Debugging the Bug
by Michael Penn MA'97
Mosquitoes have the power to kill by carrying deadly parasites. Can researchers render them powerless?
On a typically dust-choked Egyptian afternoon two years ago, Lyric Bartholomay set out with a group of researchers into the Nile River delta, looking for bioterrorists.
The delta, a region of small subsistence villages that feed off the bounty of the Nile, is prime breeding ground for the purveyors of biological warfare. They are born there, amid filth and squalor, and live for the sole purpose of preying on human beings. They have the capacity to kill, and they think nothing of doing so. They have already claimed millions of lives. And before the day is over, they will kill a few thousand more.
Forty-five minutes north of Cairo, the researchers stopped in Al-Aziziyah, a tiny hamlet connected umbilically to the great river by a long irrigation trench.
Mosquitoes have the power to kill by carrying deadly parasites. Can researchers render them powerless?
On a typically dust-choked Egyptian afternoon two years ago, Lyric Bartholomay set out with a group of researchers into the Nile River delta, looking for bioterrorists.
The delta, a region of small subsistence villages that feed off the bounty of the Nile, is prime breeding ground for the purveyors of biological warfare. They are born there, amid filth and squalor, and live for the sole purpose of preying on human beings. They have the capacity to kill, and they think nothing of doing so. They have already claimed millions of lives. And before the day is over, they will kill a few thousand more.
Forty-five minutes north of Cairo, the researchers stopped in Al-Aziziyah, a tiny hamlet connected umbilically to the great river by a long irrigation trench.
Bartholomay knelt by the edge of the canal and plunged an enamel pan into the murky stream, hoping to capture the killers. Looking at the teeming water, she knew she had found them. In the pan were thousands of mosquito larvae, little adolescent nuisances that would soon fill the air and feed on anything that moved. Each one would become an unthinking, unfeeling weapon of aerial assault - nature's perfect bioterrorist.
Few organisms succeed at wreaking havoc and spreading disease as effortlessly and thoroughly as the mosquito. The blood-sucking insect, a seemingly omnipresent annoyance in Wisconsin, is in other parts of the world the cause of catastrophe. Certain among their breed have an all-too-willing nature that allows hundreds of viruses, parasites, and other disease-causing biotics to hitch a ride between mammalian hosts, spreading infections, disease, and death. The organisms that cause malaria, yellow fever, dengue, filariasis, and a host of other ailments all travel by way of the mosquito taxi service, and, ultimately, humans end up paying the fare.
At any given time, 500 million people around the world suffer from malaria, between 50 million and 100 million from dengue fever, and around 120 million from lymphatic filariasis, a disease caused by tiny worms that infest the body and in some cases cause severe, disabling swelling of the limbs. More than one million people die each year from malaria alone. Almost all of them are poor, and most of them are children.
Few organisms succeed at wreaking havoc and spreading disease as effortlessly and thoroughly as the mosquito. The blood-sucking insect, a seemingly omnipresent annoyance in Wisconsin, is in other parts of the world the cause of catastrophe. Certain among their breed have an all-too-willing nature that allows hundreds of viruses, parasites, and other disease-causing biotics to hitch a ride between mammalian hosts, spreading infections, disease, and death. The organisms that cause malaria, yellow fever, dengue, filariasis, and a host of other ailments all travel by way of the mosquito taxi service, and, ultimately, humans end up paying the fare.
At any given time, 500 million people around the world suffer from malaria, between 50 million and 100 million from dengue fever, and around 120 million from lymphatic filariasis, a disease caused by tiny worms that infest the body and in some cases cause severe, disabling swelling of the limbs. More than one million people die each year from malaria alone. Almost all of them are poor, and most of them are children.
Humankind has been waging war against mosquito-borne diseases for more than a century, and, until recently, we thought we were winning. Industrialized nations deployed insecticides, drugs, and other defenses, and managed in some places to nearly eradicate diseases like malaria and yellow fever. After a global effort to contain mosquitoes and their various ills, by the late 1960s, malaria had almost vanished from India, Latin America, and parts of Africa.
Now, those diseases are back, and in some cases, they are sporting new immunity to the drugs designed to treat or control them. They've upped the ante.
Bartholomay, a doctoral student in the UW School of Veterinary Medicine, is among those working on an ultimate trump card. With the help of her mentor, Professor Bruce Christensen, she has been collecting mosquitoes from places such as the Nile River delta for a novel purpose. The researchers think that they can figure out the genetic wiring of the insects to learn why they're so hospitable to parasites. The plan then is to make them rude hosts - to rewire the bugs so that they don't bug people.
Now, those diseases are back, and in some cases, they are sporting new immunity to the drugs designed to treat or control them. They've upped the ante.
Bartholomay, a doctoral student in the UW School of Veterinary Medicine, is among those working on an ultimate trump card. With the help of her mentor, Professor Bruce Christensen, she has been collecting mosquitoes from places such as the Nile River delta for a novel purpose. The researchers think that they can figure out the genetic wiring of the insects to learn why they're so hospitable to parasites. The plan then is to make them rude hosts - to rewire the bugs so that they don't bug people.
Although such applications are potentially years - or even decades - away, they've opened an intriguing new possibility in the fight against some of the world's most devastating diseases. Can we build a better mosquito?
The motion is automatic: you feel that twinge of skin, the pinprick bite. Instinctively, you swat. There's no reflection or remorse. It's a mosquito, after all. Who could really care?
Well, after more than two decades of studying mosquitoes, Bruce Christensen isn't so cavalier about dispensing with them. "I don't want to kill them," the UW professor of animal health and biomedical sciences laughs. "They've been paying my rent for a number of years."
Call it a debt of professional gratitude: Christensen is now devoting most of his time to figuring out how not to kill mosquitoes. He is trying to create, as he says, "a kinder, gentler mosquito." His lab is in the process of learning how to tweak the genetics of certain types of mosquitoes so that they no longer carry the parasites that transmit diseases, downgrading their bites from deadly to merely bothersome.
The motion is automatic: you feel that twinge of skin, the pinprick bite. Instinctively, you swat. There's no reflection or remorse. It's a mosquito, after all. Who could really care?
Well, after more than two decades of studying mosquitoes, Bruce Christensen isn't so cavalier about dispensing with them. "I don't want to kill them," the UW professor of animal health and biomedical sciences laughs. "They've been paying my rent for a number of years."
Call it a debt of professional gratitude: Christensen is now devoting most of his time to figuring out how not to kill mosquitoes. He is trying to create, as he says, "a kinder, gentler mosquito." His lab is in the process of learning how to tweak the genetics of certain types of mosquitoes so that they no longer carry the parasites that transmit diseases, downgrading their bites from deadly to merely bothersome.
If it all sounds a bit futuristic, it is. "There's no question that technically we will be able to do this," Christensen says. "But that's a long, long ways away from actually thinking about using this as a viable control option in the field."
Still, in the sphere of public health - where threats keep arising, and defenses keep eroding - there are worse things than possibility.
Infectious diseases, including those borne by mosquitoes and those transmitted through other means, remain one of the leading causes of morbidity and mortality worldwide, responsible for fully half of all deaths in people under the age of forty-five. Failure to control them is a chief reason why developing nations don't develop, and why poor people stay poor. In Africa - where 95 percent of all new HIV infections, 84 percent of new tuberculosis cases, and nearly 100 percent of all new malaria cases occur - ill health has wrecked economies and contributed to political instability. A report issued this year by the World Health Organization estimates that battling malaria for the past thirty-five years has reduced the continent's overall gross domestic product by 32 percent. That's a cost of about one hundred billion U.S. dollars every year.
The loss of life from these diseases, Christensen says, compares to "anywhere from ten to eighteen jumbo jets full of children crashing every day."
Still, in the sphere of public health - where threats keep arising, and defenses keep eroding - there are worse things than possibility.
Infectious diseases, including those borne by mosquitoes and those transmitted through other means, remain one of the leading causes of morbidity and mortality worldwide, responsible for fully half of all deaths in people under the age of forty-five. Failure to control them is a chief reason why developing nations don't develop, and why poor people stay poor. In Africa - where 95 percent of all new HIV infections, 84 percent of new tuberculosis cases, and nearly 100 percent of all new malaria cases occur - ill health has wrecked economies and contributed to political instability. A report issued this year by the World Health Organization estimates that battling malaria for the past thirty-five years has reduced the continent's overall gross domestic product by 32 percent. That's a cost of about one hundred billion U.S. dollars every year.
The loss of life from these diseases, Christensen says, compares to "anywhere from ten to eighteen jumbo jets full of children crashing every day."
And, if anything, the diseases are growing more potent. Strains of drug-resistant malaria are emerging, and, despite a century-long quest, an effective vaccine for malaria has yet to be produced. The recent outbreak of the West Nile virus in the United States - which by the end of August had reached forty-one states and killed twenty-eight people - demonstrates the disregard parasites have for national borders. The Centers for Disease Control has called the spread of West Nile an "emerging, infectious disease epidemic," and, in an age where parasites hop continents as easily as do people, it almost certainly won't be the last.
With no vaccines and few drugs to work against them, the best option for controlling most mosquito-borne diseases is to control the mosquito - to eliminate the middleman, or middlebug, as the case may be. When malaria epidemics thwarted construction of the Panama Canal in the early 1900s, for example, it was only after engineers began draining the jungle swamps that harbored disease-carrying mosquitoes that the project moved forward. In recent years, insecticides have been the centerpiece of mosquito control, but they, too, are beginning to fail as mosquitoes grow immune to them. One of the most effective, DDT, a cornerstone of the global antimalaria campaigns in the 1950s and 1960s, has been shown to cause more problems than it solves, and it's mostly been shelved.
With no vaccines and few drugs to work against them, the best option for controlling most mosquito-borne diseases is to control the mosquito - to eliminate the middleman, or middlebug, as the case may be. When malaria epidemics thwarted construction of the Panama Canal in the early 1900s, for example, it was only after engineers began draining the jungle swamps that harbored disease-carrying mosquitoes that the project moved forward. In recent years, insecticides have been the centerpiece of mosquito control, but they, too, are beginning to fail as mosquitoes grow immune to them. One of the most effective, DDT, a cornerstone of the global antimalaria campaigns in the 1950s and 1960s, has been shown to cause more problems than it solves, and it's mostly been shelved.
In the early 1990s, Christensen considered this diminishing arsenal and pondered a new approach. He and a handful of vector biologists - scientists who study the organisms that carry diseases - began talking about mosquito genetics. Most mosquitoes, it turns out, are harmless. Of the 2,700 different kinds of mosquitoes buzzing around our world, fewer than one hundred transmit diseases. The rest, when confronted with a parasite hitching a free ride, trigger biological defenses to surround and kill it. If you could teach the bad bugs what the good bugs already know, Christensen thought, you might be able to break the cycle of infection.
Today, that challenge lies at the heart of the work in Christensen's lab. On the third floor of the Animal Health and Biomedical Sciences building, he and a group of doctoral students, postdoctoral researchers, and technicians are analyzing the genetic make-up of various kinds of mosquitoes and beginning to understand how they function.
The researchers maintain a warehouse of mosquitoes, housed in an environmentally controlled room the size
of a walk-in closet. The steel and mesh cages, each one covered with cloth, represent a mosquito all-star team, collected from as far away as India and Egypt. One of the key players here is Culex pipiens, the mosquito Bartholomay found in the Nile delta, which transmits some forms of filariasis.
Today, that challenge lies at the heart of the work in Christensen's lab. On the third floor of the Animal Health and Biomedical Sciences building, he and a group of doctoral students, postdoctoral researchers, and technicians are analyzing the genetic make-up of various kinds of mosquitoes and beginning to understand how they function.
The researchers maintain a warehouse of mosquitoes, housed in an environmentally controlled room the size
of a walk-in closet. The steel and mesh cages, each one covered with cloth, represent a mosquito all-star team, collected from as far away as India and Egypt. One of the key players here is Culex pipiens, the mosquito Bartholomay found in the Nile delta, which transmits some forms of filariasis.
Ringing the perimeter of the lab are sophisticated microscopes, which employ tiny tubes of suctioned air to hold mosquitoes in place while researchers analyze them or inject parasites. Within the past few years, science has developed certain molecular tools that have opened a new world to biologists. Christensen's team can now do things as detailed as identifying specific molecules within the salivary glands of a single mosquito. That, he says, has speeded up their research considerably. In fact, the early results have been quite promising. Christensen says the team is beginning to understand the genetics that underlie a mosquito's ability to kill ingested parasites.
It's hard to say, however, whether this knowledge can be used to introduce parasite-resistant genes into the millions of disease-carrying mosquitoes around the globe. "I'm not sure if it's possible," Christensen says. "But I think as scientists, we're always trying to improve on nature."
The frustrating thing about malaria, says Javier Nieto, is that it's basically preventable. Most of those who have died probably could have been saved, using something as simple as a bed net.
It's hard to say, however, whether this knowledge can be used to introduce parasite-resistant genes into the millions of disease-carrying mosquitoes around the globe. "I'm not sure if it's possible," Christensen says. "But I think as scientists, we're always trying to improve on nature."
The frustrating thing about malaria, says Javier Nieto, is that it's basically preventable. Most of those who have died probably could have been saved, using something as simple as a bed net.
Nieto, the chair of the UW Medical School's population health sciences department, ticks off a list of other such situations - running the gamut from tuberculosis to heart disease. It is a truism of public health, Nieto says, that having medical answers often isn't enough. "Medicine is only a small part of all the sciences that are related to health," he says. "I could argue that economics are as relevant, or even more relevant, to the overall well-being of people than medicine."
New drugs are great, Nieto points out, only if patients can afford them.
Preventive measures are good - if people take them. There are no panaceas. The best gains, he and other public health experts say, result from a cocktail of strategies.
In the past, American medical research and delivery has tended to emphasize individualized care and cures, but that may be changing. Nieto, who grew up and studied medicine in Spain, is working to foster more collaborative, integrated approaches to dealing with world health problems - an effort that was already beginning to take root at UW-Madison even before he arrived earlier this year.
New drugs are great, Nieto points out, only if patients can afford them.
Preventive measures are good - if people take them. There are no panaceas. The best gains, he and other public health experts say, result from a cocktail of strategies.
In the past, American medical research and delivery has tended to emphasize individualized care and cures, but that may be changing. Nieto, who grew up and studied medicine in Spain, is working to foster more collaborative, integrated approaches to dealing with world health problems - an effort that was already beginning to take root at UW-Madison even before he arrived earlier this year.
Christensen agrees, saying that vector biology is best considered not as a replacement for other measures, but as a component of a broad attack. "I don't think that anyone is bold enough to say that we're ever going to have a chance of eradicating this disease," he says. "What you want to be able to do is control it.
It's going to have to be an integrated approach."
For vector researchers, that means balancing the big picture with the little picture. While they are enthused by the aims of their work, they also realize that it may ultimately be helpful in other ways. What they are able to contribute to the knowledge of genetics, for example, may help design new drugs or insecticides. Their chief priority is understanding the infector, so that others might better understand the infection.
That's no small task, given the plasticity of most disease-causing agents. Take the schistosome worm, for example. In humans, these worms reproduce and cause schistosomiasis, an often serious infectious disease that affects two hundred million people around the world. But the worms mature inside the bodies of snails. To get from their intermediate host to their final destination, the worms have developed the capacity to sense water vibrations around their snail hosts. Once near exposed skin, they can bore directly into the new host's body.
It's hard not to be impressed with such biological adaptability, says Tim Yoshino, who studies the schistosomes and their snail hosts. "They're very complex organisms, and we don't yet know what we need to know about them," he says. "But we're starting to develop some of the tools we need to understand them."
It's going to have to be an integrated approach."
For vector researchers, that means balancing the big picture with the little picture. While they are enthused by the aims of their work, they also realize that it may ultimately be helpful in other ways. What they are able to contribute to the knowledge of genetics, for example, may help design new drugs or insecticides. Their chief priority is understanding the infector, so that others might better understand the infection.
That's no small task, given the plasticity of most disease-causing agents. Take the schistosome worm, for example. In humans, these worms reproduce and cause schistosomiasis, an often serious infectious disease that affects two hundred million people around the world. But the worms mature inside the bodies of snails. To get from their intermediate host to their final destination, the worms have developed the capacity to sense water vibrations around their snail hosts. Once near exposed skin, they can bore directly into the new host's body.
It's hard not to be impressed with such biological adaptability, says Tim Yoshino, who studies the schistosomes and their snail hosts. "They're very complex organisms, and we don't yet know what we need to know about them," he says. "But we're starting to develop some of the tools we need to understand them."
Yoshino, like Christensen a professor in the School of Veterinary Medicine, is running experiments similar to his colleague's, in which he is trying to identify and manipulate genes within snails so that they no longer provide a host for the worms. The potential of the work isn't lost on him, but he's also motivated by a simpler aim: a basic wish to know how these organisms function. "I think that, for myself and a lot of researchers, we're driven by curiosity, by our desire to know how these complex biological systems work," he says. "It's very motivating to work toward something that may be helpful to mankind. But I think even without that, I would still be interested."
The same holds true for Bartholomay, who was attracted to biology partly by attraction to the tiny subjects of her experiments. The daughter of Barry Beaty PhD'76, a Colorado State University professor who studies the mosquitoes that transmit dengue fever, she grew up appreciating the insects. Even now, she admits sheepishly, she sometimes allows a mosquito to bite her just so that she can watch it feed. "I think they're fascinating and beautiful little creatures," she says.
But she doesn't overlook the trouble that they cause. She and Christensen traveled to Egypt in 2000 and again this year to conduct experiments with researchers from Ain Shams University in Cairo. And the images from those trips are still vivid. "You can read those statistics and maybe see some pictures, but I don't think you really grasp how debilitating and terrible these diseases can be until you meet the people at risk," she says.
The same holds true for Bartholomay, who was attracted to biology partly by attraction to the tiny subjects of her experiments. The daughter of Barry Beaty PhD'76, a Colorado State University professor who studies the mosquitoes that transmit dengue fever, she grew up appreciating the insects. Even now, she admits sheepishly, she sometimes allows a mosquito to bite her just so that she can watch it feed. "I think they're fascinating and beautiful little creatures," she says.
But she doesn't overlook the trouble that they cause. She and Christensen traveled to Egypt in 2000 and again this year to conduct experiments with researchers from Ain Shams University in Cairo. And the images from those trips are still vivid. "You can read those statistics and maybe see some pictures, but I don't think you really grasp how debilitating and terrible these diseases can be until you meet the people at risk," she says.
Bartholomay tells a story about when the group of researchers went to Al-Aziziyah to collect mosquitoes. Soon after Bartholomay began sampling the water - wearing gloves to protect herself from its many threats - she noticed that she was being watched. She looked up to see the faces of a dozen children, their amber eyes widened with curiosity. A few of the boys called out to her with hopeful bits of whatever English they knew, saying things like, "I love you." After a minute, an elderly man appeared, brandishing a stick. He scolded them, yelling in Arabic, "Go away! Leave the scientists alone!" The children scattered.
But Bartholomay knew the children weren't just outsiders, but in fact were central to her work. "Those were beautiful little faces that I was looking into, and to think about how their lives could be impacted forever by these diseases ... it's tragic," she says. "Of course, it's motivating."
As we talk, Bartholomay points out a Xeroxed page taped above her desk. It features a quote from Franklin D. Roosevelt: "The test of our progress is not whether we add more to the abundance of those who have much. It is whether we provide enough for those who have too little." Because I think this helps explain how she can love mosquitoes, yet hate what they do, I ask to borrow it. Instead, she gives it to me. "It's okay," she says. "I have it in my heart."
But Bartholomay knew the children weren't just outsiders, but in fact were central to her work. "Those were beautiful little faces that I was looking into, and to think about how their lives could be impacted forever by these diseases ... it's tragic," she says. "Of course, it's motivating."
As we talk, Bartholomay points out a Xeroxed page taped above her desk. It features a quote from Franklin D. Roosevelt: "The test of our progress is not whether we add more to the abundance of those who have much. It is whether we provide enough for those who have too little." Because I think this helps explain how she can love mosquitoes, yet hate what they do, I ask to borrow it. Instead, she gives it to me. "It's okay," she says. "I have it in my heart."
