Twenty-four small images of red blood cells appear on the screen. Your job is to click on any that have a malarial parasite inside, removing the image. When you’ve removed all the infected cells, click on “Label all Negative” and another twenty-four cells appear. At the end, you’ll get a score and some information about how many correct choices you made.
The game is called MOLT, and it was designed by the Ozcan Research Group at UCLA. Anyone can register and play. The idea is that anyone can be given some basic information about what malarial parasites look like in red blood cells and then be part of an accurate means of correctly diagnosing the disease without having to rely on experts in the field. This would be a huge improvement for malaria diagnosis in parts of the world where malaria kills millions each year and people skilled in diagnosis are rare.
A pilot study of the game using 20 gamers produced results that were within 1.25% of the accuracy of actual experts adept at recognizing malaria, which is pretty impressive. One can imagine an arrangement where someone puts a blood film on a microscope somewhere in Asia or Africa, the images are sent out electronically to potentially millions of gamers around the world, and the answer comes back, positive or negative, in a very short time. If the pilot is any indication, the answer would agree, most of the time, with what an expert would have said.
This has implications for lots of other things that are done by microscopy or other types of imagery: pap smears, fecal smears for parasites, pathology slides etc. It could be improved upon by adding automated scanning techniques and actual experts to the crowd of gamers. These things, plus a larger number of gamers would likely be even more accurate than the gamers used in the pilot. It’s exciting.
I’ve played the game – a number of times. I have lots of experience with reading blood films for malaria, and my biggest issue with the game is that the resolution – the sharpness – of the images is often not good enough
for me to feel completely comfortable with my choices. Platelets sitting on top of red blood cells can look like a parasite. So can debris on the slide. A red cell that’s damaged, or crunched up against another cell, or too darkly stained, or abnormal in some way, etc. etc., doesn’t look like it should to begin with.
I always want to look around a bit, see what the rest of the slide looks like, look for those particular features of a malarial parasite that leave no doubt. In other words, I have a very difficult time deciding whether something is positive or negative on the basis of only one cell (unless the resolution is very good).
My other complaint is with the scoring. I find it ambiguous. When they say “Correct Positive Diagnosis 91%” does that mean 91% of the cells marked as positive were actually positive (false positives), or 91% of positive cases were identified (false negatives). I think it means the latter, because it seems the fussier I am about calling something positive, the more my positive diagnosis score goes down. For anyone trying to improve at the game, clarification on this is important.
Of course I understand that the point is that people who are not experts, and not demanding in terms of excellent microscopic optics and parasite features, can still get the right answer if there are enough people providing input. From that perspective, I think the game is brilliant, and I hope it changes the world.
Play the game on Biogames
Read the paper:
Mavandadi S, Dimitrov S, Feng S, Yu F, Sikora U, et al. (2012) Distributed Medical Image Analysis and Diagnosis through Crowd-Sourced Games: A Malaria Case Study. PLoS ONE 7(5): e37245. doi:10.1371/journal.pone.0037245
We’ve known for years that Lyme disease is transmitted to humans by ticks. In Europe, it’s usually I. ricinus, the sheep tick, and any of a group of closely related organisms: Borrelia burgdorferi, B. garinii, or B. afzelii; while in my area it’s the deer tick, Ixodes scapularis, and B. burgdorferi. This is enough to worry about as the woods are full of deer and the deer are full of ticks. In some areas more than 30% of deer ticks carry Borrelia, and the ticks are not fussy: they’ll jump onto deer, dogs, cats, and people without hesitation. One hates to think that other biting arthropods could also be transmitting Lyme.
But studies going back as far as the 1980s, and perhaps even farther have found Borrelia in the guts of mosquitoes. Websites devoted to Lyme disease state that mosquitoes are transmitting the disease to humans. Why, then, does the CDC website say “There is no credible evidence that Lyme disease can be transmitted… from the bites of mosquitoes, flies, fleas, or lice” (Lyme Disease Transmission)?
It’s not a matter of a mosquito or tick sucking Borrelia out of one host and then simply injecting it into another like a flying (or crawling) syringe, not like pouring liquid from one glass to another with no change in the contents. Here we are dealing with interactions between living things. Research has shown that things happen in the tick, things that are important in transmission.
In the tick’s gut, Borrelia produces a protein that enables it to persist there for long periods of time, likely aiding survival until the tick feeds again. When the tick is feeding, the spirochete cuts back on this protein and produces a different one instead, one that enables it to invade the tick’s salivary gland and then be transmitted to the new host in the tick’s saliva.
Similarly, Borrelia is able to enhance a tick protein that protects both tick and spirochete from attack by the host immune system: “Borrelia burgdorferi, the Lyme disease agent, is critically dependent on the presence of the tick protein Salp15 when infecting the host” (Schwalie and Schultz). The extended time that a tick spends feeding (days) provides plenty of time for this interaction to take place.
In contrast, while Borrelia has been detected in mosquito guts and saliva, it doesn’t appear to survive there very long, probably because the proteins that support it in ticks don’t work in mosquitoes. Salp15, too, is a tick protein that won’t be available to help out in a mosquito, and mosquitoes take only minutes to obtain a blood meal, compared to days for a tick. Put simply, mosquitoes are not competent vectors of B. burgdorferi; they just don’t have the right stuff. While it’s not impossible that a mosquito bite could contain the spirochetes, it’s unlikely, and it’s even more unlikely Borrelia would succeed in setting up an infection. Mosquitoes are not significant vectors of Lyme disease.
Fontaine et al: Implication of haematophagous arthropod salivary proteins in host-vector interactions. Parasites & Vectors 2011 4:187 doi:10.1186/1756-3305-4-187
Hovius, JWR. Tick-host-pathogen interactions in Lyme borreliosis. Dissertation, Academic Medical Center, University of Amsterdam 2009
Kosik-Bogacka D, Bukowska K, Ku?na-Grygiel W. Detection of Borrelia burgdorferi sensu lato in mosquitoes (Culicidae) in recreational areas of the city of Szczecin. Annals of Agricultural and Environmental Medicine 2002, 9, 55–57
Schwalie PC, Schultz J. Positive Selection in Tick Saliva Proteins of the Salp15 Family. Journal of Molecular Evolution Volume 68, Number 2 (2009), 186-191, DOI: 10.1007/s00239-008-9194-1
Magnarelli LA, Anderson JF. Ticks and Biting Insects Infected with the Etiologic Agent of Lyme Disease, Borrelia burgdorferi. Journal of Clinical Microbiology Aug. 1988, p. 1482-1486
Reports this week of the death of Toola, a Toxoplasma gondii-infected sea otter who lived out her days at the Monterey Bay Aquarium, reminded me of the threat that T. gondii poses to marine mammals. Toola suffered from neurological damage thought to have been caused by the parasite and required daily anti-seizure medication. Among other things, she was the poster otter for legislation and other efforts to protect marine mammals from various health risks. And she was cute too.
My impression has been that the risk of acquiring T. gondii has been rising in marine mammals, and that this is likely to be the result of runoff – oocysts being washed off the land into coastal waters. This made sense to me when considering the number of feral and roaming domestic cats, and the quantity of cat feces that must be carried into coastal waters by runoff (this has actually been studied: “domestic feline faecal deposition in communities adjacent to Estero Bay was conservatively estimated at 107 metric tonnes/year, or 26 kg/ha:” Miller et al.) I was surprised; therefore, to read that the majority of California sea otters tested in the 2008 study reported by Miller et al had a unique strain (dubbed Type X) that is not typically found in domestic cats.
Rather, the paper by Miller et al. reports that Type X T. gondii was found in wild felids (mountain lion, bobcat) and foxes. While foxes might be doing relatively well in urban areas, the number of wild felids is down from what it must have been before humans covered the west coast of North America with concrete and asphalt. So if domestic cats aren’t to blame, why are there more infected marine mammals now than before?
One answer apparently lies in all that concrete and asphalt. Hardscaping of the coast reduces the amount of runoff that’s absorbed into the ground before it spills into the sea. In addition:
- Human development has reduced wetlands, which provide natural filtration for runoff.
- Bivalves such as mussels flourish near storm sewers and have been shown to filter organisms, including T. gondii oocycts out of the water and concentrate them in tissue.
- Sea otters feed on mussels and other bivalves, consuming at least 76 mussels each day.
Studies done on land mammals have shown that a single oocyst can potentially be the source of chronic toxoplasmosis. Given those odds, its not surprising that Toola, and lots of other California sea otters (and other marine mammals) are infected with T. gondii.
Read the paper:
Miller, M.A., W. A. Miller, P. A. Conrad et al. “Type X Toxoplasma gondii in a wild mussel and terrestrial carnivores from coastal California: New linkages between terrestrial mammals, runoff and toxoplasmosis of sea otters.” International Journal for Parasitology: 38(11), 2008
A paper in PLOS Medicine (January 24, 2012) reports that “sanitation is associated with a reduced risk of transmission of helminthiases to humans.” The authors looked at 36 previously published studies that measured prevalence of intestinal helminths (A. lumbricoides, large intestinal roundworm; T. trichiura, whipworm; and hookworm) compared to availability and use of sanitary facilities. They found that “people who either had or used a latrine were half as likely to be infected with a soil-transmitted helminth as people who neither had or used a latrine.”
I submit that there are no surprises here. One acquires hookworm by coming in contact with hookworm larvae from feces contaminating the soil. They penetrate skin. Trichuris trichiura and A. lumbricoides eggs, infective a week or so after being deposited in warm moist soil in feces, must be swallowed. Obviously if feces were deposited in a pit latrine, septic system or other sanitary arrangement, instead of on the ground, those eggs and larvae would not be available to infect new hosts.
The fact that intestinal helminthes are much less common, even rare, in developed countries is no mere accident of climate, especially for the tough A. lumbricoides. It is because the majority of people in developed countries don’t defecate outside on the ground.
The best point in this paper, though understated, is that periodically treating people for intestinal worms is perhaps not the best long term approach to getting rid of these parasites. Without good sanitation, people will quickly be reinfected due to contamination of their environment. Lets build toilets.
Read the paper:
Ziegelbauer K, Speich B, Mäusezahl D, Bos R, Keiser J, et al. (2012) “Effect of Sanitation on Soil-Transmitted Helminth Infection: Systematic Review and Meta-Analysis.” PLoS Med 9(1): e1001162. doi:10.1371/journal.pmed.1001162
No human parasitic disease has ever been eradicated (although we may be close to eradicating Guinea Worm), but if ever there was a target, it would be malaria. Keeping an eye on the news and medical journals convinces me that there has never been more activity in scientific research aimed at understanding the parasites that cause malaria and finding ways to thwart them. Researchers have tried to develop malaria resistant mosquitoes. They’ve uncovered how the parasites invade red blood cells. They’ve investigated enzymes and proteins essential to the parasite’s survival. They’ve developed novel drugs. Hardly a day goes by when there is not something new. One might think we’re on the cusp of success.
But the reality is still grim. If you look at the statistics, you see that things are not really changing, at least not yet. Maps released by the Malaria Atlas Project allow us to roughly compare 2007 with 2010, and though there are clearly some changes (WHO statistics do indicate that the total number of malaria cases has dropped over the last decade), in the big picture they are minor changes that could easily reverse themselves.
This is discouraging. I wonder how long it will take for all this new research to provide us with a successful (and likely multi-pronged) approach to loosening the grip of this terrible disease.
There are a lot more maps on the Malaria Atlas Project site. Anyone interested in this should have a look.
Parasites can do you good. I didn’t discuss it at length in Parasites: Tales of Humanity’s Most Unwelcome Guests (I touched on it in chapter six), but I’m fascinated by the growing evidence that at least some of our parasites have good things to contribute to our health. The latest piece of that puzzle is research showing that hookworms can initiate an immune response in the host that actually speeds healing of tissue damage.
In their paper “An essential role for TH2-type responses in limiting acute tissue damage during experimental helminth infection,” Fei Chen et al report that in mice “IL-17 initially contributed to inflammation and lung damage, whereas subsequent IL-4 receptor (IL-4R) signaling reduced elevations in IL-17 mRNA levels, enhanced the expression of insulin-like growth factor 1 (IGF-1) and IL-10 and stimulated the development of M2 macrophages, all of which contributed” to healing (Nature Medicine, published online 15 January 2012). In other words, there was an inflammatory response to the worms at first, then inflammation was suppressed while healing was enhanced.
It’s reasonable that a healing response may have evolved to help the host’s body deal with damage done by the worms themselves, but of course the potential exists for us to use that response to help heal tissue damage from other causes. This new report also ties in with previous work that suggests the ability of some of our parasites to suppress inflammation may protect us from autoimmune diseases.
It does make sense to me that organisms that have been with us for millions of years would have a relationship of both give and take with the host. While it’s true that parasitic diseases are some of the worst we face, and hookworm is a nasty parasite, I think we need to set aside the idea that anything parasitic is utterly bad. Let’s get to know them properly before we send them to extinction. (Not that hookworm is in danger of going extinct any time soon.)
I think we still have a lot to learn about our relationship with our parasites, especially our “old friends.”
Anybody who knows anything about malaria knows that one catches it from a mosquito bite. Mosquitoes don’t just physically carry the parasite from person to person: they are a required host for Plasmodium spp., the agents of malaria. In the mosquito, the parasites multiply sexually, producing tiny forms called sporozoites which are injected into the next person the mosquito bites.
Clearly, the mosquitoes are infected just as people are, but we seldom feel sorry for the poor mosquitoes because, well, we hate them for all sorts of reasons. The mosquito, however, does have an immune system which tries to fight off invading Plasmodium sp. parasites; Mosquitoes don’t mean to transmit these dangerous parasites.
Humans have had a long and costly battle with malaria which, so far, we have not won. Though not self-evident perhaps, it makes sense that we might be able to enlist the help of the lowly mosquito to our mutual benefit, and that’s what some researchers at Johns Hopkins University have done. Yuemei Dong et al. have genetically modified the immune system of a mosquito species, Anopheles stephensi, giving it an enhanced ability to fight off invading Plasmodium falciparum, the worst of the malaria parasites in humans.
In order for this research to prove useful in the real world, the modified mosquitoes would have to be released into the wild and allowed to breed with wild populations (and hopefully do better than the wild type). Aside from the obvious need for caution when releasing a genetically modified organism into the wild, at this point we still don’t know whether:
- the resistant mosquitoes will do as well in the wild, faced with different A. falciparum strains
- other Anopheles spp., also malaria vectors, can be similarly modified (there are about 40)
- Plasmodium falciparum will develop resistance to the mosquito resistance
- all other species of Plasmodium infecting humans can be targeted this way
This breakthrough is not the answer to the battle against malaria yet, but it may be part of the answer.
Read the paper:
Dong Y , Das S , Cirimotich C , Souza-Neto JA , McLean KJ , et al. 2011 “Engineered Anopheles Immunity to Plasmodium Infection” PLoS Pathog 7(12): e1002458. doi:10.1371/journal.ppat.1002458
Leishmania donovani, agent of visceral leishmaniasis, or kala-azar, has always known how to evade the human immune system. This parasite literally uses the cells of the immune system to survive and multiply: when it enters the body via a sand fly bite it is engulfed by a macrophage – part of the immune response – and then it multiplies until the cell is destroyed.
Nonetheless, the immune system does have some control over the infection and some infections are without symptoms of disease. An interesting paper published in 2011 (Vanaerschot et al.) reports on research that suggests that strains of L. donovani that are resistant to the commonly used antimonial drugs are also able to multiply to greater numbers in the host. So these strains not only fail to respond to antimonial drug treatment, but also cause worse disease than other strains. That is unfortunate.
It seems that antimonials work by enhancing the ability of macrophages to kill the parasites they ingest. Antimonial resistant strains appear to have evolved a way to swing things the other way somehow – they don’t do just as well as the sensitive strains; they actually do better. The authors write “all [sensitive] strains caused a similar parasite burden both in the liver and the spleen… [Resistant] strains displayed… an average 8-fold higher parasite burden in the liver and 3-fold higher parasite burden in the spleen compared to [sensitive] strains” (p. 3). That is an impressive increase, and not good news for the patient.
The authors also looked at whether these strains are also more resistant to the new drug of choice, miltefosine. They didn’t find evidence of this, but note that more study and surveillance are needed to be sure it’s not the case.
Vanaerschot M, De Doncker S, Rijal S, Maes L, Dujardin J-C, et al. (2011) “Antimonial Resistance in Leishmania donovani Is Associated with Increased InVivo Parasite Burden.” PLoS ONE 6(8): e23120. doi:10.1371/journal.pone.0023120
Does your body hair help you notice when something is crawling around looking for a place to bite? Does it discourage that ectoparasite from biting? Authors Isabelle Dean and Michael T. Siva-Jothy think the answer to both questions is ‘yes.’ A report in Biology Letters reveals the findings of a study that was designed to reveal whether our fine body hairs protect us from ectoparasites such as bedbugs.
In a study of twenty-nine student volunteers, the researchers noted that bedbugs took longer to select a feeding site on hairy, as opposed to shaven, skin, (and the hairier the better) and that the volunteers were better able to detect the insects on unshaven skin. Thus, having all those fine hairs apparently helps us, in two different ways, to notice the bug before it bites.
Dean and Siva-Jothy point out that it’s already been shown that some insects that bite animals, including bedbug relatives, prefer to bite on relatively hairless parts of the body. It’s easy to see that such behavior would tend to favor bug survival if the bug goes unnoticed. In some circumstances, we can also see that hairier humans might have a survival advantage.
This study only looked at bedbugs; it would be interesting to see if the same thing happens with ticks (I can attest from personal experience that ticks have an amazing ability to traverse large areas of skin without ever being felt), kissing bugs, mosquitoes, black flies and other biting insects and arachnids.
So we know one possible reason why we have all those fine hairs all over us – and why we perhaps shouldn’t be shaving them off in a time of bedbug resurgence and increased tick-transmitted disease.
Dean, Isabelle, and Michael T. Siva-Jothy. “Human fine body hair enhances ectoparasite detection.” Biology Letters: Published online December 14, 2011, doi: 10.1098/rsbl.2011.0987
It’s more than a decade now since scientists discovered that Plasmodium spp., agents of malaria, have plastids in their cytoplasm reminiscent of chloroplasts in plants. Chloroplasts are believed to be the descendants of free living cyanobacteria that were ingested by early cells, or invaded those cells, and then became part of cell structure and function. Chloroplasts in green plants provide energy when exposed sunlight.
The plastid in malarial parasites – called an apicoplast – has the same origin as chloroplasts in plants and functions in similar ways. This suggests that Plasmodium spp. and their relatives: Toxoplasma gondii, Cryptosporidium spp., Cyclospora cayetanensis, Isospora belli, and Babesia spp., to name the main ones parasitic in humans, are more like plants than we typically think.
The plastid in Plasmodium spp. and other apicomplexans has lost the ability to produce energy from light, but it remains a vital part of the cell, synthesizing fatty acids, heme and other molecules. The organisms can’t live without their apicoplasts.
Aside from identifying an intriguing connection between some of our worst parasites and the plant kingdom, the discovery of the apicoplast has suggested new ways of treating infections with these parasites. Plasmodium spp. are notorious for developing resistance to antimalarial drugs, while Toxoplasma, Cryptosporidium, and Babesia have proven very challenging to treat and eradicate in the body. It could be that the agents to treat these infections are already in our possession – in the form of herbicides.
Lim, L., et al. The carbon and energy sources of the non-photosynthetic plastid in the malaria parasite. FEBS Lett. (2009),