The music of the night

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(This article appeared in the Winter 2008-2009 issue of NYU Physician.)

To cure sleep apnea, an ancient instrument may be best medicine of all.

Puff-cheeked and red-faced, with beads of sweat across his forehead, Kazim Yildiz, 42, is steadily vibrating his lips, much like a baby blowing bubbles. He is playing a didgeridoo, believed to be the world’s oldest wind instrument. Traditionally crafted from a branch of a eucalyptus tree, the cylindrical wooden tube is indigenous to Australia, where it’s been used in traditional Aboriginal ceremonies for thousands of years.

Now, modern medicine has found a new use for this ancient artifact. With practice, the didgeridoo produces an eerie, reverberating bellow. But to those afflicted with sleep apnea—a potentially serious sleep disorder in which breathing repeatedly stops and starts—the sound is music to their ears.

“In people with sleep apnea, the airway intermittently collapses during sleep,” explains Dennis Hwang, M.D., a researcher in the Division of Pulmonary and Sleep Medicine. “We believe that learning to play the instrument strengthens the muscles of the upper airway and reduces the airway collapsibility during sleep.”

Yildiz, an information technology expert at Merrill Lynch, is part of a 10-person study being conducted at NYU to determine whether playing the didgeridoo regularly can help to cure their disorder. Sleep apnea (Greek for “without breath”) affects as many as one in five middle-age adults, who literally stop breathing for moments while they are asleep. These stoppages cause the brain to wake up, which allows breathing to resume, but the pattern may leave him sleepy and irritable during the day. Loud snoring is a common symptom of sleep apnea, although not everyone who snores has the disorder.

Spain gives great apes legal rights

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(This article was #64 in Discover Magazine’s top 100 stories of 2008.)

On June 25 the Spanish Parliament’s environmental committee approved a resolution to grant legal rights to great apes, covering chimpanzees, bonobos, gorillas, and orang­utans. The resolution, expected to be enacted into law by June 2009, gives great apes the right to life and protects them from harmful research practices and exploitation for profit, such as use in films, commercials, and circuses.

“This is an important historical step,” says Peter Singer, a professor of bioethics at Princeton University and cofounder of the Great Ape Project. Since 1993, when Singer and Italian philosopher Paola Cavalieri established the group, its members have advocated for a United Nations declaration that great apes, like humans, are entitled to life, liberty, and protection from torture.

The great apes’ ability to use language and tools, to feel pain, and to form lasting relationships with others is evidence, the Great Ape Project maintains, that apes are part of a “community of equals” with humans. “This decision is the first step to recognizing that the gulf between human and nonhuman animals is not absolute but a matter of degree,” Singer says. “I do hope it helps people look differently at their relationship with nonhuman animals.”

The resolution also calls for the Spanish government to promote a similar declaration throughout the European Union. Singer notes that the Netherlands, Britain, and countries in Scandinavia have already taken steps to phase out research harmful to great apes.

The FDA tackles tainted drugs from China

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(This story was #3 in Discover Magazine’s top 100 stories of 2008.)

Following a series of high-profile scandals concerning tainted food and drugs imported from China, the U.S. Food and Drug Administration (FDA) announced in March that it would establish a drug-monitoring office in that country.

The most alarming report involved contaminated batches of the blood thinner heparin, which caused at least three deaths and is under suspicion in dozens of others. In February FDA officials admitted that they had never inspected Changzhou SPL, the manufacturing plant in Changzhou, China, to which they traced the contaminated heparin. When the FDA eventually inspected the Changzhou SPL plant (in February), it found a host of quality-control and hygiene problems.

Many drugs sold in the American marketplace are now imported, transforming what was once largely a domestic agency to one that must police products from more than 200 countries, notes Murray M. Lumpkin, FDA deputy commissioner for international and special programs. “The reality of globalization has hit the products for which we’re responsible very, very significantly,” he says. The pharmaceutical production process is also vastly more complex than it used to be. Individual ingredients are made in one place, put together in another, and bottled and labeled in still other sites.

Two Alzheimer’s drugs show promise

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(This story was #18 in Discover magazine’s top 100 stories of 2008.)

Two unconventional treatments for Alzheimer’s disease show promising early results. Both Rember (methylthioninium chloride) and Dimebon (dimebolin hydrochloride) appear to slow the mental decline associated with the illness.

No effective medicines exist for Alzheimer’s, which is estimated to afflict more than 4 million people in the United States alone. The disease is characterized by a decline in cognition and function and usually strikes after age 60. Most Alzheimer’s treatments have targeted amyloid, the main protein component of the associated plaques that form in the brain; Rember is the first to target the tangled, abnormal fibers of a protein called tau. At an Alzheimer’s conference in Chicago, the drug, made by TauRx Therapeutics, was reported to slow the progress of mild to moderate Alzheimer’s disease by 81 percent over the course of a year. In a phase 2 trial of 321 people with mild to moderate disease, those on the drug stayed at about the same cognitive level for up to 19 months, while those on the placebo got worse. A final trial is expected to begin in 2009.

The second drug, Dimebon, is an allergy drug used in Russia 20 years ago. A Lancet article in July reported that over 26 weeks of treatment, Dimebon significantly improved memory, thinking, and overall functioning in 68 Alzheimer’s patients, compared with a 66-member control group. Although researchers don’t know exactly how Dimebon does this, it may work by protecting mitochondria—the powerhouses of cells—from injury, says Rachelle Doody, the study’s lead author and a neurology professor at Baylor College of Medicine in Houston. A phase 3 trial for the drug began recruiting participants in June.

Cholesterol drugs are prescribed for high-risk kids

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(This article was #38 in Discover Magazine’s top 100 stories of 2008.)

In July, in an update of a 1998 policy statement, the American Academy of Pediatrics (AAP) recommended dropping the age at which at-risk children should be given statins—a class of cholesterol-lowering medication—from 10 years old to 8 years. The drugs would be prescribed to children with an LDL (the “bad” cholesterol) above 190 milligrams per deciliter, or above 160 with a family history of heart disease.

“The idea is to address risk factors as early as possible because we know plaques start to accumulate during infancy,” says Nicolas Stettler, an assistant professor of pediatrics and epidemiology at the Children’s Hospital of Philadelphia and a member of the AAP’s nutrition committee.

Critics say the drugs are a risky fix to broader lifestyle problems. Darshak Sanghavi, chief of pediatric cardiology at the University of Massachusetts Medical School in Worcester, notes that although the FDA has approved some statins for use in children with a genetic problem leading to high cholesterol, there are no studies on the drugs’ long-term side effects in children.

Sanghavi and others also took issue with the AAP’s recommendation of cholesterol screening starting at age 2 for children who are overweight or have other risk factors for heart disease. In this country, that could apply to as many as 10 million children every three to five years. “The screening costs alone will be hundreds of millions of dollars,” Sang­havi says.

New insights into an old foe: TB

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(This article is part of a series of articles on tuberculosis that I wrote for the Summer 2008 issue of NYU Physician.)

WHITE PLAGUE. KING’S EVIL. WASTING disease. Phthisis. Consumption. Tuberculosis (TB) is an old disease with many names and guises. But it wasn’t until last year that scientists discovered how old this ancient scourge really is. Egyptian mummies, skeletal remains, and genetic analysis had all suggested that TB had been around for at least a few thousand years. But in a block of rock mined from a quarry in Western Turkey, anthropologists discovered the fossil of a young male dating back some 500,000 years and infected, unexpectedly, with tuberculosis. They announced in December 2007 that the young man had lesions on the inside of his skull, the imprint of brain membranes that the disease has been ravaging humans for much longer than anyone had ever suspected.

An estimated 2 billion people — nearly one-third of the world’s population — are thought to harbor Mycobacterium tuberculosis (M. tb), the bacterium that causes TB. It grows slowly, lurking in the lungs for years, and outwits the body’s immune system, in part by waiting for the host’s defenses to weaken. In most people, that opportunity never arises, and they show no symptoms of the disease. But once M. tb takes hold, it literally consumes the body from within, eating through lung tissues and the blood vessels that run through it. Every time someone with a full-blown infection speaks, sings, coughs, or sneezes, the bacteria expelled linger in the air for hours, ready to invade the next victim.

This is why TB has so often been a disease of the poor, because it is at its most deadly in overcrowded, unsanitary conditions. In 2006, TB infected 9.2 million people worldwide, claiming the lives of 1.5 million people, most in the developing world. In some parts of South Africa, as many as 70 percent of those with TB are also infected with HIV, because TB is opportunistic.

Worst case: HIV + TB

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(This article is part of a series of articles on tuberculosis that I wrote for the Summer 2008 issue of NYU Physician.)

When HIV joins forces with TB, the results can be horrific. The neck bulges with lumps as big as an orange, filled with pus-like fluid teeming with the germs that cause TB. Occasionally, these bacteria travel through the blood and lymph vessels, forming lesions in the liver, spleen, and beyond. In chest X-rays, it looks as if the lung were studded with small nodules the size of millet seeds.

This gruesome scenario is rarely seen when TB is the sole affliction. But as HIV ravages the immune system, TB quickly and effortlessly spreads through the body. HIV’s compounding effect on TB has long been known, but recently scientists have discovered that this pernicious partnership works both ways. TB, in turn, eases the path of HIV, dismantling the system that keeps the virus under control in the lungs, allowing it to mutate and multiply.

“If you have HIV and TB, then TB 
will kill you much more rapidly,” notes Michael Weiden, M.D., associate professor of medicine and environmental medicine. In fact, TB is the leading cause of death among people who are HIV-positive, accounting for one-third of AIDS deaths worldwide.

Fighting drug-resistant TB in New York City

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(This article is part of a series of articles on tuberculosis that I wrote for the Summer 2008 issue of NYU Physician.)

For a few weeks last summer, Americans were riveted by news that Andrew Speaker, then a 31-year-old Atlanta native, may have been flying on commercial airplanes, exposing hundreds of people to a virtually untreatable type of tuberculosis (TB).

They could be forgiven for having thought of TB as strictly a third-world disease. In 2006, 13,767 people in the U.S. had TB — the lowest prevalence in the country recorded since 1953 — while elsewhere 1.5 million people died of the disease.

Speaker was diagnosed in early May 2007, but against medical advice he flew to Greece for his wedding later that month. Tracked down in Rome on his honeymoon, he was told he had extensively drug-resistant tuberculosis (XDR-TB) and was asked to stay put.

Instead he and his wife, Sarah, flew to Prague and Montreal and then drove to New York City. On May 24, officials from the Centers for Disease Control and Prevention directed Speaker to report to Bellevue Hospital, where he was served with a federal warrant that isolated him for medical evaluation, the first such order issued in 44 years.

Bellevue is no stranger to TB. The hospital’s Chest Service, established in 1903 to treat the disease, has contributed a great deal of knowledge about its pathophysiology, clinical behavior, and treatment. In the late 1980s and early 1990s, Bellevue endured a long bout with this familiar foe, grappling with nearly 4,000 cases in New York City, many of them homeless people addicted to drugs and infected with HIV.

“I came here and I found everything was all TB and AIDS,” recalls William Rom, M.D., M.P.H., director of the Chest Service.

Hope grows for new TB test

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(This article is part of a series of articles on tuberculosis that I wrote for the Summer 2008 issue of NYU Physician.)

To confirm that you have TB, the doctor will ask you to cough up at least a teaspoonful of phlegm, or sputum. You’ll have to come back to the hospital twice more to provide samples, and technicians will painstakingly culture the slow-growing bacteria from the sputum.
 A few weeks after that third visit — by which point you may have exposed others — the doctor should be able to tell you whether you have TB.

This crude sputum diagnostic test is 100 years old. “The situation is fairly horrendous,” says Dr. Suman Laal, Ph.D., associate professor of pathology and mircrobiology.

There are a
few expensive alternatives: fluorescent microscopy, automated culture systems, and tests for the bacterial DNA. But 90 percent of the disease is concentrated in the poorest parts of the world, where these options are not feasible.

Clinically, TB symptoms can be difficult to distinguish from those of
 other bacterial or fungal infections, pneumonia, or certain tumors. Diagnosis with X-rays is subjective and all but useless 
in people who are HIV-positive, and
 a commonly used skin test gives false positives in anyone who has been immunized with the BCG vaccine or 
has been infected with the TB bug’s bacterial cousins.

The ideal test for TB would be fast, cheap, and would deliver a simple Yes or No answer — much like a dipstick pregnancy test. But developing a test like that has proved challenging.

Free to fight disease

Uncategorized

I wrote this article for Nature Medicine in June 2008, after I had left my job as senior news editor for the magazine. This is a topic I have always found interesting, and there are few publications that would run a long story about it. (You can download a pdf of this article.)

Long ignored by pharmaceutical companies and global health agencies alike, ‘neglected tropical diseases’ devastate people in the poorest parts of the world. But they’re finally getting the attention they deserve, reports Apoorva Mandavilli.

It’s been 20 years since William Campbell visited the small nation of Togo in western Africa. But he still vividly recalls the remote communities he visited, with their tiny mud-thatched huts and trees so large that an entire village of 100 could gather under the leafy canopies.

That was in 1988, barely a year after the pharmaceutical giant Merck had made the unexpected announcement that it would donate its drug ivermectin—the most effective treatment for river blindness—to anyone who needed it for as long as they needed it. The drug, studied by Campbell’s team at Merck and originally used to treat parasitic diseases in animals such as horses, is known commercially as Mectizan. Seven years of trials had shown that a single annual dose of the medication could completely clear the worms that cause river blindness from the human body.

Left untreated, river blindness (known to doctors and researchers as onchocerciasis) can lead to horrible itching and irreversible loss of sight. The disease, caused by the worm Onchocerca volvulus, affects an estimated 18 million people worldwide. Black flies found near river banks transmit the disease to humans when they bite the skin and insert deposits of immature O. volvulus larvae.

Campbell, who led Merck’s parasitology division at the time of his Togo visit, remembers the children he met on his trip—”like kids anywhere, just excited to have their picture taken”—and the sense of humor of the village elders, obvious despite the language barrier. But the images he recalls most vividly are of an elder whose long robe hid the telltale white ‘leopard spots’ of the disease on his legs and of infected young adults who had the inelastic skin of old men. “I was seeing things I’d been teaching but never witnessed first hand,” says Campbell, who had traveled to Togo partly to understand the potential impact of ivermectin.

Since making its drug donation pledge two decades ago, Merck has kept its word, delivering more than 1.8 billion ivermectin tablets at an estimated total value of $2.7 billion and reaching nearly 70 million people a year in 33 countries—making it the longest running donation program by a pharmaceutical company.

These days, Merck’s program is no longer unique: in 2007 alone, Pfizer has donated the antibiotic azithromycin for trachoma, the leading cause of infectious blindness, treating more than 60 million people; Sanofi-Aventis and Bayer gave away medications for sleeping sickness in Africa; and GlaxoSmithKline contributed 150 million tablets of the drug albendazole to eliminate elephantiasis. Meanwhile, Novartis drug donations have helped cure more than 4 million people of leprosy.

The decision made by these companies to take action against neglected tropical diseases (NTDs) seems to be part of a larger movement. In February, the US government announced that, beginning in 2009, it would spend $350 million over the following five years to treat seven neglected tropical diseases, including trachoma, river blindness and another parasitic worm disease called schistosomiasis. The heads of the World Health Organization (WHO) and the United Nations have both designated neglected tropical diseases as a top priority. At the same time, several advocacy groups are pushing to include these ailments on the agenda of the annual meeting of G8 industrialized nations in July, and they are challenging donors to provide another $650 million to tackle these illnesses.

“Suddenly there is quite a lot of fervor around neglected tropical diseases,” says Christy Hanson, senior public health advisor at the US Agency for International Development based in Washington, DC. “They really aren’t neglected anymore; we’ll have to change the name.”

Neglected no longer?

A dose of hope: (This page) Malian doctor Alpha Mamadou Bah, who worked with William Campbell to treat river blindness in Togo, smiles while seated next to a village elder; A technician prepares ivermectin tablets for distribution; (Opposite page) Former US President Jimmy Carter helps administer praziquantel, a drug used to fight Schistosomiasis

Until recently, much of the world’s attention was focused on the big three—AIDS, tuberculosis and malaria—which together kill up to 6 million people each year. Calling the remaining tropical diseases ‘neglected’ may suggest that they are trivial, but these diseases collectively infect about a billion people, most of them in the poorest parts of the world, and claim up to a million lives. “More and more groups and agencies and institutions are realizing that it’s horrible to die from HIV/AIDS, but it’s also horrible to die from sleeping sickness,” says Jean Jannin, coordinator of the Innovative and Intensified Disease Management Unit at the WHO in Geneva.

Not all neglected tropical diseases are fatal, but they often blind, maim or deform their victims. And the consequences—school dropouts and loss of wages, for instance—keep affected commun

ities trapped in a vicious spiral of illness and poverty.

Crucially, most NTDs are easy to treat. In many cases, a single dose of a drug delivered once a year to a large number of people can control and even eliminate the disease from a country.

For example, Merck reported in November 2007 that an eradication campaign had succeeded in eliminating river blindness from Colombia and in halting transmission in certain areas within Ecuador and Guatemala. The number of people infected with guinea worm has also dropped from 3 million cases worldwide in 1986 to just 25,000 in 2007, thanks in part to a 20-year campaign led by former US President Jimmy Carter.

Donation programs have historically targeted a single disease at a time, but the new US program set to start in 2009 aims to deliver treatments for each of the seven NTDs. The $350 million initiative builds on a congressional scheme that began in 2006 with $15 million per year and expands the number of countries targeted from 10 to about 30 by 2013. “Where [the countries] had staff planning for one disease, now they’re able to do it for seven diseases together,” says Hanson.

Because companies such as Merck and GlaxoSmithKline together donate about $400 million worth of drugs each year, only 25% of the US funds will be used to buy drugs. The rest will cover drug distribution and community training, together estimated at an annual cost of less than 40 cents per person receiving treatment in sub-Saharan Africa.

Intelligent investments

Why would a pharmaceutical company, whose main aim (like that of any commercial enterprise) is profit, donate drugs for free? “We do it because—and people don’t like to believe this—it’s the right thing to do,” says Ken Gustavsen, director of Merck’s product donation program headquartered in New Jersey.

That may be so, but other people note that there are more prosaic reasons: companies that donate drugs can claim tax deductions of up to twice the cost of the product. The programs also improve the morale of employees. What’s more, pharmaceutical companies can use donation programs to establish a presence in new countries. “The market tomorrow will be developing countries,” notes Ulrich Madeja, head of Bayer-Schering’s social healthcare program.

Last, and perhaps more immediate, is the public relations impact. According to Carl Nathan, chair of microbiology and immunology at Weill Cornell Medical College in New York, drug companies are among the most consistently profitable enterprises in the world and, perhaps as a result, the most scrutinized by the public and the press. Their image took a severe drubbing in the late 1990s, when the world’s attention was focused on the untenable prices of AIDS drugs.

Since then, pharmaceutical companies have become more aware that the public expects them to be socially responsible—to go beyond merely donating drugs and help build health infrastructure. In an attempt to present themselves as responsible partners in public health, many are creating entire divisions dedicated to issues of access to medicines. For example, the Access to Medicines department at Sanofi-Aventis was launched in 2006 and now employs 35 people.

Profit versus philanthropy

Although pharmaceutical giants proudly tout what they call their new commitment toward access to medicines, their motives are met with a healthy dose of skepticism from some quarters. An Oxfam report released in November 2007, titled ‘Investing for Life’, concluded that companies are more interested in setting up these programs to boost their reputations than in establishing tiered-pricing systems, which could serve as a more sustainable way to make medications affordable to all who need them.

“[The companies] decide whom to give it to, for how long and at what price,” adds Beverley Snell, an essential drugs specialist at the Macfarlane Burnet Institute for Medical Research and Public Health in Melbourne, Australia. “There are always conditions, limitations, et cetera.” Snell notes that ivermectin, for example, is useful against other crippling parasitic diseases such as strongyloidiasis, ascariasis, trichuriasis and enterobiasis. But Merck donates the drug only for river blindness.

According to some experts, it’s unrealistic to expect companies to be philanthropic at the expense of their bottom line: “It’s a misunderstanding that companies exist to provide drugs,” says Nathan. “In fact they exist to make money for their shareholders.”

Nathan says it is instead up to individual governments to create a ‘medicine fund’ that would provide incentives for companies to make certain drugs. A 2002 study from Médecins Sans Frontières (Doctors without Borders) found that of 1,393 new drugs marketed between 1975 and 1999, only 13 were for tropical diseases (Lancet 359, 2188–2194; 2002). But as incentives appear—such as a $19 million cash influx from the Bill & Melinda Gates Foundation to find a drug for sleeping sickness—companies are returning to research on these diseases.

For their part, the companies have their own complaints about the way in which many countries operate. They note, for example, that African nations each have their own complex rules for drug importation and don’t make special allowances, such as waiving customs duties, for donation programs. “It’s problematic when you’re trying to get the product in, and you wind up paying a huge amount of money [in customs],” says Heather Lauver, assistant director for Pfizer’s Global Operations of International Philanthropy Programs. “It’s kind of an insult when you’re donating out of good will.”

Troubled partnerships

When Merck’s researchers first stumbled on to ivermectin’s potential in the late 1970s, they encountered skepticism from experts at the WHO. “The [WHO] sent these very imperious, wonderfully clad officials to visit us,” recalls Roy Vagelos, who served as Merck’s CEO at the time. “They looked at our data, and they were rather negative about our results. They said we had probably not done the experiment very well.”

In 1974, the WHO had launched its own river blindness program, which employed a small fleet of planes to spray insecticides on black fly breeding areas. “They were very protective of their program,” Vagelos says. Instead of working through the WHO, Merck—and later Pfizer—set up independent expert committees to approve applications from countries for their drugs. Finally, though, the WHO began providing technical advice to Merck’s program and now helps train community-based workers to organize ivermectin’s distribution.

Similar turf battles doomed the Children’s Vaccine Initiative, the forerunner to the Global Alliance for Vaccines and Immunization, and a public-private partnership intended to deliver the drug praziquantel for schistosomiasis, a disease that can cause symptoms such as abdominal pain and liver lesions.

In the past few years, drug makers have formed coalitions such as the Partnership for Quality Medical Donations and, more recently, the Partnership for Disease Control Initiatives. These organizations bring together donors who are grappling with similar logistical challenges linked to delivering free medications, such as dealing with many different government regulations.

Things are better now, all parties insist. “The relationship between us and the pharma companies has changed a lot in the past ten years,” says the WHO’s Jannin. This past November, the agency moved its neglected diseases division from communicable diseases into the same cluster as AIDS, tuberculosis and malaria. “It’s a small signal” of the WHO’s increased focus on neglected diseases, says Jannin, “but it’s an important one.”

Getting personal

Making the connection: The leg of a villager in Togo bears the telltale ‘leopard spots’ indicative of river blindness infection; William Campbell (seated second from the left) and his colleagues speak with locals in 1988 about delivering ivermectin to an additional town

Ultimately, behind the massive drug donation plans stand individuals who had the vision and determination to see the programs through many hurdles. In the case of the Merck ivermectin program for river blindness, it took at least three such people: Campbell, whose team discovered that a horse medicine effectively kills the parasite behind river blindness; Mohammed Azeez, a physician from Bangladesh who had seen the disease’s devastating effects in Africa and who foresaw ivermectin’s potential; and, perhaps most important, CEO Vagelos, who was so sure that donating was the right thing to do that he made the decision without consulting the company’s board of directors.

Campbell remembers one particular day in Togo when residents from a nearby village had gathered where ivermectin was being distributed. Their village was so remote that they had built a section of road for the doctors to reach them—but they had still not been added on the list to receive ivermectin.

Because of ethical and safety considerations, the doctors couldn’t just add a village without authorization, Campbell says. But that afternoon, another remarkable individual—Alpha Mamadou Bah, the Malian doctor who led the treatment in Togo—sent a telex to the program’s headquarters in Wagadugu, Burkina Faso, asking them to include the village. If necessary, Bah said, the cost should be deducted from his salary. Bah later received the approval to treat the village, but his dedication left a lasting impression on Campbell, who now teaches at Drew University in Madison, New Jersey.

“To me it’s striking that so many people got involved in it; it became huge and had this ripple effect,” Campbell says. “It was all a very emotional experience.”