South Africa’s President Says Mandela Looking ‘Much Better’

JOHANNESBURG — President Jacob Zuma of South Africa gave a largely upbeat assessment on Tuesday of the health of Nelson Mandela, the nation’s first black president and anti-apartheid icon, who has spent more than two weeks in the hospital for a lung infection and gallstones.

Mr. Zuma said in a statement that Mr. Mandela, 94, “is looking much better” and that “the doctors are happy with the progress he is making.”

The president visited Mr. Mandela on Christmas morning at a Pretoria hospital along with Mr. Mandela’s wife, the children’s rights activist Graça Machel.

“We found him in good spirits,” Mr. Zuma said in the statement. “He shouted my clan name, Nxamalala, as I walked into the ward.”

Mr. Mandela has been in increasingly frail health, and his latest hospitalization has been the longest since he was released from prison in 1990. His health is closely watched; local news organizations have been camped outside the hospital.

He has suffered recurrent lung infections, a legacy of the tuberculosis he contracted in prison. The government tightly controls information about his condition, releasing only occasional updates. When Mr. Mandela was first hospitalized on Dec. 8, the government said that he was in no danger, but Mr. Zuma later said that Mr. Mandela’s condition was serious.

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U.S. Civilian Is Killed at Police Headquarters in Kabul

KABUL, Afghanistan — A woman identified as a police officer shot and killed an American civilian adviser at police headquarters in Kabul on Monday, Afghan police officials said, breaking a relative lull in the so-called insider killings that have strained the relationship between Americans and Afghans here.

Shah Marai/Agence France-Presse — Getty Images

Afghan policemen at the site where a female police officer reportedly shot and killed an American civilian adviser on Monday.

A spokesman for the American-led NATO force in Afghanistan, Col. Thomas W. Collins, confirmed that the attack had taken place but said that the victim’s name was being withheld according to military policy. He described the attacker as “a suspected member of the Afghan uniformed police” and said the suspect was in Afghan custody.

Insider attacks, in which members of the Afghan security services have turned against their foreign allies, have greatly increased in the past year, with 61 American and other coalition members killed, not including the episode on Monday, compared with 35 deaths the previous year, according to NATO figures.

Monday’s attack — the first insider attack known to be committed by a woman — came after a lull in insider shootings after the military instituted a series of precautions meant to reduce them. The most recent episode was on Nov. 11, when a British soldier was killed in Helmand Province.

A person at Kabul police headquarters, where the shooting occurred at about 10 a.m., said the suspect, a woman named Nargis, was a police officer who had been detached to work in the Interior Ministry’s legal and gender equality department. The person, who spoke on condition of anonymity because he was not authorized to release information, said the attacker had used a pistol and had shot the adviser, an engineer working in construction, in the head at close range.

He said the suspect had been arrested at the scene by Afghan police officers. Although the person did not specify a motive, he said that it was not related to terrorism and that the suspect had no known connections with insurgents.

American and Afghan officials have been struggling to figure out how large a factor Taliban infiltration or coercion has been in the increase in insider killings this year. Although insurgent contact has been clear in some cases, many of the attacks have seemed to come out of personal animosity or outrage, attributed to culture clash or growing Afghan anger at what they see as an unwelcome occupation by the United States and its allies.

In other violence on Monday, a coalition member was killed in an insurgent attack in eastern Afghanistan, and an Afghan Local Police commander killed five fellow officers at a checkpoint in Jowzjan Province in the north. Dur Mohammad, the commander at the checkpoint, shot and killed five officers under his command, according to Gen. Abdul Aziz Ghairat, the provincial police chief. He said the commander fled after the shooting. General Ghairat did not offer a motive but said that Mr. Mohammad had connections with the Taliban in the area.

The Afghan Local Police program, which seeks to bring armed elements — including some former insurgents — into government service, has drawn criticism because of a series of episodes in which the armed elements have switched allegiances, sometimes repeatedly.

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Tepid Sales of Microsoft’s Windows 8 Point to Shaky Market

Mario Tama/Getty Images

Viewing Windows 8 in New York upon its debut in October.

BELLEVUE, Wash. — It used to be that a new version of the Windows operating system was enough to get people excited about buying a new computer, giving sales a nice pop.

Ted S. Warren/Associated Press

One researcher said sales of Windows devices were down compared with last year.

Not this time. Windows 8, the latest edition of Microsoft’s software, failed to pack shoppers into a Microsoft store in a mall here last week, at a time when parking lots in the area were overflowing. The trickle of shopping bags leaving the store with merchandise was nothing like the steady stream at a bustling Apple store upstairs.

Claude Ballard was among the customers at the Microsoft store who tried out Surface, a new Microsoft-designed Windows tablet. Mr. Ballard, who described himself as a “semiretired” computer systems manager for a real estate firm, said he was intrigued by the eye-catching design of Windows 8 — but not enough to scrimp to buy a new computer this year.

“It’s economics, really,” he said. “It’s going to be a better year for my mechanic than it is for me.”

Weak PC sales this holiday season suggest that the struggles of Microsoft and other companies that depend heavily on the computer business will not abate soon. Plenty of consumers already own PCs and seem content to make do with what they have, especially in a shaky economy in which less expensive mobile devices are bidding for a share of their wallets.

While there are also many tablets running Microsoft’s new, touch-friendly Windows, they have so far failed to emerge from the shadow of competing products from Apple and Amazon and other devices that are being snapped up by holiday shoppers.

Emmanuel Fromont, president of the Americas division of Acer, the world’s No. 4 PC maker, said sales of the company’s Windows 8 PCs had been lower than expected. He said one factor was the system’s unfamiliar design, which appeared to be making consumers cautious.

“There was not a huge spark in the market,” Mr. Fromont said. “It’s a slow start, there’s no question.”

The clearest evidence of Windows 8’s disappointing introduction comes from the research firm NPD, which estimates that sales of Windows machines have actually dropped from a year ago.

According to NPD, stores in the United States sold 13 percent fewer Windows devices from late October, when Windows 8 made its debut, through the first week in December, than in the same period last year.

Those figures do not include sales in Microsoft’s own stores, which were the only place to buy a Surface tablet during that period, but because the stores are scarce, analysts believe it is unlikely they made a big difference.

“I think everybody would have hoped for a better start,” said Stephen Baker, an analyst at NPD. “The thing is, this market is not the same market that Windows 7 or Vista or even XP launched into.”

Those earlier versions of Windows all came out during periods when the PC’s status as the center of computing seemed far more secure. In the intervening years, smartphones and tablets have become much more serious rivals for a share of consumer spending on technology. Sales of PCs have been declining for much of the year.

While most people are not getting rid of their PCs altogether in favor of mobile devices, analysts believe they are postponing purchases of new ones.

“What you’re seeing is not a retirement of PCs, but a push-out in the replacement cycle,” said A. M. Sacconaghi, an analyst at Sanford C. Bernstein. “If people used to buy PCs every four years and are now buying them every five years, that could lower PC sales by 20 percent over time. That’s substantial.”

Mr. Sacconaghi predicted that global PC shipments would be down 3 percent in 2012.

The shift in spending to tablets is one reason that Windows 8 is so critical for Microsoft’s future. The company overhauled its operating system with a radically different, tile-based interface that is easier to navigate on touch-screen devices. Microsoft intends the software to be flexible enough that it can still be used on conventional laptops and desktops, including newer models with touch screens.

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N.Y.U. and Others Offer Shorter Courses Through Medical School

Training to become a doctor takes so long that just the time invested has become, to many, emblematic of the gravity and prestige of the profession.

But now one of the nation’s premier medical schools, New York University, and a few others around the United States are challenging that equation by offering a small percentage of students the chance to finish early, in three years instead of the traditional four.

Administrators at N.Y.U. say they can make the change without compromising quality, by eliminating redundancies in their science curriculum, getting students into clinical training more quickly and adding some extra class time in the summer.

Not only, they say, will those doctors be able to hang out their shingles to practice earlier, but they will save a quarter of the cost of medical school — $49,560 a year in tuition and fees at N.Y.U., and even more when room, board, books, supplies and other expenses are added in.

“We’re confident that our three-year students are going to get the same depth and core knowledge, that we’re not going to turn it into a trade school,” said Dr. Steven Abramson, vice dean for education, faculty and academic affairs at N.Y.U. School of Medicine.

At this point, the effort involves a small number of students at three medical schools: about 16 incoming students at N.Y.U., or about 10 percent of next year’s entering class; 9 at Texas Tech Health Science Center School of Medicine; and even fewer, for now, at Mercer University School of Medicine’s campus in Savannah, Ga. A similar trial at Louisiana State University has been delayed because of budget constraints.

But Dr. Steven Berk, the dean at Texas Tech, said that 10 or 15 other schools across the country had expressed interest in what his university was doing, and the deans of all three schools say that if the approach works, they will extend the option to larger numbers of students.

“You’re going to see this kind of three-year pathway become very prominent across the country,” Dr. Abramson predicted.

The deans say that getting students out the door more quickly will accomplish several goals. By speeding up production of physicians, they say, it could eventually dampen a looming doctor shortage, although the number of doctors would not increase unless the schools enrolled more students in the future.

The three-year program would also curtail student debt, which now averages $150,000 by graduation, and by doing so, persuade more students to go into shortage areas like pediatrics and internal medicine, rather than more lucrative specialties like dermatology.

The idea was supported by Dr. Ezekiel J. Emanuel, a former health adviser to President Obama, and a colleague, Victor R. Fuchs. In an editorial in the Journal of the American Medical Association in March, they said there was “substantial waste” in the nation’s medical education. “Years of training have been added without evidence that they enhance clinical skills or the quality of care,” they wrote. They suggested that the 14 years of college, medical school, residency and fellowship that it now takes to train a subspecialty physician could be reduced by 30 percent, to 10 years.

That opinion, however, is not universally held. Other experts say that a three-year medical program would deprive students of the time they need to delve deeply into their subjects, to consolidate their learning and to reach the level of maturity they need to begin practicing, while adding even more pressure to a stressful academic environment.

“The downside is that you are really tired,” said Dr. Dan Hunt, co-secretary of the Liaison Committee on Medical Education, the accrediting agency for medical schools in the United States and Canada. But because accreditation standards do not dictate the fine points of curriculum, the committee has approved N.Y.U.’s proposal, which exceeds by five weeks its requirement that schools provide at least 130 weeks of medical education.

The medical school is going ahead with its three-year program despite the damage from Hurricane Sandy, which forced NYU Langone Medical Center to evacuate more than 300 patients at the height of the storm and temporarily shut down three of its four main teaching hospitals.

Dr. Abramson of N.Y.U. said that postgraduate training, which typically includes three years in a hospital residency, and often fellowships after that, made it unnecessary to try to cram everything into the medical school years. Students in the three-year program will have to take eight weeks of class before entering medical school, and stay in the top half of their class academically. Those who do not meet the standards will revert to the four-year program.

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N.Y.U. and Others Offer Shorter Courses Through Medical School

Training to become a doctor takes so long that just the time invested has become, to many, emblematic of the gravity and prestige of the profession.

But now one of the nation’s premier medical schools, New York University, and a few others around the United States are challenging that equation by offering a small percentage of students the chance to finish early, in three years instead of the traditional four.

Administrators at N.Y.U. say they can make the change without compromising quality, by eliminating redundancies in their science curriculum, getting students into clinical training more quickly and adding some extra class time in the summer.

Not only, they say, will those doctors be able to hang out their shingles to practice earlier, but they will save a quarter of the cost of medical school — $49,560 a year in tuition and fees at N.Y.U., and even more when room, board, books, supplies and other expenses are added in.

“We’re confident that our three-year students are going to get the same depth and core knowledge, that we’re not going to turn it into a trade school,” said Dr. Steven Abramson, vice dean for education, faculty and academic affairs at N.Y.U. School of Medicine.

At this point, the effort involves a small number of students at three medical schools: about 16 incoming students at N.Y.U., or about 10 percent of next year’s entering class; 9 at Texas Tech Health Science Center School of Medicine; and even fewer, for now, at Mercer University School of Medicine’s campus in Savannah, Ga. A similar trial at Louisiana State University has been delayed because of budget constraints.

But Dr. Steven Berk, the dean at Texas Tech, said that 10 or 15 other schools across the country had expressed interest in what his university was doing, and the deans of all three schools say that if the approach works, they will extend the option to larger numbers of students.

“You’re going to see this kind of three-year pathway become very prominent across the country,” Dr. Abramson predicted.

The deans say that getting students out the door more quickly will accomplish several goals. By speeding up production of physicians, they say, it could eventually dampen a looming doctor shortage, although the number of doctors would not increase unless the schools enrolled more students in the future.

The three-year program would also curtail student debt, which now averages $150,000 by graduation, and by doing so, persuade more students to go into shortage areas like pediatrics and internal medicine, rather than more lucrative specialties like dermatology.

The idea was supported by Dr. Ezekiel J. Emanuel, a former health adviser to President Obama, and a colleague, Victor R. Fuchs. In an editorial in the Journal of the American Medical Association in March, they said there was “substantial waste” in the nation’s medical education. “Years of training have been added without evidence that they enhance clinical skills or the quality of care,” they wrote. They suggested that the 14 years of college, medical school, residency and fellowship that it now takes to train a subspecialty physician could be reduced by 30 percent, to 10 years.

That opinion, however, is not universally held. Other experts say that a three-year medical program would deprive students of the time they need to delve deeply into their subjects, to consolidate their learning and to reach the level of maturity they need to begin practicing, while adding even more pressure to a stressful academic environment.

“The downside is that you are really tired,” said Dr. Dan Hunt, co-secretary of the Liaison Committee on Medical Education, the accrediting agency for medical schools in the United States and Canada. But because accreditation standards do not dictate the fine points of curriculum, the committee has approved N.Y.U.’s proposal, which exceeds by five weeks its requirement that schools provide at least 130 weeks of medical education.

The medical school is going ahead with its three-year program despite the damage from Hurricane Sandy, which forced NYU Langone Medical Center to evacuate more than 300 patients at the height of the storm and temporarily shut down three of its four main teaching hospitals.

Dr. Abramson of N.Y.U. said that postgraduate training, which typically includes three years in a hospital residency, and often fellowships after that, made it unnecessary to try to cram everything into the medical school years. Students in the three-year program will have to take eight weeks of class before entering medical school, and stay in the top half of their class academically. Those who do not meet the standards will revert to the four-year program.

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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 rebel leaders 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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Amazon Book Reviews Deleted in a Purge Aimed at Manipulation

Giving raves to family members is no longer acceptable. Neither is writers’ reviewing other writers. But showering five stars on a book you admittedly have not read is fine.

After several well-publicized cases involving writers buying or manipulating their reviews, Amazon is cracking down. Writers say thousands of reviews have been deleted from the shopping site in recent months.

Amazon has not said how many reviews it has killed, nor has it offered any public explanation. So its sweeping but hazy purge has generated an uproar about what it means to review in an era when everyone is an author and everyone is a reviewer.

Is a review merely a gesture of enthusiasm or should it be held to a higher standard? Should writers be allowed to pass judgment on peers the way they have always done offline or are they competitors whose reviews should be banned? Does a groundswell of raves for a new book mean anything if the author is soliciting the comments?

In a debate percolating on blogs and on Amazon itself, quite a few writers take a permissive view on these issues.

The mystery novelist J. A. Konrath, for example, does not see anything wrong with an author indulging in chicanery. “Customer buys book because of fake review = zero harm,” he wrote on his blog.

Some readers differ. An ad hoc group of purists has formed on Amazon to track its most prominent reviewer, Harriet Klausner, who has over 25,000 reviews. They do not see how she can read so much so fast or why her reviews are overwhelmingly — and, they say, misleadingly — exaltations.

“Everyone in this group will tell you that we’ve all been duped into buying books based on her reviews,” said Margie Brown, a retired city clerk from Arizona.

Once a populist gimmick, the reviews are vital to making sure a new product is not lost in the digital wilderness. Amazon has refined the reviewing process over the years, giving customers the opportunity to rate reviews and comment on them. It is layer after layer of possible criticism.

“A not-insubstantial chunk of their infrastructure is based on their reviews — and all of that depends on having reviews customers can trust,” said Edward W. Robertson, a science fiction novelist who has watched the debate closely.

Nowhere are reviews more crucial than with books, an industry in which Amazon captures nearly a third of every dollar spent. It values reviews more than other online booksellers like Apple or Barnes & Noble, featuring them prominently and using them to help decide which books to acquire for its own imprints by its relatively new publishing arm.

So writers have naturally been vying to get more, and better, notices. Several mystery writers, including R. J. Ellory, Stephen Leather and John Locke, have recently confessed to various forms of manipulation under the general category of “sock puppets,” or online identities used to deceive. That resulted in a widely circulated petition by a loose coalition of writers under the banner, “No Sock Puppets Here Please,” asking people to “vote for book reviews you can trust.”

In explaining its purge of reviews, Amazon has told some writers that “we do not allow reviews on behalf of a person or company with a financial interest in the product or a directly competing product. This includes authors.” But writers say that rule is not applied consistently.

In some cases, the ax fell on those with a direct relationship with the author.

“My sister’s and best friend’s reviews were removed from my books,” the author M. E. Franco said in a blog comment. “They happen to be two of my biggest fans.” Another writer, Valerie X. Armstrong, said her son’s five-star review of her book, “The Survival of the Fattest,” was removed. He immediately tried to put it back “and it wouldn’t take,” she wrote.

In other cases, though, the relationship was more tenuous. Michelle Gagnon lost three reviews on her young adult novel “Don’t Turn Around.” She said she did not know two of the reviewers, while the third was a longtime fan of her work. “How does Amazon know we know each other?” she said. “That’s where I started to get creeped out.”

Mr. Robertson suggested that Amazon applied a broad brush. “I believe they caught a lot of shady reviews, but a lot of innocent ones were erased, too,” he said. He figures the deleted reviews number in the thousands, or perhaps even 10,000.

The explosion of reviews for “The 4-Hour Chef” by Timothy Ferriss shows how the system has evolved from something spontaneous to a means of marketing and promotion. On Nov. 20, publication day, dozens of highly favorable reviews immediately sprouted. Other reviewers quickly criticized Mr. Ferriss, accusing him of buying supporters.

He laughed off those suggestions. “Not only would I never do that — it’s unethical — I simply don’t have to,” he wrote in an e-mail, saying he had sent several hundred review copies to fans and potential fans. “Does that stack the deck? Perhaps, but why send the book to someone who would hate it? That doesn’t help anyone: not the reader, nor the writer.”

As a demonstration of social media’s grip on reviewing, Mr. Ferriss used Twitter and Facebook to ask for a review. “Rallying my readers,” he called it. Within an hour, 61 had complied.

A few of his early reviews were written by people who admitted they had not read the book but were giving it five stars anyway because, well, they knew it would be terrific. “I am looking forward to reading this,” wrote a user posting under the name mhpics.

A spokesman for Amazon, which published “The 4-Hour Chef,” offered this sole comment for this article: “We do not require people to have experienced the product in order to review.”

The dispute over reviews is playing out in the discontent over Mrs. Klausner, an Amazon Hall of Fame reviewer for the last 11 years and undoubtedly one of the most prolific reviewers in literary history.

Mrs. Klausner published review No. 28,366, for “A Red Sun Also Rises” by Mark Hodder. Almost immediately, it had nine critical comments. The first accused it of being “riddled with errors in grammar, spelling and punctuation.” The rest were no more kind. The Harriet Klausner Appreciation Society had struck again.

Mrs. Klausner, a 60-year-old retired librarian who lives in Atlanta, has published an average of seven reviews a day for more than a decade. “To watch her in action is unbelievable,” said her husband, Stanley. “You see the pages turning.”

Mrs. Klausner, who says ailments keep her home and insomnia keeps her up, scoffs at her critics. “You ever read a Harlequin romance?” she said. “You can finish it in one hour. I’ve always been a speed reader.” She has a message for her naysayers: “Get a life. Read a book.”

More than 99.9 percent of Mrs. Klausner’s reviews are four or five stars. “If I can make it past the first 50 pages, that means I like it, and so I review it,” she said. But even Stanley said, “She’s soft, I won’t deny that.”

The campaign against Mrs. Klausner has pushed down her reviewer ratings, which in theory makes her less influential. But when everything is subject to review, the battle is never-ending.

Ragan Buckley, an aspiring novelist active in the campaign against Mrs. Klausner under the name “Sneaky Burrito,” is a little weary. “There are so many fake reviews that I’m often better off just walking into a physical store and picking an item off the shelf at random,” she said.

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Genetic Gamble : Drugs Aim to Make Several Types of Cancer Self-Destruct

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.

Read More..

Genetic Gamble : Drugs Aim to Make Several Types of Cancer Self-Destruct

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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Genetic Gamble : Drugs Aim to Make Several Types of Cancer Self-Destruct

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.

Read More..