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
March 18, 2011
Access Success: Getting health technologies to those who need them
by Dr. Rebecca Goulding
Given that fact that you are reading this blog, you probably already know that cheap, robust, field-appropriate health technologies that can give rapid feedback about disease states are greatly needed to improve health outcomes in developing countries. I’m not talking about CT or MRI scanners, or complex diagnostic devices that you might see at a local city hospital – but relatively simple and robust tools that can be used in a range of remote, resource-constrained areas. Examples include: risk-assessment for pre-eclampsia during child-birth, detection of infectious diseases and their drug resistant sub-types (in patients, animal hosts and the general environment), and communication devices that help community health workers and patients to interpret diagnoses or to adhere to treatment regimens. Inventing such a technology is only the first step in a long and winding road to getting it to people in need. Researchers who envisage the whole pathway – from conception of an idea through to real-world implementation – have a greater chance of achieving “access success”.
As a hypothetical exercise let’s say you are a UBC graduate student or professor with a great idea for a new Chagas disease diagnostic test that is much better than existing tools: it is tough, easy to use, gives rapid results, and best of all, it would be cheap to make. This has the potential to be a key piece of technology that could help clinicians and public health experts to decide who to treat and how to control the spread of this deadly parasitic disease. Funding from the CIHR or the NIH may help you to figure out the test’s sensitivity and specificity in the lab. It might also be possible to get funding to gather field data, for example to test whether the technology will work well under field-conditions in Bolivia, one of the countries with the highest prevalence of the disease. But what are the next steps that must be taken before this test starts being used on a much broader scale?
The process of developing your health technology into a tool that has significant impact will require significant funding. What usually happens at universities is that inventions like diagnostic tests (equipment and method) are patented. The patented invention is then often licensed, sometimes exclusively, to a third party wishing to develop the invention in exchange for a royalty payment to the inventor and the university. Any company thinking about investing the capital (often very substantial amounts of money!) to develop your diagnostic technology is likely to want you to have a strong intellectual property (IP) position (i.e. strong patent(s) protection). However, it is important to get the balance right: enough IP protection to be able to incentivize investment in development, and not too much so that others are not entirely shut out from innovating in the area.
Here exists an important stage in your products pathway to access success: will there be any interested parties willing to invest the money to develop your Chagas disease diagnostic test? There are two distinct markets for Chagas disease diagnostics: a) in developed countries (e.g. Latin American immigrant populations in California) and b) in middle-income countries (e.g. Brazil, Peru, Bolivia). Therefore it is possible that a small biotechnology company may be interested to license the IP to develop a product – but only if they can be sure to achieve a return on their investment. Some larger companies may also be willing to invest in such a project as part of their social corporate responsibility, but will still want to avoid making a loss. A product development partnership (PDP, also known as public private partnership), which funds and manages the development of technologies for neglected diseases, may also be interested in your technology. PDPs do not do in-house R&D, but instead fund development partners who do. Alternatively, it may be possible to start up your own spin-off company, by licensing the technology to a spin-off from UBC, and by securing funding for product development from other private, government or philanthropic sources.
For argument’s sake, imagine that a company is interested in licensing your Chagas disease diagnostic. What kind of things must you consider before licensing negotiations begin?
University technology transfer offices deal with the negotiations for the licensing of IP to third parties. The issue of improving access to university-discovered technologies in developing countries is increasingly on their radar, thanks to organizations such as the Bill and Melinda Gates Foundation and Universities Allied for Essential Medicines (UAEM). For example, in 2007, after discussions with UAEM and others, UBC announced it was adopting global access principles that aim to improve global economic and social impacts of UBC’s innovations and guarantee technology access to these technologies for the world’s poor. There is a range of global access licensing strategies that could potentially be used to negotiate a balanced deal that creates incentives for the company and at the same time ensures access to technologies for the people who need them the most. These include limiting field of use, including geographical restrictions, requiring at-cost production of the technology in developing countries and limiting royalty payments in exchange for other terms that promote access. While UBC and other universities are clearly on board with improving technology access, much depends on how amenable the licensee is to such concessions.
Universities may have better access success if they license such technologies to relevant PDPs who themselves have an access mandate at the very core of their business model. These PDPs have a mandate to ensure the availability and affordability of technologies and medicines, and also their adoption in developing countries (the AAA mandate). PDPs have significant funding at their disposal for product development and access to partner companies who may make in-kind contributions. Thus they have the leverage to make significant demands when negotiating licensing deals with universities and other IP holders. PDPs typically want a royalty-free exclusive license for the IP (at least for the neglected disease field of use in question), from the IP holder, which also allows them the freedom to manufacture the products in any country, presumably by any manufacturer they choose. As long as universities (and the inventor – that’s you!) are comfortable to give up the technology for free to a PDP, then this might be the most straightforward way of ensuring access success.
There are an increasing number of innovative licensing deals being made between universities and licensees – and it seems there is increasing receptivity for the goals of access. I believe it is important for university researchers at the forefront of health technology innovation, to think through what an “access success” strategy would look like, and that this needs to happen before they get to the boardroom of the licensing office to negotiate.
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.
October 6, 2010
Microfluidics for global health, Ch 2
In the last post, I began talking about microfluidics and how recent efforts are focused on applying this technology to global health diagnostics. This post is the conclusion of that one.
Other advances in microfluidics for global health have come in the form of new technologies for simplifying the methods used to fabricate microfluidic systems. Some of these advances are in materials and some are in methods. In the area of materials, the so-called Shrinky-Dink® microfluidics can be used to print a microfluidic chip pattern using a conventional printer on a special thermoplastic sheet; reheating the thermoplastic material then causes it to revert to its original size, reducing the ink patterns on the sheet as it does so. The resulting mould can be used to make microfluidic chips in minutes with very few materials and common equipment. Another advance comes in the use of Jell-O®, the popular gelatin dessert, to make microfluidic chips. This is work from Tony Yang, a student in my lab, and although the feature sizes in the final devices are larger than the usual 0.1mm, the flow is still laminar. These chips were designed for educational use, but I wonder if the use of other locally available biopolymers might make these sorts of chips useful for global health diagnostics.
The final advance comes in the form of Dean flow, a topic I have discussed previously on this blog. Using the nonlinear equations of fluid flow, it becomes possible to design microchannel geometries that focus particles by size without applying any forces other than those used to drive the flow. A simple pump could therefore be used to remove bacterial pathogens or protozoans from drinking water, to purify certain types of cells, or many other uses. I look forward to seeing where this technology base will take us in the future.
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.
May 21, 2010
Molecular rock-paper-scissors, or RuBisCo vs. the MDG: The Grudge Match
In several recent instances, I have been reminded and have reminded others of the difficulties of using biomarkers in diagnostics. First, some background: biomarkers are molecules that, ideally, indicate a specific biological state. One can use genes, gene expression (RNA), or proteins as biomarkers, as well as small molecules like metabolites. The first problem is that specific indication of a single biological state rarely happens, with any biomarker. If you look at a biochemical interaction map for even a relatively simple organism like C. elegans, a microscopic worm, what you see is that most molecules, genes, etc. interact with many different other molecules, and therefore appear at various concentrations in multiple biological states (for example, a protein biomarker that increases in abundance in prostate cancer also increases in breast and ovarian cancers). This means that at best, you will need to know the concentration of a panel of different biomarkers to get both analytical and clinical specificity.
C. elegans interactome map (N. Blow, Nature 460, 415-418, 2009)
The second problem, and one that is sometimes forgotten by those who discover biomarker candidates, is that to detect these biomarkers, especially in situations applicable to this blog, global public health, you will need to do so in the presence of every other protein in the cell of the organism you are analyzing. This is where the rock-paper-scissors analogy comes in. If you are trying to detect this biomarker using conventional technologies, you are most likely doing it at a surface (immunoassays, like ELISAs, do this, as do many optical techniques, microarrays, etc.). Nonspecific binding of contaminating proteins, especially those that are in high concentrations or like to crash out on surfaces because they are poorly soluble to begin with, will interfere with your assay. Think of it as a molecular ‘paper’ covering your expensive and exquisitely sensitive antibody ‘rock’. Unfortunately, molecular ‘scissors’, at least the kind we need here, are relatively rare. The other option, I suppose, would be a molecular laser sword. So, to those of you would discover, validate, or use biomarkers for any diagnostic purpose, particularly those conducted outside a laboratory, please keep in mind that you need to consider the complexity of detecting one type of molecule in the presence of thousands of others.
