Books: From Bang to Whimper: A Heart Drug’s Story





On June 23, 2005, American medicine managed to take a small step forward and a giant step backward at precisely the same time, with government approval of the first medication to be earmarked for a specific racial group. It was BiDil, a drug designed to treat heart failure in blacks.




Enthusiasts hailed BiDil’s approval by the Food and Drug Administration as a landmark event in the nascent field of pharmacogenomics, which aims to create drugs tailored to fit an individual’s genetic makeup as precisely as a bespoke suit drapes its owner’s shoulders. Critics just winced and clocked one more misstep in medicine’s long history of race-related disasters.


You would think that the elucidation of the human genome would have cleared up most of the hoary untruths surrounding race and health. But as Jonathan Kahn makes clear in his worthy if convoluted review of the events surrounding the birth of BiDil, the genome has in many respects only made things worse.


It has been clear for decades that race has minimal relevance to the body’s inner workings. Research has repeatedly shown that the biologic variations among individuals of the same race are reliably great enough for race to retain little utility as a biologic predictor. You might as well sort people by height. Or, in the words of an editorial writer for Nature Biotechnology in 2005, “Pooling people in race silos is akin to zoologists grouping raccoons, tigers and okapis on the basis that they are all stripy.”


But old misconceptions die hard, particularly for entrepreneurs eagerly awaiting cash bonanzas from the genomic revolution.


Race may be irrelevant; it may be, as Dr. Francis Collins, the director of the National Institutes of Health, put it, “a weak and imperfect proxy” for genetic differences. But it is also a familiar concept — and asking people what race they are is substantially cheaper than genotyping them.


So in a peculiar paradox, race has come to serve in some circles as a crude surrogate for genetic analysis until actual genomic medicine comes along — a temporary bridge from now to later, known to be flawed but still a quasi-legitimate stand-in for the real thing.


Against this background unfolds the story of BiDil, a drama of greed and good intentions.


Several observations prompted the drug’s development. Among them was the common assertion from the last century that blacks with heart failure were more likely to die than whites. (Mr. Kahn does an impressive job of researching and debunking this statistic.) Then there was the belief that blacks often reacted badly to some of the newer drugs used for treating heart failure, and the results of a study dating from the 1980s suggesting that many black patients did well with two old standby drugs.


Those two drugs were (and are) on sale as generics, costing pennies a pill. But just suppose they were combined into a single pill that could be then specifically marketed to patients who just happened to be thought in particular need of effective medication? Now there was a pharmacologic and marketing plan that would extend a lucrative new patent for decades.


And so it came to pass that a collection of eager investors and some of the nation’s foremost cardiologists smiled on the results of an industry-sponsored trial performed on self-identified black subjects with heart failure: The two cheap drugs combined into the not-so-cheap BiDil reduced mortality by 40 percent compared with placebo. This figure was impressive enough to end the trial early and speed BiDil to market.


How did whites do on BiDil? Nobody bothered to check.


Mr. Kahn deserves credit for teasing out all the daunting complexities behind these events, including the details of genetic analysis, the perils of racial determinations and the minutiae of patent law. Unfortunately, though, he suffocates his powerful subject in a dry, repetitive, ponderous read.


A law professor with a doctorate in history and longstanding interest in race issues, Mr. Kahn trudges a partisan path through the drama in which he himself was a player. (He testified before an F.D.A. advisory committee that BiDil should be approved without racial qualifications.)


He heads bravely into many statistical thickets, but omits relevant clinical data; he repeatedly refers to the trial that led to BiDil’s approval, for instance, but I could find its numerical findings nowhere in the book and had to look them up. In a story that fairly drips with potential human interest, he offers the reader not one sip.


The issues raised on every page are so important and so thought-provoking that it would be irresponsible to warn interested readers away. Still, it would be almost as irresponsible to misrepresent the difficulty of the journey.


As it happens, BiDil itself has had a remarkably inglorious career. Despite its much-trumpeted release, patients did not request the medication, and practicing doctors did not prescribe it.


NitroMed, the company that developed it, sponsored no further studies and failed in 2009.


The drug still lingers on the market; Mr. Kahn writes that BiDil may be resurrected in sustained-release form — that other time-honored technique for wringing a few more years from a drug’s patent.


For a parable of early 21st-century medicine, as it treads water between past and future and never hesitates to reach for a buck, it doesn’t get much better than BiDil.


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Syrian Airstrikes Reportedly Kill Dozens at Bakery





BEIRUT, Lebanon — A Syrian warplane was reported to have conducted airstrikes that killed dozens of people lined up for bread at a bakery in the central town of Hilfaya, according to antigovernment activists in the area.




The attack, and its toll, could not immediately be confirmed. Samer, a local activist in the town, said he ran to the bakery soon after he heard a warplane, followed by bomb explosions and finally the sound of ambulances. “There were bodies everywhere,” he said, adding that he saw tens of bodies taken away in cars.


Photographs he said he took at the bakery showed bodies in a heap on a bloody sidewalk outside a low-slung building that was blackened with soot and stained with patches of blood, high on the walls. Amateur video showing what activists said was the aftermath of the attack showed roughly a dozen people lying on the ground, some wounded and several apparently dead.


In one of Samer’s photograph, a man stared in shock at the scene, with his hands resting on his head, while another carried body parts. Bystanders searched for survivors under rubble from the building. Another man picked up a piece of bread, lying next to someone’s slippers.


The reason for the attack was unclear, but activists said that rebel fighters occupied Hilfaya last week as part of a broader offensive to seize territory around the city of Hama, where the government has kept tight control after suppressing protests in the city last year.


Civilians have been caught between the two sides. On Friday, rebel fighters posted a video threatening to attack Christian villages with artillery while asserting that the residents were shielding government loyalists. In the last few days, Hilfaya has come under repeated shelling from loyalist positions in a neighboring village, activists said.


The bakery was one of three in the city. When word spread on Sunday that a flour shipment from Turkey had come in, people began lining up around noon, waiting for their turn at its windows for bread after a stretch of days when the bakeries had been idled. At least three bombs fell near the bakery, Samer and other activists said.


The attack came as the international envoy to Syria, Lakhdar Brahimi, arrived in the capital, Damascus, where he was expected to meet with President Bashar al-Assad. His visit had been rumored but not previously announced, signaling concerns about security as the fighting between opposition fighters and the government intensified in the capital.


Mr. Brahimi made no public comment on Sunday, and the Syrian information minister said during a news conference that he had no knowledge of the envoy’s visit. Mr. Brahimi traveled by land from Beirut because of fighting between the rebels and government forces near the Damascus airport, Lebanese airport officials told The Associated Press.


His visit was likely to add fuel to the speculation about a deal to remove Mr. Assad from power. Rebel forces have claimed gains near government strongholds, and international aid agencies are warning of a growing humanitarian crisis in the winter months.


Russia, one of Syria’s most reliable allies, has recently sent signals that it is distancing itself from the Syrian president. On Saturday, the Russian foreign minister, Sergey V. Lavrov, said several countries in the region had offered Mr. Assad asylum, while adding that Moscow was not willing to mediate on their behalf.


Ellen Barry contributed reporting from Moscow; Hala Droubi from Jidda, Saudi Arabia; and Hwaida Saad from Beirut.



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Luck sets rookie record, rookie PK sets NFL mark


Andrew Luck has broken the NFL rookie record for yards passing, and rookie kicker Blair Walsh has broken the league mark for 50-yard plus field goals in a season.


On a Sunday featuring a slew of records, Luck topped Cam Newton's year-old mark for yards passing in the first half of Indianapolis' game at Kansas City. Newton's record was 4,051 yards. Luck entered the game needing 74 yards to break the mark, and had 123 at halftime.


Minnesota's Walsh kicked a 56-yard field goal in the second quarter against Houston, giving him a record ninth field goal of 50 yards or more.


Also, Redskins kicker Kai Forbath set the NFL record for consecutive field goals to begin a career with 17 straight. He had field goals of 45 and 42 yards in the first half against the Eagles. New Orleans' Garrett Hartley had 16 straight.


On Saturday, Detroit's Calvin Johnson broke Jerry Rice's single-season yards receiving record, and is at 1,892 with a game left. He also became the only NFL player with 100 yards receiving in eight straight games, and with 10-plus receptions in four straight games.


___


Online: http://pro32.ap.org/poll and http://twitter.com/AP_NFL


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News Analysis: The Perils of Yoga for Men





MEN are famous for ignoring aches and pains. It’s macho. Men get physical exams less often than women. They tend to remain silent if worried about their health. When hurt, their impulse is to shun doctors and rely on home remedies, like avoiding heavy lifting to ease backaches. Male athletes play through injuries. It’s all about virility and manliness.




The stereotype has exceptions, of course. But denial of injury and ill health — from the relatively inconsequential to the grave — is common enough that physicians seek ways to encourage men to be more forthcoming.


So it pays to listen carefully when guys start talking about intolerable pain and upended lives. Doing so led me to an unexpected finding that I have confirmed in a trove of federal data. It suggests that yoga can be remarkably dangerous — for men.


Guys who bend, stretch and contort their bodies are relatively few in number, perhaps one in five out of an estimated 20 million practitioners in the United States and 250 million around the globe. But proportionally, they are reporting damage more frequently than women, and their doctors are diagnosing more serious injuries — strokes and fractures, dead nerves and shattered backs. In comparison, women tell mainly of minor upsets.


Men who are breaking the code of silence are doing so with physicians in hospital emergency rooms, who in turn report their findings to the federal government.


Their outspokenness reveals much about modern yoga and suggests ways it can be made safer. As a practitioner since 1970, I know some of the guy hazards personally and have learned through painful experience how to live with my inflexible body.


The male disclosures help explain one of the central mysteries of modern yoga — why it is largely a feminine pursuit. As Yoga Journal, the field’s top magazine, put the question: “Where Are All the Men?”


Science has long viewed the female body as relatively elastic. Now the new disclosures suggest that women who tie themselves in knots also enjoy a lower risk of damage. It seems like common sense.


Surprisingly, evidence of the male danger has, to my knowledge, never before been made public. Nor has its flip side — that women seem less vulnerable. The subject of male risk merits discussion if only because the booming yoga industry has long targeted men as a smart way to expand its franchise.


Informal observations hint at possible explanations. Yoga experts say women tend to see classes as refuges while men see challenges — their goal at times to impress the opposite sex.


Women say men push themselves too far, too fast. Men admit to liking the intensity but say the problem is pushy teachers who force them into advanced poses while urging them to ignore pain.


I stumbled on the issue after my book, published in February, laid out a century and a half of science and, in its chapter on injuries, contradicted the usual image of yoga as completely safe. The yoga establishment makes billions of dollars by selling itself as a path to healthy perfection. Predictably, it responded with sharp denials.


I also received a surprising number of moving replies from injured yogis — male and female — including stroke victims.


A letter initiated my inquiry. In April, a man told how an agonizing back injury had turned his life into “a living hell.” Too many instructors, he wrote, are “pushing us too hard and having us do dangerous poses.”


The “us” resonated.


Suddenly, I realized his cry sounded familiar.


I raced through a correspondence file and saw that many of the letters about serious damage had come from men.


Tara Stiles, a yoga teacher who runs a popular studio in Manhattan, told me that guys have more muscle (one reason for their relative inflexibility) and can thus force themselves into challenging poses they might otherwise find impossible. It seemed a plausible explanation for blinding pain.


Other teachers echoed her analysis and cited supporting anecdotes.


Yoga poses are unisex. But in my research, I found a world of poorly known information on gender disparity.


“Science of Flexibility,” by Michael J. Alter, explained how the pelvic regions of women are shaped in a way that permits an unusually large range of motion and joint play. In yoga, the pelvis is the central pivot for extreme bending of the legs, spine and torso.


In June, I turned to the Consumer Product Safety Commission and its National Electronic Injury Surveillance System, which monitors hospital emergency rooms. In July, officials sent me 18 years of annual survey data that summarized the admission records for yoga practitioners hurt between 1994 and 2011, the maximum available span.


First, I needed a baseline that would let me compare the guy admissions to males doing yoga in the United States. Figures in the yoga literature described men as making up some 10 percent of practitioners at the beginning of the period and 23 percent at the end. So the middle ground seemed to be roughly 16 percent.


Then I dug into the medical data. The analysis took weeks, but the results spoke volumes.


William J. Broad is a science reporter for The New York Times and the author of “The Science of Yoga: The Risks and the Rewards.”



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Syrian Resort Town Is Stronghold for Alawites





TARTUS, Syria — Loyalists who support the government of President Bashar al-Assad are flocking to the Mediterranean port of Tartus, creating an overflowing boomtown far removed from the tangled, scorched rubble that now mars most Syrian cities.







The New York Times

The port city of Tartus is sheltered by a mountain range.






There are no shellings or air raids to interrupt the daily calm. Families pack the cafes lining the town’s seaside corniche, usually abandoned in December to the salty winter winds. The real estate market is brisk. A small Russian naval base provides at least the impression that salvation, if needed, is near.


Many of the new residents are members of the Alawite minority, the same Shiite Muslim sect to which Mr. Assad belongs. The latest influx is fleeing from Damascus, people who have decided that summer villas, however chilly, are preferable to the looming battle for the capital.


“Going to Tartus is like going to a different country,” said a Syrian journalist who recently met residents here. “It feels totally unaffected and safe. The attitude is, ‘We are enjoying our lives while our army is fighting overseas.’ ”


Should Damascus fall to the opposition, Tartus could become the heart of an attempt to create a different country. Some expect Mr. Assad and the security elite will try to survive the collapse by establishing a rump Alawite state along the coast, with Tartus as their new capital.


There have been various signs of preparations.


This month, the governor of Tartus Province announced that experts were studying how to develop a tiny local airfield, now used mostly by crop-dusters, into a full-fledged civilian airport “to boost transportation, business, travel and tourism,” as the official Syrian news agency, SANA, reported. The announcement coincided with the first attacks on the airport in Damascus, forcing it to close temporarily to international traffic.


More important, security forces are continuously tightening an extensive ring of checkpoints around the potential borders of an Alawite canton. The mountain heartland of the Alawites rises steeply to the east of Tartus, separating it from much of Syria. Across the mountains, the Orontes River creates a rough line separating Alawite territory from central Syria. Rebel military commanders from adjoining Hama Province said government soldiers vigorously maintain checkpoints on routes leading up into the mountains.


“If we bomb a checkpoint, it is back in place sometimes within hours,” said Basil al-Hamwi, a rebel fighter, speaking on the sidelines of a meeting of opposition military commanders in Turkey. “Once, in Hama Province, we destroyed five in one day and they were all back the next day. This area is even more important for them than Damascus.”


Mr. Hamwi and other commanders said there were about 40 government checkpoints along more than 60 miles in Homs and Hama Provinces alone. Many Alawite commanders of Mr. Assad’s army have sent their families to their home villages, so they are particularly aggressive in protecting the area, said Hassan M. al-Saloom, a rebel battalion commander. They have formed committees to guard the outskirts of their villages, he said, and often negotiate local truces.


“Nobody goes inside, and they don’t come out,” he said.


There are widespread suspicions within the opposition that the military is shipping weapons into the Alawite hinterland, or has already positioned them. “The mountains and the coast make it hard to raid,” Mr. Saloom said.


Castles left by the Crusaders dot the coastal range, a testament to its strategic value.


If Mr. Assad fled to Tartus, he could seek protection from the Russian naval base here, or flee aboard a Russian vessel. Russia announced Tuesday that it was sending a small flotilla toward Tartus, possibly to evacuate its citizens who live in Syria. But Tartus residents said that the Russian families from the naval base had already left, while the officers do not leave the base, which is little more than an enclosure near the civilian port.


An employee of The New York Times reported from Tartus, and Neil MacFarquhar from Antakya, Turkey. Hania Mourtada contributed reporting from Beirut, Lebanon, and Hala Droubi from Dubai, United Arab Emirates.



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Massive PC, Console Game Discounts Ring in Holiday Season






Black Friday, the day right after Thanksgiving, is normally the day associated with electronics sales. And while the proponents of “Cyber Monday” and “Small Business Saturday” have tried to get in on the action, it’s still common knowledge that Thanksgiving weekend is the best time to upgrade your PC or console game arsenal. Right?


Not according to online game retailers. Discounts of up to 80 percent off a game’s retail price are taking place across the web, especially in online stores which offer games in the form of digital downloads (which cost nothing to make extra copies of). Here’s a look at just a few of the sales going on right now, for Windows and Linux PCs, Macs, game consoles, and mobile devices.






Steam (Windows, Linux, Mac)


The annual Steam Holiday Sale is under way, and it’s not just blowing hot air. Complete collections of every Steam game from publishers including Valve are on sale for around the price of one retail title, and individual games can be bought from each bundle for only a few dollars. Each day new sales are available, and most of them are massive, percentage-wise. They’re tied to a personal Steam account (which will always be linked to the original name they were created with), but can be bought as gifts for others.


Also check out: Amazon.com’s PC download sales, many of which are fulfilled through Steam and are discounted about as much. Amazon’s lineup also includes many casual games, of the “$ 10 store discount rack” variety.


Humble Indie Bundle 7 (Windows, Linux, Mac)


The Humble Bundle crew has been offering cross-platform, name-your-own-price bundles of indie games for several years now, and their seventh numbered offering is timed right for the holiday season. Bundles are giftable, the games can be played on Steam, and you can choose how much of your purchase price goes to game developers and how much goes to select charities.


PlayStation Network (PS3, PSP, Vita)


Console gamers aren’t being left out. The PSN Holiday Essentials sale is putting “more than 40 titles” on sale over the next three weeks, with a new selection available every week and even lower prices available to PlayStation Plus members.


Also check out: The Xbox Live Countdown to 2013 sale, with a “Daily Deal” every day until the end of the year.


Other sales


Game publishers SEGA and Square-Enix are discounting many of their most popular titles. SEGA’s holiday sale includes PSN, Xbox Live, Android and iOS titles, with most of its mobile games selling for $ 0.99. Meanwhile, the Square-Enix Winter of Mobile sale page lists huge discounts on iPhone and iPad games, while Android Police blogger Jeremiah Rice has put together a list of which Square-Enix Android games are on sale.


Jared Spurbeck is an open-source software enthusiast, who uses an Android phone and an Ubuntu laptop PC. He has been writing about technology and electronics since 2008.
Linux/Open Source News Headlines – Yahoo! News





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Temple upsets No. 3 Syracuse 83-79


NEW YORK (AP) — Khalif Wyatt had never been in Madison Square Garden let alone played there.


The Philadelphia native left the building on Saturday after scoring a career-high 33 points and being the key to Temple beating No. 3 Syracuse 83-79 in the first Chevrolet Gotham Classic.


"I always wanted to play here because all the great players had a chance to play here," the 6-foot-4 senior said. "This was a chance for us to show everyone that Temple is a real program."


Anthony Lee had a career-high 21 points for the Owls (9-2), who were coming off a 10-point home loss to Canisius.


"I don't think we would have won today without the loss in the last game," Temple coach Fran Dunphy said. "Our guys did a great job today. I wish it was worth more than one victory."


This is the fifth straight season Temple has beaten a top 10 team while being unranked.


The latest win in that stretch game with the combination of Wyatt from the outside and Lee inside.


"We wanted to go inside and out and that meant me going up strong and fighting for rebounds," said Lee, who had nine rebounds, five offensive, and worked the baseline again and again against Syracuse's vaunted zone. "That's playing the Temple game."


Dunphy said Wyatt challenged himself after a poor game against Canisius.


"He made some really good plays when we were struggling to score and had to stay in the game," Dunphy said.


The Orange led by two at halftime but never took a lead in the second half even though there were four ties, the last at 59-59 with 10:23 to play.


C.J. Fair had a career-high 25 points for Syracuse (10-1), which had its 52-game regular-season nonconference winning streak snapped. Jim Boeheim remained at 900 wins, two behind Bob Knight for second place all-time among Division I men's coaches. Duke's Mike Krzyzewski has 938 wins.


Wyatt made all 15 of his free throw attempts and Lee was 11 of 14 as the Owls were 29 of 36 overall.


Syracuse was 19 of 34 from the line including missing four in the final 6 minutes when it was mostly a one-possession game and point guard Michael Carter-Williams finished 7 of 15.


"They made free throws, we didn't," Boeheim said. "You don't like to say it comes down to that, but when you miss 15 free throws it's tough to win any game."


Carter-Williams took the heat.


"If I make free throws we win the game," he said.


Temple hit three 3-pointers in an 11-3 run that gave it the lead for good. Scootie Randall started the run with a 3 that broke the 59-all tie. He closed the run with another 3, his only points of the game.


The 3-point line also hurt the Orange, who were 2 of 12 from behind the arc while Temple was 8 of 24.


"It was one of those nights when it wouldn't fall," said Fair, whose only 3-point attempt of the game brought the Orange within 74-72 with 3:01 left but the Owls went 11 of 15 from the free throw line over the final 2:30.


Temple's last field goal was an offensive rebound by Quenton DeCosey with 5:41 left that gave the Owls a 72-66 lead.


Rahlir Hollis-Jefferson had four points and 10 rebounds for the Owls.


Brandon Triche had 17 points for Syracuse. Baye Moussa Keita added 12 and Carter-Williams, who leads the nation in assists at 10.7 per game, had 13 points and six assists.


"Wyatt was able to create a lot of contact and that got him to the free throw line," Carter-Williams said. "They didn't play off me and I have to get used to that. We have to learn from this. It's a long season."


Temple missed 10 of its first 12 shots in falling behind 19-10. The Owls, behind Wyatt who had 20 points in the first half, started hitting shots against the Orange's zone defense and they made nine of their next 14 shots and tied the game at 35. Syracuse scored five straight points but Wyatt capped his big half with a 3-pointer with 17 seconds left and Temple was within 40-38 at halftime.


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Genetic Gamble : New Drugs Aim to Make Cells Destroy Cancer


C.J. Gunther for The New York Times


Dr. Donald Bergstrom is a cancer specialist at Sanofi, one of three companies working on a drug to restore a tendency of damaged cells to self-destruct.







For the first time ever, three pharmaceutical companies are poised to test whether new drugs can work against a wide range of cancers independently of where they originated — breast, prostate, liver, lung. The drugs go after an aberration involving a cancer gene fundamental to tumor growth. Many scientists see this as the beginning of a new genetic age in cancer research.




Great uncertainties remain, but such drugs could mean new treatments for rare, neglected cancers, as well as common ones. Merck, Roche and Sanofi are racing to develop their own versions of a drug they hope will restore a mechanism that normally makes badly damaged cells self-destruct and could potentially be used against half of all cancers.


No pharmaceutical company has ever conducted a major clinical trial of a drug in patients who have many different kinds of cancer, researchers and federal regulators say. “This is a taste of the future in cancer drug development,” said Dr. Otis Webb Brawley, the chief medical and scientific officer of the American Cancer Society. “I expect the organ from which the cancer came from will be less important in the future and the molecular target more important,” he added.


And this has major implications for cancer philanthropy, experts say. Advocacy groups should shift from fund-raising for particular cancers to pushing for research aimed at many kinds of cancer at once, Dr. Brawley said. John Walter, the chief executive officer of the Leukemia and Lymphoma Society, concurred, saying that by pooling forces “our strength can be leveraged.”


At the heart of this search for new cancer drugs are patients like Joe Bellino, who was a post office clerk until his cancer made him too sick to work. Seven years ago, he went into the hospital for hernia surgery, only to learn he had liposarcoma, a rare cancer of fat cells. A large tumor was wrapped around a cord that connects the testicle to the abdomen. “I was shocked,” he said in an interview this summer.


Companies have long ignored liposarcoma, seeing no market for drugs to treat a cancer that strikes so few. But it is ideal for testing Sanofi’s drug because the tumors nearly always have the exact genetic problem the drug was meant to attack — a fusion of two large proteins. If the drug works, it should bring these raging cancers to a halt. Then Sanofi would test the drug on a broad range of cancers with a similar genetic alteration. But if the drug fails against liposarcoma, Sanofi will reluctantly admit defeat.


“For us, this is a go/no-go situation,” said Laurent Debussche, a Sanofi scientist who leads the company’s research on the drug.


The genetic alteration the drug targets has tantalized researchers for decades. Normal healthy cells have a mechanism that tells them to die if their DNA is too badly damaged to repair. Cancer cells have grotesquely damaged DNA, so ordinarily they would self-destruct. A protein known as p53 that Dr. Gary Gilliland of Merck calls the cell’s angel of death normally sets things in motion. But cancer cells disable p53, either directly, with a mutation, or indirectly, by attaching the p53 protein to another cellular protein that blocks it. The dream of cancer researchers has long been to reanimate p53 in cancer cells so they will die on their own.


The p53 story began in earnest about 20 years ago. Excitement ran so high that, in 1993, Science magazine anointed it Molecule of the Year and put it on the cover. An editorial held out the possibility of “a cure of a terrible killer in the not too distant future.”


Companies began chasing a drug to restore p53 in cells where it was disabled by mutations. But while scientists know how to block genes, they have not figured out how to add or restore them. Researchers tried gene therapy, adding good copies of the p53 gene to cancer cells. That did not work.


Then, instead of going after mutated p53 genes, they went after half of cancers that used the alternative route to disable p53, blocking it by attaching it to a protein known as MDM2. When the two proteins stick together, the p53 protein no longer functions. Maybe, researchers thought, they could find a molecule to wedge itself between the two proteins and pry them apart.


The problem was that both proteins are huge and cling tightly to each other. Drug molecules are typically tiny. How could they find one that could separate these two bruisers, like a referee at a boxing match?


In 1996, researchers at Roche noticed a small pocket between the behemoths where a tiny molecule might slip in and pry them apart. It took six years, but Roche found such a molecule and named it Nutlin because the lab was in Nutley, N.J.


But Nutlins did not work as drugs because they were not absorbed into the body.


Roche, Merck and Sanofi persevered, testing thousands of molecules.


At Sanofi, the stubborn scientist leading the way, Dr. Debussche, maintained an obsession with p53 for two decades. Finally, in 2009, his team, together with Shaomeng Wang at the University of Michigan and a biotech company, Ascenta Therapeutics, found a promising compound.


The company tested the drug by pumping it each day into the stomachs of mice with sarcoma.


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Preoccupations: When Relocation Is a Way of Life





ON New Year’s Day, the company I work for, Four Seasons Hotels and Resorts, will move me from Washington to Paris, where I will become a regional vice president of the company and general manager of the Hotel George V, which it manages.







Daniel Rosenbaum for The New York Times

Gathering the frequent-mover miles: From left are Christian and Meg Clerc, and their daughters, Eleanor and Georgia, at home in Washington.







My wife, Meg, teaches at a Montessori school. She and our teenage daughters, Eleanor and Georgia, will reunite with me at the end of the school year. It’s the seventh move for Meg and me: about every three years for the last two decades, we’ve packed and unpacked, and left newfound schools, friends, cars, dry cleaners, banks and homes, and found newer ones.


If you want to advance in the hotel industry, you’d better be able to check “yes” next to the box that asks, “Willing to relocate?” Mobility must be in your DNA if you want to move up. Originally from Switzerland, I myself have moved eight times over 25 years of working in hotels, rising from hotel restaurant food runner to hotel general manager: from Gstaad to Lausanne, Switzerland; then to Washington, Rome, Paris and back to Washington, then to Puerto Vallarta, Mexico, and to Chicago and Washington once more. Eleanor, now 17, was born in Rome. Georgia, 14, joined the journey on our first assignment in Washington.


Meg knew the score — and welcomed the global lifestyle — when she married me. In fact, she chose a mobile career herself, knowing that there would be Montessori schools worldwide.


The company provides good logistical support when it moves its employees. And on the home front, we have grown increasingly adaptive, and the moves have become easier over the years. The process begins when I first realize that a move may be in the works. Meg and I go out for lunch or coffee and review our trusty to-do list to become move-ready. Then we take our daughters out to lunch or dinner and broach the subject, beginning with “How would you feel if we moved to X?”


The worst reaction was when we planned to move back to Washington from Chicago less than a year after arriving there from Mexico. We thought the girls would be thrilled to reunite with friends in a familiar place. We thought wrong. In unison, they broke out in tears; they had just made new friends and were starting to fit in again.


Meg, so skilled at working with children as a teacher, had them talk about the roots of their fears and sadness, which usually revolve around establishing new social networks. I, racked by guilt about upsetting their cart again, blurted that they could get the puppy they had been begging for. (I had been adamantly opposed until then.) The tears stopped. Needless to say, our pup, Snickers, will be moving to Paris, too.


To stay sane at relocation time, we keep the house we’re in as homey as possible until we move, then turn the new house into a home as fast as we can. That way, we don’t have to stare at cardboard boxes on both ends of the trip. We can pack in two weeks.


Moving makes you prioritize what’s important. You have to decide what’s crucial enough to bring, and what’s marginal enough to leave behind. With friends, you have to choose those to see before you go, and the ones you want to stay in touch with after the move.


Each of us has certain things we take along — our “transitional objects.” For example, I need the big wooden credenza that’s been in my family for generations, a great coffee machine, my A.S. Roma soccer-club shirt and my watch box — after all, I am Swiss. For Meg, it’s not about things, but about creating a cozy, well-lit new space. The girls still bring their favorite stuffed animals along with photos, but their most important transitional object is each other.


BUILDING a new network of friends can be as daunting for Meg and me as it is for the girls. We’ve found friends among new work colleagues and through tight-knit expat communities. But there’s a danger of getting stuck in a cultural bubble and never befriending local people.


Our moves have brought us a great appreciation of cultural differences. The ability to adapt quickly to change helps in all kinds of situations. The moves have also prepared our daughters to make new friends quickly. Still, we wonder and worry how it will affect their future relationships. Will they have trouble forming long-lasting bonds?


We find inspiration, meanwhile, in
the lyrics of “You’re My Home,” the Billy Joel song: “I never had a place that I could call my very own, but that’s
all right, my love, ’cause you’re my home.”


As told to Perry Garfinkel.



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U.N. Panel Votes to Help Mali’s Army Oust Extremists





The United Nations Security Council unanimously approved a resolution on Thursday that will send thousands of African troops into the desert nation of Mali to help oust Islamist extremists who have turned its northern half into a vast Qaeda enclave and training ground, menacing the stability of neighboring states and posing a potent new international terrorism threat.




But the resolution also makes it clear that such a military intervention will not happen until Mali’s own dysfunctional army is adequately trained and a framework for political stability and elections is restored in the country, which has been in turmoil since a military coup in March.


The resolution, which was sponsored by France, the former colonial power in Mali, does not specify a time frame for the first deployment of foreign troops, to be supplied by a group of West African nations that are eager to see calm restored in Mali. United Nations officials and diplomats who worked on the resolution said that a 3,300-soldier force would be sent, and that any attempt to drive the Islamists from northern Mali would not happen before September or October at the earliest.


The resolution does not explain precisely how the military expedition, which is to last for an initial period of one year, will be financed, although diplomats said they expected the cost to exceed $200 million. The resolution calls for voluntary contributions from member states into a trust fund to be created by Secretary General Ban Ki-moon.


Despite the caveats, the Security Council’s vote authorizing military force, which it is empowered to do by the United Nations Charter, represented a rare moment of decisive unanimity among its 15 member states and in particular its 5 permanent members — Britain, China, France, Russia and the United States — in a year punctuated by bitter disagreements, mostly over the Syrian conflict.


“Everyone knows the complexity of the task facing the international community to restore the territorial integrity of Mali and to put an end to terrorist activities in the north of the country,” GĂ©rard Araud, France’s ambassador, told reporters after the vote. The resolution, he said, “provides a reasonable answer.”


Ideally, Mr. Araud said, the mere threat of military intervention would persuade Islamist militia leaders to negotiate a peaceful restoration of control by Mali’s central government. “It is premature to indicate when the military operation will take place,” he said. “In fact, the question is even whether the military operation will take place. Our goal would be to have a real political process which will allow the Malian Army to go back to its barracks in the northern part of the country without fighting.”


The final version of the resolution reflected what diplomats called some compromises between France and the United States, which had been skeptical that the Malian Army could be made capable of participating in a potentially long and violent struggle to retake the country’s northern area, roughly twice the size of Germany.


The resolution specifies that the European Union will be responsible for training the Malian forces, described as “vital to ensure Mali’s long-term security and stability.” It also specifies that the secretary general must regularly inform the Council on political and military-training progress, and “confirm in advance the Council’s satisfaction with the planned military offensive operation.”


Language was also included specifically intended to guard against human rights abuses by the Malian military in any operation in the north, where ethnic tensions linked to the occupation by Islamist militants are known to be on the rise. A report released Thursday by Human Rights Watch enumerated instances of abuses in Mali committed by security forces and others since the military coup.


Tens of thousands of Malians have fled the north since Islamist militias seized control there after the coup, which left a power vacuum that has yet to be resolved. Just last week, military generals forced the resignation of Prime Minister Cheick Modibo Diarra, in office since April.


The principal Islamist militia, known as Ansar Dine, or Defenders of the Faith, has imposed harsh Shariah law based on strict Islamic tenets and enforced it with public killings, stonings and amputations. The group has also welcomed Al Qaeda in the Islamic Maghreb, the affiliate of Al Qaeda in northern Africa, which has recruited child soldiers, established training camps and reached out to other militant Islamist organizations, including Boko Haram, a particularly violent group in northern Nigeria.


Rights activists monitoring the Mali crisis had a mixed reaction to the Security Council resolution. While they welcomed action against abuses by the Islamists, some expressed concern that the Malian Army, humiliated by the loss of half the country, would be bent on revenge.


Michael Quinn, country director of the aid group Oxfam in Mali, said the Security Council “must make sure that any military planning includes humanitarian consideration to minimize harm to civilians at all stages.”


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