Modular Add-On Brings Polarized Light Microscopy, Malaria Diagnosis to Smartphones

Researchers at Texas A&M University have developed a novel point-of-care device for field-based diagnosis of malaria using a smartphone. The mobile-optical-polarization imaging device (MOPID) attaches to smartphones or tablets and co-opts the camera to detect birefringent hemozoin in histological samples, which is indicative of malarial infection.

Despite advances in diagnostic approaches and treatment, malaria remains one of the leading sources of disease and death in developing nations. The “gold standard” of detection, evaluation of Giemsa-stained blood smears via bright-field microscopy, often requires skilled technicians and laboratory environments that are few and far between in the regions that are most in need. Even when available for field-testing, white light microscopy tends to report many false positive diagnoses as well. Bench-top polarized light microscopy systems, while more definitive, are large, expensive pieces of equipment that are complex to operate, and to maintain as well.

The MOPID, though, appears to offer a highly-mobile and effective alternative, at a cost that should be palatable in underserved countries. The device in its current form has demonstrated imaging properties that compare favorably with a reference Leica DMLM polarized microscope – a resolution of 1.05 μm, system magnification in the range of 50x, and field of view measuring 0.78 mm x 0.79 mm.

Going forward towards release and dissemination of the technology, the group is currently concentrating on preparing units for in vivo field-testing in Rwanda. To do so, they will be taking efforts to lower the physical profile of the device, improve upon human factors engineering and user-interface components, and lower costs. The ultimate vision is for each MOPID diagnostic test to be priced under $1.00 per result, anywhere in the world.

The MOPID device marks another in a series of recent mobile device imaging innovations that are empowering clinicians and researchers without access to traditional acquisition tools (see our recent post on the smartphone-powered D-EYE Digital Ophthalmoscope or read about technology pioneer Jonathan Rothberg’s plan to bring ultrasound to mobile devices).

Study in Scientific Reports: Malaria Diagnosis Using a Mobile Phone Polarized Microscope…

ORIGINAL: Medgadget

ZACH KAUFMAN

SEPTEMBER 4TH, 2015 

The Deadliest Animal in the World

What would you say is the most dangerous animal on Earth? Sharks? Snakes? Humans?

Of course the answer depends on how you define dangerous. Personally I’ve had a thing about sharks since the first time I saw Jaws. But if you’re judging by how many people are killed by an animal every year, then the answer isn’t any of the above. It’s mosquitoes.

When it comes to killing humans, no other animal even comes close. Take a look:

What makes mosquitoes so dangerous?
Despite their innocuous-sounding name—Spanish for “little fly”—they carry devastating diseases. The worst is malaria, which kills more than 600,000 people every year; another 200 million cases incapacitate people for days at a time. It threatens half of the world’s population and causes billions of dollars in lost productivity annually. Other mosquito-borne diseases include dengue fever, yellow fever, and encephalitis.

There are more than 2,500 species of mosquito, and mosquitoes are found in every region of the world except Antarctica. During the peak breeding seasons, they outnumber every other animal on Earth, except termites and ants. They were responsible for tens of thousands of deaths during the construction of the Panama Canal. And they affect population patterns on a grand scale: In many malarial zones, the disease drives people inland and away from the coast, where the climate is more welcoming to mosquitoes.

Considering their impact, you might expect mosquitoes to get more attention than they do. Sharks kill fewer than a dozen people every year and in the U.S. they get a week dedicated to them on TV every year. Mosquitoes kill 50,000 times as many people, but if there’s a TV channel that features Mosquito Week, I haven’t heard about it.

That’s why we’re having Mosquito Week on the Gates Notes.

Everything I’m posting this week is dedicated to this deadly creature. You can learn about my recent trip to Indonesia to see an ingenious way to combat dengue fever by inoculating not people, but mosquitoes. (Somehow this story involved me offering up my bare arm to a cage full of hungry mosquitoes so they could feed on my blood.) You can read a harrowing account of what it’s like to have malaria and hear from an inspiring Tanzanian scientist who’s fighting it. And I’ve shared a few thoughts from Melinda’s and my recent trip to Cambodia, where I saw some fascinating work that could point the way to eradicating malaria, which would be one of the greatest accomplishments in health ever.

I hope you’ll have a look around. I can’t promise that Anopheles gambiae will be quite as exciting as hammerheads and Great Whites. But maybe you’ll come away with a new appreciation for these flying masters of mayhem.

ORIGINAL: GatesNotes

By Bill Gates 

April 25, 2014

Here’s What Happens Inside You When a Mosquito Bites

ORIGINAL: Phenomena - NatGeo
by Ed Yong

Anopheles gambiae. Credit: James D. Gathany, CDC.

The video above shows a brown needle that looks like it’s trying to bury itself among some ice-cubes. It is, in fact, the snout of a mosquito, searching for blood vessels in the flesh of a mouse.

This footage was captured by Valerie Choumet and colleagues from the Pasteur Institute in Paris, who watched through a microscope as malarial mosquitoes bit a flap of skin on an anaesthetised mouse. The resulting videos provide an unprecedented look at exactly what happens when a mosquito bites a host and drinks its blood.

For a start, look how flexible the mouthparts are! The tip can almost bend at right angles, and probes between the mouse’s cells in a truly sinister way. This allows the mosquito to search a large area without having to withdraw its mouthparts and start over.

“I was genuinely amazed to see the footage,” says James Logan from the London School of Hygiene and Tropical Medicine, who studies mosquitoes. “I had read that the mouthparts were mobile within the skin, but actually seeing it in real time was superb. What you assume to be a rigid structure, because it has to get into the skin like a needle, is actually flexible and fully controllable. The wonders of the insect body never cease to amaze me!”

From afar, a mosquito’s snout might look like a single tube, but it’s actually a complicated set of tools, encased in a sheath called the labium. You can’t see the labrum at all in the videos; it buckles when the insect bites, allowing the six mouthparts within to slide into the mouse’s skin.

Four of these—a pair of mandibles and a pair of maxillae—are thin filaments that help to pierce the skin. You can see them flaring out to the side in the video. The maxillae end in toothed blades, which grip flesh as they plunge into the host. The mosquito can then push against these to drive the other mouthparts deeper.

The large central needle in the video is actually two parallel tubes—

• the hypopharynx, which sends saliva down, and 
• the labrum, which pumps blood back up. 

When a mosquito finds a host, these mouthparts probe around for a blood vessel. They often take several attempts, and a couple of minutes, to find one. And unexpectedly, around half of the ones that Choumet tested failed to do so. While they could all bite, it seemed that many suck at sucking.
The video below shows what happens when a mosquito finally finds and pierces a blood vessel. On average, they drink for around 4 minutes and at higher magnifications, Choumet could actually see red blood cells rushing up their mouthparts. They suck so hard that the blood vessels start to collapse. Some of them rupture, spilling blood into the surrounding spaces. When that happens, the mosquito sometimes goes in for seconds, drinking directly from the blood pool that it had created.

When the mosquitoes were infected with the Plasmodium parasites that cause malaria, they spent more time probing around for blood vessels. It’s not clear why—the parasites could be controlling the insect’s nervous system or changing the activity of genes in its mouthparts. Either way, the infected mosquitoes give up much less readily in their search for blood, which presumably increases the odds that the parasites will enter a new host.

Many hours after a bite, Choumet’s team found Plasmodium in the rodents’ skin, huddled in areas that were also rife with the mosquito’s saliva. The mosquito starts salivating as soon as it probes the mouse’s skin, releasing substances that 

• prevent blood vessels from constricting, 
• stop blood from clotting, and 
• prevent inflammation. 

Sometimes, Choumet could see the saliva as small bubbles that hung around the tips of the mouthparts. And even after the mosquito stops feeding, pockets of saliva linger in the lower layers of the skin. Plasmodium parasites seem to stay in the same place—perhaps they work together with the salivary chemicals to suppress the mouse’s immune system.
The team also tested “immunised” mice, which were loaded with antibodies that recognise a mosquito’s saliva. “Some people, especially in Africa and Asia, are bitten several times every day, so we wanted to know if mosquitoes behaved differently when they bit animals that were immunised against their saliva,” says Choumet.

She found that the antibodies reacted with the insect’s saliva during a bite, forming noticeable white clumps at the tips of the probing mouthparts. This clogged up smaller blood vessels, which stopped the mosquitoes from drinking from them. But the insects got around this problem by probing around for longer, and by hitting the largest blood vessels.

Beyond the stunning videos, these discoveries are unlikely to lead to new ways of preventing or treating malaria by themselves. However, they do tell us a lot more about the event that kicks off every single malaria case—a mosquito bite. It’s a resource that other researchers will undoubtedly use. “I have submitted a grant application to investigate aspects of the interactions between mosquitoes, hosts and parasites,” says Logan. “The techniques and discoveries from this paper are very exciting to me, and will be of value to future activities of my own research group.”

Hat-tip to James Logan for alerting me to the story via Twitter, and inspiring the headline!

Reference: Choumet, Attout, Chartier, Khun, Sautereau, Robbe-Vincent, Brey, Huerre & Bain. 2012. Visualizing Non Infectious and Infectious Anopheles gambiae Blood Feedings in Naive and Saliva-Immunized Mice. PLoS ONE http://dx.doi.org/10.1371/journal.pone.0050464

New Hope for 'Crazy' Malaria Vaccine

ORIGINAL: Science Magazine
2011-09-08

Science/AAAS

Creating a buzz. A mosquito's salivary glands are removed to produce Sanaria's vaccine.

When a biotech company called Sanaria presented the results of a clinical study of its unconventional malaria vaccine last year, many researchers were disappointed. The vaccine, the only one that uses mosquitoes' bodies as bioreactors, had fully protected only two out of 44 volunteers from malaria.

But a new animal study shows that the vaccine performs much better when given intravenously instead of into the skin, as it was in the clinical trial. The results offer hope that the vaccine may have a future after all—but they could also complicate an eventual rollout in developing countries.

There are no approved malaria vaccines. The results of a large phase III study in seven African countries, which used a vaccine based on a protein snippet from Plasmodium falciparum, the malaria parasite, will be released before the end of the year. That vaccine, called RTS,S and produced by GlaxoSmithKline, has provided between 50% and 60% protection in previous studies; although it could make a major dent in malaria deaths, researchers are hoping for something far better in the long run.

Sanaria's vaccine aims for 90% protection or even higher, says CEO Stephen Hoffman, a former U.S. Navy researcher who started the company in his kitchen 8 years ago. Past results suggest that this target is possible, he says. Decades ago, Hoffman and other researchers discovered that people are almost completely protected after being bitten by hundreds of mosquitoes that carry malaria parasites inactivated by radiation.

Apparently, a vaccine made from the parasitic cells—called sporozoites when they're at this stage—triggers an immune reaction that a vaccine based on a single protein or protein fragment can't, scientists concluded. Studies suggested that sporozoites achieve this level of protection by activating so-called CD8+ T cells that secrete a molecule called interferon γ in the liver.

But vaccinating people by setting mosquitoes loose on them isn't practical. That's why Sanaria is producing the vaccine by breeding mosquitoes, infecting them, and then meticulously cutting out their salivary glands. The sporozoite cells are then purified and preserved in liquid nitrogen to make the vaccine.

Sanaria had hoped that injecting the vaccine intradermally would suffice to trigger protection, Hoffman says. But the results of the clinical trial, first presented at a meeting a year ago, showed that the vaccine failed to raise an adequate CD8+ response, and it protected only two people. "It wasn't what we were hoping for," Hoffman says.

But he wasn't ready to give up. He teamed up with Robert Seder of the Vaccine Research Center (VCR) at the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, and scientists at other labs to test immune responses to the vaccine in animals. When the team injected the vaccine into the skin of macaque monkeys, the reaction was similar to that in humans, but when injected into the bloodstream, the vaccine provided a strong and long-lasting CD8+ response in all three animals studied.

Macaques can't be infected with Plasmodium falciparum, but when the researchers repeated the experiment in mice, using a mouse model of malaria, they found they could reach levels of protection between 71% and 100% using intravenous administration. The difference with injection into the skin is "staggering," Hoffman says. "It was an 'aha' moment," Seder adds.

A new clinical trial in which the vaccine will be given intravenously to 51 volunteers is scheduled to start next month at VCR; another trial in Tanzania is on the drawing board. Given the animal data, "there's a good chance that it will work," says Brian Greenwood, a malaria researcher at the London School of Hygiene and Tropical Medicine.
But the intravenous route will pose new problems, he cautions. Although an intravenous vaccine will be fine for Western travelers or soldiers, giving the injections safely will be a challenge in poor countries where skilled health workers are scarce—especially in small children whose veins are hard to find. "That's pretty tricky," Greenwood says. Seder says there may be alternatives; for instance, intradermal administration may work better when coupled with immune-boosting compounds called adjuvants.

The vaccine's labor-intensive production—Sanaria staff members can pick apart about 100 mosquitoes an hour—could pose another obstacle. "If you talk to people in a large pharmaceutical company about it, they would say you are nuts," Seder says. But Hoffman says those problems can be overcome. He is studying ways of automating the process, and Sanaria may move its production facilities to developing countries, where the vaccine could be produced less expensively because labor costs are lower. "Our goal has always been to show that this vaccine is highly protective," he says. "Once we have done that, we'll figure out how to make it practical."

[9/8/11, 6:47 p.m. EDT] This item has been corrected. It originally said that 2 out of 80 volunteers were protected from malaria. However, of the 80 study participants who received the experimental vaccine, only 44 were later exposed to the malaria parasite.

Popular Scientist. Aydogan Ozcan (LUCAS Inventor)

ORIGINAL: UCLA MAGAZINE
By Robin Keats
Apr 1, 2013


UCLA Associate Professor of Electrical and Bioengineering Aydogan Ozcan is one of the world's "Brilliant 10" scientists, as proclaimed by Popular Science magazine. Ozcan is the director of the Bio-and Nano-Photonics Laboratory at the UCLA Henry Samueli School of Engineering and Applied Science, where he leads a team of students in creating breakthrough—and inexpensive—technological devices that bring the frontiers of medicine to ordinary individuals.

Photo by: Clara Richmond.

We could begin with any one of more than a dozen startlingly original inventions to frame the contributions of Aydogan Ozcan, but let's start with the crowd-sourced bio-game he and his team of researchers created to diagnose malaria. One thousand online gamers from around the world were directed to identify, then "kill" or "bank," infected red-blood cells that appeared on their screens as electronic images. Their success rate at identifying the disease was very comparable to that of medical experts. This decidedly non-expert methodology is designed for use in developing nations where hugely expensive diagnostic equipment is unavailable.

And then there is BigFoot, the name Ozcan gave to the monitoring software he pioneered that allows diabetes patients and others with chronic foot ailments to track their conditions at home using a conventional flatbed scanner and a PC.

These are just two of an apparently endless lineup of incredible ideas that spring from the mind of the 34-year-old scientist who already holds 22 patents, with more than 15 pending, for inventions in wide-field and lens-less imaging, nonlinear and fiber optics, critical coherence tomography and nanoscopy.

Ozcan's self-described "prize child," though, is LUCAS, an acronym for "Lens-less, Ultra-wide-field blood Cell monitoring Array platform based on Shadow imaging." It turns a cell phone into a diagnostic device by clipping on a gadget that combines an LED light, a spatial filter and a slot for a medical slide. Information is gathered by the device, which sends it off to diagnosticians anywhere in the world. Bring LUCAS into the jungle where people get little or no medical attention, and voila! Expert diagnosis.

Through the device, millions of people in such remote areas as sub-Saharan Africa who would otherwise go undiagnosed will be screened or monitored for malaria, and eventually for tuberculosis and HIV. It will also help prevent waterborne illnesses that kill about 5 million people a year. And the cost to clip LUCAS onto your cell phone? Five to 10 bucks.

No 'Aha' Moment
Ozcan was born in Istanbul, Turkey, in 1978. His father was a government worker, his mother a housewife. His education began in the small, Black Sea city of Sinope, which also gave the world Diogenes, founder of Cynic philosophy. "My family moved around a lot," he says. "Five different schools for the five years of elementary school we have in Turkey ... I think those moves caused me to develop skills that have helped me quickly adapt to things."

Ozcan went to Bilkent University in Ankara for his bachelor's degree. He earned a master's degree and Ph.D. at Stanford University, followed by two years in Boston on the research faculty of Harvard Medical School's Wellman Center for Photomedicine. Ozcan joined UCLA as an assistant professor in 2007.

What turned him onto scientific innovation? "There was," he says, "no 'aha' moment." But as early as his freshman year in high school, "the idea of proving something and learning the framework of proofs was so unique," he recalls. "That's when I said 'I love it' [and] thought I'd be in a profession that allows for the creation of useful things." 

Add caption

For his breakthrough medical diagnostic inventions, Ozcan has been honored by NASA, the U.S. Department of State, the Gates Foundation, National Geographic and Popular Mechanics, among other institutions and publications. In the photo above, he is holding a prototype of his LUCAS device in his lab.

Teaching Invention "Being a scientist and going to the frontier of knowledge requires a lot of dedication, a lot of small things put together," he says. "I insist that my students know that those who are successful in this profession are the ones who learn how to cope with failures. You improve from rejection; you write a new manuscript; you try again. Some people would say, 'It's enough.' I won't play that game."

It has to be that way, Ozcan says of his role as an educator. "Within the school of engineering, the function of a professor is to create new information and new technologies. You also have to train the next generation of engineers and scientists, so that new know-how is continually created to make life simpler."

Ozcan adds, "The definition of engineering, for me, is to make life simpler and better. That's the most important thing that differentiates an engineer's mind from that of a physicist. A physicist is looking at interesting questions, but not how a combination of disciplines could be applied to create things that will enhance life. That's the intersection of science and engineering and I want to be, professionally, at that juncture. Engineers need to be very multidisciplinary. That's what I stress in my lab."

Creating Invention
The man whose world involves complex technologies like optics, photonics and imaging has a simple vision of his own future as an innovator. "It's like a single picture," he says. "You can give yourself 10 or 15 years to paint it, but then it's going to be something you can admire. That's how I take my career. I'm in the middle of that picture now [with] the expansion of the cell phone into an array of telemedicine tools."

Cell phones, he points out, have better graphics processors than IBM supercomputers had in the late 1980s. "There are already 5 billion cell phones in use," he explains. "We manufacture 2 billion of them every year … There will be more of them everywhere on the planet."

With this phenomenal global network of smart gadgets, he points out, computation is almost free.

"Because cell-phone use is so ubiquitous and inexpensive," he adds, "I can rely on it … to design new microscopes and micro-analysis tools that look at bodily fluids using technology attached to the cell phone or running on it."

The "Nano Internet" and Beyond
The young scientist's next challenge is already obvious to him. He foresees spending the next decade or so building the "Nano Internet," which he describes as "the development of these personal micro-analysis tools [that] give us something more valuable than the tools themselves."

What he envisions are millions of his tiny devices interconnecting and streaming personal health information in real time, from brainwaves to blood-pressure counts.

"If my lab and others like it do our work well," he predicts, "then we'll have this kind of Nano Internet. The opportunities that lie ahead of us, with our eyes, with our information, channeled into the micro and Nano worlds."

These and other trails yet unimagined will be blazed from Westwood. "UCLA maintains and extends such vision," says Ozcan. "It's got everything I need to fulfill whatever I dream."

MIT's 2013 Top 10 Breakthrough Technologies - 3: Big Data from Cheap Phones

ORIGINAL: Tech Review
By David Talbot
April 23, 2013

Collecting and analyzing information from simple cell phones can provide surprising insights into how people move about and behave—and even help us understand the spread of diseases.



WHY IT MATTERS
Poor countries lack data-gathering infrastructure; phone data can provide it.

Breakthrough
Creating disease–fighting tools with cell-phone mobility data.

Key Players
• Caroline Buckee, Harvard University
• William Hoffman, World Economic Forum
• Alex Pentland, MIT
• Andy Tatem, University of Southampton

At a computer in her office at the Harvard School of Public Health in Boston, epidemiologist Caroline Buckee points to a dot on a map of Kenya’s western highlands, representing one of the nation’s thousands of cell-phone towers. In the fight against malaria, Buckee explains, the data transmitted from this tower near the town of Kericho has been epidemiological gold.

When she and her colleagues studied the data, she found that people making calls or sending text messages originating at the Kericho tower were making 16 times more trips away from the area than the regional average. What’s more, they were three times more likely to visit a region northeast of Lake Victoria that records from the health ministry identified as a malaria hot spot. The tower’s signal radius thus covered a significant waypoint for transmission of malaria, which can jump from human to human via mosquitoes. Satellite images revealed the likely culprit: a busy tea plantation that was probably full of migrant workers. The implication was clear, Buckee says. “There will be a ton of infected [people] there.”

Caroline Buckee

This work is now feeding into a new set of predictive models she is building. They show, for example, that even though malaria cases were seen at the tea plantation, taking steps to control malaria there would have less effect on the disease’s spread than concentrating those efforts at the source: Lake Victoria. That region has long been understood as a major center of malaria, but what hasn’t been available before is detailed information about the patterns of human travel there: how many people are coming and going, when they’re arriving and departing, which specific places they’re coming to, and which of those destinations attract the most people traveling on to new places.

Caroline Buckee, a Harvard epidemiologist, is using detailed data on population movements—gleaned from mobile phones— to build precise new tools for fighting the spread of malaria.

Existing efforts to gather that kind of travel data are spotty at best; sometimes public-health workers literally count people at transportation hubs, Buckee says, or nurses in far-flung clinics ask newly diagnosed malaria victims where they’ve been recently. “At many border crossings in Africa, they keep little slips of paper—but the slips get lost, and nobody keeps track,” she says. “We have abstractions and general models on travel patterns but haven’t been able to do this properly—ever.”

The data mining will help inform the design of new measures that are likely to include cheap, targeted campaigns of text messages—for example, warning visitors entering the Kericho tower’s signal zone to use bed netting. And it will help officials choose where to focus mosquito control efforts in the malarial areas. “You don’t want to be spraying every puddle for mosquito larvae all the time. But if you know there is a ton of importation from a certain spot, you want to increase your control program at that spot,” Buckee says. “And now I can pinpoint where the importation of a disease is especially important.”

Buckee’s most recent study, published last year in Science and based on records from 15 million Kenyan phones, is a result of a collaboration with her husband, Nathan Eagle, who has been working to make sense of cell-phone data for more than a decade. In the mid-2000s, after getting attention for his work mining data from the phones of volunteers at MIT, Eagle started to get calls from mobile carriers asking for insight into questions like why customers canceled their phone plans. Eagle began working with them. And when the couple spent 18 months in Africa starting in 2006—Buckee was doing work on the genetics of the malaria parasite—he studied call data for various purposes, trying to understand phenomena like ethnic divisions in Nairobi slums and the spread of cholera in Rwanda. Buckee’s results show what might be possible when the technology is turned on public-­health problems. “This demonstrated ‘Yeah, we can really provide not just insight, but actually something that is actionable,’” says Eagle, now CEO of Jana, which runs mobile-phone surveys in the developing world. “This really does work.”

“This is the future of epidemiology. If we are to eradicate malaria, this is how we will do it.”

That demonstration suggests how such data might be harnessed to build tools that health-care workers, governments, and others can use to detect and monitor epidemics, manage disasters, and optimize transportation systems. Already, similar efforts are being directed toward goals as varied as understanding commuting patterns around Paris and managing festival crowds in Belgium. But mining phone records could be particularly useful in poor regions, where there’s often little or no other data-­gathering infrastructure. “We are just at the start of using this data for these purposes,” says ­Vincent Blondel, a professor of applied mathematics at the University of Louvain in Belgium and a leading researcher on data gleaned from cell phones. “The exponential adoption of mobile phones in low-income settings—and the new willingness of some carriers to release data—will lead to new technological tools that could change everything.”

Blank Slate

The world’s six billion mobile phones generate huge amounts of data—including location tracking and information on commercial activity, search history, and links in social networks. Innumerable efforts to mine the data in different ways are under way in research and business organizations around the world. And of those six billion phones, five billion are in developing countries. Many of them are cheap phones that can do little besides make calls and send text messages. But all such activity can be tracked back to cell-phone towers, providing a rough way to trace a person’s movements. Throw in the spread of mobile payment technology for simple commerce and you have the raw material for insights not only into epidemiology but into employment trends, social tensions, poverty, transportation, and economic activity.

This map, a product of cell-phone data analytics, shows the most important sources of malaria infections (darker shades)—taking into account the potential for further transmission caused by human travel—as well as the major destinations of people exposed to the disease (lighter shades). It can be used to determine where best to focus warnings and mosquito control techniques.