The Demon in the Freezer

Dr. Chen’s Viruses

Unanswered questions hung over variola, and not just the question of whether ring vaccination would work if there was a terror attack with smallpox. The more troubling question was how molecular biology would affect the future of smallpox. Poxviruses are used in laboratories all over the world precisely because they are easily engineered. Commercial kits for the process are available at no great cost. It should not be forgotten that the director of the Iraqi virus-weapons program, Dr. Hazem Ali, was a pox virologist trained in England, and one assumes that he is not the only professional bioweaponeer in the world with advanced credentials in biology.

The Australian team of mouse researchers led by Ronald Jackson and Ian Ramshaw had put the IL-4 mouse gene into mousepox and had created a superpox that appeared to break through the mice’s immunity. The Jackson-Ramshaw virus was harmless in people, but it seemed to be devastating in immunized mice.

Bioterror planners wondered: if the human IL-4 gene were put into smallpox, would it transform smallpox into a super variola that would devastate immunized humans? The Jackson-Ramshaw virus had been a narrow beam of light shining across a dark landscape of the future. It had shown dim outlines of virus weapons to come.

When an experiment gives a result, the first thing scientists do is try to repeat the experiment to see if they can get the same result. The essence of the scientific method lies in the repeatable result: if you perform an experiment in the same way, nature will do the same thing again. This is the heart of science and is the sign that an observable phenomenon in nature has been found. Would the results of the Jackson-Ramshaw experiment bear out? Could a poxvirus be engineered to crash through a vaccine?

One day in early 2002, I parked my car in a downtown neighborhood of St. Louis and walked along an uneven sidewalk toward the St. Louis University School of Medicine. The neighborhood is humble but neat, and is largely African-American. There are row houses with porches tucked up against the street. American flags hung from several porches or were on display in windows. The school of medicine is a stately neo-Gothic brick building, trimmed with pink midwestern sandstone, and on that day it glowed with warmth in winter light.

The façade gives way to a concrete, fortresslike structure, five stories tall, with small windows, where the research laboratories are located. In a group of rooms on the fourth floor, a pox virologist named Mark Buller leads a group of researchers who do experiments with mousepox virus and with vaccinia. They work mainly with mice — the mouse is the standard animal used in biomedical research. Most of the important discoveries about how our immune systems work were made originally in experiments done with mice.

Mark Buller is a tall, lanky, self-effacing man in his fifties, a dual citizen of Canada and the United States, with curly black hair, a black mustache, intelligent brown eyes behind round glasses, and a voice that has an attractive Canadian softness. He grew up in Victoria, British Columbia. He often walks around the lab in nylon wind pants, a T-shirt, and running shoes. He keeps a spare jacket and tie hanging on the wall of his office, in case an important meeting comes up. Buller is known and respected among pox virologists, although he seems to deliberately avoid the limelight. “My goal in life is to be prominently in the shadows,” he said to me.

Buller began hearing a lot about the Jackson-Ramshaw experiment from Peter Jahrling and Richard Moyer. Right after it was published, Moyer, especially, raised alarms — he began saying, quietly, to Buller that either he or Buller should try to repeat the experiment. The Australian smallpox expert Frank Fenner had advised Jackson and Ramshaw to publish their work, partly on the grounds that nobody would really make an IL-4 smallpox, since it might be too devastating and perhaps even suicidal. In the wake of September 11th, the release of a genetically engineered smallpox into the United States did not seem quite so impossible.

Mark Buller decided to create an IL-4 mousepox, to see if it would blow through a vaccine. He wanted to get a sense of whether a human IL-4 smallpox could become a supervirus, and if so, what vaccination strategy for people would work against it. I arrived at Buller’s lab as the experiment was getting under way. I wanted to hold an engineered superpox in my hands and get a feel for where the tide of modern biology was taking us.

Mark Buller leaned back at his desk, his hands clasped behind his head. His office was crowded with books and papers, and there was an exercise mat on the floor. On a whiteboard on the wall, his daughter, Meghan, had drawn a caricature of him as a science nerd, with Coke-bottle spectacles, a brushy mustache, and a bunch of pens in his shirt pocket.

“If there is a bioterror release of smallpox, currently the main strategy is ring vaccination,” he said. “In order for ring vaccination to work, the vaccine has to block severe smallpox disease in people. But what if a smallpox that’s expressing IL-4 blocks people’s immune responses?”

Buller explained that his group would make four different engineered mousepox virus strains. They would all have the IL-4 gene in them, but they would be slightly different from one another. One of them would be almost the same as the Australian engineered pox. “We want to get a feeling for what the IL-4 gene does in mousepox,” Buller said. “I’ve always found that whenever I try to predict Mother Nature I’m wrong.”

Buller’s lab was a group of rooms with white floors and cluttered black counters and shelves. Four or five people were working on different projects, and it was a crowded place. In a corner, under a window, a scientist named Nanhai Chen was in the middle of the virus engineering. He was working at a counter that was three feet long and a foot and a half wide. Virus engineering doesn’t have to take up much real estate. Mousepox virus, even engineered mousepox, is harmless to humans, because the virus simply can’t grow inside the human body, so the work was safe for the people in the room.

Nanhai Chen is a quiet man in his late thirties. He grew up on a collective near Shanghai called the Red Star Farm, where his father was a farmer and where some of his sisters still live. In high school, Chen decided he liked biology, and he went on to have a fast-track career at the Institute of Virology at the Chinese Academy of Preventive Medicine in Beijing, which is probably the top virology center in China. He became an expert in the DNA of vaccinia virus. Mark Buller hired him out of China.

Nanhai Chen has a fuzzy crew cut, hands that work rapidly, wire-rimmed spectacles, and restrained manners. He and his wife, Hongdong Bai, who is also a molecular biologist, have given their children American names, Kevin and Steven. He wears only two outfits, one for winter and one for summer. His winter outfit is a blue cotton sweater, blue slacks, and white running shoes. I spent days with Chen during the time he engineered the mouse supervirus. “It’s not difficult to make this virus,” he said to me one day. “You could learn how to do it.”

A virus that has been engineered in the laboratory is called a recombinant virus. This is because its genetic material — DNA or RNA — has genes in it that come from other forms of life. These foreign genes have been inserted into the virus’s genetic material through the process of recombination. The term construct is also used to describe it, because the virus is constructed of parts and pieces of genetic code — it is a designer virus, with a particular purpose.

The DNA molecule is shaped like a twisted ladder, and the rungs of the ladder — the nucleotides — can hold vast amounts of information, the code of life. A gene is a short stretch of DNA, typically about a thousand letters long, that holds the recipe for a protein or a group of related proteins. The total assemblage of an organism’s genetic code — its full complement of DNA, comprising all its genes — is the organism’s genome. Poxviruses have long genomes, at least for viruses. A pox genome typically holds between 150,000 and 200,000 letters of code, in a spaghettilike knot of DNA that is jammed into the dumbbell structure at the center of the pox particle. The poxvirus’s genome contains about two hundred genes — that is, the pox particle has around two hundred different proteins. Some of them are locked together in the mulberry structure of the particle. Other proteins are released by the pox particle, and they confuse or undermine the immune system of the host, so that the virus can amplify itself more easily. Poxviruses specialize in releasing signaling proteins that derange control systems in the host. For example, insect poxes release signals that cause an infected caterpillar to stop developing and grow into a bag packed with virus.

The human genome, coiled up in the chromosomes of every typical cell in the human body, consists of about three billion letters of DNA, or perhaps forty thousand active genes. (No one is certain how many active genes human DNA has in it.) The letters in the human genome would fill around ten thousand copies of Moby-Dick: a person is more complicated than a pox.

The IL-4 gene holds the recipe for a common immune-system compound called interleukin-4, a cytokine that in the right amounts normally helps a person or a mouse fight off an infection by stimulating the production of antibodies. If the gene for IL-4 is added to a poxvirus, it will cause the virus to make IL-4. It starts signaling the immune system of the host, which becomes confused and starts making more antibodies. But, paradoxically, if too many antibodies are made, another type of immunity goes down—cellular immunity. Cellular immunity is provided by numerous kinds of white blood cells. When a person dies of AIDS, it is because a key part of his or her cellular immunity (the population of CD4 cells) has been destroyed by HIV infection. The engineered mousepox seems to create a kind of instant AIDS-like immune suppression in a mouse right at the moment when the mouse needs this type of immunity the most to fight off an exploding pox infection. An engineered smallpox that triggered an AIDS-like immune suppression in people would be no joke.

To create a construct virus, you start with a cookbook and some standard ingredients. The basic raw ingredient in Chen’s experiment was a vial of frozen natural wild-type mousepox virus, which sat in a freezer around the corner from his work area. The other basic ingredient was the mouse IL-4 gene. Chen’s cooking, so to speak, involved splicing the gene into the DNA of the poxvirus and then making sure the resulting construct virus worked as it was supposed to.

Chen ordered the IL-4 gene through the Internet. It cost sixty-five dollars, and it came by regular mail at Mark Buller’s lab in November 2001, from the American Type Culture Collection, a nonprofit institute in Manassas, Virginia, where strains of micro-organisms and common genes are kept in archives. The gene arrived in a small, brown glass bottle with a screw top. Inside the bottle was a pinch of tan-colored dry bacteria—E. coli, bacteria that live in the human gut. The bacterial cells contained small rings of extra DNA called plasmids, and the plasmids held the IL-4 gene. The IL-4 gene is a short piece of DNA, only about four hundred letters long, and it is one of the most common genes used in medical research. To date, more than sixteen thousand scientific papers have been written on the IL-4 gene.

The standard cookbook for virus engineering is a four-volume series in ring binders with bright red covers, entitled Current Protocols in Molecular Biology, published by John Wiley and Sons. Nanhai Chen took me to a shelf in the lab, pulled down volume three of Current Protocols, and opened it to section 4, protocol 16.15, which describes exactly how to put a gene into a poxvirus. If anyone puts the IL-4 gene into smallpox, they may well do it by the book. “This cannot be classified,” Chen said, running his finger over the recipe. “No one ever thought this could be used for making a weapon. The only difficult part of it is getting the smallpox. If somebody has smallpox, all the rest of the information for engineering it is public.”

“Are you personally worried about engineered smallpox?”

“Yes, I am,” he answered, holding the cookbook open as he spoke. “I was talking last week with my mentor in China. His name is Dr. Hou, and he’s a very famous virologist in China. He told me the Russians have a genetically modified and weaponized smallpox. My mentor didn’t say where he learned this, but I think he has good access to information, and I think it is probably true. Smallpox was all over the world thirty years ago. It could be anywhere today. It’s not hard to keep back a little bit of smallpox in a freezer.”

I will omit the subtleties of Chen’s work for the sake of general readers, but the outline of a recipe for making the biological equivalent of an atomic bomb is in these pages. I would hesitate to publish it, except that it’s already known to biologists; it just isn’t known to everyone else. It doesn’t take a rocket scientist to make a superpox. You do need training, though, and there is a subtle art to virus engineering. One becomes better at it with experience. Virus engineering takes skill with the hands, and in time you develop speed. Chen felt that with a little luck he could engineer any sort of typical construct poxvirus in about four weeks.

Chen took the little brown glass bottle of dry bacteria that contained the IL-4 gene and cultured the bacteria in vials. Then he added a detergent that broke up the bacteria, and he spun the material in a centrifuge. The cell debris fell to the bottom of the tubes, but the DNA plasmid rings remained suspended and floating in the liquid. He ran this liquid through a tiny filter. The filter trapped the DNA that held the IL-4 gene. He ended up with a few drops of clear liquid.

Next, Chen spliced some short bits of DNA, known as promoters and flanking sequences into the plasmid rings. He did this basically by adding drops of liquid. Promoters signal a gene to begin making protein. The various promoters were going to cause the strains of engineered mousepox to express the IL-4 protein in differing amounts and at different times in the life cycle of the virus as it replicated in cells.

The next step was to put the engineered DNA into the virus, using a genetic-engineering kit called a transfection kit. Transfection is the introduction of foreign DNA into living cells. A transfection kit is essentially a small bottle filled with a reagent, or biochemical mix; a bottle of it costs less than two hundred dollars. You can order transfection kits in the mail from a variety of companies. Nanhai Chen used the Lipofectamine 2000 kit from Invitrogen.

Chen grew monkey cells in a well plate, and then he infected them with natural mousepox virus. He waited an hour, giving the virus time to attach to the cells. Then he added the IL-4 DNA, which he’d already mixed with the transfection reagent. He waited six hours. During that time, the IL-4 DNA was taken up into the monkey cells, which were also infected with natural mousepox. Somehow, the IL-4 DNA went into some of the mousepox particles, and the IL-4 gene ended up sitting in the DNA of the mousepox virus.

Chen had long days of work ahead of him, for he had to purify the virus strains. Purification of a virus is a core technique in the art of virus engineering.

A virus is a very small object, and the only way to handle it is to move around cells that are infected with it. A poxvirus growing in the layer of cells at the bottom of a well plate will kill the cells, forming dead spots in the layer. These spots are like the holes in a slice of Swiss cheese, and they are known as plaques. You can remove the dead or dying cells with a pipette. The cells that come out of that spot will contain a pure strain of the virus.

“Would you like to do some plaque picking?” Chen asked me one day. He led me into a small room behind his work area, where there were a couple of laboratory hoods, a couple of incubators (which are warming boxes that keep cell cultures alive), and, tucked away in a corner, a microscope with binocular eyepieces.

Chen put on a pair of latex gloves, opened the door of an incubator, and slid out a well plate. It had six wells, glistening with red cell-culture medium, and a carpet of living cells covered the bottom. He carried the well plate across the room and placed it on the viewing stand of the microscope. You could see with the naked eye the holes in the cell layers. The cells were infected with a strain of engineered IL-4 mousepox.

I sat down at the microscope, and Chen handed me a pipette that had a cone-shaped plastic tip with a hole in it, like a very fine straw. You put your thumb on a button on the pipette, and when you pushed the button you could pick up a small amount of liquid and deposit it somewhere else.

I was beginning to feel a little strange. We were handling a genetically engineered virus with nothing but rubber gloves. “You’re sure it’s not infective?”

“Yes, it is safe.”

I sat down at the microscope and looked into a carpet of monkey cells growing at the bottom of a well. Each cell looked like a fried egg; the yolk in the cell was the nucleus. I started looking for holes in the carpet, where the virus would be growing.

“I can’t find any plaques,” I said. I began moving the well plate around. Suddenly, a huge hole appeared. It was an infected zone, rich with engineered virus. The cells there were dying and had clumped up into sick-looking balls. The cells had caught the engineered pox.

I was holding the pipette in my right hand. I maneuvered the tip into the well plate. “I can’t see the tip,” I said, jabbing it around in the well.

I was wrecking Chen’s careful work, but he made no comment. Then the tip of the pipette heaved into view. It looked like the mouth of a subway tunnel.

“You need to scratch the cells off,” Chen said.

I moved the tip around, scraping it over the sick cells. I let the button go, and a few cells were slurped up into the pipette. Chen handed me a vial, and I deposited a picked plaque of engineered poxvirus into it. “I don’t think I’d make a good virologist.”

“You are doing fine.”

The work of creating four engineered mousepox strains took five months — the work was painstaking, and Chen had to check and double-check every step of the process. He believes that the total cost of laboratory consumables ran to about a thousand dollars for each strain. Virus engineering is cheaper than a used car, yet it may provide a nation with a weapon as intimidating as a nuclear bomb.

It was time to infect some mice with the engineered virus, to see what it would do. The mouse colony was kept in a Biosafety Level 3 room on the top floor of the medical school. Mark Buller and I put on surgical gowns, booties, hair coverings, and latex gloves. We pushed through a steel door into a small cinder-block room, where hundreds of mice were living in clear plastic boxes, set on racks behind glass doors. The mice had black fur. They were a purebred laboratory mouse known as the Black 6, which is naturally resistant to mousepox.

Buller opened some boxes, removed some mice, and placed them in a jar that had an anesthetic in it. The mice went to sleep. One at a time, he held a mouse in his hand, stuck the needle of a syringe into its foot, and injected a drop of clear liquid. The liquid contained about ten particles of engineered IL-4 mousepox — an exceedingly low dose of the virus.

Seven days later, my phone rang early in the morning. It was Mark Buller. One of the lab techs had just checked on the mice, he said, and some of them had a hunched posture, with ruffled fur at the neck. “They’re going to go fast,” he said.

The next morning, Buller, Chen, and I put on gloves and gowns and went into the mouse room. There were two boxes of dead mice. Two of the strains of IL-4 mousepox had wiped out the naturally resistant mice. The death rate for those groups was one hundred percent.

Buller carried one box inside a hood and opened it. The dead mice were indeed hunched up, with ruffled fur and pinched eyes. Natural mousepox does not cause a Black 6 mouse to become visibly sick at all.

“Wow. Wow,” Chen said. “They’re all hunched over. This IL-4 has a really funny effect. This is really a strong virus. I’m really surprised.” He hadn’t expected his virus to wipe out all the mice. It disturbed him that he could make such a powerful virus, but he also felt excited.

“It’s really impressive how fast this virus kills the mice at such a low dose,” Buller said.

I sat on a chair before the hood, peering into it beside Buller. He reached in and lifted a dead mouse out of a box, and held the creature in his gloved hand. Without the mouse, there would be no cures for many diseases, and dead mice had been responsible for the saving of many a human life, but what he held in his hand was not a reassuring thing.

Buller showed me the standard way to dissect a mouse: you slit the belly with scissors. He spread open the abdomen with the scissors, looking to see what the pox had done.

The virus had blasted the mouse’s internal organs. The spleen had turned into a bloated blood sausage that was huge (for a mouse’s spleen) and filled much of the mouse’s belly. It was mottled with faint grayish-white spots, which Buller explained is the classic appearance of a mouse’s organs infected with pox. Doctors who opened humans who had died of hemorrhagic smallpox saw the same cloudy effect in their organs. With the tip of the scissors, he pulled out the mouse’s liver. It had turned the color of sawdust, destroyed by the engineered virus. With ten particles of the construct virus in its blood, the pox-resistant mouse had never stood a chance.

There are two ways to vaccinate a mouse against mousepox. One way is to infect it with natural mousepox. When it recovers (if you vaccinate a resistant breed of mouse, it will recover), it will be immune. The other way is to vaccinate the mouse with the smallpox vaccine — that is, you infect the mouse with vaccinia, and its immunity to mousepox goes up in the same way that a human’s resistance to smallpox goes up after a vaccinia infection.

Mark Buller and his group began testing IL-4 mousepox on vaccinated mice, and they got strange results. They were not able to completely duplicate the Jackson-Ramshaw experiment. They discovered that mice immunized with natural mousepox become completely immune to IL-4 mousepox — it did not break through their immunity after all. That was very encouraging. It contradicted part of the Jackson-Ramshaw experiment. But in doing preliminary experiments with the smallpox vaccine, they had begun to see something more troubling (the experiments were in progress, and Buller wasn’t able to report any real findings yet). It seemed that the IL-4 mousepox could crash through the smallpox vaccine, killing the mice if they had been vaccinated sometime previously. But if their vaccinia vaccinations were very fresh, they were protected against the engineered pox. It suggested that an engineered IL-4 smallpox might be able to break through people’s immunity, but not if the vaccinations were recent, perhaps only weeks old.

Buller didn’t sound as if he thought the world was coming to an end. “We showed that you could find a way to vaccinate mice successfully against the engineered mousepox,” he said to me. “Even if IL-4 variola can blow through the smallpox vaccine, I feel there are drugs we can develop that will nullify the advantage a terrorist might have by using IL-4 variola. We really need an antiviral drug,” he said. He argued that a drug that worked on pox was not only needed as a defense against an engineered superpox, but was also needed in order to cure people who were getting sick from the vaccine during a mass vaccination after a smallpox terror attack.

Any nation or research team that wanted to make a superpox would have to test it on vaccinated humans to see if it worked. “If you’re talking about a country like Iraq,” Buller said, “human experimentation with smallpox is imaginable. If you’ve got a guy like Saddam Hussein, and his scientists tell him they need some humans so they can check out an engineered smallpox, he’ll say, ‘How many do you need?’ There are people like that in every age.”

Nanhai Chen seemed a little less optimistic. “Because the IL-4 mousepox can evade the vaccinia vaccination, it means that IL-4 smallpox could be very dangerous,” he said. “This experiment is very similar to the human situation with the smallpox vaccine. I think IL-4 smallpox is dangerous. I think it is very dangerous.”

The main thing that stands between the human species and the creation of a supervirus is a sense of responsibility among individual biologists. Given human nature and the record of history, it seems possible that someone could be playing with the genes of smallpox right now. And what if a fire began to flicker in the hay in the barn, and we poured a glass of water on it, but the water could not put the fire out? No nation that wanted to have nuclear weapons had a problem finding physicists willing to make them. The international community of physicists came of age in a burst of light over the sands of Trinity in New Mexico. The biologists have not yet experienced their Trinity.

A Child

In the years just before the Eradication began, two million people a year were dying of smallpox. The doctors who ended the virus as a natural disease have effectively saved fifty to sixty million human lives. This is the summit of Everest in the history of medicine, and yet they have never received the Nobel Prize. These days, several times a year, Dr. Stanley O. Foster takes a trip to revisit places he’s worked at before. In 2000, he decided to take a cruise aboard the Rocket. He arrived at the landing at Dhaka, carrying a small knapsack, and there she was at the dock, the steam paddle wheeler, completely unchanged, looking exactly as she had in 1975, stained with rust and jammed with humanity. He spent the night aboard her, leaning on the rail and watching the islands pass, smelling the river and the rising scent of the sea, and shortly after sunrise he disembarked at Berisal, where he rented a speedboat and crossed the bay to Bhola Island. He went inland by Land Rover, threading his way among crowds of people, until he came to the house of Rahima.

The young woman had moved to a different village when she had married. She was now twenty-five years old, and she was most happy to see him, though she was just about as shy as she had been on the day when she had dived into the burlap sack. Rahima had two daughters, was expecting a third child, and was hoping for a son. She presented Dr. Foster with a small gift, and he gave her kids some crayons.

At sunrise one day in November 2001, a month after the anthrax attacks, I drove south through Gettysburg, past the Gettysburg battlefield. It is an open country of rolling farms, and it looks not very different than it did at the time of the Civil War. The earth was a rich brown, dotted with crows, which flew up into a yellow sky. Little Round Top passed, the hill where Joshua Chamberlain and his men from Maine turned the tide with a charge. It was just another hump of bare trees. The road took me to Frederick, and I walked through the corridors of USAMRIID, along with Peter Jahrling, Lisa Hensley, and Mark Martinez. The light was sickly green, and the air smelled of roasting equipment — giant autoclaves baking things to sterilize them. Corridors branched to the left and right. Martinez was dressed in fatigues, with a black beret tucked in his belt. He swiped his security card over a sensor and pushed open a door, and we walked into the pathology suite — a cold suite, where there are no dangerous pathogens. Martinez took us into a small, windowless room with green walls. It was a bare-bones room, with some filing cabinets, some work counters, and a hood.

“I’ll be right back,” Martinez said and left the room.

We leaned up against the cabinets and waited. He was going to a storage area that was, apparently, a secret.

“What you are about to see is a national resource,” Jahrling remarked.

“I’ve never seen it,” Hensley commented.

Martinez returned, carrying a white plastic bucket. He popped open the lid and removed something that was wrapped in a yellow disposable surgical gown inside a plastic bag. He placed the bag inside the hood, opened it, and slid out the lump wrapped in the gown. Very slowly and carefully, he peeled the gown away and revealed it.

It was the arm of a child, covered with smallpox pustules. The arm had been severed during autopsy.

The child had been American, white, three to four years old, and had died of variola major. That was about all the information the Army scientists had been able to come up with.

In the spring of 1999, a professor at the Indiana University School of Dentistry had been exploring a dark basement corridor of the school with a flashlight, and he had come across a collection of jars that had belonged to William Schaffer, a long-dead pathologist. One of them was a jar with the arm in it, labeled “M 243 Smallpox.” No one knew where Professor Schaffer had obtained it. The professor had phoned officials at the CDC and had asked them if they wanted it. The CDC did not want a pickled arm covered with smallpox, so the professor gave it to a pharmaceutical company that was working on drugs for smallpox. Jahrling had shown up at the company one day to talk about smallpox drugs, and company scientists had mentioned to him that they had a smallpox arm, and did he want it?

“Heck, yes,” Jahrling said to them.

There weren’t any living people with the disease, and an arm covered with variola pustules was a magnificent clinical specimen. He had wanted to wrap the arm in plastic and bring it back in his carry-on luggage, but he began to wonder what airport security people would do if they found it, so he made arrangements to have the arm shipped to USAMRIID by express delivery.

The WHO forbids any laboratory except the CDC and Vector to have more than ten percent of the DNA of the smallpox virus. The chemicals in the jar had caused the smallpox DNA to fall apart into tiny fragments, and thus it was a legal smallpox arm.

The arm was lying palm downward. Mark Martinez turned it slowly, holding it with great care, until the palm came upward. He took the index finger and bent it ever so slightly, opening the palm, revealing the erupting centrifugal rash. The arm was covered with dark brown pustules. The child had died at the moment the pustules were beginning to crust over. The crusts were very dark.

Lisa Hensley stared at it through the glass. “I never had any idea how bad smallpox was until I saw the lesions in the monkeys. You can see the same lesions here.”

Martinez stood up, leaving the arm inside the hood. I put on a pair of latex gloves, sat down on the stool, reached into the cabinet, and picked up the arm. I could smell a faint, sweet smell of preserved human flesh. For a moment, I wondered if it was the foetor of smallpox. I turned the arm over and scabs began falling onto my hands. The lifeboats of variola were coming off.

The appearance of a child’s arm covered with smallpox pustules was something that our ancestors knew, but the arm had become a relic of history and an object of horror, alien to us. That we had never seen an arm like this in our lives was an extraordinary thing, a gift, unasked for, unexpected, and now unnoticed. A handful of doctors had given it to us, joined by thousands of village health workers. They had forged themselves into an army of peace. With a weapon in their hands, a needle with two points, they had searched the corners of the earth for the virus, opening every door and lifting every scrap of cloth. They would not rest, they would not stand aside, and they gave all they had until variola was gone. No greater deed was ever done in medicine, and no better thing ever came from the human spirit.

As I reflected on the death of variola, I thought also about our future. More and more people are living in cities. Soon more than half of the people in the world will be city dwellers. According to projections made by the United Nations, by the year 2015, the earth will likely contain twenty-six extremely big cities. Twenty-two of those cities will be in developing nations. Perhaps four of them will be in industrial countries. New York and Los Angeles will be medium-sized cities then.

These big cities will be in tropical nations. Bombay will have twenty-six million people living in it by 2015, Lagos twenty-four million. The population of California is currently thirty-five million. Take two thirds of the people in California and cram them into one city, with poor sanitation and inadequate health care and ineffective government. Twenty-five million people living within a couple of hours of one another… this is a leap beyond any sort of crowding a poxvirus would have found in ancient Egypt. If there is not enough vaccine to stop an outbreak of smallpox in a giant city, or if the virus cuts through the vaccine because human beings have done something to its genes, then the virus will move fast. The cities of the world are linked through a web of airline routes. A virus that appears in Bangladesh will soon arrive in Beverly Hills. An engineered virus could bring a bit of invisible bad news to every community on earth.

I opened the child’s hand and spread the fingers out on my palm. The child’s palm was one entire pustule. The fingers had gone confluent, so that there was almost no skin left that was not pustulated. I could see the whorls of the fingerprints, the mounts of fate and the future. The line of life and the line of love had been broken.

What was not present any longer in this hand was the suffering of the child who had endured it. I recalled when my son had been born, and how, minutes afterward, I had held his tiny hand, impressed with its perfection. I recalled the times when my children had been sick or had needed comforting, and I had held their hands. I recalled the sense of time slipping by as I noted how their hands were growing, gradually filling more of my hand. They might one day hold my hand when the life had left it.

We will never find an explanation for the suffering etched in that child’s hand, or for the evils done by people against other people, or for the love that drove the doctors to bring smallpox to an end. Yet after all they had done, we still held smallpox in our hands, with a grip of death that would never let it go. All I knew was that the dream of total Eradication had failed. The virus’s last strategy for survival was to bewitch its host and become a source of power. We could eradicate smallpox from nature, but we could not uproot the virus from the human heart.