In a paper to appear Jan 20 in Cell, researchers from Notre Dame University report on a newly-discovered mechanism for malaria parasites to target red blood cells. The researchers found that malaria host-targeted proteins bind to lipid phosphatidylinositol 3-phosphate, PIP, in the endoplasmic reticulum. According to the press release from Notre Dame, “Their interdisciplinary collaboration reveals a fundamental, novel cellular function…” You can check out the full paper here.
January 20, 2012
January 6, 2012
Open Source Drug Discovery for Malaria
There is a cool new effort unifying several themes of interest to us here, namely global health, drug discovery, and open science efforts. Open Source Drug Discovery for Malaria (OSDD for Malaria) is a venture started recently by the lab of Dr. Matthew Todd, an organic chemist, at the University of Sydney and the Medicines for Malaria Venture (MMV). Basically, OSDD for Malaria will act as a hub for global efforts in open source drug discovery for malaria. You can ready more about the project at the link above or on the Highlight Health blog. Be sure also to circle them in G+ if you are into that sort of thing.
November 15, 2011
Debate European Health Care
I was forwarded a link today to an interesting set of discussions on European health care. Debating Europe is a platform for discussion supported by the European Parliament. The site interviewed David Byrne, patron of Health First Europe and former EU Commissioner for Health & Consumer Protection, and Professor Finn Borlum Kristensen, Chairman of the Executive Committee of the European Network for Health Technology Assessment, and launched a discussion on the issue.
I have posted my comments on the issue, and I think you should, too. Given the reforms happening across Europe right now, this debate is timely and critically important. You can read the current debate thread at:
http://www.debatingeurope.eu/2011/11/14/what-should-european-healthcare-look-like/
January 16, 2011
Helminth sequencing continues
I hope you have not eaten recently – today’s post is gross. Fair warning.
Helminth infections are one of the greatest detractors to global health. It is estimated that millions upon millions of people are infected by helminths every year (see Figure 1). Helminths comprise several classes of parasitic worms, including those that cause schistosomiasis, elephantiasis, river blindness, and others. Some of these helminth infections are known to be easily treatable, but many others are not. As a result, DNA sequencing efforts for several species of helminth are ramping up or underway already.
Figure 1. Prevalence of helminths infections world-wide. Taken from Disease Control Priorities in Developing Countries | Peter J. Hotez, Donald A. P. Bundy, Kathleen Beegle, and others
One of the better-known parasitic worm infections is guinea worm disease, or dracunculiasis (Figure 2). Unlike other global health phenomena, the best treatment for this disease is abstinence: simply don’t get it.
Figure 2. Guinea worm emerging from an infected person’s foot.
Infection results from drinking contaminated water, and filters are now widely available at feasible price points so that most people can screen out the larvae that cause the disease. The other major advantage here is that there is no environmental reservoir, meaning that the parasite has to pass through human hosts every year to survive. Therefore, if infection of all humans can be avoided, the disease can be completely eradicated. For many other helminth species, however, there are environmental reservoirs for the parasites, necessitating the development of screening, diagnosis, and treatment tools to combat infection. Here, DNA sequencing can play a role.
The first helminth species to be fully sequenced was Brugia malayi, the species that causes elephantiasis (see Figure 3). Other genomes are currently in the assembly stage, like Onchocerca volvulus, which causes river blindness. Finally, there are several species currently being sequenced, including Schistosoma mansoni, the causative parasite of schistosomiasis.
Figure 3. “Bellevue Venus” Oscar G. Mason’s portrait of a woman with elephantiasis. Taken from wikipedia.org.
As sequencing technology continues to improve, the speed with which these species may be sequenced will also increase, meaning we will soon have lots of genomic information to mine regarding how best to detect and treat these devastating diseases.
December 11, 2010
The challenges of detecting diseases that are constantly evolving
It has been an interesting couple of weeks around here. First of all, we hear of the mystery disease afflicting Uganda, from which at last count 35 people have died. Closer to home, we heard a seminar by Dr. Jesse Bloom, who is doing amazing work predicting influenza’s future resistance to Tamiflu. Finally, we hear about the WHO promulgating a new 2-hour TB detection test, saying it should be rolled out worldwide. What do all of these items have in common? Two things. First, the need for diagnostics is ever-present. Even when treatments and vaccines are available, there will be a need for diagnostics. Second, these diagnostics need to be adaptable, because sure as birds fly, the causative agents will eventually mutate and skirt around both the diagnostics and the treatments that are currently available.
The challenge of how to make diagnostics sensitive, specific, but also adaptable is a tough problem. Usually, to make diagnostics specific and sensitive you have to target a part (usually molecular) of the causative agent that is very well known and characterized. This takes time, effort, and assumes that this molecule isn’t changing on the time scale that you characterize it. For this reason, most diagnostics and treatments typically target highly conserved parts of the organism, like critical metabolic enzymes, transporters, or signaling molecules. However, these can and do change. The Tamiflu example is evidence of this. Tamiflu (actually known as oseltamivir) targets the influenza nueraminidase enzyme, which is used by the virus to enter host cells. However, the authors of this work showed that it was not even the main known mutation of this enzyme that is allowing the virus to evade oseltamivir, but secondary mutations in the gene sequence that are acquired over time as the virus propagates throughout the world. These secondary mutations in combination with the main mutation (a single amino acid change, by the way) allow the virus to evade the drug. Not good.
The other examples of diagnostics above are equally challenging. TB is caused by Mycobacterium tuberculosis, a bacterium that, like all other bacteria, evolves on a very rapid timescale. Luckily, TB evolves more slowly because it grows more slowly than other bacteria, making the time between generations longer. The final example, this mystery disease in Uganda, is suspected to be a new variant of amoebic dysentery. In this case, there is no molecular diagnostic even available, and the most common diagnostic method, microscopy, requires multiple samples due to the rapidly changing number of amoeba in the stool.
So, what is the solution? I suggest high-throughput DNA sequencing. Our new ability to sequence organisms from complex samples at a fraction of he time and cost of previous methods makes it simple to detect the mutations that may cause immune, diagnostic, or therapeutic evasion. H1N1 was a good example of this (see the previous post on this). If we know what the mutations are, we can apply emerging computational, directed evolution, and molecular modeling tools to design new diagnostics and drugs. The final step of this, though, is the time and effort required to validate these new diagnostics and drugs and get them cleared for public use. Stay tuned for my next post about this issue.
November 7, 2010
Synthetic biology meets global health: iGEM Jamboree 2010
Synthetic biology, the emerging field of biology in which organisms’ genes are engineered to perform non-natural tasks, promises to revolutionize the future of medicine. iGEM is an undergraduate competition in which teams from universities all over the world compete to engineer the most amazing new functions using standardized genetic parts, called BioBricks. The rate at which these teams innovate is unbelievable. I am the advisor for the UBC iGEM team, and our project this year was to develop a way to break down Staphylococcus aureus biofilms by using engineered bacteriophage cloned directly into the genome of the host organisms to make a “suicide bomber” cell strain that would only go off and express the phage when it encountered quorum sensing signals indicating a Staph biofilm nearby. Amazing project, but others were even more amazing. This year, several teams latched onto critical global health problems and attacked them using synthetic biology. The University of Washington iGEM team invented two new antibiotics, one a broad-spectrum antibiotic-expressing strain of bacteria that would exist as sentinels in the body and only demonstrate antibiotic effects when they detect a Gram-negative pathogen. The other antibiotic was a modification of this system against a specific species of Gram-positive pathogens. Imperial College London invented a synthetic biology diagnostic for schistosoma parasites in water before they infect human hosts. They even developed a plastic diagnostics chamber with a clear window for the user to see the color change caused by the genetic expression of a yellow-colored product. The best part? Their system was designed to be low-cost and modular so that it could be modified to detect other parasites, including Chagas, leishmania, and more. Other teams developed systems to fight celiac disease, yeast cells that kill TB, and re-engineered the bacteria that live is mosquito guts to try and kill off malaria at the source. Remember these are teams of mostly undergraduate students. This is what I mean when I say that science will prevail over antibiotic resistance and other biomedical challenges. In all, there were 130 teams from 26 countries at this year’s iGEM competition, the Jamboree. An amazing job was done by all – see the 2010 iGEM website for more details or follow the #IGEM2010 hashtag for up-to-the-minute details. I am tweeting using the #iGEM hashtag, so you can follow those, too.
October 31, 2010
Mushrooms – the next vaccine powerhouse?
This time of year in the Pacific Northwest is mushroom season. As the rains come, the fruiting bodies of thousands of species burst forth from trees, the ground, other mushrooms, and just about anywhere you can imagine (e.g., my car trunk). One can’t help but be fascinated by the variety and abundance of these amazing organisms, and recent research is indicating that mushrooms may be a huge boon to global health.
One of the first realizations one makes as an amateur mycologist is that there is deep understanding about very few mushrooms. Even professionals lump entire genera into terms like “LBM” (little brown mushrooms), perhaps to indicate that the effort required to identify them to the species level would be prohibitive. However, with the advent of genetic sequencing, entire worlds open up to research. Genbank, the world’s genome repository, lists a single basidiomycete (filtamentous fungus) fully sequenced, and that one is a yeast pathogenic to humans (Cryptococcus neoformans). This is out of a total of 31,515 species that are thought to exist. However, 15 other species’ genomes are in the assembly stage, and 44 more are in progress. One of these in-progress projects is Agaricus bisporus, the common white button mushroom found in stores the world over and a major commercial crop. There are multiple ascomycetes (the other “mushroom” phylum) fully sequenced and in progress, but many of these are yeasts commonly used on research or fermentation. Time will tell where these genomes lead us, but many mushrooms produce toxins, antimicrobials, antifungals, and anti-cancer drugs. Understanding precisely how will be a major source of future research efforts.
Even if a mushroom’s genome isn’t sequenced, there are many efforts underway to synergize what mushrooms do (generally, break down complex organic matter to simpler forms without the need for sunlight) with other ongoing poverty reduction efforts. Some cool examples can be found in pairing mushroom cultivation with toilets in Bolivia, choosing edible mushrooms to break down sisal decortications in Tanzania, and producing drugs in Canada. Basically, fungi form an entire branch of life that to date has been underutilized in efforts to make sustainable agricultural systems in developing parts of the world.
A final example of how cool mushrooms are is found in the work of Paul Stamets, a Pacific Northwest fungi researcher (see his TED talk here). He speaks widely about how the mycelia of fungi can protect against soil erosion, provide nutrients to entire forests, and support the ecological web of life in old-growth forests. Look up mycoremediation and mycofiltration for even more examples.
It seems that leveraging the fungus among us is going to be essential for future sustainable efforts in poverty reduction, treatment of disease, and global health generally. I look forward to learning more about this heretofore neglected weapon against poverty and disease.
October 2, 2010
Microfluidics for global health, Ch 1
This is the first of two posts on an area of work close to my heart and expertise. I have so much to say here that I have split it into two posts. Stay tuned for Chapter 2 in the next few days.
Recently, there has been a growing focus on applying microfluidics for global health challenges. Microfluidics (exactly what it sounds like) is the science and engineering of fluid flows through channels with dimensions of 0.1 mm or smaller. For reference, 0.1 mm is the width of a single human hair. The field began in earnest in the early 1990s, when it was surmised that the same techniques used for making computer chips could be used to fabricate small fluid-handling elements, which could in turn enable chemistry at small length scales. This has many advantages, including tiny volumes (one billionth of a liter, 10-9 L, is a typical volume) that save on reagent costs, faster reactions due to reductions in diffusion lengths, and the ability to integrate much functionality on a single substrate. Many amazing advances have occurred in this field since its inception, but recently the field has been moving in an interesting direction: backwards.
The first decade of microfluidics witnessed an expansion in the range of technologies and complexity of the systems fabricated, including many by yours truly. The dream was to integrate an entire “lab on a chip” to achieve on a 4”-diameter substrate what took an entire chemistry lab up to that point. However, the last five or ten years have seen a recognition that one of the best application spaces for microfluidics, that of global health, had an entirely different set of constraints that were not being met by making things more complicated. Realizing the dream of a portable chemistry lab could enable remote diagnostics at low power, short assay times, and therefore better treatment of neglected and other diseases. However, even the low power systems required batteries for heating, cooling, or powering detection modules, buffers requiring cold chains were still mandatory, and the systems required trained operators, a rarity in the areas with the most need. Recently, given the realization of the actual constraints, engineers have sought to make devices that are not just low-power, but no-power, and that perform a diagnostic test within minutes by untrained operators using a minimum of reagents.
Paper microfluidics has been one of the more significant advances. Just as in home pregnancy tests, a detection of a specific molecule can be made by having biological fluids move through the pores in a piece of paper using capillary action, a result of the type of liquid and the type of paper used. The fluid moves on its own, without the need for pumps, valves, or other complicated technologies. George Whitesides and colleagues, with funding from the Bill and Melinda Gates Foundation, have developed a suite of paper microfluidic chips for performing a variety of diagnoses in remote regions. Another fascinating example of this was recently published in Analytical Chemistry, in which the authors devised a rapid blood typing assay using only antibodies and paper, without the need for an indicator dye or particle as is necessary in other tests. It will be interesting to see where these advances lead in the near future.
September 21, 2010
Maternal mortality: still knowledge gaps
Recently, Ban Ki-moon, the UN Secretary General, said that there would be a massive focus on healthy mothers in the last five years of the Millennium Development Goals. Many have wondered why progress on MDG #4 and #5 have not been better. In part, this is because the money is going to other diseases and problems in parallel, partly because these MDGs are inherently politicized, but I think mostly it’s because mother mortality is the least well-understood from a scientific standpoint. We as a species do not have a good understanding of the reasons for or treatments for several of the major causes of mother mortality before, during, and after childbirth. Perhaps chief among these is our lack of understanding of the causes of pre-eclampsia and eclampsia. As the brother-in-law of a woman who had a stroke at age 31 while pregnant with her second child, pre-eclampsia is something I have seen perhaps more closely than others. I should point out that my sister-in-law lives in the United States, meaning this is not a problem restricted to the developing world (although it kills 99 times more women in these settings compared to resource-rich settings). Luckily, there is progress both on detecting and understanding pre-eclampsia as well as engineering devices for field-based detection in resource-poor settings. Last week, a paper published in the journal Hypertension described 14 metabolites that serve as biomarker candidates for re-eclampsia. They were identified by an international team of doctors operating in the UK and Australia and may serve as the basis of future diagnostics devices. On the $2-a-day level, physicians at various universities across the world, including here at UBC, have introduced methods for detecting elevated blood pressure, a major symptom of pre-eclampsia, in expectant mothers. More than that, current efforts seek to identify software models that may be able to use blood pressure measurement as an input to refine prediction of this devastating condition. Finally, nanotechnology-based methods are also being tested, perhaps leading to faster assays for detection. In the meantime, if you want to contribute to saving mothers’ lives, please purchase an obstetric kit and donate it to a clinic in an underserved region.
August 30, 2010
NDM-1 and the power of modern biology
There has been much talk recently of the new NDM-1 gene moving quickly around the world, and how it makes bacterial pathogens resistant to every antibiotic that we have available. The lead author of the study is quoted as saying that there is “a bleak window of maybe 10 years” before all the major pathogens have acquired NDM-1 and we have nothing to treat them with. Is this really true? Is this the end of antibiotics as we know them?
Yes and no. The age of antibiotics discovered the traditional way is over or will be soon. But biology has advanced at such a ferocious rate recently that a new form of science is emerging. Take for example the sequencing of the swine flu that caused the global pandemic recently. This virus was sequenced, annotated, and published in less than a month. This kind of speed was unthinkable even 5 years ago, and gave clinicians and scientists a jump-start on how to diagnose and treat swine flu, lessening the impact of the pandemic. As proof of the power of this approach, the vaccination rate for swine flu was as low as 35% in parts of Canada, and yet the pandemic ended so quickly that many thought it was alarmist to declare it a pandemic at all. Granted, had this been Ebola, we would have seen a different outcome, but my point stands: faster science and faster communication allows more people to make more progress faster.
The same speed is being applied to NDM-1. The initial discovery, sequencing, and studies of this gene are already complete, allowing detailed study of the mechanism by which it provides antibiotic resistance, and thereby allowing the discovery of new classes of antibiotics that will treat it. Further, the technology of high-throughput biology and in-vitro selection of molecules has advanced, allowing the selection of new antibiotics from large libraries of potential candidates quickly. My research group is but one working on developing and refining such methods, and I am therefore confident that we have tools in our toolbox that will allow us to find new molecules that will treat bacterial infections in the future.
Bacterial pathogens and humans have been in a molecular arms race for millennia, and the bugs were winning until about 1940. Now, the bugs have acquired a new missile, and so we need to develop a new anti-missile gun. The struggle between phyla continues.
