FORBES.COM, November 12, 2008, by Robert Langreth & Matthew Herper — Peter DiBattiste spent years as an interventional cardiologist clearing out heart patients’ arteries. The depressing reality: All too often the patients would be back in the hospital just a few months later with another heart attack or stroke.

Now DiBattiste finally has a chance to do something about it. As head of cardiovascular drugs at Johnson & Johnson, he is helping lead the testing of a powerful new blood thinner in late-stage tests in heart patients at J&J and Bayer. J&J hopes the drug will one day be a huge best seller, reviving its slumping drug unit.

Getting there will be tricky. Results from a mid-stage study presented at a meeting of cardiologists showed the drug, rivaroxaban, slashed heart attacks and strokes by 31% when taken with aspirin and also, in some patients, Plavix, an anti-clotting drug from Bristol-Myers Squibb and Sanofi-Aventis. But the results also showed significantly higher rates of bleeding in patients who took the drug. Very dangerous bleeding episodes took place in 1.2% of the patients studied.

The J&J/Bayer data illustrate the huge hurdles drug developers face these days in the cardiology field. There are so many effective drugs already on the market that it is tough to top them. A few years back, AstraZeneca thought it had developed a replacement for warfarin, the notoriously tricky-to-use blood thinner, but it fell through when the compound was linked to serious liver problems. Rivaroxaban, the J&J drug, is essentially another attempt to come up with a better warfarin. Eli Lilly has a new thinner it hopes can replace Plavix, but it has been delayed for months at the FDA for unclear reasons.

The blood thinners remain the last hot area in cardiology drug development. Pfizer is exiting most heart research but sticking with blood thinners, including a rivaroxaban-like drug called apixaban it is testing with Bristol-Myers Squibb. An anti-clot drug that might not cause increased bleeding is by far the most important experimental drug at Schering-Plough.

It’s easy to see why companies keep going. Plavix is the second-best-selling drug in the world. A tenth of patients with heart attacks and other acute coronary syndromes have repeat events within the next year, says Harvard Medical School interventional cardiologist C. Michael Gibson, who led the J&J/Bayer study “There is tremendous amount of activity [in testing new blood thinners], because this remains a significant area of unmet need,” he says.

“The opportunity here is really great,” J&J’s DiBattiste says.

There are two different ways the blood clots. Cell fragments called platelets clump together; Plavix and prasugrel block these. But there are also fibers in the blood called thrombin and fibrin that stitch the clot together. Rivaroxaban and apixaban block the formation of these by inhibiting an enzyme called factor Xa. Schering’s drug, called a thrombin receptor antagonist (TRA), blocks communication between the two systems–potentially working late in the clotting cascade and not thinning the blood as much.

“There is a definite efficacy signal” for rivaroxaban and apixaban, says Paul Gurbel, director of the Sinai Center for Thrombosis Research in Baltimore. He is working with Schering on TRA, and says he hopes that it will prevent heart attacks and strokes without causing bleeding. “We won’t know until we do a clinical trial.”

Is such a breakthrough possible? Cardiologists say they’ve heard talk of clot-preventers that didn’t increase bleeding before, but none panned out. “I want to believe,” says Deepak Bhatt, chief of cardiology at the Veterans Affairs Health Systems in Boston. “But do I really think it’s true? You’ll have to show me a clinical trial.” He is working with rivaroxaban, and thinks the data look “terrific” enough to justify going forward with larger studies.

The current rivaroxaban study was designed mostly to find a safe dose for the drug and is anything but definitive. Next month, J&J and Bayer plan to begin a final-stage trial in 16,000 patients that will provide a definitive answer. So far, J&J says it has seen absolutely no sign of liver problems caused by its drug, another side-effect problem that felled the AstraZeneca blood thinner a few years back. Bayer invented rivaroxaban.

To reduce the potential for bleeding, J&J and Bayer are only going ahead with the two lowest daily doses used in this second-stage trial. Moreover, they will give the drug twice a day instead of once a day; the hope is that the bleeding risk is related to peak blood-drug levels, which will be lower when the dose is split up into two daily portions.

“So far there hasn’t been any free lunch, every time we have new [blood thinner] drug we reduce clinical events, but it comes at the cost of bleeding,” says Gibson.

Rivaroxaban works via a different mechanism than aspirin and Plavix for heart patients today. Those act to stop platelets from clumping together. Rivaroxaban instead blocks the formation of a fibrin mesh that holds the clot together.

Even if the coronary applications fail, rivaroxaban could do well in other uses. It has already successfully completed trials to prevent vein clots in patients after orthopedic surgery and is also being tested as a replacement for warfarin in atrial fibrillation patients.

“We are hoping this will be the first agent to both succeed in reducing events in the arterial and venous side of the circulation and have a profile to that allows for convenient and safe use,” says DiBattiste. Now he has to prove it.


AHA Meeting

Taking Heart Medicine Beyond Heart Drugs

FORBES.COM, November 12, 2008, by Matthew Herper — For anyone looking for new treatments to reduce the 860,000 deaths that occur every year in the U.S., the annual meeting of the American Heart Association was pretty scant on hope.

No major studies of new drugs and devices were presented. But many cardiologists say the drought is less worrisome than the fact that many existing drugs are not being used enough.

Patients in clinical trials are getting such a big benefit from existing medicines that it is difficult for a new one to add much. But patients in the real world are not getting the same level of treatment as those in clinical trials.

“We’ve made so much progress,” says Elliott Antman of the Harvard-affiliated Brigham & Women’s Hospital. “There is a greater need to use the drugs we have.” Adds Raymond Gibbons of the Mayo Clinic, “We’re not doing very well delivering the standard of care.”

After a series of high-profile failures, many companies are cutting back research on heart drugs in a big way. Pfizer, for instance, is stopping work on a whole swath of cholesterol drugs. That’s astounding, given that, right now, the two best-selling drugs in the world–Pfizer’s Lipitor and Plavix from Bristol-Myers Squibb and Sanofi-Aventis–are heart drugs.

Just about the last big class in development are drugs to prevent the blood clots that cause heart attacks and strokes. But these are risky, because so far they also increase bleeding. Small differences in bleeding rates can be the difference between a blockbuster and a niche product, and the only way to know is with a gigantic clinical trial. Bayer and Johnson & Johnson presented their entrant, rivaroxaban, at the conference. (See “J&J’s High-Wire Heart Drug.”)

Even the one big success of the meeting, a trial called Jupiter, in which Crestor from AstraZeneca dramatically reduced the rates of heart attacks and strokes, is in a sense a last hurrah. Crestor is the last-to-market of the legendary drug class called the statins, and this was probably the last big study to test a statin for preventing a first heart attack.

Meanwhile, Gibbons points out, many of the people who entered Jupiter should already have been taking aspirin to prevent heart attacks but weren’t.

A blood pressure drug made by Bristol and Sanofi failed to prevent death and hospitalization in heart failure, a chronic weakening of the heart muscle that leaves patients short of breath. A study in which patients were directed to exercise showed the treatment was safe and might be effective, but it didn’t meet its main goal. Again, the reason is partly that patients in clinical trials take their treatments, and these treatments work.

“The good news is that we can make patients feel and do better,” says Clyde Yancy, medical director of the Baylor Heart and Vascular Institute. “So now, the invention we need isn’t necessarily a new drug or device. The invention is a new process of care.”

Sidney Smith, a cardiologist at the University of North Carolina, says doctors need money to do trials examining different ways of getting patients to take medicines that will help them. Harvard’s Antman says he’s hopeful that under an Obama administration, those types of studies might happen. Right now, most trials are funded by industry, which explains the focus many researchers have had on new drugs.

“We do need more discoveries, because the disease has not been cured,” says Yancy. Meanwhile, they’ll need to look beyond drugs to improve patient care.

Growth spurt. Crushed optic nerve axons (green) normally don’t regenerate (bottom), but in mice missing a signaling molecule called PTEN (top), axons can grow several millimeters.

Credit: K. K. Park et al., Science

ScienceNOW/Daily News, November 2008, by Greg Miller — The adult central nervous system has limited ability to repair itself. That’s why spinal cord injuries leave people permanently paralyzed. Now a study with mice finds that removing a particular signaling molecule in adult neurons restores their ability to regenerate damaged axons, the long extensions that convey signals from one neuron to another. The find potentially paves the way for repairing spinal cords and other nervous system injuries. “It’s one of the most dramatic results in the history of this field,” says Ben Barres, a neurobiologist at Stanford University in Palo Alto, California.

Researchers suspect that adult nerves don’t regenerate for two reasons: One, neurons have lost the flexibility they had at about the time of birth, when the brain was still developing; two, compounds near the site of injury inhibit axon growth. A great deal of research has focused on identifying and blocking these compounds, but so far these manipulations have prompted only limited regrowth, says Zhigang He, a neurobiologist at Children’s Hospital Boston and Harvard Medical School. In the new study, He and his colleagues searched for a way to help neurons recapture their youthful ability to grow new axons.

They began with a list of candidate genes involved in cell growth and several strains of mice in which each of these genes could be individually deleted once the mice had grown to adulthood. Deleting the gene for a signaling molecule called PTEN had a dramatic effect on nerve regeneration, He’s team reports in tomorrow’s issue of Science (7 November, p. 963). PTEN inhibits a cell-signaling cascade called the mTOR pathway, which is involved in protein synthesis and cell growth. Normally, axons in the optic nerve of adult mice do not regenerate when crushed–and worse yet, about 80% of the neurons with severed axons die. But in mice lacking PTEN, 50% of neurons survived and about 10% of axons in the optic nerve regrew–as far as 4 millimeters in 28 days.

A few millimeters may not sound like much, but it’s a huge distance compared with other studies of axon regeneration, says Barres. “To have any manipulation that can make these axons grow from where they were severed near the retina all the way down the optic nerve is just amazing.”

Even so, many questions remain, including whether the regenerating axons are capable of forming working connections with other neurons (He’s team did not examine whether the mice lacking PTEN regained their sight) and whether manipulating PTEN or other components of the mTOR pathway can promote axon regeneration in the spinal cord, which many researchers contend is a more hostile environment for regrowth. He says experiments to address these questions are already under way.

Meanwhile, another paper the same issue of Science (7 November, p. 967) provides what may be an important piece of the axon-inhibition puzzle. Previous work had identified several compounds that block axon regeneration and found that they bind to the aptly named Nogo receptor on the surface of neurons. Puzzlingly, however, deleting or blocking the Nogo receptor has not spurred much regeneration. Now, Marc Tessier-Lavigne and colleagues at Genentech in South San Francisco, California, have identified another receptor for these inhibitory compounds. Blocking this receptor, called PirB, enabled cultured neurons to regrow severed axons, and blocking both PirB and the Nogo receptor enabled even more regrowth.

In the long run, the optimal strategy for treating spinal injuries may involve a combination of therapies that restore neurons’ ability to grow axons and ones that counteract inhibitory signals near the injury. “You want to do each, and you may need to do both,” says Tessier-Lavigne.

By Constance Holden, Eli Kintisch, Jeffrey Mervis, and Rachel Zelkowitz
ScienceNOW Daily News
November 2008

Barack Obama made history by becoming the first African American to be elected president of the United States. The many scientists who had campaigned for the Democratic senator from Illinois reveled in last night’s election returns. “We’re just very thrilled,” says physicist Bernice Durand, who had assembled a grassroots coalition of researchers supporting Obama (Science, 31 October, p. 658).

The election brought mostly good news for research as well. Here’s a roundup of other developments that could have an impact on science:

Stem cells
Arguably the result most directly affecting researchers was in Michigan, where voters passed a measure that will free scientists from state restrictions on stem cell research. Proposal 2, a constitutional amendment that will go into effect next month, allows researchers to derive new human embryonic stem cell lines from embryos that would otherwise be discarded by fertility clinics.

The measure supersedes a 1978 state law prohibiting the use of embryos in research. It was opposed on ethical grounds by right-to-life groups and the Catholic Church, which also raised the specter of science gone wild. Opponents even suggested that “we might try to clone cow-people,” says stem cell researcher Sean Morrison of the University of Michigan (UM) Medical School in Ann Arbor. In fact, all cloning, including somatic cell nuclear transfer for research, is still banned.

Each side reportedly spent more than $5 million in the public battle over the measure, with supporters receiving a big financial boost from Michigan developer A. Alfred Taubman. Scientists were particularly active, participating in public debates and visiting newspaper editors to lobby for the measure.

The amendment didn’t include funding to support stem cell research, but Morrison is optimistic that new funding will be forthcoming from both government and private sources. Meanwhile, “we’ll be spending the next few months going through the regulatory process,” he says. “It’s important for people to understand this research will be very highly regulated.” Research material will not be a problem. “We’ve been getting calls from patients this morning who want to donate embryos,” says Morrison. Another UM researcher, Doug Engel, says, “We already have the embryos in our IVF clinic from donors who did not want them donated to other couples and who did want them used for biomedical research.”

Michigan researchers expect that they’ll soon be able to use federal money for that research when the Obama Administration follows through on its promise to lift restrictions on federal funding of embryonic stem cell work that were imposed by President George W. Bush in 2001. Only two states–Louisiana and South Dakota–still forbid research on human embryos.

Green energy
Efforts at the polls to boost green power had a mixed day, with voters in Missouri passing a state ballot initiative requiring power companies in the state to produce 15% of their power from renewable sources by 2021. But two ballot initiatives in California intended to bolster renewable energy failed. One would have mandated power companies to produce 40% of their energy from renewable sources by 2020, while the other was a $10 billion renewable energy state bond.

Democratic science powerbrokers have retained their seats in Congress. But there will likely be a major reshuffling of Senate committee posts that could affect research and training issues.

In the 435-member House of Representatives, where incomplete returns showed Democrats gaining 18 seats, the leadership of the House Science Committee will remain unchanged after victories by Representative Bart Gordon (D–TN), the chair, and Representative Ralph Hall (R–TX), the ranking minority member. The House also retained its contingent of three Ph.D. physicists–representatives Vernon Ehlers (R–MI) and Rush Holt (D–NJ) easily won their eighth and sixth terms, respectively, while Representative Bill Foster (D–IL) parlayed a victory in a March special election (Science, 14 March, p. 1470) into a full 2-year term by defeating Republican Jim Oberweis. Foster’s election was marked by an unusual reliance by the candidate on scientists for contributions and volunteer manpower–namely hundreds of physicists from his district’s Fermi National Accelerator Laboratory, where Foster worked as a researcher until 2006.

The chairs of the 12 House appropriations subcommittees, who together oversee all federal research budgets, also retained their seats, as did Representative David Obey (D–WI), the head of the full committee.

In contrast, the more heavily Democratic Senate will see several new faces in leadership positions. Senator Daniel Inouye (D–HI) is in line to take over the appropriations committee if the ailing Senator Robert Byrd (D–WV), 90, relinquishes his seat. Health considerations may also force Senator Edward Kennedy (D–MA) to step down as chair of the health, education, and labor panel. Senator Joe Lieberman (I–CT) could be ousted from the Democratic caucus and as chair of the government affairs panel for his vigorous support of Republican Senator John McCain’s presidential candidacy. These changes at the top of the committees that oversee important science agencies could also have an impact on the lineup of the 12 spending panels in the Senate if some subcommittee chairs move into different posts amid the reshuffling.

Political scientists
A number of challengers with backgrounds in science failed in their bids for a seat in Congress. In Washington state, Democrat Darcy Burner, a former computer scientist, was challenging Republican incumbent David Reichert in a race that’s still too close to call.

Truthdig, November 12, 2008, by Chris Hedges — We live in two Americas. One America, now the minority, functions in a print-based, literate world. It can cope with complexity and has the intellectual tools to separate illusion from truth. The other America, which constitutes the majority, exists in a non-reality-based belief system. This America, dependent on skillfully manipulated images for information, has severed itself from the literate, print-based culture. It cannot differentiate between lies and truth. It is informed by simplistic, childish narratives and cliches. It is thrown into confusion by ambiguity, nuance and self-reflection. This divide, more than race, class or gender, more than rural or urban, believer or nonbeliever, red state or blue state, has split the country into radically distinct, unbridgeable and antagonistic entities.

There are over 42 million American adults, 20 percent of whom hold high school diplomas, who cannot read, as well as the 50 million who read at a fourth- or fifth-grade level. Nearly a third of the nation’s population is illiterate or barely literate. And their numbers are growing by an estimated 2 million a year. But even those who are supposedly literate retreat in huge numbers into this image-based existence. A third of high school graduates, along with 42 percent of college graduates, never read a book after they finish school. Eighty percent of the families in the United States last year did not buy a book.

The illiterate rarely vote, and when they do vote they do so without the ability to make decisions based on textual information. American political campaigns, which have learned to speak in the comforting epistemology of images, eschew real ideas and policy for cheap slogans and reassuring personal narratives. Political propaganda now masquerades as ideology. Political campaigns have become an experience. They do not require cognitive or self-critical skills. They are designed to ignite pseudo-religious feelings of euphoria, empowerment and collective salvation. Campaigns that succeed are carefully constructed psychological instruments that manipulate fickle public moods, emotions and impulses, many of which are subliminal. They create a public ecstasy that annuls individuality and fosters a state of mindlessness. They thrust us into an eternal present. They cater to a nation that now lives in a state of permanent amnesia. It is style and story, not content or history or reality, which inform our politics and our lives. We prefer happy illusions. And it works because so much of the American electorate, including those who should know better, blindly cast ballots for slogans, smiles, the cheerful family tableaux, narratives and the perceived sincerity and the attractiveness of candidates. We confuse how we feel with knowledge.

The illiterate and semi-literate, once the campaigns are over, remain powerless. They still cannot protect their children from dysfunctional public schools. They still cannot understand predatory loan deals, the intricacies of mortgage papers, credit card agreements and equity lines of credit that drive them into foreclosures and bankruptcies. They still struggle with the most basic chores of daily life from reading instructions on medicine bottles to filling out bank forms, car loan documents and unemployment benefit and insurance papers. They watch helplessly and without comprehension as hundreds of thousands of jobs are shed. They are hostages to brands. Brands come with images and slogans. Images and slogans are all they understand. Many eat at fast food restaurants not only because it is cheap but because they can order from pictures rather than menus. And those who serve them, also semi-literate or illiterate, punch in orders on cash registers whose keys are marked with symbols and pictures. This is our brave new world.

Political leaders in our post-literate society no longer need to be competent, sincere or honest. They only need to appear to have these qualities. Most of all they need a story, a narrative. The reality of the narrative is irrelevant. It can be completely at odds with the facts. The consistency and emotional appeal of the story are paramount. The most essential skill in political theater and the consumer culture is artifice. Those who are best at artifice succeed. Those who have not mastered the art of artifice fail. In an age of images and entertainment, in an age of instant emotional gratification, we do not seek or want honesty. We ask to be indulged and entertained by clichs, stereotypes and mythic narratives that tell us we can be whomever we want to be, that we live in the greatest country on Earth, that we are endowed with superior moral and physical qualities and that our glorious future is preordained, either because of our attributes as Americans or because we are blessed by God or both.

The ability to magnify these simple and childish lies, to repeat them and have surrogates repeat them in endless loops of news cycles, gives these lies the aura of an uncontested truth. We are repeatedly fed words or phrases like yes we can, maverick, change, pro-life, hope or war on terror. It feels good not to think. All we have to do is visualize what we want, believe in ourselves and summon those hidden inner resources, whether divine or national, that make the world conform to our desires. Reality is never an impediment to our advancement.

The Princeton Review analyzed the transcripts of the Gore-Bush debates, the Clinton-Bush-Perot debates of 1992, the Kennedy-Nixon debates of 1960 and the Lincoln-Douglas debates of 1858. It reviewed these transcripts using a standard vocabulary test that indicates the minimum educational standard needed for a reader to grasp the text. During the 2000 debates George W. Bush spoke at a sixth-grade level (6.7) and Al Gore at a seventh-grade level (7.6). In the 1992 debates Bill Clinton spoke at a seventh-grade level (7.6), while George H.W. Bush spoke at a sixth-grade level (6.8), as did H. Ross Perot (6.3). In the debates between John F. Kennedy and Richard Nixon the candidates spoke in language used by 10th-graders. In the debates of Abraham Lincoln and Stephen A. Douglas the scores were respectively 11.2 and 12.0. In short, today’s political rhetoric is designed to be comprehensible to a 10-year-old child or an adult with a sixth-grade reading level. It is fitted to this level of comprehension because most Americans speak, think and are entertained at this level. This is why serious film and theater and other serious artistic expression, as well as newspapers and books, are being pushed to the margins of American society. Voltaire was the most famous man of the 18th century. Today the most famous “person” is Mickey Mouse.

In our post-literate world, because ideas are inaccessible, there is a need for constant stimulus. News, political debate, theater, art and books are judged not on the power of their ideas but on their ability to entertain. Cultural products that force us to examine ourselves and our society are condemned as elitist and impenetrable. Hannah Arendt warned that the marketization of culture leads to its degradation, that this marketization creates a new celebrity class of intellectuals who, although well read and informed themselves, see their role in society as persuading the masses that “Hamlet” can be as entertaining as “The Lion King” and perhaps as educational. “Culture,” she wrote, “is being destroyed in order to yield entertainment.”

“There are many great authors of the past who have survived centuries of oblivion and neglect,” Arendt wrote, “but it is still an open question whether they will be able to survive an entertaining version of what they have to say.”

The change from a print-based to an image-based society has transformed our nation. Huge segments of our population, especially those who live in the embrace of the Christian right and the consumer culture, are completely unmoored from reality. They lack the capacity to search for truth and cope rationally with our mounting social and economic ills. They seek clarity, entertainment and order. They are willing to use force to impose this clarity on others, especially those who do not speak as they speak and think as they think. All the traditional tools of democracies, including dispassionate scientific and historical truth, facts, news and rational debate, are useless instruments in a world that lacks the capacity to use them.

As we descend into a devastating economic crisis, one that Barack Obama cannot halt, there will be tens of millions of Americans who will be ruthlessly thrust aside. As their houses are foreclosed, as their jobs are lost, as they are forced to declare bankruptcy and watch their communities collapse, they will retreat even further into irrational fantasy. They will be led toward glittering and self-destructive illusions by our modern Pied Pipers–our corporate advertisers, our charlatan preachers, our television news celebrities, our self-help gurus, our entertainment industry and our political demagogues — who will offer increasingly absurd forms of escapism.

The core values of our open society, the ability to think for oneself, to draw independent conclusions, to express dissent when judgment and common sense indicate something is wrong, to be self-critical, to challenge authority, to understand historical facts, to separate truth from lies, to advocate for change and to acknowledge that there are other views, different ways of being, that are morally and socially acceptable, are dying. Obama used hundreds of millions of dollars in campaign funds to appeal to and manipulate this illiteracy and irrationalism to his advantage, but these forces will prove to be his most deadly nemesis once they collide with the awful reality that awaits us.

Chris Hedges, a Pulitzer prize-winning reporter, is a reporter for The New York Times. He has a B.A. in English Literature from Colgate University, a Master of Divinity from Harvard Divinity School. In addition to English, he speaks Arabic, French and Spanish and knows Latin and ancient Greek. He has written for numerous publications including Foreign Affairs, Harper’s Magazine, and The New York Review of Books. His latest book is Collateral Damage: America’s War Against Iraqi Civilians.