Protomag

Inside a Medical Home

2010-05-13T12:35:28-05:00

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Longevity Research: Is Aging a Disease?

2010-04-27T13:02:16-05:00

When David Harrison began studying aging, he had yet to experience its effects. In his late twenties, he was fit, healthy and impervious to harsh New England winters; on all but the coldest days, he’d strap on cross-country skis and head for the Maine hills. Now, though, at age 67, he sees in himself the progressive decline he has long observed in the mice and other animals of his research. A decade ago, doctors removed a prostate tumor before the cancer spread to his bones, but other problems have accumulated. Some, such as high blood pressure and high cholesterol, are easily treated, but they’re accompanied by elevated insulin levels and weight gain—a constellation of disorders called “metabolic syndrome,” which often precedes heart disease, diabetes and stroke. Dieting, exercise and drugs only slow its progression. And he now spends winters in North Carolina, where the milder climate seems to help him dodge another apparent symptom of his advancing years: chest colds that linger for weeks. “I feel the shadow of aging’s progression growing closer,” Harrison says.

He’s careful to say “aging,” not “age,” a crucial distinction in his work as a gerontologist at the Jackson Laboratory in Bar Harbor, Maine. Some lucky people reach their nineties or beyond without being struck down by any of the diseases on a long list—heart failure, diabetes, stroke, Alzheimer’s, Parkinson’s, cancer—that become much more common after middle age and kill most Americans. And though those maladies are often grouped together as “diseases of aging,” that’s usually just a convenient catchall—they’re what tends to happen when you get old. Each illness has its own phalanx of researchers striving to understand its unique causes and find ways to prevent or treat the damage it does. But some scientists take a more holistic view. They think aging itself is the issue, and that when you trace heart disease, cancer and Alzheimer’s back to their roots, they all seem to stem from the same problems that span multiple body systems and lead them to ultimately malfunction.

To support this argument, researchers point to the fact that many diseases of aging seem to share networks of genes and molecular pathways. Harrison, like other longevity researchers, emphasizes that his work to decipher and improve those biological processes is not a quest for a fountain of youth—he doesn’t think people can live indefinitely. Indeed, “longevity research” may be a misnomer. Though these scientists routinely produce lab animals with exceptionally long lives, their goal for humans is less to help them live longer than to fulfill their allotted span in good health. They’re working to develop drugs that might delay the onset of multiple diseases of aging by acting on shared causes. That’s preferable, they say, to standard practice today—fighting off diseases one at a time in a process that provides not health but prolonged decrepitude.

Despite their success in producing long-lived animals, however, scientists so far have only a fragmentary understanding of the extraordinarily complex mechanisms that appear to determine why some mice and other species, under certain circumstances, survive so much longer than others do. One method—caloric restriction—has been a particular focus because it has seemed to be a surefire method for extending longevity and thus might reveal biological secrets that could help push back the age at which so many human diseases take hold. Yet the approach now appears to work only in some animals, further complicating research that was thought to be well understood. Meanwhile, other scientists are approaching this puzzle from a different angle, studying people who live long, healthy lives to find out what makes them special—an approach that advances in genomic analysis should make increasingly productive.

Julien Pacaud

Modern longevity research traces its roots to the early 1930s, when a nutritionist at Cornell University, Clive McCay, set up an experiment. Reasoning that slowing an animal’s growth could help extend its life—the candle that burns half as fast burns twice as long, so to speak—he fed rats roughly a third less than normal. They tended to live about 40% longer than their well-fed counterparts. What’s more, the rats on normal diets became scruffy and weak with age, but McCay’s calorie-restricted rats stayed sleek and healthy. Autopsies revealed little evidence of the heart disease, cancer and diabetes that kill rats as well as humans.

Subsequent generations of researchers picked up where McCay had left off, replicating his results up and down the animal chain. Whatever mechanisms had extended the life spans of his rats weren’t unique to that species but rather appeared to be preserved through aeons of evolution—perhaps extending to primates, even humans. University of Wisconsin researchers announced in July 2009 that after 20 years of caloric restriction, 38 rhesus monkeys had markedly lower rates of heart disease, diabetes, cancer and brain disease than members of a control group. And the calorie-restricted animals were bushy-haired and bright-eyed at an age when physical decline is ordinarily as visible in monkeys as in humans.

Yet mice on strict diets seem vulnerable to infectious diseases and, despite their vigorous appearance, may have weaker muscles and frailer bones. Caloric restriction also decreases libido. “Even if we thought caloric restriction was generally beneficial, we’d want to create something that mimicked its most beneficial parts and left out the others,” says Steven Austad, a gerontologist at the University of Texas Health Science Center.

The impact of caloric restriction may also be less clear-cut than it has long appeared to be. In December 2009, researchers led by James Nelson, a colleague of Austad’s, tested caloric restriction on a genetically diverse array of 41 mouse strains. Though some of the mice on a restricted diet had extended life spans, others seemed to derive no benefit or to die earlier than normal. “The results raise the possibility that life extension by dietary restriction may not be universal,” the two wrote in the journal Aging Cell.

Nelson speculates that some mouse strains, already predisposed to long life—just as people in some families routinely live into their nineties and beyond—may naturally experience the biochemical changes that low-caloric intake induces. He thinks being put on an extreme diet may push those changes too far, canceling out the beneficial impact, just as increasing the dose of a drug too high can make it toxic. Regardless, the study’s results don’t invalidate earlier research, and Austad considers them a boon for longevity research. “How do you slow aging? What are the cellular mechanisms? Now we’re in a better position to investigate, because we can compare mice in which restricting calories works with those mice in which it doesn’t,” he says.

Answering such questions is really the point of this research: to provide a window on the aging process at a molecular level. Originally researchers used caloric reduction to catalogue gene and protein changes in single-cell organisms. Then they looked at what happened when they tweaked just one factor—say, switching a particular gene on or off. “In the 1990s, the forefront of this field was in the discovery of longevity genes in simple organisms,” says David Sinclair, a Harvard University gerontologist. Most of the next decade, he says, was spent asking whether those genes are also in mammals and whether they play a similar role in prolonging life by delaying aging’s normal diseases. Now that we know they do have that effect, the next research phase is to find out how these genes, identified in piecemeal fashion, fit together.

After decades of studying caloric restriction, researchers have a general idea how it works. Low nutrient levels prompt cells to conserve energy and improve self-repair mechanisms, enabling the cells to live longer and function more effectively. Hundreds of genes, proteins and enzymes are involved, and though most roles are not yet known, some genes seem more important than others. Sinclair’s specialty is SIRT1, one of seven sirtuin genes that produce enzymes active in metabolism-related cell functions. It has been in the news partly because it’s activated by resveratrol, a compound that occurs naturally in grape skins and red wine (though a human dose of resveratrol comparable to what’s used in mouse studies would require consumption of about 750 bottles of wine a day).

Julien Pacaud

Like many genes implicated in longevity, SIRT1 has multiple functions. It appears to accelerate the conversion of fat into energy, in part by revving up mitochondria—the cell’s molecular power plants—in muscle. SIRT1 increases production of insulin in pancreas cells and of bone-rebuilding cells in marrow. More broadly, SIRT1 enzymes seem to be beacons for proteins that repair damaged DNA.

One major source of DNA damage that can contribute to aging is the oxygen free radical. By-products of mitochondrial activity, free radicals bind quickly and corrosively to other molecules; they also damage mitochondria, which have their own DNA. High levels of mitochondrial malfunction have been found in diseased heart and brain tissue, and some researchers think it may be a cause rather than an effect of such diseases as type 2 diabetes, Parkinson’s and heart disease.

In 2004, Sinclair co-founded Sirtris Pharmaceuticals, which has developed a series of compounds that activate SIRT1. In tests of obese mice, the compounds have prevented diabetes. In thinner mice, the drugs have slowed aging, leaving the mice with thicker bones, cataract-free eyes and stronger hearts. One study produced an iconic image: a resveratrol-dosed mouse running effortlessly on a treadmill, with an untreated mouse beside it keeping up only when its tail was shocked.

“So far, in mice, these molecules work in staving off many diseases of aging,” Sinclair says. GlaxoSmithKline bought Sirtris in 2008, and the company is now doing human trials of a SIRT1 activator for diabetes and heart disease. It also plans to test the drugs on the skin disease psoriasis and on a neurodegenerative disease such as Alzheimer’s. In both diseases, inflammation causes tissue damage that is reduced in animals taking SIRT1 activators. While that research seems promising, some longevity researchers, including Austad, are skeptical. They contend that Sirtris’s mouse studies were run on a few select strains rather than on genetically diverse varieties. Further clouding the picture, a different group of researchers reported that Sirtris’s molecules may not directly activate SIRT1 but do activate other genes that seem linked to SIRT1 function.

Austad, however, has been impressed by the potential of another drug, rapamycin, already approved as an immunosuppressant for people receiving organ transplants. As a potent inhibitor of cell growth, it caught the attention of longevity researchers, who found that rapamycin produced caloric-restriction-like changes in lower-model organisms.

Rapamycin’s mechanisms aren’t fully understood, but like SIRT1, they appear to involve cell breakdown and mitochondrial function. The drug acts on mTOR, one of several genes in a network that regulates cell growth and metabolism. (One of the other genes is insulin-like growth factor 1, or IGF-1. Valter Longo, a University of Southern California gerontologist, has used IGF-1 inhibition to engineer yeast that lived for 10 weeks—10 times its normal life span.) In an experiment published last July, Jackson Laboratory’s Harrison led one of three teams that independently studied rapamycin’s effect on a selection of genetically diverse mice. They were 20 months old when they received the drug, roughly comparable to 60-year-old people. Rapamycin extended the normal life span for males by 28% and for females by 38%. Austad now plans to study rapamycin’s effects on marmosets, which are small primates.

But rapamycin isn’t on a fast track to approval as a human longevity drug. Its side effects—including immune system suppression and cancer—are known to be dangerous. Yet because the drug is used in people for other purposes, it may be possible to analyze whether it also slows aging. Such studies would be extremely difficult—people taking rapamycin by definition have serious health problems, which would complicate any analysis—but signs of effects on age-related diseases might be detected among thousands of patients getting the drug.

All of this longevity research follows a bottom-up approach, looking for life-lengthening effects in simpler species and then ultimately experimenting with humans. Thomas Perls, in contrast, works from the top down. He’s the director of the New England Centenarian Study of 2,200 people born more than a century ago.

Most people who live to be 100 are surprisingly healthy; they’ve somehow avoided many of the debilitating diseases that claim the vast majority of humans. By looking for patterns in their genetic makeup, lifestyles and histories, Perls and others hope to shed light on what makes the difference. (The Long Life Family Study, an offshoot of the New England Centenarian Study, has enrolled 250 long-lived families; and the LonGenity study at New York City’s Albert Einstein College of Medicine has recruited 500 Ashkenazic Jewish centenarians.) They’re aided by ongoing advances in genomic analysis that provide powerful tools to map the genes of long-lived humans and compare those configurations both with those of other centenarians and with the genomes of people less resistant to diseases of aging.

That broad approach, just beginning in these human studies, may eventually corroborate, expand or disprove some of what longevity work in animals has shown. There’s an intuitive appeal in going at the puzzle from this direction, and even the researchers doing the animal studies acknowledge that their painstaking protein-by-protein tracing of genes and pathways can seem limited when the consensus is that aging almost certainly involves hundreds or thousands of genes operating in concert.

Yet Felipe Sierra, who directs the National Institute of Aging’s Division of Aging Biology, thinks the piece-by-piece approach has been necessary and continues to be crucial. He notes that the top-down research is new, whereas scientists have been scrutinizing the genes and molecular pathways activated by caloric restriction for many years. “We’re not ready to put everything under one big tent yet,” Sierra says.

So far, Perls says, studies of centenarians suggest that commonsense behavioral factors play a major role in longevity. Eating lots of vegetables and little red meat, not smoking, exercising the body and mind, and learning to manage stress are all important. Still, there’s undoubtedly a genetic component, as well as a role for therapies that can compensate for the usual process of systemic breakdown. And Perls doesn’t doubt that many of the maladies that show up late in life have a common biological root. “It’s absolutely true,” he says. “That’s what makes age-related diseases related to aging.”

According to a Robert Wood Johnson Foundation estimate, some three-quarters of the $2.3 trillion the United States spends on health care each year goes to treat chronic diseases—most of which are diseases of aging. If scientists identify drugs that could push back the onset of several of those diseases, there could be an enormous economic benefit. But most people aren’t as frightened by aging’s economic burdens as they are by the prospect of lingering for years as mind and body fail. Avoiding that is the most tantalizing promise of longevity research, and in animals, at least, it seems possible. Describing an especially long-lived strain of mice, Washington University calorie restriction researcher Luigi Fontana says that as many as half die with no obvious cause of death. “There are no major pathological lesions,” he says, comparing the manner of their passing with that of many human centenarians: They’re healthy until almost the very end.

Death itself is still inevitable and—in these seemingly symptom-free cases—a fascinating scientific puzzle. “Maybe it’s a systemic failure, where you can’t maintain homeostasis,” Sierra says. But the puzzle of those deaths is perhaps less important than their nature. “The fact that we can’t ascertain the cause of death might be a good thing,” he says. “We all want to die in our sleep, in perfect health. That’s the ideal.”

The Time of Your Life

2010-04-27T13:11:18-05:00

61
Percentage of Americans who die of heart disease, cancer, stroke, diabetes or Alzheimer’s, five of the most common diseases of aging — a group whose ailments might one day be treated by drugs that target an as-yet-unknown common underlying cause

1,826
Number of twins in a recent Danish study that found the greater the difference between how old each one looked to subjective assessors, the more likely the older-looking twin died first

24
Number of studies that have examined the association between low grip strength and premature mortality

3
Times by which one’s chance of dying or suffering a significant disability within six years increases if one cannot walk a quarter-mile

43
Percentage of people 100 and older who have had a history of significant age-related disease after age 80

3
Percentage of people 110 and older who have had such disease after age 80 — suggesting that these people might share an underlying biological similarity that those who don’t live that long do not

Screening's Strange Math

2010-04-27T13:22:05-05:00

Organizations formulating guidelines to ensure that tests are doing more good than harm must consider how often tests produce false-positive results. The U.S. Preventive Services Task Force, for example, has concluded that almost 2,000 women in their forties would have to be screened to prevent one death from breast cancer, and this could produce as many as 200 false positives, sometimes leading to unnecessary biopsies and even, in some cases, unnecessary surgery, chemotherapy or radiation. This hypothetical example of a test, put forth by mathematician John Allen Paulos, illustrates the type of arithmetic involved.

Please click here for the full image.

Protein Misfolding: Origami Medicine

2010-04-26T12:58:35-05:00

The proteostasis network has always existed, but the name is new, and only recently emerging is the notion that the network is as essential to life as a beating heart or DNA. Proteostasis is what the cell aspires to: a state of equilibrium in which the many proteins inside it coexist and interact. When the network is perfectly balanced, it’s a hallmark of a healthy cell—and of any healthy organism, from the primitive worm Caenorhabditis elegans to the gloriously complex human. But when it’s unbalanced—because of defective proteins, aging, physiological stress or other factors—disease results.

Despite its name, proteostasis is anything but static. There’s constant activity, as every day the cells of the human body pump out thousands of proteins that carry out a remarkable range of functions, from preventing lung tissue damage to transporting crucial ions across membranes and stabilizing nerve cells. To achieve these functions, proteins must fold into specific three-dimensional shapes, find their way to their destinations and, if defective or no longer needed, degrade to make way for newly synthesized replacements. A network of more than 1,000 enzymes, molecular chaperones and other components controls these processes. Numerous signaling molecules work together in pathways that respond to cues from the cell or its environment to regulate the number of chaperones, enzymes and components.

William Balch, professor of cell biology at the Scripps Research Institute in La Jolla, Calif., whose work focuses on the pathways of proteostasis, describes the process of folding, transporting and chaperoning a protein: “It’s like raising a kid. After he’s born, you don’t just put him out on the street. You work with him. The cell is working all the time with the proteins that it makes on a minute-by-minute basis.” Each cell must ensure that proteins are made to proper specifications, maintained in the three-dimensional shape that allows them to work properly, and launched into adulthood in a way that supports the cell’s overall health.

Though many scientists are now focused on deciphering the details of the system, progress has been frustratingly slow, and the more researchers learn, the more complexities they unearth. Discovering the processes and interactions involved in just one pathway may take years. But there’s an urgency underlying this work, because folding errors and other protein defects are known or suspected to be implicated in many devastating diseases, from cystic fibrosis to Huntington’s, Alzheimer’s and type 2 diabetes.

One tack medical science has taken is to try to treat these disorders with gene therapy—replace the defective gene that produces the aberrant protein. Researchers have also looked for ways to introduce a “normal,” or “wild type,” version of the protein into a cell. For example, with a degenerative nerve disease known as transthyretin (TTR) amyloid polyneuropathy, caused by a misfolded protein produced by the liver, a transplanted liver cures the condition by making perfect, wild-type TTR that doesn’t cause problems. But in most cases, these methods haven’t proved effective, so the treatment of misfolding disorders has usually been relegated to relieving symptoms.

Recently, however, researchers have begun exploring ways that science can influence parts of the process, tweaking the diseased system with drugs designed to bring proteostasis back into balance. In some cases, they’ve been able to make partial molecular fixes that help a misfolded protein achieve its original purpose. Sometimes, it turns out, perfection isn’t needed, and “good enough” solutions, hurried from concept to drug discovery through a process of high-technology trial and error, may get the job done—often years in advance of more complete or elegant therapies.

Denise Bosco for Proto

Many genetic disorders stem from mutations in DNA that produce a protein with a slightly different sequence of amino acids than normal, which causes the protein to misfold. In one main category of these illnesses—loss-of-function diseases such as cystic fibrosis, Gaucher’s disease and related lysosomal storage diseases—the errant protein is targeted for early destruction and is never able to do its job (exactly how this happens differs from one disease to another and in some cases isn’t fully understood). That’s more or less the opposite of what occurs with a second big classification of folding disorders: gain-of-function diseases, which include Huntington’s, Alzheimer’s, type 2 diabetes and a group of illnesses called familial amyloidoses. In this case, instead of being destroyed, a misfolded protein breaks down and is put back together in an aggregate form that causes toxic damage—it does things that were never intended to occur (here, too, specific mechanisms are still being studied).

The symptoms of a particular disease depend on the type of tissue that holds the misfolded protein. In the most common mutation that causes cystic fibrosis, ΔF508, a protein called the cystic fibrosis transmembrane regulator, or CFTR, misfolds and is destroyed, and the lack of CFTR causes thick, sticky mucus, which builds up in the lungs and the pancreas. In Huntington’s disease, the misfolded huntingtin protein breaks down, then re-forms into an aggregate in the brain that causes neurological damage. In TTR amyloid polyneuropathy, the liver makes the protein TTR, which misfolds and ends up in peripheral nerve tissue as the aggregate TTR amyloid, which results in loss of sensation, muscle weakness and autonomic nerve problems that may affect the gastrointestinal and urinary tracts, among other systems.

During protein folding, ribosomes—small cellular structures in the cytoplasm—translate genetic information into long strings of amino acids known as polypeptides. From these chains, the protein folds itself into an intermediate structure and then into its final three-dimensional form. Proteins constantly fold and refold as they interact with other proteins and enzymes. And although many of the ins and outs remain poorly understood, research has shone light on the roles of chaperones and signaling pathways, which moderate this dynamic process. Chaperones are molecules that promote proper folding by binding to misfolded or aggregated proteins and providing a second chance for them to fold correctly. For their part, signaling pathways respond to cues from the environment to regulate not just how proteins fold but also how they’re made, moved, aggregated and degraded.

One of the best understood pathways is the heat shock response. Richard Morimoto, a professor of molecular biology at Northwestern University, began working with heat shock genes more than 30 years ago, just after their discovery, and he and other researchers found that cells have a molecular thermometer that can turn genes on and off—thus increasing or decreasing production of the proteins associated with those genes. When a cell’s temperature was raised, the cell began to synthesize great numbers of heat shock proteins, or HSPs. This same pathway turns out to exist in all organisms, from yeast to humans. A substance called heat shock factor, or HSF, controls the response.

Extrapolating from what they have learned about this and other pathways and chaperones, researchers have been pushing to find treatments for proteostasis disorders. They’re studying small molecules that can bind to and stabilize misfolded proteins, such as CFTR, the protein thought to cause many symptoms of cystic fibrosis. In its most common mutation, ΔF508, CFTR is missing one amino acid, phenylalanine, which causes it to fold improperly. The endoplasmic reticulum—a tubular transport network that winds from the membrane of the cell nucleus to the outer cell membrane—then destroys the mutant CFTR before it can reach the cell membrane. When CFTR, which lets chloride into and out of the cell, is lacking, the amount of water in tissues is altered. In the lungs, for example, a layer of mucus depends on water to keep it diluted and not sticky.

In an alternative scenario, a small molecule known as a pharmacologic chaperone might bind to CFTR while in the endoplasmic reticulum and somehow partially repair the misfolded protein, possibly by making it “look” like normal CFTR. Even though such a repaired protein isn’t identical to its perfectly folded counterparts, it avoids destruction and seems to function effectively. And if enough ΔF508 CFTR makes it to the cell membrane, the symptoms of CF could be much milder or even disappear entirely.

For gain-of-function diseases, in which misfolded proteins aren’t destroyed but rather break down and are reassembled into toxic aggregates, a type of chaperone that researchers call a kinetic stabilizer could bind to and stabilize a protein before the damage begins, preserving it in its functional state.

Yet another approach is to use something called a proteostasis regulator to influence a signaling pathway and, by increasing its ability to work with the mutated proteins, protect proteins from early degradation and allow them to reach their destination. “We don’t have to fight the system,” Balch emphasizes. “We can work with it.” This concept of “using biology to correct biology”—a phrase several researchers employ—could allow cell problems to be corrected at a very early stage, by nudging the pathways that target mutated proteins for destruction or reaggregation so that they are preserved and remain functional.

A recent paper by Balch and his colleagues shows remarkable potential for this approach. The researchers used a compound that inhibits a specific part of the proteostasis system, the HDAC signaling pathway. They knew that CFTR folding requires a particular heat shock protein, Hsp90, whose production is influenced by HDACs, and that by manipulating the Hsp90 system in a certain way, they could rescue the mutated CFTR. This led them to speculate that a drug that blocked the action of the HDAC pathway might also save the mutated CFTR protein from destruction and get it to the cell membrane. They tried various HDAC inhibitors and found success with suberoylanilide hydroxamic acid (SAHA), already in use as a chemotherapy drug.

“Lo and behold,” Balch says, “we saw the most striking rescue ever of CFTR activity on the cell surface.” In cultured human lung cells, SAHA seemed to restore the protein’s function, raising it to 28% of the level that an undamaged, wild-type CFTR would provide. “You saw a remarkable degree of stability,” he says. “The proteins degraded very slowly, compared with extremely rapid decay in a cell that had not been treated with an HDAC inhibitor.” The next step, Balch adds, is to “dig in and really understand how” an HDAC inhibitor achieves that desirable result.

Yet the lack of deeper understanding hasn’t prevented drugs that affect the proteostasis network from proceeding to clinical trials. When researchers know what they want a pharmaceutical agent to do—in this case, to restore the function of the CFTR protein—but are unclear about some of the mechanisms and pathways underlying the problem, they can use a process called high-throughput screening. This screening employs automated, computerized systems to rapidly test hundreds of thousands of molecules to begin the search for an effective drug. Though the great majority of compounds tested won’t be effective, that doesn’t really matter, because it’s relatively fast and easy to run through whole libraries of chemicals.

Denise Bosco for Proto

About a dozen years ago, the Cystic Fibrosis Foundation approached Aurora Biosciences, a company experienced in high-throughput methods, and asked it to develop a programto screen for compounds to treat CF. At the time, the idea of doing something to get the CFTR protein to the cell surface—rather than trying to correct the underlying gene, which hadn’t worked—was relatively new. After Aurora was acquired by Vertex Pharmaceuticals in 2001, scientists at Vertex used high-throughput screening and eventually found a compound the company calls VX-770, a “potentiator” molecule that increases the activity of CFTR once it reaches the cell membrane and helps it function more effectively. But this compound is thought to work only if CFTR lies on the cell surface (and some gene mutations that cause CF do allow some CFTR to reach the surface, though it doesn’t function properly once there). So Vertex scientists simultaneously searched for a second kind of compound—a “corrector”—that would restore ΔF508 CFTR to its normal shape, allowing it to get to the surface. They found it and named it VX-809.

Eric Olson, project leader for cystic fibrosis at Vertex, says the company developed both compounds in part because research had shown that when the temperature of cells was reduced, ΔF508 CFTR could get to the cell surface, but once there it seemed to function less efficiently than wild-type CFTR. Further research has revised that view, showing that ΔF508 CFTR does work correctly if it can reach the cell membrane. But Vertex’s potentiator drug VX-770, which fared well in 2008 Phase II clinical trials, can boost the effectiveness of the protein further. So even if the corrector doesn’t fully fix the mutated protein and restore a normal quantity to the cell surface, the potentiator can help the CFTR that does arrive to transport more chloride ions.

In February, Vertex released the results of a clinical trial of its corrector compound, VX-809. While the drug didn’t improve lung function, it did have an impact on patients’ sweat chloride tests, a marker of how effectively skin cells are transporting chloride, and thus an indication of how much CFTR protein is getting to the cell surface and functioning properly. According to Olson, the company plans to conduct a clinical trial using both VX-809 and the potentiator, VX-770. Judging from in vitro studies that used a combination of VX-809 and VX-770, he thinks the combined therapy could help reduce CF symptoms in patients with the ΔF508 mutation.

Other potential therapies for gain-of-function disorders are also emerging. Jeffery Kelly, chair of the department of molecular and experimental medicine and professor of chemistry at the Skaggs Institute for Chemical Biology at Scripps, and his colleagues have discovered a kinetic stabilizer for the protein implicated in TTR amyloid polyneuropathy, keeping it functional and preventing it from unfolding and aggregating into its toxic form. FoldRx Therapeutics, a company Kelly founded, has developed a drug, tafamadis meglumine (FX-1006A), now in clinical trials, and preliminary results show that it significantly slows progression of the disease. FoldRx is also researching treatments for Parkinson’s, Huntington’s and a form of amyotrophic lateral sclerosis using the same strategy of stabilizing defective proteins.

Denise Bosco for Proto

Many gain-of-function disorders, including Parkinson’s and Alzheimer’s, are considered diseases of aging; work with the C. elegans worm, which researchers often use as a model for how human diseases develop, suggests that as cells age, misfolding may become increasingly commonplace. In studying Huntington’s disease in C. elegans, Morimoto and his colleagues discovered that as the worm aged, the huntingtin protein did, in fact, become more likely to misfold, aggregate and become toxic. One of the researchers, Jim Morley, decided to experiment with a version of the worm that carries a life-span-extending mutation as well as the genes that cause Huntington’s. In those worms, in which aging was long delayed, the huntingtin protein didn’t misfold. “That was an aha! moment,” Morimoto says, “because by enhancing life span, we had suppressed protein misfolding.”

As Morimoto and his team looked more closely at the proteostasis system, they found that as a cell ages, proteins become very unstable, and misfolding and aggregation grow rampant. Morimoto says it’s beginning to appear that the same components of the network that malfunction in Huntington’s, Alzheimer’s and other age-related, gain-of-function disorders are also implicated in the aging process itself.

Yet while research aimed at restoring cells’ protein machinery to health and preventing age-related deterioration is gaining momentum, there are some concerns. One is that increasing the proteostatic capability of a cell might activate latent viruses by allowing the cell to begin producing the enormous amounts of proteins they need for replication. Another essential question is how much protein in a particular disease must be restored or prevented from becoming toxic before the symptoms of a disorder will disappear. Researchers surmise that 100% is not needed because carriers of one copy of the cystic fibrosis mutation, who have one good gene and one that produces mutated protein, have only half the normal CFTR function but show no signs of the disease. In other folding disorders, the calculation isn’t always as straightforward. It remains to be seen how much protein will suppress disease symptoms, and it will take more trials like those at Vertex to find out how much restoration of protein is adequate for a particular protein misfolding disorder.

As more of these questions are answered, however, new drugs for misfolding disorders are likely to be developed, and some of those may even prove effective against multiple diseases. If they involve the same molecular pathway, even seemingly unrelated disorders may respond to the same drug. “It could be that half a dozen molecules would treat 50 to 60 diseases,” Kelly says. Because it would be relatively easy to test a compound that shows promise against one disease on several others, the time it takes to find effective treatments could be shortened.

At the same time, combination therapies involving multiple drugs may be required to eradicate the symptoms of misfolding disorders. “You might need two or three drugs to create the best situation for the cell,” says Pamela Zeitlin, professor of pediatrics at the Johns Hopkins University School of Medicine and a CF researcher and clinician who studies proteostasis. Some researchers now think it may be possible to find widely acting proteostasis regulators, and such drugs might boost the effectiveness of therapies that work on a specific pathway. Or, similar to the Vertex strategy with its corrector and potentiator compounds, two compounds focusing on a single problem may work better than just one.

Regardless of which drugs eventually pass muster in clinical trials, researchers are optimistic that by focusing on proteostasis, they’re getting closer to finding treatments that do more than put a patch on symptoms for disorders caused by misfolded proteins. They’re looking toward a future in which new pharmacologic therapies may fix these disorders at their root.

Evidence-Based Medicine: Burden of Proof

2010-04-26T13:19:59-05:00

Last November the U.S. Preventive Services Task Force unleashed a maelstrom when it recommended against routine mammography for women younger than age 50 and advised physicians not to teach women how to do breast self-exams. The response was swift and fierce, with such celebrities as Jaclyn Smith and Sheryl Crow—both breast cancer survivors—leading the vanguard in proclaiming the new recommendations to be misguided and dangerous.

Physicians lined up right behind them. “This is a giant step backward and a terrible mistake,” oncologist Marisa Weiss told the New York Times. “We know mammography overperforms and finds things that will never be life-threatening, and we know it underperforms,” said Weiss, who is the founder of Breastcancer.org. “But it has no chance to perform in women who don’t get it.” Added Christine Hodyl, director of breast surgery at South Nassau Communities Hospital in Oceanside, N.Y., “I can’t tell you how many times we pick up a cancer in a young woman who comes in for a baseline mammogram before age 40.”

But the USPSTF’s recommendations were based on the best research and decision-making that medicine has to offer. A panel of primary care physicians and scientists—not oncologists or radiologists, who might have a financial stake in breast cancer treatment or prevention—considered the results of numerous randomized trials and commissioned its own study before concluding that 1,904 women in their forties would have to be screened with mammography to prevent just one death from breast cancer. That benefit did not outweigh the risks of false-positive findings, which would subject women to unnecessary biopsies, anxiety and treatment of benign breast conditions, according to the USPSTF, which urged women to discuss the benefits and tradeoffs with their doctors. The panel also found no evidence to support the utility of breast self-exams, citing data indicating that most lumps women find are benign and don’t merit the biopsies that often follow.

The new mammography recommendations joined a growing body of research that falls under the rubric of evidence-based medicine. This approach is based on the belief that medical care will be better, safer and more efficient if physicians base clinical judgments on solid empirical science. Backed by such evidence, government agencies, specialty medical societies, disease associations and large health plans have developed guidelines that set out exactly which drugs, tests and treatments doctors should use to manage a vast array of medical conditions. Insurers follow evidence-based guidelines to make decisions about which interventions they will cover. And Medicare and private health plans have utilized guidelines to extrapolate hallmarks of quality and hold physicians and hospitals accountable for meeting them.

Instead of receiving gratitude for improving care, however, the USPSTF found itself at the center of controversy. “Breast cancer is a topic of great emotional and physical meaning for women, and the guidelines were created by a group whose name suggested it was a governmental body with an interest in controlling costs,” says Steven Pearson, a physician and president of the Institute for Clinical and Economic Review. Based at Massachusetts General Hospital’s Institute for Technology Assessment and affiliated with Harvard Medical School, ICER is a policy group that weighs the effectiveness and the cost of medical treatments. In fact, says Pearson, the USPSTF is an independent organization. “The announcement explaining why the recommendations had changed was very badly managed,” he explains. “And the battles over health care reform going on at the same time just turned up the volume.”

The furor illustrates one of the biggest problems with evidence-based medicine—that it can be almost impossible to produce the kind of rock-solid evidence that will convince physicians (and the public) that a particular intervention, preventive measure or diagnostic test really is the best medicine. Though the USPSTF recommendations were never meant to apply to every patient, nuance was quickly lost in the uproar. Those who objected to the organization’s conclusions simply found medical evidence they liked better: the American Cancer Society’s guidelines calling for women to receive yearly mammograms once they turn 40. “It can be challenging to make medical decisions when august groups of clinical experts look at the same evidence and, based on their beliefs about its strength, come to very different conclusions,” Pearson says.

Yet there are compelling medical—and financial—reasons to persist in attempts to rationalize how medicine is practiced. The Institute of Medicine has estimated that only half the treatments that doctors prescribe are effective, and according to an analysis by the New England Healthcare Institute, a health policy group, $760 billion is wasted each year in the United States because of unnecessary diagnostic tests and medical procedures, medical errors and the need to treat hospital-acquired infections. These problems might be reduced through effective practice guidelines. Many politicians and policy experts are banking on evidence-based medicine to improve the quality of U.S. medical care and rein in its cost, which now stands at an unsustainable 17.3% of gross domestic product. “The last thing you want to do is turn away from the evidence in the name of physician intuition,” says Alan Garber, director of the Center for Health Policy at Stanford University. “Physicians do a great job of making decisions when they have compelling data to work with, but in many cases the data have been missing.”

Nigel Cox for Proto

When the phrase “evidence-based approach” first appeared in the medical literature in 1990, describing the need to anchor medical decisions to scientific evidence, it reinforced what some health policy experts had been saying for decades—that physicians’ clinical judgment was based on too much art and not enough science. In 1973 John Wennberg from Dartmouth Medical School began mapping how practice patterns varied geographically, and he ultimately concluded that tradition, physician preferences and the numbers of physicians and hospital beds per capita were behind many of the differences. What’s more, subsequent studies suggested that patients often got the wrong care. One study, for example, found that for a third of patients who had carotid arteries unblocked surgically, the procedure’s risks outweighed the benefits.

Among the first evidence-based guidelines came from physician and mathematician David Eddy, who in 1980 was a professor at Stanford University’s School of Engineering. Eddy says he was motivated by the sheer complexity of medical decision-making. His initial guideline, for the American Cancer Society, held that women should be screened for cervical cancer every three years rather than annually—a recommendation that didn’t become standard practice for 20 years. Later, Eddy, as a consultant for Blue Cross/Blue Shield, urged the insurer to use evidence—or the lack of it—as a criterion for making coverage decisions. When Blue Cross, under his guidance, refused to pay for a breast cancer treatment that combined high-dose chemotherapy with a bone marrow transplant, Eddy got hate mail from physicians. A subsequent study confirmed that the therapy did not extend patients’ lives.

Soon medical societies got in on the act, not only consulting the available evidence to determine when people should be screened for various diseases but also coming up with guidelines that sought to show the best approaches for treating everything from hemorrhoids to various cancers. Government health agencies and private insurers took things one step further, turning evidence-based guidelines into quality standards for doctors and hospitals. More than 100 “pay for performance” programs now tie reimbursement to such yardsticks as how many patients receive recommended blood pressure or diabetes monitoring. In Massachusetts some insurers assign physicians to one of three tiers according to their relative performance on cost and/or quality measures—and increase out-of-pocket payments for patients who choose to see the lowest-scoring doctors (patients are made aware that they are paying higher fees).

Supporting the push to justify how medicine is practiced, Congress appropriated $1.1 billion in 2009 for comparative-effectiveness research, commonly known as CER, which evaluates the strengths and weaknesses of treatment options for particular medical conditions. Though evidence-based guidelines and effectiveness research aren’t supposed to factor in cost, that issue is never far from view. One hope among proponents is that physicians will be swayed by the coming government-funded research to choose proven, older treatments with the same outcomes rather than automatically prescribing the latest, most expensive technology—and that insurers will integrate comparative effectiveness into coverage decisions.

Nigel Cox for Proto

From the start, however, the quest to produce evidence-based guidelines covering every medical treatment has been hampered by a persistent question: Just how good is the evidence? In the hierarchy of medical knowledge, the results of randomized, controlled clinical trials come out on top. There is no stronger scientific proof of whether a treatment, drug or medical device is effective than a trial that compares what happens to people who receive a new intervention with outcomes for those who had a different treatment or a placebo. Even with this kind of research, there may be concerns about the design of a study or how its data is interpreted, but evidence from a randomized trial has the greatest power to shape doctors’ beliefs and practices—and to be turned into a quality benchmark in pay-for-performance programs. “You can create medical standards only if there is very good evidence that this is the best way to treat a patient,” Eddy says. Yet at a cost of $10,000 to $50,000 per patient per year, controlled clinical trials are multimillion-dollar propositions, and the guidelines based on them are in a distinct minority.

More frequently, standards are “consensus-based”—developed by panels of disease specialists or other physicians who rely on their own expertise and studies that don’t have the scientific rigor of large, controlled trials. These guidelines constitute recommended care, and physicians can follow them or not as they choose. “Some of these guidelines are self-serving and intended to ensure referrals or reimbursement for certain services, but others are really done for the right reasons”—to help physicians deliver the best care, says Richard A. Deyo, professor of evidence-based medicine at Oregon Health and Science University and author of Hope or Hype: The Obsession With Medical Advances and the High Cost of False Promises.

But even guidelines that seem to have been done in the right spirit may be viewed suspiciously by physicians worried about the behind-the-scenes influence of pharmaceutical companies or medical device manufacturers. Those companies often pay specialists to extol new technologies or drugs to other physicians. “The influence of the drug and device industries has become ever stronger, so you may wonder whether you’re looking at accurate information when you read a guideline,” Deyo says.

To counter such criticism, many specialty societies have begun disclosing conflicts of interest and are trying to make sure their guideline panels include diverse points of view. But Rodney Hayward, director of the Center for Practice Management and Outcomes Research at the Ann Arbor Veterans Administration and professor of public health and internal medicine at the University of Michigan, would prefer to take this job away from specialists—partly because he considers it unrealistic to expect doctors with a stake in the outcome to make unbiased decisions.

“Guidelines are being made by people who couldn’t pass my epidemiology course—they wouldn’t even come close,” Hayward says. “That means they interpret the evidence in very simplistic ways and treat patients as though they were interchangeable.” The result is rigid guidelines that leave no room for physicians to give nuanced care to individual patients, says Hayward, who notes that clinical trials report the average benefit of an intervention for an average patient. But the reality is that a drug or a treatment does not affect every patient equally.

That’s why Hayward opposed a guideline that advocated using multiple drugs to keep a diabetic’s glycosylated hemoglobin level—as gauged by the A1C test, which measures blood glucose levels over a period of months—below 7%. There’s plenty of evidence to suggest the drug metformin lowers a diabetic’s risk of heart attack, and it may slow progression of diabetes as well, Hayward says. But he thinks that adding other drugs solely to reduce a moderately elevated A1C may lead to inappropriate care. Those additional treatments could cause significant side effects, and they may not have been tested for long-term safety when used in combination with metformin.

What’s more, a hard-and-fast A1C guideline doesn’t take into account the circumstances of a particular patient. A 45-year-old, for example, might be willing to suffer the side effects of multiple drugs if the drugs reduced his risk of becoming blind in 20 years. But the same tradeoff might look different to a 65-year-old, says Hayward. “We shouldn’t use medications in low-risk individuals for small amounts of gain,” he says. The guideline was modified in 2008 after a trial of aggressive glucose-control treatment was halted because of excessive numbers of deaths among elderly diabetics.

Hayward’s choice for creating guidelines would be a group of internists and family physicians trained to interpret trial data so that it would more accurately reflect the benefits to patients with wide-ranging disease risk profiles. “Generalists who understand that treatment benefits and safety vary tremendously—and that optimal care includes considering which compromises patients are willing to make—would produce guidelines that physicians and patients could actually follow,” he explains.

But even flexible guidelines that accommodate a patient’s circumstances and preferences might fall short if they cover only a single disease or condition. Many patients have diverse medical problems, and treating one effectively can sometimes aggravate another, says Cynthia Boyd, assistant professor at the Johns Hopkins University School of Medicine. When she applied the best evidence-based guidelines she could find to a hypothetical 79-year-old woman with five common chronic diseases—osteoporosis, osteoarthritis, type 2 diabetes, hypertension and chronic obstructive pulmonary disease—Boyd discovered that the treatment recommendations were unrealistic and potentially harmful, in part because the guidelines included limited information about potential drug interactions. One guideline called for treating osteoarthritis with nonsteroidal anti-inflammatory drugs, which have side effects that include heightened blood pressure and impaired kidney function—not a good choice for a hypertensive patient. Following the separate guidelines to the letter also meant that her fictional patient would have had to take 12 medications in 19 combinations 5 times a day. “Guidelines have an important role, but they have been developed from a single-disease perspective,” Boyd says.

Boyd also worries that physicians who receive financial bonuses for adhering to guidelines may not be motivated to develop customized treatment plans for patients with complex problems. “If your income is tied to doing everything the guidelines say, you may be less inclined to talk to patients about what health outcomes they value most, think through the drug interactions and figure out the right treatment,” she says. “Even when there isn’t a financial incentive, most physicians want good grades on their performance report cards.”

While evidence-based medicine in its purest form is blind to the cost of interventions, many of its champions believe cost should be part of evidence-based policy decisions. “Many countries apply cost-effectiveness analysis when they develop clinical guidelines in part because they find it useful for identifying patients who will receive the greatest benefit from a health intervention,” says Stanford’s Garber. But in the United States, where the cost of care often isn’t factored in, expensive drugs and procedures are more likely to be used and covered by insurers regardless of how little benefit they might provide. “We won’t have an efficient health care system until we learn the value of individual interventions,” Garber says.

A process known as cost-effectiveness analysis uses clinical outcomes data in mathematical models to determine how many extra years of healthy life a person receives for every dollar spent on a particular treatment or procedure. That determination, in which improvements are measured in quality-adjusted life years, or QALYs, varies to a “stunning” degree across the range of medical procedures, says Milton Weinstein, professor of health policy and management at the Harvard School of Public Health, who helped pioneer cost-effectiveness analysis almost 40 years ago. According to research by his colleagues Jane Kim and Sue Goldie, annual screening for cervical cancer detects only a few more cases of cancer than tests done every other year. Doing the more frequent screening gains mere days or even hours in average life expectancy—and costs about $800,000 more for every year of life gained.

Alternative treatment protocols for some diseases, such as using trastuzumab in addition to standard chemotherapy to treat metastatic breast cancer, may have both a lower price and a better payoff—in this case, each gain of a QALY (which already factors in chemotherapy) costs between $125,000 and $150,000. But it would be very hard economically to justify routinely performing a CT scan for lung cancer in 60-year-old former heavy smokers, at a cost of $2.3 million per QALY, compared with no screening.

Some countries routinely weigh and act on such comparisons. In the United Kingdom, the National Institute for Health and Clinical Excellence evaluates cost-effectiveness when recommending which new medical technologies the country’s national health service should cover. Treatments that cost more than £30,000 (about $46,000) per QALY are generally denied. (Cancer drugs that prolong lives by just a few months were unlikely to make the cut, until NICE recently enacted a compassionate care exception.)

Although the United States may be a long way from adopting a NICE model, some U.S. panels are starting to weigh costs. The result, in some cases, is to recommend more care, not less. A revised guideline for HIV/AIDS treatment, for example, recommends that all newly diagnosed patients receive “genotypic resistance” tests when they begin antiretroviral therapy. “Our analysis showed that the cost-effectiveness of routine genotypic testing is excellent,” Weinstein says.

But such determinations aren’t automatically linked to payment decisions. Historically, Medicare, which decides which treatments are covered by government health programs, has not considered the cost of medical services. Private health plans also tend not to factor in costs in deciding what to cover. Those insurers can, however, decide they won’t pay for treatments or diagnostic tests that are more expensive but only slightly more effective than an alternative.

One health care payer, though, is only too happy to admit to using costs in deciding what to cover—and to invite the public to scrutinize its deliberations. In 2006 the legislature in Washington State approved a law that permits considering costs in making coverage decisions for about a million state employees, prisoners, and recipients of Medicaid or workers’ compensation. A panel of physicians makes choices about surgical devices and procedures, treatments and diagnostic tests based on their efficacy, safety and cost-effectiveness. Anyone can suggest a treatment for the panel to review, all meetings are public, and the panel’s decisions are posted for comment before being finalized. Now in its fourth year, the panel has made 15 rulings, and 10 more are pending.

The panel can decide to flat-out deny coverage for a procedure, as it did when it deemed an implantable drug pump for chronic noncancer pain to be unsafe. A second option is to rule that an intervention is necessary only in some cases. The panel has approved artificial lumbar and cervical disks for people younger than 60 and drug-eluting stents for those considered at high risk of having their coronary arteries narrow again after angioplasty. On rare occasions, the panel has even opted to expand coverage, as when it decided to pay for bariatric surgery for young obese people.

For help finding the best science on which to base its decisions, Washington State relies on a handful of organizations that attempt to quantify the clinical and economic value of various treatments. Their research blends evidence-based medicine with cost-effectiveness analysis. One of these organizations, the MGH’s ICER, accepts funding from government agencies, health plans, and pharmaceutical and device manufacturers. Still, says ICER president Pearson, the institute maintains its impartiality by directing its own research agenda and putting its results in the public domain. “Our work is most useful when there is conflict about the strength of particular evidence,” he says. Health plans use ICER appraisals to make coverage decisions; medical societies employ them in creating guidelines.

Only government groups can commission studies from ICER, and the state of Washington asked for two. One was for virtual colonoscopy, a noninvasive imaging technology that offers an alternative to traditional colonoscopy. After evaluating studies that have looked at the new procedure, ICER concluded that virtual colonoscopy was as effective as, but likely to be more expensive than, a traditional colonoscopy. Moreover, ICER did not find that the technology would help persuade people to undergo colorectal cancer screening because they still must go through unpleasant colon cleansing. Based on ICER’s evaluation, Washington State decided not to cover the new imaging procedure.

More complicated was ICER’s appraisal of the benefits of cardiac CT angiography, a test that employs scanning technology instead of invasive angiography to diagnose coronary artery disease. ICER concluded that the new imaging test and the traditional approach worked equally well. But the more expensive CT angiography was cost-effective only in the emergency room, where it could quickly identify those who were not in imminent danger of a heart attack and could safely be sent home. The state of Washington decided to pay for CT angiography in the ER but not in outpatient settings.

So far, evidence-based coverage decisions have saved Washington State about $27 million a year. That’s a modest beginning, given that the state’s most recent budget allocated $2.9 billion for health care. But it’s not about to abandon the experiment, and the national push toward using evidence-based medicine and cost-effectiveness analysis is also certain to continue. Yet, as the mammography controversy suggests, new clinical guidelines—particularly when they recommend less care and may be suspected of economic motivations—are likely to face skepticism from the public as well as from physicians.

“Today it’s no longer tenable to say that evidence-based medicine is irrelevant,” Garber says. “But it’s certainly possible to argue that current efforts promise more than they can deliver.” Those attempts have been hampered by everything from a lack of good evidence to questions about whether guidelines are corrupted by specialty biases and conflicts of interest. The issues of addressing patient differences and patients with multiple diseases further complicate progress.

There’s also a long tradition of physician and patient autonomy in medical decision-making in the United States—one of only two countries (New Zealand is the other) that allow direct medical advertising to consumers. “We can create evidence-based guidelines, but we also have marketing campaigns that appear on the nightly news that contradict those guidelines,” Oregon’s Deyo says.

Still, the stakes are too high to abandon the effort, Pearson says. “There will always be natural tensions and very strong interests in our health care system that will make interpretations of evidence challenging,” he says. “But we shouldn’t throw up our hands. Evidence-based medicine remains an important reason for optimism that we can improve our system, although there is a lot of work ahead.”

Could Electronic Trials Provide Better Evidence?

2010-04-26T13:47:39-05:00

Just as he evangelized about the need for physicians to base medical decisions on empirical evidence, physician and mathematician David Eddy is now promoting a mathematical model to fill the evidence gaps of the movement he helped start 30 years ago. The model, which he calls Archimedes, is built from hundreds of equations that represent human physiology and the effects of disease, and is overlaid with hundreds more simulating tests, treatments and physician behaviors. Archimedes expands upon clinical trial data to answer questions that trials can’t, Eddy says.

For instance, it can project how changing the dose of a drug or combining it with other medications may affect patient health. It can also estimate how a broader population than the one studied might benefit from a new intervention.

What’s more, Archimedes can be much faster and cheaper than a clinical trial. In two months, at a cost of several hundred thousand dollars, Eddy was able to replicate a seven-year, multimillion-dollar controlled clinical trial studying whether the drug atorvastatin could prevent heart attacks and strokes in diabetics—and Archimedes was almost spot-on in predicting the trial results before they were announced.

The model can’t replace clinical trials, however. “First you need empirical evidence from a trial that a test or treatment is effective,” Eddy says. Only then, after Eddy has developed an accurate model based on those results, can Archimedes apply it to untested applications.

But if physicians find fault with guidelines created from actual trials, why would they trust a model? “All we can do is show that the model can reproduce what is seen in reality,” says Eddy.

Spinning Scaffolding for Skin Grafts

2010-04-26T14:00:51-05:00

SMALL BLOOD VESSELS under a microscope look strikingly similar to cotton candy. So observed graduate student Leon Bellan while working with plastic surgeon Jason Spector on a major problem involving tissue engineering: A skin graft often dies because it can’t generate blood vessels quickly. The two researchers and their team at Weill Cornell Medical College in New York City and the Cornell University College of Engineering in Ithaca, N.Y., used a cotton candy machine to make the wispy treat, then coated it in a polymer and dissolved the sugar, leaving behind a microchannel network that could serve as scaffolding on which to grow tissue implants.

John Nance: A Flight Plan for Hospitals

2010-04-26T14:12:24-05:00

Every airplane crash spurs a hue and cry over the tragedy—and questions about how it could have happened. Yet the thousands of deaths that occur yearly because of medical errors pose a problem that receives far less attention. John Nance argues that the same basic steps that have made the skies much safer during the past few decades could prevent thousands of hospital deaths.

Since 1964, Nance has clocked more than 13,000 hours flying commercial and Air Force jets. When the medical director of a health insurance company read Nance’s 1986 book about human-driven aviation errors, he noticed the parallels with challenges at U.S. hospitals and called on Nance for help. By 1997, Nance was a founding member of the National Patient Safety Foundation. His book Why Hospitals Should Fly depicts a fictional Denver hospital, St. Michael’s, to demonstrate how principles pioneered in the airline industry can be adapted to every aspect of a hospital, including the operating room, with salubrious results. The keys: following checklists, conducting presurgical “time-outs,” reading back medication orders and working in respectful teams rather than dictatorial hierarchies—ideas that have since become the subject of two books by physicians.

Q: Has the airline industry been more proactive than hospitals when it comes to improving safety?

A: It had to be: Thousands of passengers were dying in accidents. As the mechanical side became better and better, all that was left was human failure. Humans are always going to make mistakes.

Q:The changes the industry made seem astoundingly simple.

A: They were. For example, pilots sometimes started on the wrong runway, an error that they typically caught immediately, before it became lethal. But now no takeoff can begin without a cross-check: One pilot reads off the name of the runway, and the other confirms the compass direction.

Q: What’s the lesson for hospitals?

A: In hospitals, communication is garbled: Medical orders are snapped back and forth and are not read back by the doctor or nurse. In a cockpit, by contrast, pilots routinely repeat the instructions from air traffic control.

Q: Why is that important?

A: Repeating instructions engages both minds to make sure the information being conveyed is correct. I have a friend, an orthopedic surgeon, who says he never understood the importance of reading back until a few months ago. He was standing at a nurse’s station as a nurse was calling in an order for a pizza. She started to hang up the phone, then pulled it back to her ear because the guy was reading back her order. A few seconds later, the phone rang. It was a physician calling with an urgent medication order. She took the order, wrote it down and said, “Okay, Doc,” then click. No read back.

Q: What’s another key way to improve communication?

A: Surgical teams should carry out the equivalent of an airline pilot’s predeparture checklist, which includes checking the flight instruments and the positioning of the airplane’s flaps, among other details. Clinicians need to make sure they have the right patient, the right operation, the right expertise and the right tools. Such procedures would virtually end surgeries performed on the wrong body part.

Q: You note, though, that physicians resist these presurgical time-outs.

A: Sometimes a surgeon comes breezing into the operating room and doesn’t want to talk to anybody. He just wants to make an incision. In the average hospital, physicians have been trained to think they are omnipotent and infallible. A physician can be perfect for a time: maybe 36 years, or 36 minutes. But sooner or later, every physician will make a mistake. So we have to ask, How do we minimize the possibility of human error? In aviation we do it by working in teams, rather than making one person Captain Kirk—a person everyone follows and no one challenges.

Q: How is that done?

A: By training physicians to be leaders, not commanders—by working in teams and developing relationships that breed communication. If there’s push back, sometimes a hospital’s board of directors has to step in and say, “There is a line here. If you cross it, you are not practicing here anymore. Take your $10 million a year in thoracic surgery revenue and go down the road to Our Lady of Pretty Good Outcomes.”

Q: It seems physicians are beginning to listen. Surgeon and author Atul Gawande’s recent book, The Checklist Manifesto, is a call for patient safety that’s much like yours.

A: The journey of a physician—particularly a surgeon—from total and absolute personal autonomy to admitting that he or she cannot achieve adequate safety levels alone and without such unfamiliar tools as checklists is a torturous trek into reality. Atul has just provided immense assistance to his entire cadre of colleagues in making that journey; the immediate need for physicians to do so cannot be overstated.

Needlestick Injuries: Sticking Points

2010-04-26T14:21:25-05:00

Getty Images

600,000 to 800,000
Number of needlesticks and related percutaneous injuries from syringes and other “sharps” reported annually by U.S. health care workers

59
Percentage of surgeons in training who were accidentally stuck by a needle while attending medical school, according to a recent Johns Hopkins study

99
Percentage of residents who had sustained a needlestick injury by their final year of training, according to a 2007 paper in The New England Journal of Medicine

1 in 300
Chance that a health care worker will contract HIV if stuck or cut by a medical instrument contaminated with an HIV patient’s blood

35
Estimated number of HIV cases each year that result from occupational percutaneous injuries

3,000
Cost, in U.S. dollars, of treatment and follow-up for a high-risk exposure

1992
Year the FDA recommended that all health care facilities use needleless or recessed-needle IVs

2001
Year OSHA modified its Occupational Exposure to Bloodborne Pathogens Standard to specifically mandate the use of needleless IV systems and other  “safer medical devices”

74
Percentage of nurses in the 2008 Study of Nurses’ Views on Workplace Safety and Needlestick Injuries who said they would not accept a job from an employer that did not provide safety syringes