Big drug companies have little interest in
developing medicines for parasitic diseases. Michael
Wall peers through the microscope as university researchers
take the initiative. Illustrated by Liz Bradford
and Zel Stolzfus.
Illustration: Liz Bradford
Ramadhan Shehe sweated his way through malaria infections while
growing up in Ngozi, a clay-street town of 22,000 in northern
Burundi. In 1996, ethnic clashes chased him to Tanzanian refugee
camps, where he picked up the disease again and again. Shehe's
wife, Jazira, also had malaria. So did the couple's only son,
four-year-old Adam, who was born in the camps.
The
Shehes don't have to worry about malaria anymore: The United States
granted them asylum in 2006, and they settled in Tucson, Arizona,
that August. But when they lived in Africa, malaria was a fact of
life, another hardship piled atop poverty, governmental corruption,
and endless war. It was something to live with, and live through.
In Africa, everyone gets malaria, Shehe says,
shrugging.
Shehe's passive acceptance mirrors
that of the big pharmaceutical companies. For the most part, they
stand by while malaria and other parasitic diseases ravage the Third
World. More than 500 million people have malaria, and two million
die from it every year. Schistosomiasis, caused by a liver-dwelling
worm, afflicts 250 million more. Such infections help keep the
developing world poor, sapping worker productivity and discouraging
foreign investment. Malaria alone stunts the economic growth of
hard-hit countries like Burundi by up to 1.5 percent every year,
according to research by Harvard economists Jeffrey Sachs and Pia
Malaney.
Drug companies are businesses,
and tackling diseases of the poor is not a good way to make money.
Fighting parasitic ailments may demand a new, non-profit approach,
and now university researchers in the San Francisco Bay Area are
pioneering one. Funded by government grants and private donations,
they have joined the battle against parasites. And they're making
headway.
Our mission is developing drugs
for these neglected tropical diseases, says James McKerrow, director of the Sandler Center
for Basic Research in Parasitic Diseases at the University of
California, San Francisco. We're filling a gap that's been left
by the pharmaceutical industry."
Also
at UCSF, biochemist Joe
DeRisi is turning his attention to malaria. His lab recently
unlocked a secret of the malaria parasite's life cycle, an advance
that has propelled drug and vaccine research. And DeRisi has just
embarked on a self-described crazy project to attack malaria in an
unprecedented way.
Both teams give other
scientists free access to their discoveries. In the proprietary
world of Big Pharma, that openness simply doesn't exist.
Tough customers
Parasites
are formidable foes. They're so complex that it's tough to knock
them out at a stroke. For example, the single-celled parasite that
causes Chagas diseasea heart-swelling infection that kills tens of
thousands every year in Latin Americahas 12,000 genes, about half
as many genes as humans have. Viruses, in contrast, typically have
between four and 100 genes.
The bug responsible
for African sleeping sickness has 1,500 genes devoted solely to its
constantly shifting protein coat, which hides the parasite from the
immune system. It cruises unchecked through the
body, killing when it finds the brain.
And
parasites know us very well. Unlike opportunistic infections such
as Severe Acute Respiratory Syndrome (SARS), which leapt from fowl
to people in 2002, parasites are geared to slip through the cracks
in our defenses.
They have existed with us
since the dawn of our species, so they have extremely highly adapted
means of evading our immune response, McKerrow says. That's why
they've been successful."
But by and
large, Big Pharma has not taken them on. A recent article in the
journal Health Affairs estimated that drug companies spend
$500 million to $2 billion bringing each new medicine to market.
They recoup this investment by selling drugs that treat chronic
conditionssuch as cancer, diabetes, and hypertensionto the wealthy
West.
Parasitic diseases flip this business
model on its head. The customers are poor, and they don't keep
coming back to the till. In many cases, a couple of pills will zap
the protozoans coursing through their bloodstream. The money doesn't
roll in.
In 2001, for example, the Swiss
company Novartis entered into an agreement with the World Health
Organization to sell its anti-malarial drug Coartem at reduced
rates. A 2003 WHO audit found that Novartis lost 80 cents on every
dose sold. The companies say, 'We're a business, not a philanthropy,'
McKerrow says.
Big Pharma has increased its
anti-malaria efforts in recent years. The World Bank, Western
governments, and philanthropies like the Bill and
Melinda Gates Foundation have helped to fund new research.
However, other parasitic diseases receive almost no attention, and
effective malaria drugs are still hard to come by in the Third
World. When he lived in Burundi, Ramadhan Shehe simply fought
through his malaria infections. You get a fever, you lie down, he
says. There was no medicine.
Video (10.9
mb): Mike Wall interviews the Shehe family of Tucson, Arizona, about
their experiences with malaria in Burundi and Tanzania. Slides
present statistics about malaria's impacts in the Third World. Requires QuickTime Player
The
drugs people do get their hands on are often old and ineffective,
defeated by parasites' ability to evolve resistance. For instance,
the German government developed the anti-malarial drug chloroquine
in the 1930s for its soldiers. The drug is still used widely
throughout sub-Saharan Africa, even though it no longer kills
Plasmodium falciparum, the deadliest of the four malaria-causing
parasite species.
Melarsoprol, the best
current treatment for African sleeping sickness, was developed in
1949. The drug is becoming less and less effective, but that's not
the only reason to look for something better. Melarsoprol is made
from arsenic, and it kills patients 3% to 10% of the time.
Another way
McKerrow decided
years ago that Big Pharma's profit-driven model couldn't be counted
on to develop anti-parasite drugs. He and others at UCSF began
targeting schistosomiasis, malaria, and Chagas in the early 1990s.
In 2002, the non-profit Sandler Foundation noticed the team's
progress and poured in money to broaden the fight.
McKerrow, a small man with a close-trimmed white
beard, sits in his fifth-floor office at UCSF's Byers Hall. To the
east stretches the deep blue finger of San Francisco Bay. To the
north the layered spires of the San Francisco skyline gleam in the
cold light of a January morning. His back is to these brilliant
views, yet his large, pale-blue eyes shine.
[The
Sandler Foundation's] charge to us was, 'Let's see what you can do
now looking at the five big neglected diseases,' says McKerrow, who
became director of the new Sandler Center. The big five are Chagas,
African sleeping sickness, leishmaniasis, schistosomiasis, and
malaria.
So McKerrow started his parasite
collection. Down the hall from his office, gray incubators line
one wall of a room the size of a large walk-in closet. Bright
orange Biohazard stickers spangle their doors, warning of the nasties
multiplying within. A few feet down, thirty plastic shoeboxes fill
shelves from ceiling to floor. They're full of aquatic snails,
which are packed with schistosome larvae.
McKerrow
also brought in hordes of chemists, parasitologists, and computational
biologistshis team numbered more than 100 at last count. He organized
the Sandler Center like a pharmaceutical company, with ten different
groups specializing in various stages of drug discovery and design.
But the Center wasn't in the game to get rich. McKerrow's colleagues
resolved to post their best leads on a free website they've named
Low Hanging Fruit. And they got to work.
Looking for hits
At the
Center, the search for new drugs starts on the computer. Scientists
troll through huge databases of compounds, then run computer
simulations to see how a target chemical might take out a vital
parasite part. This technique was pioneered at UCSF.
If a compound clears this hurdle, it's tested
against the actual bug. The researchers can run thousands of
chemical-vs-parasite bouts every day. They use a high-speed system
that automates everything: Robots drip drabs of chemical into
hundreds of tiny dishes, and computers count the dead parasites at
trial's end.
The next step is a test in a
parasite-infected rodent. The most promising chemicals are further
analyzed and tweaked before finally advancing to human trials. One
compound, a treatment for Chagas, is now ready for human testing.
While its therapeutic use may be years off, this is big news for
both McKerrow's team and Chagas sufferers. Current treatments don't
always get rid of the disease, and the parasite has evolved resistance
even to these substandard drugs. A few other chemicalstreatments
for schistosomiasis and African sleeping sicknessare also moving
along the pipeline.
The onerous process
of generating new medicines was off limits to academic researchers
until recently. "The expertise and infrastructure existed
only in industry until maybe five or six years ago," McKerrow
says. But the Sandler Center is doing it now. Groups at the
University of North Carolina, the University of Dundee in Scotland,
and other institutions are following suit. Industry is beginning
to collaborate with these efforts, according to McKerrow; Novartis
is now testing drugs against parasites using screens the Sandler
Center developed.
These early signs are
promising, but, McKerrow says, there is still a long way to go.
Some other groups are loath to share their findings, because they
want to cash in if they create a profitable medicine. They argue
that a for-profit company could make a proprietary claim on their
open-source data, potentially blocking a drug's development.
But that's bogus, McKerrow says. If there was
a great new drug for kids in Africa with malaria, and some company
came along and blocked it to develop a pimple drug instead, this
company would be on the front page of The New York Times.
They'd be blasted to hell."
University
groups like McKerrow's will have to carry more of the load in the
future, says Stephen Frye, director of the Center for Integrative
Chemical Biology and Drug Discovery at the University of North
Carolina, Chapel Hill. "Industry is moving away from drug
discovery," he says. "All they care about is what's close
to the market"medicines nearly ready to be advertised and
sold.
Pharmaceutical mega-mergers, such as
a $68 billion deal between Pfizer and Wyeth in January 2009, have
accelerated this trend, according to Frye. Fewer drug companies
means fewer risk-takers, fewer corporations willing to try new and
different things. And mergers are disruptive. "Pfizer-Wyeth
is going to be a disaster for drug discovery," Frye says.
"It takes 10 to 15 years for things to get back to normal after
a big shakeup like that." This shift away from early-stage
research helped drive him out of industry. Before agreeing to lead
UNC's new center in late 2007, Frye had been head of GlaxoSmithKline's
discovery medicinal chemistry branch. He had worked for GSK for
20 years.
Fighting malaria
One floor down from McKerrow's office, UCSF
biochemist Joe DeRisi is taking apart pieces of his DNA-chip arrayer.
The machine deposits tiny samples of germ DNA onto 261 glass slides,
which researchers examine to screen for unknown viruses, bacteria,
and parasites. If a mystery disease pops up somewhere on the planet,
a sample of the bug's DNA can be sprinkled across these slides. If
it matches one of the reference samples, it will react, glow, and
be identified. In 2003, DeRisi's group helped characterize the
SARS virus using this method, which he developed. Though he could
have made a lot of money, he didn't patent the technology. Instead,
he posted a free instruction manual on his website.
Today, however, things aren't going smoothly.
The machine, a gleaming silver platform about half the size of a
ping-pong table, is acting up. A robotic arm zips around the
platform, painting each slide with DNA. But the paint is thin in
one spot, so DeRisi is tinkering. He should know what to do. He
designed and built this thing himself, from the sturdy metal skeleton
to the software coding the green Start button on the computer screen
interface.
Do you know how much time I spent
on that start button? he asks, laughing. I put the rivets in the
corners and everything.
DeRisi is 39 but
looks younger. He has a thick mop of curly strawberry-blond hair
and a thin, angular face. With his wiry build, khaki cargo shorts,
and running shoes, he looks more like a high-school cross-country
star than the recipient of a MacArthur Foundation Genius Grant,"
which he got in 2004.
DeRisi fixes the
problem, and the arrayer is off and running. Today it's making
chips to test for bee diseases. The lab is investigating the cause
of colony collapse disorder, a mysterious malady killing honeybees
around the world. But more often, the machine is pressed into
service against malaria. DeRisi says he spends half his time
dreaming up ways to knock malaria out.
A
few years ago, DeRisi programmed the arrayer to create DNA chips
covered with 4,500 of Plasmodium falciparum's 5,400-odd
genes (another research group sequenced the parasite's genome in
2002). In one part of its life cycle, P. falciparum
invades and camps out in red blood cells. This stage, during which
the fevers, chills, and nausea of malaria develop, lasts 48 hours.
Every hour, the scientists exposed ground-up parasite innards to
the DNA chips, looking for hits. The process mapped out which genes
P. falciparum turns on as it invades red blood cells,
feeds on hemoglobin, and multiplies.
This
had never been done before. Learning what genes do, and how they're
regulated, opened a window into the parasite's vulnerabilities.
Researchers have historically tried to attack the parasite during
this red-blood-cell stage, and they now have many more targets for
drugs and vaccines.
The experiment also
held a surprise. P. falciparum turns on at least 60% of
its genes during the red-blood-cell stage. Most of those genes are
active only once, and at a specific time. Everything is rigidly
structured, like an assembly line. DeRisi thinks this inflexibility
is a major chink in P. falciparum's armor: It probably
cannot switch genes on and off to deal with environmental changes.
"It's like a big virus," he says.
DeRisi's group also collaborates with McKerrow and other researchers.
He and Phil Rosenthal, another UCSF malaria researcher, are examining
the genomes of drug-resistant P. falciparum from Africa,
trying to determine how the parasites fend off medicinal arsenals.
Now, DeRisi also wants to engineer bacteria
to attack and kill malaria-infected red blood cells. It's kind of
a nutty idea, he says. But it does have potential. The Gates
Foundation thinks so. In November 2008, they gave DeRisi $100,000
to test it out.
Some bacteria attack human
red blood cells without causing major symptoms. One example DeRisi
gives is Bartonella, the bug responsible for cat-scratch
fever. He's working with a UCSF Bartonella expert, hoping
to learn enough to genetically engineer a bacterium that will attack
only red blood cells swarming with P. falciparum.
Still beyond reach
While
McKerrow, DeRisi, and other academics wage war against parasites,
the Shehes are making Tucson their home. Ramadhan does the laundry
at a nursing home, and Jazira works as a thrift-store stocker. Adam
loves Elmo and sings along to all of Barney the dinosaur's songs.
But there is still a lot of Africa in their
life. Jazira buys cassava at the Nigerian market, and she cooks
tilapia in palm oil. Their apartment complex has the sense of
community that prevails in much of the Third World. Friends from
dozens of refugee familiesBurundians, tall, lean Somalis, and single
mothers from Sierra Leonewander in at all hours. They fill plates
with rice and beans and flop on the couch to watch TV.
Jazira calls her folks in Burundi when she can.
Ramadhan's parents are dead, but he talks to his sister in Ngozi.
When he called a few months back, she was weak and nauseated,
freezing cold one moment and burning up the next. She got sick,
she lay down. No medicine. But, like Ramadhan, Jazira, and Adam,
she pulled through.
Sidebar: Could an Old Foe Come Back?
Illustration: Zel Stolzfus
Pack loads of insect repellent.
Wear long pants and long-sleeved shirts. Sleep under a mosquito
net. Avoid being bitten.
Such advice is
standard for travelers to Cameroon and Cambodia. But it would have
been just as relevant for someone visiting New Orleans or Atlanta
in the 1930s.
Malaria was a problem in the
United States for most of its history. Colonization and commerce
brought this Old World disease to the New, and it took hold, hard.
By the 1800s, malaria stretched from Montana to Texas, from
Massachusetts to Florida. It killed thousands of soldiers during
the Civil War. Abraham Lincoln suffered from it growing up.
In the late 1890s, scientists discovered that
mosquitoes spread the disease. After that, intensive mosquito
control effortsdraining swamps, soaking homes with insecticideknocked
malaria back. Rising prosperity and rural-to-urban migration also
helped. But the southern U.S., hot and wet and poor, remained a
stronghold for decades.
When the U.S.
Centers for Disease Control and Prevention (CDC) was founded in
1946, its charge was to put a boot on malaria's throat. That's why
the CDC is in Atlanta and not Washington, D.C. The CDC ran a blitzkrieg campaign against
malarial mosquitoes, drenching entire counties with the powerful
new insecticide DDT. By the early 1950s, the U.S. was effectively
malaria-free.
But is this just a temporary
respite? According to the CDC, malaria-transmitting Anopheles
mosquitoes are found in every state except Alaska and Hawaii.
And at least some of the insects are sucking up infected blood:
Travelers and immigrants from the developing world bring 1,000 to
1,500 new malaria cases into the country every year.
Occasionally, mini-outbreaks pop up. In 2002-03,
three Virginia teenagers from the same neighborhood got malaria.
None had traveled to the Third World, received a blood transfusion,
or done anything else high-risk. Palm Beach County, Florida,
recorded eight cases of locally acquired malaria in 2003. Many
other states report similar clusters.
No
cluster has exploded into an epidemic. Health authorities quashed
the outbreaks early, or they petered out. There's certainly a risk
malaria could come back, says Paul Arguin, chief of the domestic
response unit at the CDC's Malaria Branch. But it's unlikely to
happen on a massive scale. It probably couldn't fester without
being noticed. Most Americans have screened windows and access to
health care, however spotty. This is a wealthy nation, and malaria
these days is a disease of the poor.
Michael Wall B.S. (ecology and evolutionary biology) University
of Arizona B.A. (history) University of Arizona Ph.D.
(evolutionary biology) University of Sydney Internship: Idaho
National Laboratory news office
If
they don't have legs, how come they're not snakes? I get that
question a lot when telling people about my Ph.D. research on
Australian legless lizards. When I explain that it's all about
ancestrythat snakes are merely the most successful of many lizard
lineages to have evolved limbless, elongated bodiespeople's eyes
usually widen. Evolution is a strange and wonderful thing.
An ignorance of reptilian phylogeny is no badge
of shame. But the scientific illiteracy afflicting this country
is serious, and I want to help combat it. After working for years
as a biologist, struggling to reconcile my scientific and artistic
natures, I now realize that my heart is in communicating science.
In my reporting about the natural world, I intend to widen many
more eyes in surprise and appreciation.
Liz Bradford B.A.
(art and design) and B.S. (textile technology) North Carolina State
University, Raleigh Internship: Dinosaur National Monument,
Dinosaur, CO
It began when my sixth
grade science teacher nominated me to the Girls in Science program
at the Natural History Museum. I was thrilled to learn special
lessons behind the scenes at one of the most magical and mysterious
places on earth. Here I learned to quickly sketch the animals we
observed out in the field, or the aquatic life we found under the
microscope. Art became a tool to discover the world around me. I
am thrilled to still be doing what I love, combining my passion for
art and science through my illustrations.
Zel Stolzfus B.S.
(biology) Millersville University, Millersville, PA Internship:
Carnegie Museum of Natural History, Pittsburgh, PA
Over the years I've grown accustomed to the feel
of a pencil in my hand. Drawing is my natural outlet and has been
since I was a very little boy growing up at the edge of the Serengeti
National Park in Tanzania, East Africa. Upon returning from Africa
to Pennsylvania, I began following a biology track through high
school and college. Although biology was tons of fun and a completely
natural fit, every time I strayed too far from my university's art
department the drawing urge pulled me back in. After college I
went to northwestern England to study Science and Natural History
Illustration at Blackpool and the Fylde College of Art and Design.
The year after that I landed in the Science Illustration Program
at UCSC. I've still got that pencil in my hand, gripped tighter
than ever now. I'm not letting go.