In Tiny Worm, Unlocking Secrets of the Brain

By NICHOLAS WADE NY TIMES In an eighth-floor laboratory overlooking the East River, Cornelia I. Bargmann watches two colleagues manipulate a microscopic roundworm. They have trapped it in a tiny groove on a clear plastic chip, with just its nose sticking into a channel. Pheromones — signaling chemicals produced by other worms — are being pumped through the channel, and the researchers have genetically engineered two neurons in the worm’s head to glow bright green if a neuron responds.

These ingenious techniques for exploring a tiny animal’s behavior are the fruit of many years’ work by Dr. Bargmann’s and other labs. Despite the roundworm’s lowliness on the scale of intellectual achievement, the study of its nervous system offers one of the most promising approaches for understanding the human brain, since it uses much the same working parts but is around a million times less complex.

Caenorhabditis elegans, as the roundworm is properly known, is a tiny, transparent animal just a millimeter long. In nature, it feeds on the bacteria that thrive in rotting plants and animals. It is a favorite laboratory organism for several reasons, including the comparative simplicity of its brain, which has just 302 neurons and 8,000 synapses, or neuron-to-neuron connections. These connections are pretty much the same from one individual to another, meaning that in all worms the brain is wired up in essentially the same way. Such a system should be considerably easier to understand than the human brain, a structure with billions of neurons, 100,000 miles of biological wiring and 100 trillion synapses.

The biologist Sydney Brenner chose the roundworm as an experimental animal in 1974 with this goal in mind. He figured that once someone provided him with the wiring diagram of how 302 neurons were connected, he could then compute the worm’s behavior.

The task of reconstructing the worm’s wiring system fell on John G. White, now at the University of Wisconsin. After more than a decade’s labor, which required examining 20,000 electron microscope cross sections of the worm’s anatomy, Dr. White worked out exactly how the 302 neurons were interconnected.

But the wiring diagram of even the worm’s brain proved too complex for Dr. Brenner’s computational approach to work. Dr. Bargmann was one of the first biologists to take Dr. White’s wiring diagram and see if it could be understood in other ways.

Cori Bargmann grew up in Athens, Ga., a small college town in the Deep South where her father taught statistics at the University of Georgia. Both her parents had been translators and met while Rolf Bargmann was working at the Nuremberg trials. Her mother, Ilse, would read to her in German the works of the Austrian animal behaviorists Konrad Lorenz and Karl von Frisch, planting the seeds of an interest in neuroscience.

“I went into science because I loved the labs,” Dr. Bargmann says. She liked the machines and instruments, the fun of building things with one’s own hands, of learning what no one else knew. An outstanding student, she chose for her Ph.D. degree to work in the M.I.T. lab of Robert A. Weinberg, a leading cancer biologist. The first mutated genes capable of causing cancer were being isolated. “It was an incredibly exciting time,” she says.

Her task was to clone a rat gene called neu. When mutated, the gene causes a tumor, but one that the rat’s immune system can attack and destroy. Several years later, the human version of neu, called HER-2, was found to be amplified in breast cancer, and its receptor protein product is the target of the artificial antibody known as Herceptin, a leading breast cancer drug.

For her postdoctoral work, Dr. Bargmann decided to work on animal behavior. The mouse is a standard organism for such studies, but she did not like hurting furry animals. “In Weinberg’s lab I would start to cry every time I had to do anything with a mouse,” she says. A nonfurry alternative was the fruit fly. She interviewed with a leading laboratory in California, but her husband at the time did not wish to move there.

That left the roundworm. There are now several hundred worm labs around the world, of which perhaps 30 or so, like Dr. Bargmann’s, focus on the worm’s nervous system. In 1987, “worms weren’t entirely respectable,” Dr. Bargmann says. But right there at M.I.T., H. Robert Horvitz had established one of the first serious worm labs in the United States. She joined his lab and read everything written on the worm, including all the back copies of the little field’s informal journal, The Worm Breeder’s Gazette.

She noticed that a particular behavior of C. elegans had been described but not well explored: it can taste waterborne chemicals and move toward those it finds attractive. Dr. White’s wiring diagram had been published the year before, in 1986. With this in hand, she told Dr. Horvitz she planned to identify which of the worm’s 302 neurons controlled its chemical-tracking behavior.

He thought the project was too ambitious, but said she could spend six months on the attempt. Each neuron in the worm’s brain is known, and is assigned a three letter name. Specific neurons can be identified under a microscope and zapped with a laser beam, allowing the neuron’s role to be deduced from whatever function the worm may seem to have lost.

Dr. Bargmann slogged her way through the task of killing each neuron one by one. Telling one neuron from another under the microscope is not easy. “It’s like knowing each grape in a bunch is different, but not quite being able to see it,” Dr. Horvitz said. “The first thing she had to do was learn the worm’s neuroanatomy, and she did so in a way only one other person has ever done.” (He was referring to John E. Sulston, who traced the lineage from the egg of all 959 cells in the adult worm’s body).

She discovered, by accident, the neurons that control the worm’s switch into hibernation, a survival strategy for when food is scarce or neighbors too many. Finally, she found the neurons that control taste, showing that without them the worm could not track chemicals, and that it retained this ability even if she killed all the other neurons in the worm’s body.

She also discovered that the worms have a sense of smell — the ability to detect airborne chemicals — as well as a sense of taste. Since worms eat bacteria that feed on decaying plants and carcasses, she figured they should be able to detect and home in on the aromas of putrefaction. The redolent draft from these experiments caused a certain degree of complaint in Dr. Horvitz’s lab. After she succeeded, she says, “Horvitz told me that my great strength as a scientist was that I could think like a worm.”

“Cori is talented beyond thinking like a worm,” Dr. Horvitz now says. “She can think like very few other people in a rigorous and creative way, and so has repeatedly developed new kinds of approaches.”

Dr. Bargmann moved in 1991 to the University of California, San Francisco, to start her own lab. She began by following up her finding that worms have a sense of smell. In 1991, Richard Axel and Linda Buck discovered the molecular basis for the sense of smell: there are about a thousand genes, at least in rats, that make odorant receptors, proteins that stud the olfactory nerves’ endings in the nose and respond to specific odors.

The C. elegans genome had just been decoded, and Dr. Bargmann was able to identify the worm’s odorant receptor genes. In fact, they have 2,000 of them, twice as many as the rat.

“This is what they do,” Dr. Bargmann says. The worm cannot see. Its world is one of smells, not sights. It needs to scent the soil bacteria that are its prey, while avoiding those that are poisonous to it. Ten percent of its genes are dedicated to making it a champion connoisseur of odors, mostly unpleasant.

With the odorant genes in hand, Dr. Bargmann could apply genetics to figuring out how the worm’s sense of smell worked. By working with mutant worms, she showed that a specific odor receptor recognizes a specific odor, a finding that was implied by the Axel-Buck discovery but that no one had managed to nail down.

She found that worms with a mutation in a gene called odr-10 could not smell diacetyl, a chemical that gives butter its odor and is also produced by a bacterium that is a favorite worm food. The odr-10 gene, which makes the odor receptor protein that detects diacetyl, is active in neurons that guide the worm toward a scent.

Dr. Bargmann switched things around so that odr-10 was expressed only in a neuron that detected scents repulsive to the worm. These worms backed away from the buttery odor, showing that it is not the odor receptors but the wiring of the nervous system itself that determines whether the worm deems an odor delicious or detestable.

This was a surprising result because most people thought that sensory information was perceived as neutral, with the brain deciding later from the context whether it was good or bad. Some scientists said that only worms behave this way, but the same result was later obtained in mice.

Dr. Bargmann sees the arrangement in evolutionary terms. “The more reliable a piece of information is, the more it will be shifted into the genome,” she says. That way, an organism does not have to risk learning what is good or bad; the genes will dictate the right behavior by wiring it into the nervous system. Worms are wired up to know that diacetyl means good eating.

Having studied the worm by mutating its genes, Dr. Bargmann then looked at natural variation in the genetic basis of worm behavior. Most worms in nature like to congregate in clumps, but the laboratory version of C. elegans has developed an unusual liking for being on its own. She linked this difference in behavior to the switch of a single amino acid unit in a protein called npr-1 (for neuropeptide Y receptor-1).

It took several more years to learn how the system worked. It turns out that social behavior in the worm is controlled by a pair of neurons called RMG. The two RMG neurons receive input from various sensory neurons that detect the several environmental cues that make worms aggregate. RMG integrates this information and sends signals to the worm’s muscles.

The usual role of the RMG neurons is to promote social behavior, but when the npr-1 gene is active, the RMG neurons cannot receive input from their sensory neurons, and the worms switch to solitary behavior.

While working out the worm’s sense of smell, Dr. Bargmann fell in love with another olfactory researcher, Richard Axel. Dr. Axel works at Columbia University, and she was able to join him in New York by finding a place at Rockefeller University. Dr. Axel was helping her clear out her apartment in San Francisco when he heard he had won the Nobel Prize.

Right after that pleasant news, he had to drive to the local Goodwill store to drop off the stuff to be given away. “People think that if you’re married to a scientist you talk about science all the time,” Dr. Bargmann says. They read each other’s papers before publication, but they don’t plan experiments together. Dr. Axel works on how olfactory information is handled in the cortex, the highest level of human and mouse brains.

“Probably once or twice a week we are sitting at dinner and Richard says, ‘The cortex is hopeless,’ and I say, ‘That’s why I work on the worm.’ ” Dr. Bargmann said.

After studying the little animal for 24 years, she believes she is closer to understanding how its nervous system works.

Why is the wiring diagram produced by Dr. White so hard to interpret? She pulls down from her shelves a dog-eared copy of the journal in which the wiring was first described. The diagram shows the electrical connections that each of the 302 neurons makes to others in the system. These are the same kind of connections as those made by human neurons. But worms have another kind of connection.

Besides the synapses that mediate electrical signals, there are also so-called gap junctions that allow direct chemical communication between neurons. The wiring diagram for the gap junctions is quite different from that of the synapses.

Not only does the worm’s connectome, as Dr. Bargmann calls it, have two separate wiring diagrams superimposed on each other, but there is a third system that keeps rewiring the wiring diagrams. This is based on neuropeptides, hormonelike chemicals that are released by neurons to affect other neurons.

The neuropeptides probably help control the brain’s general status, or mood. A strong hint of how they work comes from the npr-1 gene, which makes a protein that responds to neuropeptides. When the npr-1 gene is active, its neuron becomes unavailable to its local circuit.

That may be a reason why the worm’s behavior cannot be computed from the wiring diagram: the pattern of connections is changing all the time under the influence of the worm’s 250 neuropeptides.

The connectome shows the electrical connections, and hence the quickest paths for information to move through the worm’s brain. “But if only a subset of neurons are available at any time, the connectome is ambiguous,” she says.

The human brain, too, has neuropeptides that set mood and modify behavior. Neuropeptides are probably at work when the pain pathways are cut off in acute crises, allowing people to function despite serious wounds.

The human brain, though vastly more complex than the worm’s, uses many of the same components, from neuropeptides to transmitters. So everything that can be learned about the worm’s nervous system is likely to help with the human system.

Though the worm’s nervous system is routinely described as simple, that is true only in comparison with the human brain. The worm has 22,000 genes, almost as many as a person, and its brain is a highly complex piece of biological machinery. The work of Dr. Bargmann’s and other labs has deconstructed many of its operational mechanisms.

What would be required to say that the worm’s nervous system was fully understood? “You would want to understand a behavior all the way through, and then how the behavior can change,” Dr. Bargmann says.

“That goal is not unattainable,” she adds.

This article has been revised to reflect the following correction:

Correction: June 20, 2011

A previous version of this article misstated the number of neurons in the human brain. The number is up to 100 billion, not 100 million.

After N.Y. Senate Vote, Governor Cuomo Signs Gay Marriage Bill

By NICHOLAS CONFESSORE and MICHAEL BARBARO NY TIMES

ALBANY — Lawmakers voted late Friday to legalize same-sex marriage, making New York the largest state where gay and lesbian couples will be able to wed and giving the national gay-rights movement new momentum from the state where it was born.

The marriage bill, whose fate was uncertain until moments before the vote, was approved 33 to 29 in a packed but hushed Senate chamber. Four members of the Republican majority joined all but one Democrat in the Senate in supporting the measure after an intense and emotional campaign aimed at the handful of lawmakers wrestling with a decision that divided their friends, their constituents and sometimes their own homes.

With his position still undeclared, Senator Mark J. Grisanti, a Republican from Buffalo who had sought office promising to oppose same-sex marriage, told his colleagues he had agonized for months before concluding he had been wrong.

“I apologize for those who feel offended,” Mr. Grisanti said, adding, “I cannot deny a person, a human being, a taxpayer, a worker, the people of my district and across this state, the State of New York, and those people who make this the great state that it is the same rights that I have with my wife.”

Senate approval was the final hurdle for the same-sex marriage legislation, which was approved last week by the Assembly. Gov. Andrew M. Cuomo signed the measure at 11:55 p.m., and the law will go into effect in 30 days, meaning that same-sex couples could begin marrying in New York by late July.

Passage of same-sex marriage here followed a daunting run of defeats in other states where voters barred same-sex marriage by legislative action, constitutional amendment or referendum. Just five states currently permit same-sex marriage: Connecticut, Iowa, Massachusetts, New Hampshire and Vermont, as well as the District of Columbia.

At around 10:30 p.m., moments after the vote was announced, Mr. Cuomo strode onto the Senate floor to wave at cheering supporters who had crowded into the galleries to watch. Trailed by two of his daughters, the governor greeted lawmakers, and paused to single out those Republicans who had defied the majority of their party to support the marriage bill.

“How do you feel?” he asked Senator James S. Alesi, a suburban Rochester Republican who voted against the measure in 2009 and was the first to break party ranks this year. “Feels good, doesn’t it?”

The approval of same-sex marriage represented a reversal of fortune for gay-rights advocates, who just two years ago suffered a humiliating defeat when a same-sex marriage bill was easily rejected by the Senate, which was then controlled by Democrats. This year, with the Senate controlled by Republicans, the odds against passage of same-sex marriage appeared long.

But the unexpected victory had a clear champion: Mr. Cuomo, a Democrat who pledged last year to support same-sex marriage but whose early months in office were dominated by intense battles with lawmakers and some labor unions over spending cuts.

Mr. Cuomo made same-sex marriage one of his top priorities for the year and deployed his top aide to coordinate the efforts of a half-dozen local gay-rights organizations whose feuding and disorganization had in part been blamed for the defeat two years ago.

The new coalition of same-sex marriage supporters brought in one of Mr. Cuomo’s trusted campaign operatives to supervise a $3 million television and radio campaign aimed at persuading several Republican and Democratic senators to drop their opposition.

For Senate Republicans, even bringing the measure to the floor was a freighted decision. Most of the Republicans firmly oppose same-sex marriage on moral grounds, and many of them also had political concerns, fearing that allowing same-sex marriage to pass on their watch would embitter conservative voters and cost the Republicans their one-seat majority in the Senate.

Leaders of the state’s Conservative Party, whose support many Republican lawmakers depend on to win election, warned that they would oppose in legislative elections next year any Republican senator who voted for same-sex marriage.

But after days of contentious discussion capped by a marathon nine-hour closed-door debate on Friday, Republicans came to a fateful decision: The full Senate would be allowed to vote on the bill, the majority leader, Dean G. Skelos, said Friday afternoon, and each member would be left to vote according to his or her conscience.

“The days of just bottling up things, and using these as excuses not to have votes — as far as I’m concerned as leader, it’s over with,” said Mr. Skelos, a Long Island Republican who voted against the bill.

Just before the marriage vote, lawmakers in the Senate and Assembly approved a broad package of major legislation that constituted the remainder of their agenda for the year. The bills included a cap on local property tax increases and a strengthening of New York’s rent regulation laws, as well as a five-year tuition increase at the State University of New York and the City University of New York.

But Republican lawmakers spent much of the week negotiating changes to the marriage bill to protect religious institutions, especially those that oppose same-sex weddings. On Friday, the Assembly and the Senate approved those changes. But they were not enough to satisfy the measure’s staunchest opponents. In a joint statement, New York’s Catholic bishops assailed the vote.

“The passage by the Legislature of a bill to alter radically and forever humanity’s historic understanding of marriage leaves us deeply disappointed and troubled,” the bishops said.

Besides Mr. Alesi and Mr. Grisanti, the four Republicans who voted for the measure included Senators Stephen M. Saland from the Hudson Valley area and Roy J. McDonald of the capital region.

Just one lawmaker rose to speak against the bill: Rubén Díaz Sr. of the Bronx, the only Democratic senator to cast a no vote. Mr. Díaz, saying he was offended by the two-minute restrictions set on speeches, repeatedly interrupted the presiding officer who tried to limit the senator’s remarks, shouting, “You don’t want to hear me.”

“God, not Albany, has settled the definition of marriage, a long time ago,” Mr. Díaz said.

The legalization of same-sex marriage in the United States is a relatively recent goal of the gay-rights movement, but over the last few years, gay-rights organizers have placed it at the center of their agenda, steering money and muscle into dozens of state capitals in an often uphill effort to persuade lawmakers.

In New York, passage of the bill reflects rapidly evolving sentiment about same-sex unions. In 2004, according to a Quinnipiac poll, 37 percent of the state’s residents supported allowing same-sex couples to wed. This year, 58 percent of them did. Advocates moved aggressively this year to capitalize on that shift, flooding the district offices of wavering lawmakers with phone calls, e-mails and signed postcards from constituents who favored same-sex marriage, sometimes in bundles that numbered in the thousands.

Dozens more states have laws or constitutional amendments banning same-sex marriage. Many of them were approved in the past few years, as same-sex marriage moved to the front line of the culture war and politicians deployed the issue as a tool for energizing their base.

But New York could be a shift: It is now by far the largest state to grant legal recognition to same-sex weddings, and one that is home to a large, visible and politically influential gay community. Supporters of the measure described the victory in New York as especially symbolic — and poignant — because of its rich place in the history of gay rights: the movement’s foundational moment, in June 1969, was a riot against police inside the Stonewall Inn, a bar in the West Village.

In Albany, there was elation after the vote. But leading up to it, there were moments of tension and frustration. At one point, Senator Kevin S. Parker, a Brooklyn Democrat, erupted when he and other supporters learned they would not be allowed to make a floor speech.

“This is not right,” he yelled, before storming from the chamber.

During a brief recess during the voting, Senator Shirley L. Huntley, a Queens Democrat who had only recently come out in support of same sex marriage, strode from her seat to the back of the Senate chamber to congratulate Daniel J. O’Donnell, an openly gay Manhattan lawmaker who sponsored the legislation in the Assembly.

They hugged, and Assemblyman O’Donnell, standing with his longtime partner, began to tear up.

“We’re going to invite you to our wedding,” Mr. O’Donnell said. “Now we have to figure out how to pay for one.”

Danny Hakim and Thomas Kaplan contributed reporting from Albany, and Adriane Quinlan from New York.

Getting Serious About Saudi Arabia

Abraham R. Wagner

School of Internatinal & Public Affairs, Columbia University

HUFFINGTON POST

If nothing else, the events of the Arab Spring in the Middle East have served as a wake-up call for U.S. policy in the region, and demonstrate a compelling need to examine our relationships there. At the top of the list should be a realistic assessment of the role and future of Saudi Arabia. This is not a partisan issue -- both parties have assiduously avoided dealing honestly with the matter for decades, for economic and political reasons that amount to an ongoing state of denial. Leaving aside politically correct language, that nation remains a corrupt, 12th-century feudal monarchy that is a minority government fueled by billions of petrodollars, and making no serious contribution to the planet other than more oil and money. Decades of billions have enabled the Saudis to purchase a veneer of culture and science, touted by equally well-paid public relations firms, but the simple facts remain.

For decades now, any analysis of the viability of the Saudi regime has been a taboo subject in Washington. If any intelligence estimates have been done, they rank among the country's best kept secrets; and clearly none of the nation's leaders have seen them. This is in no small part due to the efforts of Prince Bandar bin Sultan, for many years the Saudis' long-time ambassador to the U.S., and close friend to five Presidents and numerous CIA directors. Not surprisingly, there was an unwritten rule in government to never speak evil of the Saudi regime, let alone discuss its hatred for Israel and the Jews; support for terrorists; abuse of women; or even speculate about long-term threats to the regime's viability. To make matters worse, the army of experts and consultants who inhabit the Beltway have fallen prey to the same delusion. Most are directly or indirectly supported by Saudi money, or derive their incomes from U.S. government officials who do not want to hear ill of the Saudis or even of the possibility that the regime may be in trouble.

Since the emergence of "modern" Saudi Arabia in 1932, U.S. interests in the kingdom have been almost entirely tied to oil, developed by U.S. corporations in the mid-1930s and resulting in a partnership known for most of its existence as "Aramco." Between 1973 and 1980, the Saudis basically stole the U.S. half of the Aramco partnership, keeping ever-increasing billions of petrodollars for themselves. Indeed, the Tea Party might consider championing the return of the U.S. half of Aramco -- it would be more than enough to bail out the health care system and then some. Alas, this theft of the American interest has been relegated to being an historical artifact, and nobody seems to care any more. Saudi royals continue to convert the billions into more palaces and other forms of grossly opulent spending unseen since the time of Nero's Rome.

Since at least 1973, U.S. policy has consisted of either treading very lightly, or of outright sucking up to the Saudis no matter what the actual politics or morality might be, largely in fear of another oil embargo lest the Saudis be in any way offended. Promising change in government, the new President Obama quickly rushed off to Saudi Arabia to kiss up to the King, but has yet to visit Israel, America's only democratic ally in the region. An honest assessment might show that such U.S. efforts are sadly misplaced. Saudi Arabia is increasingly vulnerable and needs the U.S. a great deal more than the U.S. needs the Saudis. The Saudi regime faces increasing external and internal threats, and desperately needs both intelligence and possibly military support. The U.S. should be in the driver's seat and not continuously begging this aging and crooked regime with a tin cup.

If the Saudi regime were to fall, the needed oil would continue to flow. Other than sand, it's all the country has; and no successor government could survive by cutting off their national income. Were a new regime to try and do so, military action by the U.S. to restore the flow of oil would be quick and decisive. Forget Afghanistan, where that nation's only economic contribution is an endless supply of illegal drugs -- oil is serious business, and without question any President would be forced to keep the oil coming.

Following 9/11, the U.S. looked to the Saudis as another ally in the "Global War on Terror." Far less attention was paid to the facts that some of the 9/11 al Qaeda terrorists came from Saudi Arabia and that Saudis have long been major financial sponsors of terrorist organizations, such as al Qaeda. The U.S. and other allies refuse to declassify information documenting these links, while heroic independent researchers such as Dr. Rachel Ehrenfeld, author of Funding Evil, have been endlessly harassed in court by the Saudis when they expose these links. To its credit, the government has made some effort to stem this embarrassing and lethal flow of Saudi petrodollars to terrorists, but success here is far from complete. The time is long past to make information public, without going through WikiLeaks, and to demand that the Saudi regime stop these flows or face some realistic consequences.

Since the 1973 Middle East War, the U.S. has half-heartedly attempted to enlist the Saudis in the process to achieve an Arab-Israeli peace, with limited success at best. For a nation that does not recognize Israel, and has an overt national policy of anti-Semitism, it would be silly to expect more. As a U.S. "ally" they probably could have and should have done more. At a minimum the Saudis might have been urged to stop funding organizations seeking Israel's destruction, and play a more positive role with their Arab allies in the region. But remember, this is Saudi Arabia, whose long-standing national policy is to fling money at anybody and everybody in the hopes that it will buy short-term peace for the regime.

The Arab Spring of late 2010 and early 2011 came as a shock to almost everybody, including the U.S. and the Saudis. Interestingly the movements that began in Iran and Tunisia, and which quickly spread to Egypt, Syria, Bahrain, Jordan and elsewhere, are not anti-Israel; anti-U.S; nor are they a further manifestation of Islamic extremism. In all cases, they are local reactions to aging, despotic, and corrupt regimes that have forestalled democratic processes and failed to deal with increasingly severe economic issues. None of these nations have Saudi Arabia's small population and huge oil revenues, yet there is substantial reason for the Saudis to take great pause at these events and seriously question when and if their time is coming.

There is simply no escaping what Saudi Arabia is, and what it is not. The nation has no political parties; national elections are not permitted; and, according to The Economist's 2010 Democracy Index, the Saudi government is the seventh most authoritarian regime from among the 167 countries rated. No amount of political spin by Obama or Clinton can change this fact. Women in Saudi Arabia are not allowed to drive cars; to go outdoors without a male escort; or to do much of anything else. The Saudi record on human rights is appalling to say the least. Saudi justice still consists of chopping off hands and heads as part of Sharia law. Any pretense of that nation evolving into a modern democratic state under the present regime is not a credible proposition.

As the U.S. must now look to a broader and more realistic strategy in the Middle East, a serious approach to Saudi Arabia must be an essential element of the process. Critical here is an intelligence estimate of the near and longer-term viability of the Saudi regime, not unlike that undertaken with respect to Yugoslavia before the death of Tito. A public version of this estimate should also be made available to inform public debate. Clearly change is coming, whether by death or revolution. King Fahd, never an enlightened or benevolent monarch, suffered a stroke in 1995 and has not been "dealing with a full deck" in years. His relatives and potential heirs aren't much better.

Bearing in mind that change is inevitable, the U.S. needs to look seriously at opposition groups and potential rivals for power, expanding contacts where they appear to be potentially useful. The U.S. needs to face the fact that this king, as well as his gluttonous and greedy family may not be the Saudi leadership forever. All good things come to an end, and their end may be coming sooner than anybody now thinks. As the Arab Spring has shown, there are many forces at work, driven by Twitter, Facebook and the modern news media. Ignoring these forces and their result is not a basis for sound policy in the Middle East or anywhere else

Yelena Bonner dies at 88; wife of Andrei Sakharov was a Soviet human rights activist

Bonner and her husband, who won the Nobel Peace Prize, led and inspired the

human rights movement in the former Soviet Union.

By Sergei L. Loiko, Los Angeles Times

Reporting from Moscow.—

Yelena Bonner, human rights activist and widow of Soviet dissident and Nobel Peace Prize

winner Andrei Sakharov, has died. She was 88.

Bonner died Saturday afternoon in Boston after a long illness, said her daughter, Tatiana

Yankelevich. Bonner had lived in the United States since 2003.

"Sakharov and Bonner together had done more for our country than a huge number of

politicians," Boris Nemtsov, leader of the Solidarity opposition movement and a former

deputy prime minister of Russia, said Sunday. "The demise of such a Soviet dissident as

Yelena Bonner is a huge loss for our society, which is badly disoriented by cynicism and

cruelty and where humanism and dignity are no longer valued."

Bonner was born Feb. 15, 1923, in the town of Merv in Soviet Central Asia to parents who

later were victims of the Stalin regime. Her father, a Communist Party official, was detained

in a 1937 purge and executed the next year. Her mother was sent to a prison camp for eight

years.

At the age of 15, Bonner refused to denounce her parents as enemies of the people and was

expelled from the Young Communist League. In World War II, she enlisted as a nurse and

was sent to the front near Leningrad, where she was seriously injured in a bombing raid.

After recovering in 1942, she returned to the front and served as a nurse until the war ended

in 1945.

She later received a general practitioner's degree at a Leningrad medical school and worked

until the late 1960s, even joining the Communist Party in 1965, the same year she divorced

her first husband.

In the late 1960s, she joined the dissident movement after the Soviet invasion of

Czechoslovakia to crush the Prague Spring democratic movement.

In 1970, while attending a dissident's trial in the Russian provincial city of Kaluga, she met

Sakharov. The nuclear physicist, one of the fathers of the Soviet hydrogen bomb, had by that

time been expelled from his role in the Soviet nuclear program because of his dissident

activities.

Bonner discarded her Communist Party membership in 1972, the year they married. Until his

death in 1989, the couple worked together to lead and inspire the growing human rights

movement in the Soviet Union.

"Many in our country still think that Yelena … played the role of the evil genius for Sakharov,

influencing him to become a staunch opposition leader," Lev Ponomaryov, head of the For

Human Rights movement, said in an interview. "But they really loved each other and

respected each other's views on life and politics, most of which they always shared."

Bonner represented Sakharov when he was awarded the Nobel Peace Prize in 1975. Sakharov

had been denied an exit visa so Bonner, who was getting medical assistance in Italy at the

time, went to Oslo on his behalf and delivered his Nobel Prize speech.

She later joined him in Gorky, a provincial capital 250 miles east of Moscow, where he was

exiled in 1980 without a trial after he lashed out at the Kremlin leadership for the Soviet

invasion of Afghanistan.

Her son and daughter were expelled from universities for Bonner's opposition activities in

the 1970s and emigrated to the United States. When Sakharov's daughter-in-law was not

allowed to leave the country in 1981, Sakharov and Bonner went on a hunger strike until

authorities gave in.

As a goodwill gesture in 1985, then-Soviet leader Mikhail Gorbachev allowed Bonner to travel

to the United States to visit her children. In 1986, Gorbachev ended Sakharov's exile in

Gorky, and he and Bonner returned to Moscow where they were given a warm reception by

opposition activists.

The couple then devoted themselves to help make Gorbachev's perestroika policies

irreversible.

Bonner continued her human rights activities after her husband's 1989 death and after she

moved to the U.S. in 2003, where she lived with her daughter in Boston. She continued

corresponding with dozens of Russian activists and expressing her views on every important

event back home, her daughter recalled.

"My mother took very closely and very personally everything happening in Russia, and she

was bitterly disappointed with where Russia is heading," Yankelevich said Sunday in a phone

interview from Boston. "She was one of the first to insist that [Mikhail] Khodorkovsky

[Russian jailed tycoon and opponent of Prime Minister Vladimir Putin] be called a prisoner

of conscience and from the first day of Putin's reign she was warning that Putin's regime was

purposely eradicating the budding democracy in Russia."

In addition to her daughter, Bonner is survived by son Alexey Semyonov, five grandchildren

and three great-grandchildren.

sergei.loiko@latimes.com

Lessons in Longevity, From I.B.M.

By STEVE LOHR NY TIMES

AS it turned 100 last week, I.B.M. was looking remarkably spry. Consumer technologies get all the attention these days, but the company has quietly thrived by selling to corporations and governments. Profits are strong, its portfolio of products and services looks robust, and its shares are near a record high. I.B.M.’s stock-market value passed Google’s earlier this year. Not bad for a corporate centenarian.

Yet, not so long ago, I.B.M.’s corporate survival was at stake. In the early 1990s, it nearly ran out of money. Its mainframe business was reeling under pressure from the lower-cost technology of personal computing.

New leadership was brought in, and thousands of workers were laid off. It was part of the company’s painful journey to what might be called “post-monopoly prosperity” — that is, a new path to corporate success once a dominant product is no longer the turbocharged engine of growth and profit it once was.

“I.B.M. faced the challenge that all great companies do sooner or later — they dominate, they lose it, and then they re-create themselves or not,” observes George F. Colony, the chief executive of Forrester Research.

I.B.M. met the challenge, moved beyond the mainframe and built a business increasingly based on software and services. So as it celebrates a milestone, the company holds lessons for others.

Evolving beyond past success is a daunting task for companies in all industries. But that problem is magnified in the technology arena, where companies can quickly rise to rule a market, seemingly invincible, until a shift in the technological landscape opens the door to a new generation of corporate dynamos.

That is certainly the test that Microsoft is struggling with today, as it seeks growth beyond its lucrative stronghold in personal computer software. If they are to prosper for the long haul, Google and Apple, too, must reach beyond their dominant businesses. Each of these companies, in its way, is trying.

So, then, what broader insights are to be drawn from the I.B.M. experience?

One central message, according to industry experts, is this: Don’t walk away from your past. Build on it. The crucial building blocks, they say, are skills, technology and marketing assets that can be transferred or modified to pursue new opportunities. Those are a company’s core assets, they say, far more so than any particular product or service.

In I.B.M.’s case, the prime assets included strong, long-term customer relationships, deep scientific and research capabilities and an unmatched breadth of technical skills in hardware, software and services.

Though once a mainframe company, I.B.M. has recast itself as the supplier that can best manage and stitch together diverse technologies in modern data centers. Mainframes still have a role, and I.B.M. has invested heavily in them — $5 billion in mainframe research in the last decade — so that different kinds of software can run on them and new kinds of processors can plug into them.

But it is the technology surrounding the mainframe that really pays off for I.B.M. today. Mainframe hardware alone accounts for less than 4 percent of its revenue. But when the software, storage and services contracts linked to mainframe computers are included, the figure rises to 25 percent — and as much as 45 percent of operating profit, estimates A. M. Sacconaghi, an analyst at Sanford C. Bernstein & Company.

I.B.M. has redirected its research labs and sales force to focus on services and software, retraining thousands of people, and supplementing in-house programs with acquisitions. In big, complex services contracts, from running smart-grid projects for utilities to traffic-management systems for cities, I.B.M. acts as a high-tech general contractor whose expertise spans research, software, hardware and services. These so-called Smarter Planet projects build on its legacy of broad technical skills and deep knowledge in fields like energy, transportation and health care.

AT the moment, Microsoft is the tech company that most squarely confronts the post-monopoly predicament, as I.B.M. once did. Some of the similarities are striking, right down to the long-running federal antitrust suits that both companies endured.

But unlike I.B.M. in the early 1990s, Microsoft is not a company in crisis. It is growing steadily and remains immensely profitable. It has nurtured new businesses beyond its lucrative stronghold in personal computer software: the Windows operating system and its Office programs for word processing, spreadsheets and presentations.

Microsoft has invested for nearly two decades to build up business database software and server operating systems that run larger data-serving computers in data centers. An I.B.M. executive once declared that Microsoft’s attempt to move into data center computing would be its “Vietnam,” a humbling setback. And many analysts predicted that Microsoft would be thwarted in data centers by competition from Linux, the free operating system.

Linux has done well, but so has Microsoft. Today, Microsoft’s server software division is a comfortably profitable business, with $16 billion a year in revenue. If that unit were a separate company, it would be among the top five in the software industry.

Microsoft’s other sizable business beyond PC software — also more than a decade in the making — is its Xbox video-game console, software and online gaming franchise. That division of Microsoft is a solidly profitable, $8 billion-a-year business.

But the long-term problem for Microsoft is that more than 80 percent of its operating profit still comes from its PC software franchise. “Microsoft has delivered some singles and doubles, but is there going to be another home run?” asks David B. Yoffie, a professor at Harvard Business School.

Because of such concerns, Microsoft’s stock price has stagnated for years. The anxiety has been magnified by the company’s trailing position in fast-growing new markets in search and online advertising, as well as smartphone and tablet software. Some big investors are uneasy — and one, David Einhorn, the hedge fund manager, last month publicly called for Microsoft’s chief executive, Steven A. Ballmer, to be replaced.

Whether Microsoft can find a new foundation for prosperity is uncertain. But like I.B.M., it has deep reservoirs of technical and research expertise. Kinect, its add-on device to the Xbox gaming console, suggests one promising path. The device, which went on sale last November, recognizes people’s faces, their gestures and simple voice commands.

Microsoft acquired some of the sensor technology used in Kinect, but designed the hit $150 product itself, helped by seven different groups in its research labs. To date, Kinect is a gaming device. Yet personal computers that can see you, hear you and respond would be a breakthrough, bringing artificial intelligence into the mainstream.

GOOGLE, meanwhile, has the purest engineering culture among the major technology companies. Its founders, Larry Page and Sergey Brin, former Stanford graduate students in computer science, set the tone. And the assets most prized at the company are brains and data.

“Google is all about information — searching, discovering and sharing information more intelligently,” says Peter Sondergaard, senior vice president for research at Gartner.

In essence, Google sees itself as an artificial-intelligence factory. Its programmers use machine learning and natural language techniques to mine vast troves of Web data to deliver smarter search results and more finely directed ads. Its offerings beyond search all scoop up more data and afford potential opportunities for serving up more ads. They include online e-mail, calendars, maps, shopping, word processing and spreadsheets, as well as videos on its YouTube service and photographs on Picasa. It’s all grist for Google’s data mavens.

Google’s natural habitat is the wide-open Web. But it is also moving into the more closed realm of software for devices, mainly for smartphones and tablets, with its Android operating system. The move is partly defensive. More and more searches are being started from these mobile devices, and it is easier to steer users to Google search and other services from its own operating system. Yet the move could also put it in a powerful position to shape the future of mobile devices, which are eclipsing PCs as the center of gravity in computing. In smartphones, at least, Google is doing well. Android, which Google distributes free, has rapidly become the leader, with 36 percent of the market for smartphone operating systems.

IN recent years Apple has been unmatched in applying its core assets to new markets. Its hallmark skills are the intuitive usability of its software and the inspired design of its hardware — talents long appreciated by loyal Mac users. Yet in the PC industry, Apple machines are still dwarfed by those running Microsoft’s Windows. Apple’s stunning success has come in taking its skills beyond PCs with pioneering new designs in markets that it has redefined or created: digital media players (the iPod), smartphones (the iPhone) and tablet computers (the iPad).

Apple looks to be riding a money train for some time. Its current model is focused on selling its stylish devices; the company’s online software and marketplace (for digital media and mobile apps) are mainly servants of the hardware, pleasing consumers so they are more apt to buy iPods, iPhones and iPads.

Yet Apple’s product designs, however impressive, will eventually be mimicked and come under price pressure, just as the mainframe did, predicts Michael A. Cusumano, professor at the Sloan School of Management at the Massachusetts Institute of Technology. In time, he says, Apple may want to borrow a page from I.B.M. and rely increasingly on software and services for its livelihood.

Apple, he suggests, can build a large business around offerings like its new iCloud online storage and syncing service for music, photos and software, announced two weeks ago, applying Apple’s usability magic to woo users.

Once millions of people use a service, Mr. Cusumano says, there will be ample money-making opportunities with advertising, marketing or charges for premium services. Those can produce steady revenues, quarter after quarter, year after year. “Becoming a platform for delivering digital services is the way Apple can make big money in future decades,” Mr. Cusumano says.

FOR the powerhouse companies of today, the I.B.M. story holds a cautionary lesson as well: the danger of delay. Mr. Yoffie of Harvard Business School recalls that in 1990 he had finished a case study on I.B.M. His research included extensive interviews with the company’s top executives, who spoke of the need to wean I.B.M. from its dependence on mainframes and to shift toward software and services.

But I.B.M., he notes, didn’t pursue that strategy until after the company was in peril, and an outsider, Louis V. Gerstner Jr., was installed as its leader in 1993. As Mr. Yoffie says, “It’s really hard to move a company when it’s doing well and not facing a crisis.”