sneak attack

NinjajenlucHypochondriacs must have a love/hate relationship with the TV series House. On the one hand, the nonstop parade of obscure diseases and strange symptoms that feature in every episode are like crack cocaine to a person constantly worrying that s/he has some life-threatening condition. On the other hand, the same litany of disease breeds paranoid fear that what most people would dismiss as a slight case of the sniffles is, in reality, a harbinger of a painful imminent death. I'm a fan of the show, especially Hugh Laurie's portrayal of the irascible, addicted-to-pain-killers-and-sarcasm title character, but even I sometimes find myself Googling the odd nonexistent symptom after watching a particularly unsettling episode. WebMD is my friend, oh yes…

Here's a differential diagnosis worthy of Gregory House. A patient checks into the ER complaining of mild, flu-like symptoms: fever, fatigue, body aches, headache, loss of appetite, diarrhea and/or vomiting. But there's also a slight rash. Is it flu, or the onset of Something Far More Serious? A cursory physical examination reveals a slightly enlarged liver, and swollen glands, and you note that the patient also has a mysterious slight swelling of the eyelids on one side of his face. Then he mentions he has just returned from an six-month archaeological expedition in Guatemala. House_323sc17_0680_f

If you guessed the patient was in the initial acute phase of Chagas' disease, congratulations! You win Cyber-bragging rights at the cocktail party for, oh, at least the rest of the week. I've only just heard about Chagas' disease, having spent my science writing career covering physics rather than epidemiology (although I wrote a post on cholera back in May). But it's a fascinating disease. It gets its name from a Brazilian physician, Carlos Chagas, who discovered, in 1909, that the intestines of the Triatominae sub-family of insects, commonly known as "kissing bugs," harbored a parasitic flagellate protozoan in its gut, that he called Trypanosoma cruzi (T. cruzi for short), in honor of famed epidemiologist Oswaldo Cruz (credited with fighting off epidemics of yellow fever, smallpox and bubonic plague in Rio de Janeiro at the start of the 20th century) . Chagas conducted experiments with marmoset monkeys and squirrel monkeys and determined that the parasite could be transmitted if a subject were bitten by an infected bug.

Chagas sketched out a pretty complete description of this new infectious disease, identifying its pathogen, vector, host, symptoms, and so forth. The only aspect he got wrong was the means of infection. He assumed the parasite was transmitted into the victim's bloodstream by the actual bug bite, when in fact, it's a bit more complicated. The kissing bug is a stealthy nocturnal critter. It lurks in the nooks and crannies of  adobe homes in Mexico or the thatched roofs common in Guatemala, for example, dropping down at nightfall onto your face like a silent, Ninja assassin from above (hence Jen-Luc Piquant's Ninja attire).  The bugs are attracted to the carbon dioxide exhaled by sleeping mammals, which is why it tends to bite near the mouth (hence the nickname "kissing bug"). It's got a long, nasty-looking proboscis the better with which to pierce your skin and drink heartily of your rich, red blood. Kissing bugs are gluttonous gorgers: they'll feed for a good five minutes straight, stuffing themselves with your blood until they are twice their normal size, and then, as the final ignominy, they will leave a "fecal droplet" at the site.  Yes, they defecate. On your face. Ewww!

Okay, the droplet is mostly water, but it also contains a nasty surprise in the form of the T. cruzi  parasite, which up to that point has been comfortably ensconced in the gut of the kissing bug. You will be blissfully unaware of all this as you sleep, of course, and in the morning will rub your eyes, wipe your mouth, maybe scratch at a slight itchy spot on your face –  and the parasite enters your bloodstream.  You become  one of between 16 and 18 million infected persons worldwide, most (as many as 11 million, according to the Center for Disease Control) residing in Mexico, Central America, and South America, and most of whom won't even know they're infected until the disease eventually kills them. Charles Darwin is suspected to have suffered from the disease, recording being bitten by the Great Black Bug of the Pampas in The Voyage of the Beagle. A year after returning to England (1837), he began to suffer from odd symptoms consistent with chronic Chagas' disease, which continued for the rest of his life.

It's also possible to acquire the parasite through eating uncooked food contaminated with the feces of infected bugs; from a pregnant woman to her baby (although breastfeeding after birth is safe, unless the mother has cracked nipples of blood in the breast milk); via organ transplantation; and via infected blood transfusions. In fact, the FDA just approved new tests last December for screening units of blood for Chagas' disease. Estimates vary, but between 100,000 to 500,000 people in the US are infected already,  mostly immigrants. In Los Angeles, with such a large immigrant population hailing from Central and South America, the chances of getting a unit of potentially infected blood is a whopping 1 in 2000. I say, bring on the more stringent blood screening tests. Because make no mistake: Chagas' disease is  nasty, killing some 50,000 people each year.

The good news for our fictitious patient is that the early acute phase is quite treatable with conventional antiparasitic remedies if it's caught right away, although in rare cases, infants may die from swelling of the brain if there's a delay in treatment. The news is not so good if the patient dismissed his symptoms as "just the flu" (something I would totally do, being of the "It's just a flesh wound" mental framework when it comes to my own health).

That's because the acute phase runs its course within a couple of weeks, and he will then enter the chronic phase of the disease, which is much sneakier, and far more deadly in the long run. He might not have another symptom for the next 10 years or so, but gradually he will develop cardiac complications (an enlarged heart, arrhythmia, even sudden cardiac arrest), as well as intestinal complications (enlarged esophagus or colon) and in rare cases, neurological difficulties such as swelling of the brain and/or dementia. The available treatments for the chronic phase tend to be highly toxic, and ineffective. Jack Hitt, writing about Chagas' disease for the New York Times in 2001, described the initial "symptom" as "a slight itching on your face. When you scratch, you rub the parasite into the tiny wound nearby. Twenty years later… your heart will explode." Or your intestines will rupture. And all because of a seemingly innocuous occurrence of a single bug bite. You might want to rethink that planned excursion to Central America.

Several countries managed to pretty much eradicate Chagas' disease for awhile by spraying rural areas with massive amounts of pesticides, most notably in Guatemala and Argentina. But the toxic pesticides brought the bad with the good: in Guatemala, rates of pediatric asthma are much higher in homes treated with pesticides, with corresponding higher rates of neurological effects like weakness and numbness. Pesticides are also a bit on the pricey side for the average developing country — or even an otherwise prosperous country fallen on hard times, like the economic crash of Argentina around 2000. Faced with tough decisions on where to spend its limited funds, the government cut back on the pesticide program. The result: increasing cases of Chagas' disease are showing up, particularly in the Grand Chaco region. Even worse, the insects gradually develop resistance to the pesticides, making them far less effective.

So pesticides work as a short-term fix, nothing more, which is why scientists are keen on finding an alternative control measure, preferably one that focuses on the transmission phase, rather than just wiping out the kissing bugs (who, after all, aren't inflicting their gut parasites on us in malice). Enter Ravi Durvasula, an associate professor of medicine at the University of New Mexico, who's been working the problem for almost a decade now, and come up with a truly ingenious strategy for combating the spread of Chagas' disease: a genetically altered "Frankenbug" version of T. cruzi that acts as a kind of Trojan Horse (or sneaky Ninja assassin), producing a protein that destroys itself by punching holes in the parasite. Scientists have gotten fairly adept at genetically modifying things like bacteria — a process known as paratransgenesis: Durvasula's team has also developed a version of the genetically engineered protein that simply flushes the parasite out of the insect harmlessly. This could help solve the problem of T. cruzi building up a resistance: "The idea is to create a kind of genetic factory of different mechanisms," Durvasula told the New York Times in 2001. "Like beads on a necklace, we can shift from one to the next in order to anticipate mutations."

The tricky part is getting the new version into the gut of the kissing bug. Kissing bugs need the T. cruzi and other gut-friendly bacteria, just like human beings need certain types of "good" bacteria in our own digestive systems. Baby kissing bugs aren't born with said bacteria: they acquire them shortly after birth by probing the fecal droplets left by adults nearby. This gave Durvasula and his colleagues the idea for a nifty delivery mechanism for their Frankenbug: a decoy version of the fecal droplets. They created Cruzigard, a "synthetic, dung-like paste," which contains a massive dose of the transgenic bacteria. Those altered bacteria take up residence in the insect's gut, lying in wait, and should the Chagas parasite appear, it is quickly wiped out. The Trojan Horse analogy is quite apt, don't you think?

This does away with health concerns about pesticides, while raising new concerns. In general, the public tends to freak out a bit at the thought of genetically modified anything, and the thought of releasing millions of genetically modified bacteria into the broader environment is certainly going to cause concern. Durvasula & Co. are well aware of potential risks, and have been conducting various studies to demonstrate the safety, as well as efficacy, of their technique. When I spoke briefly with Durvasula this week, he said they'd already shown, via experiments with mice, that there isn't a problem with human toxicity: Cruzigard doesn't make us sick, or cause allergic reactions, even in large doses.

The biggest sticking point has to do with something called horizontal gene transfer (HGT), which I blogged about earlier this year when talking about the work of Rice University's Michael Deems. It's possible for the modified gene to jump across species and show up in other bacteria or insects. So The UNM folks have been studying this effect under controlled lab conditions using houseflies — because unlike the kissing bugs, which tend to be homebodies once they set up shop in your thatched roof (thereby limiting the spread of the disease a little bit), houseflies travel all over the place. If it acquires the genetically modified bacterium and incorporates the gene, it's quite possible it could then spread to other species and regions — with unforeseen consequences. "Just the fact that a gene can move is cause for concern," says Durvasula.

Initially, they constructed 6'x6' thatched roof huts in a Level II Biological Hazard greenhouse on the campus of the Centers for Disease Control and Prevention, and the plan is to eventually use 16 similar structures in an actual field test, using a goat as a blood source for the kissing bugs' sustenance — because you know, it takes a mock-up village sometimes to determine if the altered gene "jumps" to other bacteria or insects.  (Rest assured, they are using a "marker gene" only for the experiment, not the version that actively works to kill or flush the parasites.) Lately, they've been looking specifically at how long the flies retain the Frankenbug. The good news is that they haven't found evidence of any long-term retention; the less-good news is that the flies can retain the Frankenbug for a couple of hours, which might be long enough to effect HGT. And there's always the reality that no matter how hard you try, it's impossible to predict everything that might happen. Durvasula's primary goal is to demonstrate safety and efficacy of his technique to the point where the benefits to be gained by employing it clearly outweigh any potential risks.

On a broader scale, paratransgenesis is a potentially powerful technique for combating the spread of all manner of so-called vector-borne diseases (in the case of Chagas' disease, the kissing bug is the vector), via the creation of "symbiotic bacteria of a disease-transmitting arthropod… genetically transformed to produce molecules that kill the pathogen within the arthropod itself," if you want to get all technical about it. Durvasula isn't just working on Chagas' disease; he's applying a similar strategy to other areas, such as halting the spread of the parasite leishmaniasis in places like India and Nepal; the parasite is passed to humans by sandflies. He's also working on genetically engineered algae and cyanobacteria, a primary food source for shrimp. Shrimp populations are vulnerable to viral diseases like White Spot Syndrome Virus, against which antibiotics haven't been very effective, and vaccines are not available.

Risky? Sure. But it could help save a lot of lives. It's just the sort of thing Gregory House would love.

7 thoughts on “sneak attack”

  1. This is fun. Here is another awful tropical disease
    Jimmy Carter, if he did nothing else in his life, would be remembered for reducing guinea worm disease, dranunculosis, from 3 million cases in 1986 to 12000 last year
    For untold generations here, yardlong, spaghetti-thin worms erupted from the legs or feet — or even eye sockets — of victims, forcing their way out by exuding acid under the skin until it bubbled and burst. The searing pain drove them to plunge the blisters into the nearest pool of water, whereupon the worm would squirt out a milky cloud of larvae, starting the cycle anew.
    Love
    Marvin

  2. I would like to know when something so inovative will be used in America to battle Lyme desease. My yard, in Missouri, is literally crawling with tiny ticks, (I have to use two 3x sets of magnifying glasses to see the markings clearly) which are reported to be small Dear Ticks known for carrying Lyme Desease. I have been loth to use insectisides against them because I dont want to kill anything but the ticks, and so far I have only found an all purpose insectiside.

  3. I am a film director and Chagas activist from Argentina. Thanks for writing about this disease. And, by the way, Chagas IS present in the US and Europe, where it is transmitted thorugh blood transfusions and organ donations, and congenitally from mother to child.
    For more information about “Chagas/ A Hidden Affliction”, my documentary that was broadcast on PBS regional in Virginia a year go, please go to http://www.chagasthemovie.com
    We have ust set up the Chagas Foundation Disease, Ltd. Please go to http://www.chagasfound.org
    Thanks again for mentinoning this.
    Rick Preve
    http://www.prevefilms.com

  4. Interesting – I have a friend from Uruguay who has Chagas’ disease; I believe he has had it since he was a child. He looks and feels perfectly normal, but all the moms (when we were little) were always saying “oh, poor thing, he won’t make it past 40″…I guess the general popular thinking was that you can live a normal, albeit shortened life with Chagas’ disease. And, that is one evil-looking bug!

  5. Regarding the post about Lyme disease. I’ve had Lyme disease for about 12 years and thanks to a diet I discovered for stopping symptoms of other skin parasites such as Morgellons, Collembola… the diet has kept me healthy and has controlled the symptoms of the skin parasites. My e-book descirbes disinfection, bathing, the diet, medical approaches… for these terrible skin parasites. The diet has worked to alleviate symptoms of several types of skin parasites (most dwell internally in the organs and blood stream as well) and it might work for Chagas’ disease–it’s worth a try.

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