with sensory receptors for salty, sour, bitter, sweet and the more recently recognized umami taste, which comes from the Japanese word for savory.
The canonical view stated there was a sweet receptor present in animals, much smaller than the large families of receptors involved in smell and bitter taste perception—vital for sensing safe food or dangerous predators.
Some animals have lost certain taste abilities. The panda, for example, feeds exclusively on bamboo and lacks savory taste receptors. Carnivores, notably cats, are indifferent to sweet tastes. The gene for tasting sweetness is present in their genomes, but it's nonfunctional. Scientists suspect that an interplay between taste receptors and diet may effectively relegate the sweet taste receptor into a pseudogene that does not get turned on and eventually disappears.
The chicken genome is another story: It has no trace of a sweet-taste receptor gene. Faced with this all-or-nothing scenario, Maude Baldwin, co-first author of the paper, had one reaction.
"The immediate question to ornithologists or to anybody who has a birdfeeder in the backyard was: What about hummingbirds?" she recalled. "If they are missing the single sweet receptor, how are they detecting sugar?"
More bird genomes were sequenced, and still no sweet receptor.
So began Baldwin's quest to understand how hummingbirds detected sugar and became highly specialized nectar feeders. A doctoral student in organismic and evolutionary biology and the Museum of Comparative Zoology, she is a member of the lab of Scott Edwards, Professor of Organismic and Evolutionary Biology and Curator of Ornithology in the Museum of Comparative Zoology. She sought out Liberles at a meeting of the International Symposium on Smell and Taste in San Francisco. They agreed to work together on experiments that would eventually reveal how hummingbirds evolved and diversified, based on a change in their taste receptor.
After cloning the genes for taste receptors from chickens, swifts and hummingbirds—a three-year process—Baldwin needed to test what the proteins expressed by these genes were responding to. She joined forces with another scientist at another International Taste and Smell meeting. Yasuka Toda, a graduate student of the University of Tokyo and co-first author of the paper, had devised a method for testing taste receptors in cell culture.
Together they showed that in chickens and swifts the receptor responds strongly to amino acids—the umami flavors—but in hummingbirds only weakly. But the receptor in hummingbirds responds strongly to carbohydrates—the sweet flavors.
"This is the first time that this umami receptor has ever been shown to respond to carbohydrates," Baldwin said.
Toda mixed and matched different subunits of the chicken and hummingbird taste receptors into hybrid chimeras to understand which parts of the gene were involved in this change in function. All told, she found 19 mutations, but there are likely more contributing to this sweet switch, Baldwin and Liberles suspect.
"If you look at the structure of the receptor, it involved really dramatic changes over its entire surface to accomplish this complex feat," Liberles said. "Amino acids and sugars look very different structurally so in order to recognize them and sense them in the environment, you need a completely different lock and key. The key looks very different, so you have to change the lock almost entirely."
Once the mutations were discovered, the next question was, do they matter? Does this different taste receptor subunit drive behavior in the hummingbirds?
Back at the feeding stations, the birds answered yes. They spat out the water, but they siphoned up both the sweet nectar and one artificial sweetener that evoked a response in the cell-culture assay, unlike aspartame and its ilk. It's not nectar, with its nutritional value, but it's still sweet.
"That gave us the link between the receptor and behavior," Liberles said. "This dramatic change in the evolution of a new behavior is a really powerful example of how you can explain evolution on a molecular level."
This work underscores how much remains to be learned about taste and our other senses, Liberles said.
"Sensory systems give us a window into the brain to define what we understand about the world around us," he said. "The taste system is arguably a really direct line to pleasure and aversion, reward and punishment, sweet and bitter. Understanding how neural circuits can encode these differentially gives us a window into other aspects of perception."
The work was supported by National Science Foundation grants DDIG 1110487, SICB, Sigma Xi; the Fulbright Commission and Science Foundation Ireland Research Frontiers Program EOB2673; National Institutes of Health RO1DC013289; and JSPS, LS037.
What Grandma Ate
When a pregnant mother is undernourished, her child is at a greater than average risk of developing obesity and type 2 diabetes, in part due to so-called 'epigenetic' effects.
A new study led by an HMS researcher at Joslin Diabetes Center and a scientist at the University of Cambridge demonstrates that this 'memory' of nutrition during pregnancy can be passed through sperm of male offspring to the next generation, increasing risk of disease for grandchildren as well. In other words, to adapt an old maxim, 'you are what your grandmother ate.'
The study also raised questions over how epigenetic effects are passed down from one generation to the next—and for how long they will continue to have an impact.
The mechanism by which we inherit characteristics from our parents is well understood: We inherit half of our genes from our mother and half from our father. However, epigenetic effects, whereby a 'memory' of the parent's environment is passed down through the generations, are less well understood.
The best understood epigenetic effects are caused by a mechanism known as 'methylation' in which the molecule methyl attaches itself to our DNA and acts to switch genes on or off.
In the study, published in the journal Science and funded mainly by the Medical Research Council and the Wellcome Trust, the international team of researchers showed that environmentally-induced methylation changes occur only in certain regions of our genome (our entire genetic material)—but, unexpectedly, that these methylation patterns are not passed on indefinitely.
Researchers examined the impact that under-nutrition during pregnancy had on offspring in mouse models and looked for the mechanisms by which this effect was passed down through the generations. The male offspring of an undernourished mother were, as expected, smaller than average and, if fed a normal diet, went on to develop diabetes. Strikingly, the offspring of these were also born small and developed diabetes as adults, despite their own mothers never being undernourished.
"When food is scarce, children may be born 'pre-programmed' to cope with undernourishment. In the event of a sudden abundance in food, their bodies cannot cope and they can develop metabolic diseases such as diabetes. We need to understand how these adaptations between generations occur since these may help us understand the record levels of obesity and type 2 diabetes in our society today," said Anne Ferguson-Smith, from the department of genetics at the University of Cambridge.
To see how the effect might be passed on, the researchers analyzed the sperm of offspring before the onset of diabetes to look at the methylation patterns. They found that the mouse's DNA was less methylated in 111 regions relative to a control sperm.
These regions tended to be clustered in the non-coding regions of DNA—areas of DNA responsible for regulating the mouse's genes. They also showed that in the grandchildren, the genes next to these methylated regions were not functioning correctly. The offspring had inherited a 'memory' of its grandmother's under-nutrition.
Unexpectedly, however, when the researchers looked at the grandchild's DNA, they found that the methylation changes had disappeared: the memory of the grandmother's under-nutrition had been erased from the DNA, or at least, was no longer being transmitted via methylation.
"This was a big surprise: dogma suggested that these methylation patterns might persist down the generations," added co-author and HMS assistant professor of medicine Mary-Elizabeth Patti, director of the Joslin Genomics Core and director of the Hypoglycemia and Severe Insulin Resistance Clinic at Joslin.
"From an evolutionary point of view, however, it makes sense. Our environment changes and we can move from famine to feast, so our bodies need to be able to adapt. Epigenetic changes may in fact wear off. This could give us some optimism that any epigenetic influence on our society's obesity and diabetes problem might also be limited and/or reversible," Patti said.
The researchers are now looking at whether epigenetic effects no longer have an impact on great-grandchildren and their subsequent offspring.
Adapted from a Joslin Diabetes Center news release.
Aspirin's Two Sides
Aspirin is the gold standard for antiplatelet therapy and a daily low-dose aspirin is widely prescribed for the prevention of cardiovascular disease.
Now, a new study suggests that common genetic variation in the gene for catechol-O-methyltransferase (COMT) may modify the cardiovascular benefit of aspirin and, in some people, may confer slight harm. The findings, from Harvard Medical School investigators at Beth Israel Deaconess Medical Center and Brigham and Women's Hospital, are published in the American Heart Association journal Arteriosclerosis, Thrombosis, and Vascular Biology.
"This is one of the few cases where you can identify a single genetic polymorphism which has a significant interaction with aspirin such that it affects whether or not it protects against cardiovascular disease," said first author Kathryn Hall, an HMS research fellow and investigator in the Division of General Medicine and Primary Care at Beth Israel Deaconess.
COMT is a key enzyme in the metabolism of catecholamines, a group of hormones that include epinephrine, norepinephrine and dopamine. These hormones are implicated in a broad spectrum of disorders, including hypertension.
"We were initially interested in finding out if the COMT gene affected people's susceptibility to cardiovascular disease, such as myocardial infarction or ischemic stroke," Hall said.
Knowing that aspirin is commonly prescribed for the prevention of cardiovascular disease, the investigators also wanted to learn if genetic variation in COMT would influence aspirin's potential benefit.
To answer these questions, the researchers used data from the Women's Genome Health Study, a cohort of more than 23,000 women who were followed for 10 years in a randomized double-blind, placebo-controlled trial of low-dose aspirin or vitamin E for the primary prevention of cardiovascular disease. Their analysis focused on val158met, a common variant in the COMT gene. Individuals who have two copies of the gene for the enzyme's high-activity valine form, the "val/vals," have been shown to have lower levels of catecholamines compared to individuals who have two copies of the gene for the enzyme's low-activity methionine form, the "met/mets." The val/met people are in between.
"When we examined women in the placebo arm of the trial, we found that the 23 percent of the women who were 'val/vals' were naturally protected against cardiovascular disease," said senior author Daniel Chasman, HMS associate professor of medicine at Brigham and Women's. He is also a genetic epidemiologist in the Division of Preventive Medicine at the hospital. "This finding, which was replicated in two other population-based studies, was in itself of significant interest."
The investigation further revealed the surprising discovery that when the women with the val/val polymorphism were allocated to aspirin, this natural protection was eliminated.
"As we continued to look at the effects of drug allocation, we found that val/val women who were randomly assigned to aspirin had more cardiovascular events than the val/vals who were assigned to placebo," says Chasman. Among the 28 percent of women who were met/met, the opposite was true, and these women had fewer cardiovascular events when assigned to aspirin compared to placebo. The benefit of aspirin compared to placebo allocation for met/mets amounted to reduction of one case of incident cardiovascular disease for 91 treated women over 10 years of study follow-up. By contrast, the harm of aspirin compared to placebo allocation for the val/val women was an increase of one case per 91 treated.
The researchers further found that rates of cardiovascular disease were also reduced in met/met women assigned to vitamin E compared to those assigned to placebo.
The authors stressed that the findings will require further research and replication to understand their potential for clinical impact. Nonetheless, they note that because aspirin is preventively prescribed to millions of individuals and the COMT genetic variant is extremely common, this study underscores the potential importance of individualizing therapies based on genetic profiles.
"What this study suggests is that we can be smarter about the groups of patients that would most likely benefit from aspirin," said study coauthor Joseph Loscalzo, chairman of the Department of Medicine and physician-in-chief at Brigham and Women's. He is also the Hersey Professor of the Theory and Practice of Physic at HMS. "Rather than give aspirin to all patients with risk factors for heart disease, we need to use modern genomics and genetics to identify those individuals for whom aspirin has the greatest benefit and the lowest risk of adverse effects."
One possible reason for the val/val protection could lie in COMT's role in the breakdown of epinephrine, the "fight or flight" hormone, which is tightly linked to regulation of the cardiovascular system.
"When epinephrine levels rise in response to stress, blood pressure goes up and high blood pressure is a precursor to heart disease," said Hall. "One possibility is that val/val individuals have less epinephrine than met/met individuals because their COMT is more efficient at breaking it down. This might help to naturally protect them against cardiovascular disease—that's our working hypothesis. It's harder to explain why the effect is modified by aspirin and that's what we're in the lab aggressively trying to figure out."
The Women's Genome Health Study is supported by HL043851 and HL080467 from the National Heart, Lung, and Blood Institute and CA 047988 from the National Cancer Institute. This study was also supported by NIH grants T32A5000051; R01AT004662; K24AT004095; R21AT002860; 3R01AT004662-02S1from the National Center for Complementary and Alternative Medicine.
Adapted from a Beth Israel Deaconess news release.
A Crisper Version of CRISPR
A next-generation genome-editing system developed by Harvard Medical School investigators at Massachusetts General Hospital substantially decreases the risk of producing unwanted, off-target gene mutations. In a paper published in Nature Biotechnology, the researchers report a new CRISPR-based RNA-guided nuclease technology that uses two guide RNAs, significantly reducing the chance of cutting through DNA strands at mismatched sites.
"This system combines the ease of use of the widely adopted CRISPR/Cas system with a dimerization-dependent nuclease activity that confers higher specificity of action," said J. Keith Joung, HMS associate professor of pathology at Mass General and senior author of the report. "Higher specificity will be essential for any future clinical use of these nucleases, and the new class of proteins we describe could provide an important option for therapeutic genome editing."
Engineered CRISPR-Cas nucleases are genome-editing tools that combine a short RNA segment matching its DNA target with a DNA-cutting enzyme called Cas9. The tools have been the subject of much investigation since their initial development in 2012. Easier to use than the earlier zinc finger nuclease (ZFN) and transcription activator-like effector nuclease (TALEN) systems, they have successfully induced genomic changes in several animal model systems and in human cells. But in a previous Nature Biotechnology paper published in June 2013, Joung's team reported that CRISPR-Cas nucleases could produce additional mutations in human cells, even at sites that differed from the DNA target by as much as five nucleotides (the subunits of DNA).
To address this situation, the investigators developed a new platform in which the targeting function of Cas9 was fused to a nuclease derived from a well-characterized enzyme called Fokl, which functions only when two copies of the molecule are paired, in a relationship called dimerization. This change essentially doubled the length of DNA that must be recognized for cleavage by these new CRISPR RNA-guided Fokl nucleases, significantly increasing the precision of genome editing in human cells. Joung and his colleagues also demonstrated that these new RNA-guided Fokl nucleases are as effective at on-target modification as existing Cas9 nucleases that target a shorter DNA sequence.
"By doubling the length of the recognized DNA sequence, we have developed a new class of genome-editing tools with substantially improved fidelity compared with existing wild-type Cas9 nucleases and nickases," the enzymes that cleave a single DNA strand, said Joung, who is associate chief for research in the Mass General Department of Pathology.
The research team also has developed software that enables users to identify potential target sites for these new RNA-guided Fokl nucleases. The freely available software package is ZiFiT Targeter.
The study was supported by National Institutes of Health Director's Pioneer Award DP1 GM105378; NIH grants R01 GM088040, P50 HG005550 and R01 AR063070; and the Jim and Ann Orr Massachusetts General Hospital Research Scholar Award. Joung is a co-founder of Editas Medicine Inc., which has an exclusive option to license the new CRISPR RNA-guided Fokl nuclease technology for therapeutic applications.
Adapted from a Mass General news release.
Breast Cancer Clue
Inherited mutations in the BRCA1 or BRCA2 tumor suppressor genes are by far the most frequent contributors to hereditary cancer risk in the human population, often causing breast or ovarian cancer in young women of child-bearing age. Attempts to test the role that the BRCA genes play in regulating a repair process associated with genome duplication have proven frustratingly difficult in living mammalian cells.
Now Harvard Medical School investigators at Beth Israel Deaconess Medical Center report a new mechanism by which BRCA gene loss may accelerate cancer-promoting chromosome rearrangements. The new findings explain how the loss of BRCA1 or BRCA2 function impairs homologous recombination, a normally accurate repair process used to fix DNA breaks, and actually stimulates faulty, error-prone homologous recombination repair.
Described online in the April 28 issue of Nature, the discovery could ultimately provide clinicians with valuable new information to help them ascertain risk and guide patient treatment when faced with BRCA mutations of uncertain significance. The finding also offers a potentially valuable new tool for the development of cancer therapeutics.
"Mutations in the BRCA genes cause breast and ovarian cancers that affect thousands of women throughout the U.S. and around the world, often striking them in the prime of life," said senior author Ralph Scully, HMS associate professor of Medicine at Beth Israel Deaconess in the hospital's Breast Cancer Oncology program. "For almost two decades, scientists have been striving to better understand the tumor suppressor functions of BRCA1 and BRCA2."
Potentially harmful breaks in DNA strands commonly occur during DNA replication, a prerequisite for cell division. These breaks occur when the replication fork that duplicates the genome stalls at sites of DNA damage. If not properly repaired, the breaks can promote genomic instability, leading to cancer and other diseases.
"Some years ago, we and others suggested that BRCA1 and BRCA2 regulate homologous recombination at sites of stalled replication," explains Scully. "We believe that this function is critical to how these genes suppress breast and ovarian cancer. Until now, we haven't had the tools necessary to study in molecular detail the homologous recombination processes at sites of replication fork stalling in the chromosomes of a living mammalian cell."
To solve this problem, first author Nicholas Willis, HMS research fellow in medicine in the Scully laboratory, created a new tool by harnessing a protein-DNA complex that evolved in bacteria.
"We found that the Escherichia coli Tus/Ter complex can be engineered to induce site-specific replication fork stalling and chromosomal homologous recombination in mouse cells," explained Willis. "In its essence, E. coli bacteria—a standard model organism in science—has evolved a very simple system to arrest replication forks in a site-specific manner."
This system is composed of short DNA elements called Ter sites, which are 21 to 23 base pairs long and tightly bound by the protein Tus. "Tus binds these Ter elements with extremely high affinity and, upon replication fork approach, acts as a barrier to fork progression along the DNA. Tus/Ter effectively sets up a 'roadblock' and stalls the replication fork."
The acid test for the new tool, said the authors, came when this same short Ter sequence was placed into a reporter, a slightly larger DNA sequence that can undergo certain rearrangements within a chromosome when triggered to do so. "When it engaged in homologous recombination, a change in the sequence caused the cells to express green fluorescent protein," said Willis. "When the cells glowed green, we knew we had a positive event."
The team adapted the reporter sequence to distinguish between error-free/high-fidelity homologous recombination and an error-prone/aberrant form of homologous recombination. "Remarkably, when we studied cells lacking BRCA1 or BRCA2, we found that the frequency of aberrant homologous recombination events triggered at Tus/Ter-stalled replication forks had actually increased compared to normal cells. We knew at this point that we had discovered a new and important process by which BRCA gene loss promotes cancer."
The discovery provides a promising bridge between basic science and the clinic, said Scully. "Sometimes a genetic sequencing test reveals a mutation in BRCA1 or BRCA2 that has not been definitively associated with cancer," he said. Often described as "variants of uncertain significance," these mutations are not found in high enough frequency in healthy women or in women with breast or ovarian cancers to allow the specific BRCA1 or BRCA2 mutations to be reliably classified as high risk or low risk. This is an important issue because a woman with a known high-risk BRCA gene mutation may elect to undergo potentially lifesaving prophylactic mastectomy or oophorectomy, Scully said.
"There is a growing appreciation that careful measurement of the homologous recombination functions of BRCA1 and BRCA2 variants-of-uncertain-significance mutants might help to classify them into high-risk or low-risk groups," he said. "It would be gratifying if our system could contribute new information to help ongoing efforts to classify these mutants."
Furthermore, understanding the mechanisms that regulate homologous recombination at stalled replication forks might hold additional promise for the development of novel cancer therapeutics. "If we could use this tool to help develop new cancer therapies, it would be a grand slam," said Scully. "This new system might also be useful in genome editing, which is considered a groundbreaking technology used for the development of new gene therapies."
This study was funded, in part, by National Institutes of Health grants R01CA095175, R01GM073894, R21CA144017, and R37GM26938; by National Institutes of Health /National Cancer Institute postdoctoral fellowship 5T32CA081156; and by ACS postdoctoral fellowship PF-12-248-01-DMC.
Adapted from a Beth Israel Deaconess news release.
Aspirin Tied to Lower Colon Cancer Risk for Some
The humble aspirin may have another beneficial effect beyond easing the pain of headache and reducing the risk of heart attack: lowering colon cancer risk among people with high levels of a specific enzyme.
The finding comes from a multi-institutional team that analyzed data and samples from two long-term studies involving nearly 128,000 participants. The researchers discovered that people who took aspirin and had high levels of a specific enzyme in their colons had half the risk of developing colorectal cancer compared with people who also took aspirin but whose colons showed low levels of the enzyme, called 15-hydroxyprostaglandin dehydrogenase, or 15-PGDH for short. About half of the population possesses high levels of 15-PGDH.
The results appear in the April 23 edition of Science Translational Medicine. While previous trials and prospective studies have shown that aspirin use reduces colorectal cancer risk, this retrospective study may explain why aspirin benefits some people, but not others.
The research team included scientists from Brigham and Women's Hospital, Case Western Reserve School of Medicine, Dana-Farber Cancer Institute, Harvard Medical School, Massachusetts General Hospital and University Hospitals Case Medical Center.
"If you looked at the folks from the study who had high 15-PGDH levels and took aspirin, they cut their risk of colon cancer by half," said senior author Sanford Markowitz, Ingalls Professor of Cancer Genetics at Case Western Reserve School of Medicine. "If you looked at the folks from the study who were low for 15-PGDH, they did not benefit at all from taking aspirin. These findings represent a clean Yes-No about who would benefit from aspirin."
According to the American Cancer Society, colorectal cancer is the second leading cause of cancer-related deaths in the United States, with predictions that 137,000 Americans will develop the disease and 50,000 will die from it in 2014.
In the current study, the scientists built on earlier research indicating that regular use of non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin, reduces the risk of developing colon cancer for some but not all individuals. Markowitz, also a medical oncologist at University Hospitals Case Medical Center, joined co-senior author Andrew Chan, HMS associate professor of medicine and a gastroenterologist at Mass General, to explore whether the presence of 15-PGDH led to different outcomes in developing colon cancer.
They hope to develop a test to guide physicians and patients in determining whether aspirin would help them.
The team examined tissues of 270 colon cancer patients who were among 127,865 participants followed for more than 30 years in the Harvard-based Nurses' Health Study and Health Professionals Follow-up Study. Previous reports from the Mass General and Dana-Farber team showed that participants in these studies who regularly took aspirin had a lower risk of colorectal cancer. In earlier research, Case Western Reserve investigators and Monica Bertagnolli, HMS professor of surgery at Brigham and Women's, had found that 15-PGDH appeared to enhance the ability of celecoxib, an anti-inflammatory medication commonly known as Celebrex, to prevent colon tumors in mice and in 16 humans tested. But when 15-PGDH was low or absent, celecoxib did not prevent colon tumors in mice or humans.
In the latest study, the investigators combined forces in a larger study to examine whether 15-PGDH levels might also be associated with the colon cancer-preventing benefits of aspirin, which lacks the adverse cardiovascular side effects of celecoxib.
The Mass General and Dana-Farber team dissected normal colon tissue from the pathology specimens of participants who developed colon cancer over the studies' follow-up periods. The team at Case Western Reserve then analyzed these colon tissues to identify which among them had high or low levels of colon 15-PGDH. The investigators at Mass General and Dana-Farber examined how participants' aspirin use and levels of 15-PGDH might be related to the risk of colorectal cancer.
The study's results could lead to a test that would allow more personalized decisions about treatment to prevent colorectal cancer. People whose 15-PGDH levels indicate aspirin would have little benefit might choose to avoid the potential gastrointestinal side effects—such as stomach ulcers—that can accompany aspirin use. The researchers plan to develop a cost-effective and accessible test for measuring 15-PGDH in the colon. Chan and Markowitz believe such a test could become part of current medical practice.
"During a colonoscopy, a gastroenterologist could easily and safely take an additional biopsy from the colon in individuals for whom preventive aspirin treatment might be appropriate," Chan said.
"There would be no reason why a good hospital pathology laboratory could not establish the test for 15-PGDH," Markowitz said.
To confirm their findings, the study authors hope to launch a randomized, prospective clinical trial in which high-risk patients would be identified, treated with aspirin or a placebo, and monitored for development of colorectal tumors.
The mechanisms of action in 15-PGDH and in aspirin make them key players in colon cancer, the scientists said. Prostaglandins promote development of colon cancer. Aspirin helps prevent colon cancer development by blocking prostaglandins from being generated, while 15-PGDH helps prevent colon cancer development by catalyzing a reaction that "chews up" prostaglandins. Markowitz refers to the gene that produces 15-PGDH as the body's genetic form of aspirin. The study suggests that both aspirin and 15-PGDH must work together to effectively prevent colon cancer, bringing the most benefit to individuals who have high levels of 15-PGDH.
"This study highlights the benefits of the relatively new practice of molecular pathological epidemiology, " said co-senior author Shuji Ogino, HMS associate professor of pathology at Brigham and Women's and Dana-Farber. "The molecular pathology part relates to analysis of 15-PGDH gene expression level in the normal colon to classify cancer based on molecular pathogenesis, while the epidemiology part relates to collection and analysis of aspirin use data in a population. This is an integration of these analyses."
Other researchers involved in the study include first author Stephen Fink, an instructor at Case Western Reserve; co-authors Mai Yamauchi and Reiko Nishihara, HMS research fellows at Dana-Farber; and senior author Charles S. Fuchs, HMS professor of medicine at Dana-Farber.
The study was supported by the Entertainment Industry Foundation's National Colorectal Cancer Research Alliance; the National Cancer Institute's GI-SPORE program (Specialized Programs of Research Excellence in Gastrointestinal Cancers) and Early Detection Research Network; National Institutes of Health grants P01 CA87969, P01 CA55075, 1UM1 CA167552, R01 CA136950, P50 CA127003, R01 CA151993, P50 CA150964, U01 CA152756, R01 CA137178 and K24 DK 098311; the Damon Runyon Cancer Research Foundation; and gifts from the Cleveland-based Marguerite Wilson Foundation, the Leonard and Joan Horvitz Foundation, the Richard Horvitz and Erica Hartman-Horvitz Foundation, and the Boston-based Bennett Family Fund for Targeted Therapies Research.
Adapted from a joint Case Western Reserve and Mass General news release.
Genes and Galaxies
If you haven't thought about reworking the human genome so people can colonize other planets, don't worry. Plenty of people are on it.
Scientists of many stripes have been figuring out what barriers would keep us from calling distant, inhospitable galactic real estate "home" if—or when, depending on your point of view— we damage the Earth enough to face extinction. And then there's the whole question of whether we should try to win a stay of execution for our species. After all, what makes us so special?
Those questions were just the beginning of a free-form symposium hosted March 13 by the HMS Department of Genetics on "Genetics, Biomedicine, and the Human Experience in Space," the standing-room-only crowd in attendance fueled by pizza and unbridled curiosity.
Speakers quickly made clear why space travel and exploration over vast, uncharted distances depends on numerous, unknown factors hidden in our genes. Living with microgravity while being bombarded with cosmic rays can affect different people different ways. Scientists want to know why—and which genes might make it better or worse.
Also, space is just cool.
The Role of Genetics
The session unleashed uninhibited discussion, with a fairly even split between prepared presentations and informed thinking-out-loud improv from the audience.
Before the event, symposium co-organizers Ting Wu and Susan Dymecki, both HMS professors of genetics, stated their belief that genetics will play a huge part in the success of humans off the planet.
"We are a medical school. Whether or not you agree with sending people into space, we are responsible for their health on and off the planet," said Wu.
Well-known muscle and skeletal weakness and sleep disruption are not the only problems humans encounter in space. Physical concerns ride along with behavioral and neuropsychiatric issues aboard current spacecraft, not to mention whatever vehicles might ferry people farther away. It's lonely out there.
Thinking about travel to Mars, one of our nearest neighbors, is daunting for robots, much less people. Just ask symposium guest Adam Steltzner, mechanical systems lead at the Jet Propulsion Lab, about the prodigious work that brought back what we know about the planet. Or Dorit Donoviel, deputy chief scientist and industry forum lead of the National Space Biomedical Research Institute, and assistant professor in the Department of Pharmacology and Center for Space Medicine at Baylor College of Medicine, who studies astronauts and the challenges they face, including problems with vision and headaches.
Focusing on Space
HMS geneticists spoke about the intersections between their scientific focus and space. Susan Dymecki said she began thinking about why cosmonauts in the former Soviet Union's space program were forbidden from playing chess on board space flights. The answer involves aggression and impulsivity.
For HMS professor of genetics David Sinclair, this intersection involves the potential advantages of extant human variation and rallying our genetics to counter aging during long-distance travel spanning hundreds of thousands of years.
Bruce Yankner, HMS professor of genetics, talked about protecting the brain and memory in space. Wu presented her vision for using ultraconserved elements, which some consider to be among the most mysterious sequences of the human genome, to orchestrate chromosome behavior
to and thus protect genomes against cosmic radiation in space.
Mary Bouxsein, a biomechanical engineer and HMS assistant professor of orthopedic surgery at Beth Israel Deaconess Medical Center, a last minute addition to the program, showed the devastating effects of space flight on bone, and how that might be prevented in space—and on Earth -- with a newly developed therapy.
Genetics professor Gary Ruvkun, whose talk was entitled "What's true for E. coli is true for the elephant" and our speculative kin on Gliese 667 Cf, (a potential Class M planet in the Gliese 667 star system), peppered the meeting with a positive view of the extinction of the human species and then proposed that, rather than travel to another planet, we "print" ourselves there. Conversely, we could print extraterrestial life on Earth.
George Church, the Robert Winthrop Professor of Genetics, suggested using genomics to identify and engage human protective variants, speculating that, by ridding ourselves of our microbiome and taking advantage of variants that suppress pain, we might create a habitat in which surgeries can occur without anesthesia or need for sterilization.
Space is vast, cold and hard for us humans, and outside of Earth, its planets, and moons—too hot, too cold, too toxic for life that evolved here— are not much more welcoming. Should we want to go there, and decide who is best suited to do so, a great deal more work needs to be done not only in jet propulsion but in human genetics.


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See the winners, hosts and more of Hollywood's elite at 70th annual Golden Globe Awards
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Jennifer Lawrence poses with the award for best performance by an actress in a motion picture comedy or musical for Silver Linings Playbook backstage at the 70th Annual Golden Globe Awards at the Beverly Hilton Hotel on Sunday Jan. 13, 2013, in Beverly Hills, Calif.
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JAN 18, 2013 - Yahoo! News
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"Obama for America" is becoming "Organizing for Action." The grassroots political network that made history in 2008 and 2012 is being morphed into a nonprofit advocacy group to help advance President Obama's agenda. First Lady Michelle Obama made the announcement in a video message to...
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Wanted - Your Opinion on the Twitter Widgets in TheAquarium
By pelegri on Sep 26, 2009
I have mixed feelings about the current arrangement of Twitter widgets at TheAquarium. I like that they help me track conversations and discover news and opinions but the widget takes some time to load and too often the content is blank - I assume infrastructure problems, which they now have money to fix. A reader recently complained about the widgets and I promised to collect feedback via a survey.
So, if you care about the widgets, one way or the other, please go fill in this 3-question Survey...


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Undercover Gig Gives Portfolio Company Exec "A Worm's Eye View"
This Sunday, Dina Dwyer-Owens, chief executive of The Dwyer Group, will have an identity crisis.
The chairwoman of the TZP Group -backed portfolio company, which the firm bought from The Riverside Co., will be a contestant on the reality show Undercover Boss in the episode airing January 22. The show's premise, of course, is getting executives to go undercover at his or her own company to get a raw look at how the business is really run.
Waco-based Dwyer Group is a platform of residential and commercial cleaning and maintenance services operating under brands like Glass Doctor, The Grounds Guys and Mr. Appliance. Riverside had sold the company in December 2010 to TZP for roughly $150 million, netting a three-times gross cash-on-cash return.
The details (and outcome) of the episode are, of course, kept mum, but the private equity portfolio boss did reveal that she goes undercover as a woman named Faith, who is being trained by Dwyer Group employees. (The preview on CBS' website depicts Dwyer-Owens, who is blonde, as a brunette with generous makeup and pearls attempting to navigate a lawn mower.)
"I'm so busy doing acquisitions and working out our strategic goals that I have this bird's eye view of the company," she said over the phone. "On the show, I got a worm's eye view."
Sure, Dwyer-Owens gets to see how her company is run on the inside, but the show does have 17.7 million viewers, according to CBS, garnering a significant amount of publicity for the company. Private equity has historically erred on the discreet side, but neither TZP nor Riverside see much of a problem with it.
"At the end of the day, whether or not you own a company privately or by public means, you want the brand to be enhanced however it can and gain good exposure," said Sam Katz, a managing partner at TZP. "In this case, it could attract more franchisees. We really didn't hesitate, and gave Dina our full support."
TZP had actually looked at investing in another company whose chief executive had also been on the show. (They watched his episode for due diligence.) The show had made a very positive impact on its earnings, although the firm ultimately passed on the opportunity, Katz said.
There were a few close calls, however, where Dwyer-Owens teetered close to revealing her identity. For example, one team member shared his concern about how a franchise owner was compensating him, voicing worries that perhaps he was being exploited. Dwyer-Owens, however, knew the franchisee well, and felt "that was last thing he would do."
She recalled: "I was in the garage, getting ready to install a water heater, and was just thinking, do I yank my wig off right now and say, 'That's not what's happening here?' Of course when they started talking to me about their code of values, it was hard for me to pretend I didn't know what they were talking about."
Come Sunday, we'll know of at least two private equity firms glued to the tube.
"Actually, we're going to Waco to watch it," Katz said.