Edward Wenger and Philip Eckhoff’s recent publication in the Malaria Journal,  A Mathematical Model of the Impact of Present and Future Malaria Vaccines, studies the impact of potential malaria vaccines within the framework of the EMOD malaria model. This individual-based model couples a detailed description of the vector lifecycle with a comprehensive, mechanistic representation of within-host parasite and immune dynamics. The model additionally includes a flexible and powerful framework for configuring and distributing arbitrarily specified campaign interventions to targeted groups of individuals.

The objectives in these studies were to quantify the potential impact of first-generation vaccine candidates as components in multi-intervention elimination strategies, to elucidate which geographical settings in a wide range of transmission intensities and entomological behaviors enable the greatest impact, and to estimate efficacy targets for future vaccines as a function of desired impact.

The first study quantifies the regions in baseline transmission and vector feeding behavior where local elimination is enabled by layering pre-erythrocytic vaccines of various efficacies on top of high and sustained insecticide-treated net coverage.

The second study examines the expected reduction in clinical disease burden as part of an intervention targeted at young children through an expansion of routine immunization. Especially relevant as we begin to consider deploying existing and future vaccines is the question of where they will be most effective. The results quantify the impact over a broad range of transmission intensity, insecticide-treated net coverage, and vector behavior. These results highlight that the maximum-impact setting is one in which the impact of increasing bed net coverage has saturated and where largely outdoor-feeding vectors leave transmission just above the threshold where small perturbations from a vaccine intervention result in large community benefits.

With an encouraging pipeline of vaccine candidates – including the ongoing Phase III trial of RTS,S – mathematical modeling is today an especially important tool to inform decisions and policy going forward.

The parasite causes human malaria, when it is passed from one human to another by the bite of an infected Anopheles mosquito. In 1898, Italian physician Giovanni Battista Grassi proved that human malaria could only be transmitted by the Anopheles genus. In order to cause malaria, the Plasmodium parasite must go through complex and multistage life cycle, infecting both humans and mosquitoes as it matures and develops.

The cycle begins when a female mosquito bites a human in search of a blood meal to produce eggs—in fact only the female has the physiology necessary for sucking blood.  The parasite is transferred through the mosquito saliva to the human host as the mosquito is taking her blood meal. After infecting its human host, the parasites, in sporozoites form, travel through the bloodstream to the liver and invade liver cells. Over 5-16 days (time-frame is dependent on the parasite species) the sporozoites grow, divide, and produce tens of thousands of merozoites, per liver cell.

The Life Cycle of Malaria in Humans. Source: Wikimedia

The parasites as merozoites exit the liver and re-enter the blood stream where they invade red blood cells to feed on hemoglobin, an iron-bearing molecule that allows the cells to ferry oxygen to all parts of the body. The merozoites multiply inside the red blood cells, which eventually break open allowing the parasite to infect additional cells.  Merozoites continue their cycle of invading red blood cells, asexual replication, and then releasing newly formed merozoites repeatedly for over 1-3 days, resulting in thousands of parasite infected cells in the blood stream.  These blood stage parasites cause the illness and symptoms associated with malaria that can last for months if not treated.

Some of the merozoite-infected blood cells leave the cycle of asexual replication and instead develop into sexual forms of the parasite, male and female gametocytes, that circulate in the human blood stream.  When a mosquito bites an infected host, it ingests the gametocyte.

When the gametocytes enter a female Anopheles mosquito during a blood meal, they begin another, different cycle of growth and multiplication in the mosquito knows as the sporogonic cycle.  Inside the misquoto’s gut, the infected human blood cell bursts, releasing the gametocytes that mature into sex cells called gametes.  Male and female gametes then fuse forming zygotes.  The zygotes develop into active elongated ookinetes, which burrow into the mosquito mid-gut wall to form oocysts.  The oocysts grow and divide producing thousands of sporozoites; after 8-15 days, the oocyst ruptures releasing the sporozoites inside the mosquito.  The sporozoites travel within the mosquito body eventually invading the salivary glands. The human plasmodium cycle begins again when the female mosquito takes a blood meal, injecting the sporozoites from its salivary glands into the human bloodstream.

As a protist, Plasmodium is a eukaryote of the phylum Apicomplexa. Unusual characteristics of this organism in comparison to general eukaryotes include the rhoptry, micronemes, and polar rings near the apical end. Source: Wikimedia

At IV Lab, our team of entomologists, epidemiologists, physicists, other scientists and engineers are working on innovative ways to help reduce and eradicate malaria. Click the links to learn more about our efforts in diagnostics, epidemiological modeling, mosquito control, and vaccine cold chain.

To learn more about the Plasmodium life cycle, check out this informative video or visit the Center for Disease Control’s website.

Presentation Abstract:

We demonstrate a dark-field imaging technique capable of automated identification of individual bacteria on a dry slide with greater than 95% accuracy without staining or tagging.

Water has lots of odd properties. Normally, we think of fluids as being less dense when they get warmer. Hot air balloon rides, for example, would be much less exciting if warmer things tended to sink. However, one of the weirder properties of water is that unlike most liquids, its density doesn’t always decrease with temperature. Up until about 4 degrees C, the density of water actually increases as a function of temperature. There are some fascinating physical chemistry reasons behind this involving the various supramolecular structures of water.

However, let’s take a look as it relates to engineering…

We are working on insulative technology for temperature sensitive vaccine storage, which requires very low thermal transfer to keep vaccines cold for long periods of time. Our current protocol to measure the thermal transfer in a device involves a technique we affectionately refer to as CoW (cold water warm-up). In CoW, the device is first filled with a large volume of near freezing water. Then, we place the device inside a warm environmental chamber and measure the temperature of the water inside the device as it warms up.  We can then fit the temperature response to a model that predicts how long the system will last when it’s loaded up with vaccines and ice instead of just cold water.

Interestingly, over the several days that it takes for our device to warm up by a few degrees, we can actually observe the density inversion of water inside our own system! Plotted above is the temperature trace from two thermocouples that were inserted into the device at the beginning of an experiment. You can see that, right at the temperature where fresh water has its density maximum (3.9 degrees), very interesting fluid dynamics show up. Before the inversion point, the bottom (green) thermocouple is in contact with water that is slightly warmer, and thus denser than the top (blue) thermocouple. Once the inversion hits, and density laws as we commonly think of them take over, the denser water at the bottom thermocouple is colder than the water at the top thermocouple. Looking at the graphs in reverse, the bottom graph shows that the denser liquid is always on the bottom, as we’d expect. But, when we cross-reference this with the top graph, we can see that the hotter fluid is on the bottom before the inversion, and on top after!

Also note that before the inversion, the two traces are fairly close together, but after the inversion, they are much further apart. This is because heat leak in the device is highest in the “neck,” which is at the top of the device. So, below the inversion point, water is warmed most rapidly at the neck, which then increases in density, rapidly sinking to the bottom of the device. And, voilà, we have an efficient convective cell (at least, efficient on the time scale of our multiple day experiment). However, after the inversion, the warm fluid tends to stay at the top, the cold fluid stays at the bottom, and heat transfer is dominated by slower conduction, instead of “efficient” convection.

You can learn more about EMOD’s work here and follow their progress on our blog as updates are available.

Tola at the Saint-Louis Regional Pharmaceutical Warehouse in Senegal performing final assembly and inspection on a vaccine storage device

A: I received a degree in mechanical engineering and then took a job selling and providing support for engineering computer programs; specifically, finite element analysis (FEA) and rigid body dynamics (RBD). FEA deals with creating mathematical models of physical prototypes to figure out how and when they will bend, break, or otherwise structurally deform. RBD is all about determining the effect of external forces on a mechanical system. However, you never really get to see the fruit of your labors as a salesperson, so I decided to try my hand in the aerospace industry. For the next 8 years, I worked as a practicing engineer for Blue Origin in Kent, Washington. There, I was able to drive good ideas into real hardware, or in this case, scribbles on a cocktail napkin to spacecraft.

Q: What is unique about working at the IV Lab?

A: I am constantly impressed by the Lab’s ability to integrate and coordinate intellect from many different fields. When you bring together a bunch of brilliant people, it often devolves into huge ego clashes and gridlock. On the other hand, at the Lab, each person is able to bring something to the table and work constructively towards common goals.

On a more personal level, the ethos of the Lab is such that everybody has space to do his/her job. I rarely feel micromanaged and I am empowered to be as efficient as I can be. As with the best jobs, my job at the Lab allows me to go from technical development to product development. I can hammer out details on paper and then consult on product design and field tests.

Q: Of the projects you have worked on, which one is your favorite?

A: I have only really worked on one project at the Lab (a vaccine storage device we call “P6″), but my favorite aspect of the process was the P6 Quick Start. Two other engineers and I had 6 weeks to crank out the core parts of the design for the P6 before passing it along to our build partner. It was 6 weeks of pure engineering.

Q: Who was an important influence along your path?

A: Mr. Macky was my high school math teacher. I’m positive he didn’t like me since I was kind of a troublemaker back then. Anyway, one day he says to my mother, “Tola could be a lot of things, but he has a strong mathematical nature. If he doesn’t choose a career that will allow him to scratch that itch he will be unhappy.” Up until that point, I was sure I was going to be theatre major in college, but Mr. Macky’s opinion started to make me think about going into engineering. He helped provide clarity to my career path and it was the best investment I ever made.

Q: Who is your favorite scientist, engineer, or inventor?

A: I would have to say Ernest Shackleton (an early explorer of Antarctica). Even though his ship was crushed and he had to resort to using long boats, he didn’t lose any of his men and managed to take photographic prints of his journey. Unfortunately, when he returned, the world was at war and his accomplishments were largely ignored.

Q: What are you reading right now?

A: I am currently reading the third volume of William Manchester’s biography of Winston Churchill. I have actually been waiting to read this book for over 20 years, since Manchester died before he was able to finish his trilogy. It was well worth the wait. Churchill is actually one of my greatest heroes and role models, and I try to use his example to guide my own course through life.

Q: What are you listening to right now?

A: Music is one of my greatest loves. I actually worked at a record store as a teenager and through college. In fact, if you asked me, I think it would be worse to lose your hearing than to lose your sight. Right now, I’m listening to The Who Sell Out by one of the best rock bands of all time (The Who). It’s like stepping into a time capsule to late 1960s England.

Note:

Tola was elected to the Issaquah City Council in 2009, and served as Council President in 2012. He also works on bonds and levies for the Issaquah School District.

Pablos did a short interview with 90 Seconds TV at the London Web Summit about how we are supporting and funding inventors.  This might be the fastest way ever to understand what Intellectual Ventures is all about.

Our insectary is expanding! The new insectary increases our available workspace and will allow us to expand our mosquito-rearing program and take on new projects. Inside the insectary, we raise species from both the Aedes and Anopheles mosquito genera, and use these mosquitoes in a variety of ways ranging from understanding how they reproduce and carry malaria to what it takes to kill them with a laser.

The Insectary Chamber

The new insectary increases our available workspace and will allow us to expand our mosquito-rearing program and take on new projects. The insectary is currently divided into two main workspaces: a larval rearing room/work room that is kept at ambient temperature and humidity but equipped with a couple of environmentally-controlled incubators to keep growing larvae happy and a room reserved just for adult mosquito colonies that is set and monitored at 75°F/75%RH.

Since we now have a larger space to keep a thriving colony,  we are able to increase our rearing capacity..  This will help expedite experimental work for a variety of projects as well as keep up with the mosquito needs for Photonic Fence.

Does comfort for these pesky mosquitoes really matter?

Surprisingly, yes. In order to maintain the utmost health of our mosquito colonies for projects, we have to give in to their specialized needs. Essentially this falls under the category of controlled temperature, humidity and light cycles. Previously, this required us to have heaters and humidifiers that needed to be filled daily. Now, we have regulating heat and temperature modes inside the insectary that can be easily monitored from outside of the insectary. This system allows us to monitor the consistency of the climate inside the insectary rooms and if the temperature or humidity fluctuates too much, an alarm will sound.

Successfully rearing mosquitoes, or any insect for that matter, is challenging.  In fact, each mosquito species has slightly different environmental requirements and life-cycle characteristics.  Generally speaking, mosquitoes have four stages in their life cycle, three of which are aquatic: eggs to larvae to pupae. The adult stage of the mosquito’s life-cycle requires air, in the aerobic stage the mosquito requires high temperature and high humidity.  We raise both Anopheles freeborni and Anophelse stephensi in our insectary, and although both are within the same family and genus, A. freeborni might as well be the distant cousin of A. stephensi. It takes between 5-7 days for A. freeborni to be matured enough to lay eggs, 4 days for the eggs to be laid, after which 10-14 days for the eggs to go through the different instar stages to pupation and a further two days for the adults to emerge. Altogether, A. freeborni takes almost twice as long to grow as A. stephensi.

FIG. 5. Plot of the number of particles of species u 1 undergoing the reaction u 1 + u 2 → 2 u 1 with α = 1/2 (grey), α = 1 (magenta), α = 3/2 (blue), α = 2 (red). ζ ( x ; t ) represents the number of particles of u 1 at position x at time t .

Learn about more about our Epidemiological Modeling program here or check out other recent EMOD publications on our blog.

Published Paper

Bayati, B.S. (2013) Fractional diffusion-reaction stochastic simulations.  Journal of Chemical Physics 138, 104117.

First, Some History

In January of 1985, Apple released its LaserWriter printer. Although the first traditional laser printer had been developed in 1969 by Xerox, Apple’s new product was the first commercially successful printer and played a key role in the Desktop Publishing Revolution. This technology empowered average Janes and Joes across the world to self-publish on a scale and level of quality never before seen on a home appliance. Now, what if I told you that the seeds are being sown for a Desktop Manufacturing Revolution, based on a concept nearly as old as the LaserWriter?

Makerbot founders with an early prototype of their 3D printer (Credit: Makerbot Industries)

The “3D printer” was first patented in 1995 by two MIT graduate students, who went on to start a company called ZCorp. Another early initiative was RepRap, a project that developed printers that ran on free and open source software (FOSS) and were capable of printing many of their own parts. Much of the initial innovation and growth behind 3D printing was driven by the hacker/early-adopter/DIY communities. However, the potential of this new technology not only being used to rapid prototype, but to rapid manufacture, soon became realized. Today, “commercial” 3D printing is dominated by two companies: 3D Systems and Stratasys. There are also a variety of off-the-shelf personal use printers, the most popular of which is the Makerbot (recently featured in TIME magazine and Wired).

The Nitty Gritty

An important distinction that must be made about any type of printing is that it is fundamentally a process, not a product. The exciting prospect about 3D printing is that it employs a process of additive manufacturing. This means that instead of cutting down a block of marble like Michelangelo, or milling down a piece of metal like a modern machinist, an object can be built up layer by layer. The advantages of such a process range from the obvious to the subtle. For one, building something up does not require as much material to be wasted as when building something down. Alternatively, some 3D objects that require a lot of creativity and/or craftsmanship to construct using subtractive manufacturing, can easily be created using additive technologies. A great example is a ship in a bottle. Using a 3D printer, the bottle can literally be built around the ship.

(Credit: ALoopingIcon)

 The process behind additive manufacturing starts with creating a virtual 3D model of your object on a computer using CAD (computer aided design) or animation software. These specialized programs then “slice” the object into layers of thin, horizontal cross-sections. The 3D printing machine will build these layers one on top of another until a final physical object is constructed.

There are three main families of 3D printers, organized by the method they use to print: extrusion, granular, and light polymerized.

• Light Polymerized (using light): Stereolithography is the original method for 3D printing that uses an ultraviolet beam to selectively harden layers of a liquid photopolymer. This would essentially look like a vat of liquid wherein the 3D object is traced out layer by layer. Stereolithography remains one of the most accurate methods of printing with a layer resolution of 0.06mm.

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• Extrusion (using liquid): Fused deposition modeling (FDM) is an extrusion process developed by Stratasys that quickly became one of the most popular techniques for 3D printing. FDM involves using a computer-controlled nozzle to emit a molten thermoplastic that quickly hardens. The ability for FDM printers to use a variety of different materials (i.e. food (icing, cheese, chocolate), cement, cells, etc.) has made them the most versatile of 3D machines. Here’s a cool video showcasing Objet’s new Polyjet Matrix 3D printing process.

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• Granular (using powder): The process of selective laser sintering starts out with a bed of powdered material (i.e. wax, polystyrene, nylon, glass, ceramics, various metal alloys, and even sugar). Then, as the name suggests, a laser is used to selectively melt together granules of the powder until the object is created.

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“Oh the Places you’ll go”

In two words, 3D printing has “great potential.” The possible applications of additive manufacturing range from the recreational to the practical to the paradigm shifting. As such, many classify 3D printers as a “disruptive technology,” heralding the birth of a “niche market for one” and the extinction of the “killer app.”

While realists assert that the technology will primarily be used to complement existing subtractive manufacturing methods, it is not inconceivable that 3D printing could impact the entire global economy (think of a time when you can print your own smartphone without the countless intermediaries between the manufacturer and your pocket).  Mass manufacturing of identical items may become a thing of the past as economies of scale become obsolete.

However, we still have a few more generations (at least) to go before this technology can really take off. In particular, printers need to be able to process higher resolutions, work with a variety of different materials simultaneously, and most importantly, get faster. Nevertheless, 3D printing is currently being utilized on the production end of manufacturing in the consumer, architecture, construction, automotive, aerospace, medical, and education fields.

A few cool examples are:

• Perfactory Digital Dental Printer from envisionTEC, capable of printing customized crowns and bridges
• Personalized designer sunglasses from Make Eyewear and Protos Eyewear
• Home and personal appliances from Freedom of Creation
• Neri Oxman, a head researcher/artist at the MIT Media Lab, is using 3D printing technology (specifically the Connex 500 from Objet) to create designs inspired by nature (video link)

3D printed sugar (Credit: Oskay)

• 3D concrete printing that could someday be used to build city structures
• 3D printing a Moon base out of space dust
• Sad Keanu Reeves!
• “Bioprinting”: engineering specialized tissue by printing cloned versions of your own cells
• Engineering chemical compounds

3D printed replica of a 2.8 million year old fossilized inner ear (Credit: Didier Descouens)

• Printing replicas of ancient artifacts, fossils, and body parts
• Relatively cheap pre-assembled 3D printers for consumer use: UP! Personal Portable 3D Printer, Cube Personal 3D Printer
• 3D printed designs created by the Mediated Matter group at the MIT Media Lab

Earlier, I briefly touched on another inherent advantage to additive manufacturing: the enticing concept of perfect efficiency. By being able to control the design of every slice of an object, manufacturers will be able to optimize for material usage. For example, Stratasys has partnered with a small firm in Winnipeg that is developing an innovative 3D printed car called the Urbee. This automobile is being touted as the first in a new breed of highly durable and aerodynamically efficient transports achieved through additive technology. Similarly, at the University of Washington, three engineering students have built a relatively inexpensive 3D printer called “Big Red,” capable of making large objects out of shredded plastic. The students hope to replicate this technology in developing countries and have even prototyped a watertight canoe built out of 250 milk cartons.

The Urbee (Credit: Brent Toderash)

It is highly doubtful that the average consumer will be busting out coffee machines, pagers, light fixtures, and designer shoes from his/her 3D printer anytime soon. One of the greatest underestimations in all the speculation over 3D printing is the intense time and effort required to design something that can easily be ordered online or purchased at a store. If anything, the revolution spurred by 3D printing will instill a deep appreciation for the art of craftsmanship. Thus, a more realistic vision of the effect of 3D printing over the next few years is the average consumer being able to download base models of a variety of different products from the internet. Then, using a 3D printer, the consumer can customize the product to match his/her personal taste. Already, online forums such as Thingiverse, are popping up for people to share, upload, and download their own 3D designs.

Regardless, it seems like the sky’s the limit for the 3D printer and the myriad of possible applications for additive manufacturing. Here at the Intellectual Ventures Laboratory, 3D printers play an important role in meeting the demand for rapid prototyping among the various projects. Staff engineers and machinists can simply create a design on their computer and print out a model by the end of the day. This model can then be tested for viability, and can serve as a basis for a sturdier model milled from metal or cast. A 3D printer was even used to print out scaled down versions of a nuclear reactor for the TerraPower’s Traveling Wave Reactor.

Our in-house 3D printer is a member of the Dimension family. Check it out in action: