Medicine

Year In Science

Sunday, January 13, 2002

I See, I Cut, I Sew
On September 7, Jacques Marescaux and Michel Gagner became the Charles Lindberghs of the medical world. Hands on joysticks and eyes glued to video monitors, these doctors at Mount Sinai Medical Center in New York City used telesurgery to remove the gallbladder of a 68-year-old woman lying on an operating table in Strasbourg, France.

This first transatlantic operation combined two other remarkable medical technologies: laparoscopy and robotic surgery. Laparoscopy, developed in the late 1970s, uses a minute camera and microsurgical instruments to access the body through tiny incisions, providing a finer degree of accessibility to the surgeon and eliminating the risk of large, open surgical areas. The size of the incision reduces cutting, pain, bleeding, and recovery time. In robotic surgery the operator sits at a computer console, observing the surgical field on a monitor while using instruments that resemble joysticks to manipulate miniaturized instruments inside the body via data transfer over computer cables. Telesurgery is essentially robotic surgery performed with very long cables—in this case, a sophisticated fiber-optic system specially engineered by France Telecom.

Two hurdles stood in the way of telesurgery: how to transmit robotic movements and how to trim time lags in data transfer. "Even a delay of one-fifth of a second—less than half the time it takes to blink—can be fatal if an artery is nicked," says Gagner. "By the time you realize what's happened, blood will have obscured your view, increasing the time it takes to repair the artery. A patient can bleed to death." The new technology, designed by Computer Motion of Santa Barbara, California, allowed surgeons to work in near real time. Although the $750,000-per-hour price tag still prohibits bringing bandwidth bedside, Gagner foresees a global network of wired hospitals as the costs of data transmission decrease. "This will make the expertise of any doctor available to any patient," he says. "Eventually it could even be used on astronauts." Maybe telehousecalls will be next.
— Jocelyn Selim


A Walking Miracle
When he woke up on July 2, Robert Tools, 59, could barely lift his head off his pillow. A decade of heart troubles, made worse by his diabetes, had left the six-foot-three-inch former librarian and teacher so debilitated that his weight had dropped from more than 200 pounds to 140. Tools was too sick for a heart transplant. So he agreed to let two surgeons at Jewish Hospital in Louisville, Kentucky—Laman A. Gray Jr. and Robert D. Dowling—try something that had never been done before. That afternoon Tools became the first person ever to be implanted with a self-contained artificial heart.

Eighty days later Tools left the hospital for the first time to take a stroll through a city park, with the two-pound hunk of titanium and plastic pumping blood through his body. The heart, made by Abiomed Inc. of Danvers, Massachusetts, is powered by a battery implant that holds a 30-to-40-minute charge. The battery is recharged via a subcutaneous induction coil that can be attached to a two-pound external battery pack good for two hours, which Tools wears on a belt. Or the coil recharger can be plugged directly into a wall outlet. A microchip-packed controller, also implanted in the chest, regulates blood flow. The controller used 19 years ago in the Jarvik-7, the first artificial heart, was the size of a refrigerator; the one for Tools's heart is palm-sized. The tiny controller can run on autopilot, automatically compensating when Tools stands, sits, walks, or otherwise alters his body's need for higher or lower blood-flow rates. But his mobility is still limited. Most of the time, a transmitter implanted in his chest broadcasts data to a computer console in his hospital room so that doctors can continually monitor and fine-tune the blood flow.

Tools says living with an artificial heart entails adjusting to some strange new sensations. "The biggest thing is getting used to not having a heartbeat, except a whirring sound, and that makes me realize that I'm alive because I can hear it without a stethoscope."
— Tom Dworetzky


Breathing Easier
Designer Brian Frankowski holds a temporary artificial lung, which is scheduled for human trials this year.
Photograph by Kai Weichmann
For patients with lung ailments who get a breathing assist from massive external ventilators, the cure can be worse than the disease. Of the 75,000 patients who die each year of pulmonary stress, some expire as a result of the strain put on their bodies by powerful mechanical lungs that take over and do all their breathing for them. "We have long thought that if we could find another way to introduce oxygen into the bloodstream effectively, we could significantly decrease mortality," says William Federspiel, a bioengineer at the University of Pittsburgh School of Medicine.

An alternative was unveiled last May by Brack Hattler, a surgeon at the University of Pittsburgh who invented an artificial lung, and by Federspiel, who is chief scientist on the project. The device consists of a balloon surrounded by tiny plastic tubes. After a hole is cut in the patient's thigh, the lung is threaded through a catheter up the femoral vein and inserted into the vena cava, the major vein that returns blood to the heart. Oxygen vacuumed from a tank next to the patient's bed travels through the catheter and into the device, which then expands so that it can deliver the oxygen to the bloodstream. "The temporary device provides between 40 and 60 percent of the body's oxygen needs," says Federspiel. The rest is supplied by the natural movement of the patient's lungs.
— Curtis Rist


After the Rain
The Texas Medical Center in Houston, one of the largest medical-research facilities in the world, is normally a beehive of highly focused, disciplined activity. But tropical storm Allison created havoc at the center on June 9. Labs flooded, 35,000 research animals drowned, and experimentation came to a screeching halt.

Insurance and federal funds should help cover the hundreds of millions of dollars' worth of damage, but some researchers suffered losses that money alone cannot repair. At Baylor College of Medicine, one of two medical schools housed at the center, entire strains of genetically engineered mice were destroyed and must be painstakingly re-created. "This was devastating," says Katherina Walz, a geneticist whose entire body of work on Smith-Magenis syndrome, a disease that can cause mental retardation, was wiped out when her 150 mice died. "It was difficult for me to believe that I lost everything," she says.

Neighboring colleges and universities have offered lab space, technicians, and supplies to help the medical center get up and running again. Other research institutes have even offered to send copies of genetically engineered mice originally created at the medical center. "One of the good things that came out of this is seeing how wonderful people have been about helping us," says Jim Patrick, Baylor's vice president and dean of research. Adds Walz: "I think that in another nine months, I may be in the same position I was on that Friday."
— Maia Weinstock


Hope for Huntington's Patients
Huntington's disease, an incurable, untreatable inherited illness, affects 30,000 Americans, slowly killing their brain cells and eroding muscle coordination, memory, judgment, and emotional stability. Since 1993, researchers have known that repeated gene sequences, or stutters, in a single mutated gene cause the disease. But they haven't known how the mutation kills so many brain cells. Last year scientists got a glimpse of what goes wrong and how it might be fixed.

The repeated mutation that causes Huntington's disease lies within a gene that codes for a protein called huntingtin. Anyone with more than 36 repeats in the huntingtin gene will develop Huntington's disease. The stutters produce long stretches of the amino acid glutamine in the huntingtin protein, and the resulting misshapen protein clumps up within neurons, destroying brain cells.

A group at Johns Hopkins University hypothesized that the long stretch of glutamine snarls cell signaling because it gloms onto a stretch of glutamine in another key brain protein, CBP. In March Chris Ross and his colleagues reported that cells bearing mutant huntingtin could survive if they produced extra CBP. Giving the cells a form of CBP that lacked a stretch of glutamine also rescued them.

In July, Elena Cattaneo and her colleagues at the University of Milan reported that mutant huntingtin affects another key neuron-survival protein called brain-derived neurotrophic factor (BDNF). They found that cells lacking BDNF suffered the same pattern of cell death observed in Huntington's patients. In addition, they found that cells with mutant huntingtin produced almost no BDMF.

Finally, new hope for a possible treatment came in October. Leslie Thompson's team at the University of California at Irvine reported that compounds called HDAC inhibitors curbed a neural degeneration like Huntington's in fruit flies.

"It's been a remarkable year for Huntington's research," says Ross.
— Christine Soares


The Debate Over Stem Cells Gets Hot
Each human life begins in a bundle of cells, indistinguishable from one another, that wait for the go-ahead from DNA to begin a process called differentiation. Once acti-vated, these blank embry-onic cells commit themselves wholeheartedly to the production of specialized tissues for the heart, brain, and other parts of the body.

This versatility has made embryonic stem cells attractive to scientists since they were first isolated in 1997. If one could reliably manipulate these cells, the theory goes, damaged organs could be replaced with new, made-to-order organs. Repairing weak hearts or brains could be as easy as patching a tire. And an estimated 3,000 people who die every day might be saved.

Turning tiny cells into usable body parts is hardly new. Since the 1970s tissue engineers have been figuring out how to grow skin, bone, cartilage, and even parts of vital organs using cells harvested directly from patients. To perform this lifesaving work, scien-tists use adult stem cells derived from the cells of mature or recently born humans or animals.

Not all stem cells are alike: A) A colony of stem cells culled from a human embryo could in theory be used to grow or repair any body part. B) A stem cell from discarded placenta is more readily available—and less versatile. But last year researchers turned placental stem cells into C) neurons and D) cartilage cells.
Photographs: clockwise from top left, courtesy of Bresagen Inc.; courtesy of Dr. Harari/Anthrogenesis Corporation (3).
In theory, embryonic stem cells should be infinitely more useful than mature cells. They grow faster than adult cells and aren't married forever to a single type of organ or tissue. Despite these pluses embryonic stem-cell research is still very much in its infancy. Success has been hampered by a seemingly insurmountable ethical issue: To grow the endless sup-ply of flesh and blood patients will require, physicians would need un-limited access to human embryos. And, as Americans learned in the year of the stem cell, that won't be happening anytime soon.

When President Bush announced last summer that the government would fund embryonic stem-cell research using only existing cell lines—distinct genetic lin-eages—his decision was hailed as a brilliant compromise. But when scientists searched for those lines, it soon appeared that the National Institutes of Health, which tracked down the lines for the president's staff, had been guilty of a kind of irrational medical exuberance. In fact, fewer than 30 are now available. As long as embryonic stem-cell access is so limited, researchers will gravitate toward less controversial building blocks.

Even if someday the president allows access to every frozen embryo out there—at most 100,000 embryos—the numbers aren't sufficient to provide a breakthrough in medical treatment. "You'd still have to ration the therapy," cautions Robert Hariri, chief researcher at Anthrogenesis in Cedar Knolls, New Jersey, which announced this year that it had morphed human placental stem cells into nerve, blood, cartilage, skin, and muscle cells. "That's why it makes sense to pursue other approaches," he says. "There are 4.5 million births in this country every year, and we just throw the placentas away."

By contrast, embryonic stem cells are culled from embryos created and frozen in fertility labs. When a couple has had all the children they want, remaining embryos are tossed out or given to research labs. The notion of creating and then destroying potential human life, even to save another one, still offends many Americans. "It's a democratic country," says Allan Robins, chief scientific officer of Bresagen, a biotech firm based in Australia and Athens, Georgia, that isolated four of the federally funded cell lines. "Those who object to embryonic stem-cell research are entitled to their point of view. People have to realize that these embryos will be discarded anyway. We've found a very good use for cells that would otherwise be sitting around in liquid nitrogen. If you don't agree with the science, you don't have to use it. We aren't going to force anyone to have a stem-cell transplant."

The national debate took place against a backdrop of rapid developments in stem-cell research. We offer a review of significant breakthroughs below.
— Joseph D'Agnese

News from the World of Adult-Stem Cell Research
At the University of California at Los Angeles, Marc Hedrick's team used human adult fat cells extracted during liposuction to make cells resembling cartilage, bone, and muscle.

Fred Gage and his colleagues at the Salk Institute in La Jolla, California, harvested brain cells from human cadavers and used them to form neural progenitor cells, precursors to adult human brain cells. Media pundits dubbed the cellular transformation "Frankenstein science," but most researchers were fascinated to learn that the same inactive tissue that indicates a patient is beyond resuscitation might someday be coaxed into becoming therapeutic tissue.

A Columbia University team headed by Silviu Itescu used human bone marrow to build new blood vessels in the hearts of rats.

PPL Therapeutics of Edinburgh in Scotland and Blacksburg, Virginia, said it had extracted stem cells from bovine skin cells.

Piero Anversa at New York Medical College in Valhalla, New York, and Donald Orlic at the National Human Genome Research Institute in Bethesda, Maryland, used mouse bone marrow to repair damaged mouse hearts.

A Yale research team led by Diane Krause turned a single stem cell from the bone marrow of an adult mouse into lung, liver, intestinal, and skin cells for other mice.
— —J. D.

News of Embryonic Stem Cells
A University of Wisconsin team used human embryonic cells to form cells that manufacture platelets as well as red and white blood cells. This achievement could be the first step toward overcoming organ rejection, the chief obstacle to organ engraftment. The work was led by Dan S. Kaufman, a hematologist, and James A. Thomson, the first scientist to grow human embryonic stem cells in culture. The pair work for WiCell, a nonprofit company that makes five embryonic cell lines available to other scientists for a nominal fee.

A team led by Ron McKay at the National Institute of Neurological Disorders and Stroke in Bethesda, Maryland, turned mouse embryonic stem cells into isletlike cells, another step down the long road to a cure for diabetes.
— —J. D.

A Reverse Brain-Drain?
Roger Pedersen, a noted professor of obstetrics, gynecology, and reproductive sciences, announced he was leaving his laboratory at the University of California at San Francisco and moving to Cambridge University because British laws do not restrict work on embryonic stem cells. Pedersen has long been regarded as one of the top stem-cell researchers in the United States. His five-person laboratory was one of the first in the world to derive stem cells successfully from human embryos.

President Bush's announcement in August that 64 cell lines were ready for research was greeted with disbelief by researchers, who scoured the literature and databases looking for them. They have since learned that as many as 40 of those lines may never be fully developed; some may even have been contaminated by mouse cells used to sustain them in the lab.
— —J. D.


Mad Cow on the March
Mad cow disease has arrived in Asia. Last September the first regional case of the disease was diagnosed in a 5-year-old Holstein on a dairy farm in Shiroi, a suburb of Tokyo. Fear began to spread through Japan, which joined a growing number of nations affected by the epidemic. Beef prices plummeted, and nearly 2,000 public schools pulled beef off their lunch menus. Yet the news should have come as no surprise. Japan not only continues to feed meat-and-bone meal to cows—the source of the original epidemic in Britain—but has also failed to ban imports of it from Europe, despite a 1996 government directive to farms to find alternative feeds. Moreover, the fate of the hapless Holstein should send shivers down the spine of any Japanese meat-eater. Instead of being destroyed, the cow was slaughtered and its carcass sent to a rendering plant, where it was recycled into meat-and-bone meal for chickens and pigs.
— Josie Glausiusz


Staph Killers
Last year researchers began to better understand one of the most formidable foes of the human body: Staphylococcus aureus. The bacterium causes a variety of swift and deadly infections including toxic shock syndrome and sepsis—and rapidly develops resistance to antibiotics. Last year, a full map of the staph genome created in one lab revealed just how quickly and easily the bacteria acquire new genetic weapons. At the same time, researchers in other labs made significant advances toward conquering some of the bugs' best defenses.

In April Keiichi Hiramatsu, a bacteriologist at Juntendo University in Tokyo, published the genome of S. aureus. Hiramatsu proved staph acquire abilities by swapping genes with other bacteria. He identified dozens of genes staph had snatched from a wide array of organisms, ranging from fellow bacteria to humans. This capacity, Hiramatsu warned, means that even strains which are now harmless could quickly turn nasty.

In another study, James Musser at the National Institute of Allergy and Infectious Disease showed different strains of staph could steal genes and transform themselves simultaneously in different places around the world. He analyzed genes in 36 strains of staph to determine their evolutionary relationships and showed that many had picked up the same virulence and resistance genes independently. The gene for methicillin resistance, for example, had been acquired by five separate strains in five different places.

Nearly half of all life-threatening staph infections in U.S. hospitals are caused by strains resistant to methicillin. The drug belongs to a class of antibiotics, including penicillin, that destabilize bacterial cell walls, causing them to collapse. Methicillin-resistant staph protects itself by producing an enzyme, beta-lactamase, that neutralizes the drug.

Hong-Zhong Zhang and colleagues at the University of California at San Francisco deciphered the signaling system between a protein in a resistant staph cell that keeps watch for beta-lactams and a second protein that it tells to turn on the gene for beta-lactamase when the drugs are present. The UCSF team believes that finding a way to disrupt that signal might restore staph's vulnerability to all beta-lactam drugs.

Better still, of course, would be a medication that kills all staph strains so quickly and effectively that they never have time to develop resistance. Such a completely new type of antibiotic is in the works at the Scripps Research Institute, where Reza Ghadiri and colleagues have created peptide molecules that home in on bacterial cells, leaving mammalian cells alone. Once these peptides find a bacterium, they nestle into its outer membrane, then shape-shift themselves into nanotubes, which act as spigots, draining the cell and killing it within minutes. Even if the staph somehow develop a way to resist the peptides, the synthetic molecules can simply be reconfigured, allowing humans to take a cue from the bugs themselves and constantly upgrade our own arsenal.
— Christine Soares


Eat Your Pasta, Get Your Vitamins
Vitamin B9— folic acid— is essential for the formation of the neural tube that gives rise to the brain and spine of unborn babies. But not all pregnant women take their vitamins. So in 1998 the Food and Drug Administration mandated that grain producers add folic acid to enriched grain products, including bread, pasta, rice, and cereal. The result: Last June, Margaret Honein, an epidemiologist at the Centers for Disease Control and Prevention, announced that the incidence of neural-tube defects such as spina bifida, which leaves part of the spinal cord exposed and can result in paralysis, fell by 19 percent.
— Diane Martindale


Precision Cancer Bomb
The war on cancer rarely offers hope of victory: Since 1938, the National Cancer Institute has pumped close to $50 billion into research, yet twice as many Americans die of cancer every year than were killed in World War II, and five-year survival rates for most types of the disease have hardly changed in 20 years. Nevertheless, this year the tide of battle seemed, at least momentarily, to turn: In May the Food and Drug Administration approved a new drug called Gleevec, manufactured by Novartis. In clinical trials, 90 percent of patients in early stages of chronic myeloid leukemia, a rare blood cancer, had their blood counts return to normal two months after taking the medication.

Gleevec belongs to a new class of targeted cancer drugs designed to destroy tumor cells while sparing healthy ones. Rather than carpet bombing cancers, as radiation and traditional chemotherapies do, Gleevec homes in on a single enzyme. Known as Abl, it is one of a family of enzymes that usually help guide normal cell growth, but a mutation of it drives white blood cells to divide incessantly. Gleevec incapacitates the enzyme by docking into a pocket on the enzyme's surface that is usually reserved for a signaling molecule known as ATP. Once deprived of Abl, the tumor cells stop reproducing and die. "Imagine if you could lift the hood of a car, see all the engine pieces, figure out what's broken, and just replace the broken part," says Brian Druker, a cancer researcher at Oregon Health and Science University who helped develop Gleevec. "That's what we've done."

Gleevec blocks the ATP pocket in Abl and in two other proteins, but it doesn't incapacitate the hundreds of other enzymes that also rely on ATP. One enzyme it does block, known as c-kit, causes gastrointestinal stromal tumors. (In an early clinical trial of nearly 200 patients with the tumors, Gleevec therapy was effective in about 60 percent of the cases.) The drug is also being tested against a type of brain cancer in which the platelet-derived growth-factor receptor goes awry.

For all these early successes, biologists see targeted cancer therapy as a treatment rather than a cure. In some patients, particularly those with advanced disease, the drugs may only keep the tumor in check: If patients stop taking a daily dose, the cancer comes back. In some cases, patients' tumors develop resistance to Gleevec—either the Abl protein mutates so that the drug can no longer bind to it, or the protein accumulates in such quantities that the drug can't keep up, even at the highest dose. "Cancer cells are genetically malleable, and they find ways to escape no matter how clever we think we've been," says Tony Hunter, a molecular biologist at the Salk Institute in La Jolla, California.

Biologists believe that a combination of drugs may be needed to target cancer pathways, much as drug cocktails target HIV. But it could be another decade before the strategy pays off, if it does so at all. "Just because you see the light at the end of the tunnel doesn't mean you are near the end of the tunnel," says Larry Norton, head of medical oncology at Memorial Sloan-Kettering Cancer Center in New York City. "It just means you know which direction to walk."
— Diane Martindale


A Worts-and-All Remedy
St. John's wort has developed a large and devoted following in recent years as an over-the-counter remedy for depression. But the effectiveness of the herb is still an open question. In a study of 200 adults diagnosed with major depression that was published last April by the Journal of the American Medical Association, St. John's wort worked no better than a placebo. Other studies, however, suggest it may be effective for the treatment of mild to moderate depression. "About 30 studies show that it is better than a placebo, and about 10 show it is equivalent to conventional antidepressants such as Prozac," says Edvard Ernst, professor of complementary medicine at the University of Exeter in England.

In any case, taking St. John's wort is not without risks. It appears to activate a liver enzyme called CYP3A, says Ernst, which breaks down many toxic compounds in the body—as well as many powerful medications. Researchers reported that the herb has dramatically interfered with HIV treatments, anticlotting drugs, and immune suppressants. The Food and Drug Administration warns that women using birth control pills should not take St. John's wort because it may trigger a breakdown of the synthetic hormones designed to prevent pregnancy.
— Curtis Rist


Controversial Surgery in the Womb
Fetal surgery was first performed in the United States in 1981 by physicians at the University of California at San Francisco in an attempt to save an unborn child from obstructive uropathy, a dangerous blockage of the urinary tract. In ensuing years, an increasing number of fetuses have undergone similar procedures. But until 1994 fetal surgery was generally avoided unless the fetus was likely to die. Seven years ago, surgeons Joseph P. Bruner and Noel B. Tulipan at Vanderbilt University in Nashville, Tennessee, began to operate in utero to repair spina bifida, a rarely fatal lesion on the spine that can lead to a lifetime of suffering. Since then, the procedure has been performed about 200 times at a handful of medical centers around the country, 135 times at Vanderbilt. And 70 to 90 percent of children with spina bifida also have some degree of hydrocephalus, which requires a shunt to drain fluid from the brain.

Although three children have died at Vanderbilt after the operation, surgeons there argue that the procedure is valuable and relatively safe. Nonetheless, there is no clinical evidence that closing the spina bifida lesion before birth produces a better outcome than surgery performed in the first week after delivery. In addition, the vast majority of children who undergo fetal surgery are born prematurely and thus may be subject to higher rates of blindness, cerebral palsy, and brain hemorrhage.

The controversy came to a head in March when the National Institutes of Health issued a notice of a competition soliciting participation in a large-scale clinical trial to evaluate the effectiveness of fetal surgery as a treatment for spina bifida.

Bruner said in October that he approves of a study, but he does not believe the procedure should be suspended pending an analysis. "Significant short-term benefit has been demonstrated," he says, "especially a more normally shaped brain that appears to function better, as evidenced by less fluid buildup." In the meantime, a spokesman for the National Institutes of Health says that no study has yet been funded and the institute's policy is "not to comment on whether such a grant was submitted or is under review."
— Tom Dworetzky

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