Saturday, February 4, 2017

Papers, Please

Since my last post, I've started a Twitter account, @reviewer3blog.  Right now I'm mostly retweeting cool science articles and pretty pictures of space, but I'd like to think that it's worth checking out if you want to keep up with fun stuff in between my blog posts.

There's a lot going on in the US science scene right now, politically speaking, but I'm going to let that lie for now.  Instead, I want to talk about the science scene in developing countries.  Specifically about medical diagnostics and treatment in developing countries.  As a disclaimer: Most of the research I'll be talking about focuses on populations in sub-Saharan Africa.  I am well aware that a lot of the problems I'll be discussing apply to other areas as well, but I'm working with the research I have available to me, so some extrapolation is necessary.

Developing nations in sub-Saharan Africa face a host of issues when it comes to medical care, that have been addressed with varying degrees of thoroughness.  For the past few decades, the main use for the resources provided by non profit and global health organizations has been disease prevention and actually providing care.1  Despite that, the leading causes of death in sub-Saharan Africa fall into the category of "communicable, maternal, neonatal, and nutritional diseases".  This category includes HIV, malaria, and tuberculosis, among others, and accounts for 76% of premature deaths in the region.2  As prevention and treatment efforts have increased, there's been an increase in deaths from non-communicable diseases like cardiovascular disease and cancer as well.  Although increasing treatment opportunities is obviously a critical aspect of reducing mortality rates, far fewer financial resources have been allocated to improving diagnostics in the area, and it's difficult to treat someone without a diagnosis.3  Not only is trustworthy diagnostic testing necessary for treating a person suffering from an illness and preserving their lifespan, it can play a role in making treatment simpler by identifying diseases earlier, preventing the spread of communicable diseases, and reducing the number of antibiotics being prescribed unnecessarily, making treatments more effective.  As an example of this phenomenon, fewer than half of patients treated for malaria in a Tanzania hospital actually had blood tests that confirmed that diagnosis, meaning thousands of patients weren't properly treated.4  This may have resulted in extraneous deaths that could have been avoided if doctors were considering a wider range of possible diagnoses.5

A good number of these diseases can be diagnosed by blood tests, but in developing countries, that can be far more difficult than it sounds.  Even in hospitals, understaffing and lack of disposable equipment like blood vacuum tubes and lumbar puncture kits mean that diagnostic testing is performed far less frequently than it should be.6  When laboratory testing is an option, it is still often underutilized due to ideas on the unreliability of tests,7 but that is an issue I'm not even going to get into this week, since a) I only have so many words to work with, and b) I have no idea how to approach it.  The cost of diagnostic testing can be hugely prohibitive to people living on less than a dollar a day, making it impractical for  patients as well as practitioners.  Even if you manage to get over all those humps, places outside of major hospital centers may have limited access to electricity and other infrastructure elements that are necessary for running the equipment and keeping samples refrigerated.

In terms of developing new fast, accurate, and cheap diagnostic tests, the focus currently seems to be on "point of care" tests.8   Many of these tests are designed to work similarly to glucose testing that a diabetic might do: a few drops of blood on a strip or some other sort of reader, and a yes/no determination can be made within minutes.  Many of these tests can be done for under five dollars and show promising accuracy, which is a huge step forward.  However, there are still many barriers to implementing these tests outside of the laboratory environment that range from cultural to staff availability to economics.  While an individual test may be inexpensive, the initial investment in the equipment is often prohibitive, and since they are often limited in their testing application (designed to diagnose one illness), multiple pieces of equipment may be necessary to be able to accurately diagnose.9

Some researchers are attempting to take advantage of devices that are already ubiquitous, even in developing countries: your everyday smartphone.  David Erickson's team at Cornell University developed an app paired with a device that attaches over a smartphone's camera, called Nutriphone.  A few drops of blood are collected on a strip, similar to the aforementioned glucose test, and then the strip is read by the camera to diagnose nutritional deficiencies, specifically Vitamin D deficiency.10  The team followed this up with a polymerase chain reaction (PCR), which performs a vital function in a lot of diagnostic testing by allowing a technician to visualize DNA.  Their KS-Detect again uses a device attached to a smartphone to use solar energy to power the PCR device for up to 70 hours in the diagnosis of Karposi's Sarcoma, a cancer associated with the herpes virus.11  Their current project is a device that communicates with a smartphone to perform blood tests in the diagnosis of malaria and dengue fever.  This grant is ongoing, so keep an ear out for new smartphone diagnostic tests.12

One issue with these tests is that a huge number of specimen tests require preprocessing: essentially, it has to be spun super fast in a centrifuge, which separates the different parts of the blood, urine, feces, whatever, and allows you to test, for example, the blood plasma only.  This centrifuging step has been a huge hurdle in more widespread lab testing in the developing world, but recently, a kids' toy may have made a breakthrough.  Researchers at Stanford University spent a while studying whirligigs to come up with a solution to the centrifuge problem.  You know, these things that all the kids were playing with on your family trip to Colonial Williamsburg?
They used the physics of the way the whirligig spins when you pull the strings to make a paper centrifuge that's pretty much literally string, two pieces of paper, and wooden handles.  It costs less than 20 cents to make, requires no electricity, and is portable and lightweight enough to be useful outside of laboratory centers.  The specimen is placed in between two sheets of paper, and the string is pulled to spin the paper at speeds of 125,000 RPM, well above the 90,000 RPM required for centrifuging.  In trials, it separated plasma from whole blood in roughly a minute and a half, and was able to isolate malaria parasites in about 15 minutes of spinning.  This is absolutely amazing, and I don't think that I can remotely describe the device with justice, so check out this video from the paper they published.13

Paper science doesn't stop with centrifuges, though.  The Whitesides Research Group out of Harvard is working on a series of paper based diagnostic tests that aren't quite as easily made as the paperfuge, but still only require printers with special inks.  They've created a test for certain liver enzymes by printing wax channels onto paper with a standard printer.  Stacking these channels on top of each other allows for the creation of a microfluidic (tiny amounts of liquid) device that, with the introduction of an ion specific membrane, allows for the recognition of those liver enzymes at the cost of a few cents per test and relatively low start up costs.14  By using screen printing with conductive inks, they can actually print electrodes onto paper that can measure the concentration of glucose or other metabolites in the blood.15  Finally, by embossing paper, they've created wells similar to a  well plate, and then by coating the paper in a hydrophobic chemical allows the wells to hold a liquid.  By combining this with the aforementioned electrode printing, they have created a paper based system for performing an ELISA assay, which is pretty much the most basic type of test for detecting antibodies.16 

My final brilliant paper-based diagnostic innovation comes from the same Stanford lab as the paperfuge: the Foldscope.  The Foldscope is incredibly aptly named; it's an origami based microscope.  It takes about 10 minutes to create a Foldscope, and you're rewarded for that 10 minutes with 2,000 times magnification power.  It costs less than a dollar, is lightweight, and fits in your pocket, making it ideal for use in the field and not laboratories.  They emphasize that it can survive being stepped on by a person, so if that's a problem you regularly have with your microscopes, it might be worth looking into.  The light for the scope is provided by a simple and widely available LED and allows for multiple types of imaging, including flourescence, brightfield, and darkfield, means that the scope allows you to view different kinds of images under it, for example, both your traditional huge version of a sample, but also stained proteins in a sample.17  Using the scope to look at specimen samples could allow for the identification of all kinds of markers that can be used for diagnosis.  I couldn't let this one go without a video too.



I'd be remiss if I didn't mention that a lot of these technologies aren't going to be the game changers they seem like they could be.  For one thing, getting funding for trials is going to be difficult because, as mentioned, diagnostics isn't really where the money is at right now.  In terms of private funding, these tests aren't really profitable for pharmaceutical companies, which puts a damper on things.  A lot of these technologies only solve one part of a problem, and would need to be used in combination with others, or still have some of the problems that we've seen before.  Even if we get past those hurdles, we still have to contend with changing the opinions of doctors in developing counties about how useful, important, and reliable these tests are, plus find ways to get them into more rural areas and train in their usage.  While encouraging, these aren't yet the silver bullet for developing countries, though that doesn't hamper their potential adoption in developed countries.

Follow me on Twitter, look out for my next post on February 18, and give a thought to whether a 2,000 year old material might just be the future of medicine. 

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