Manu Prakash: A pocketful of inventions

In July, in a flooded rainforest in the Ecuadorian Amazon, Margaret Fuller, a professor of human biology at Stanford and a pioneer in stem cell research, photographed the head of a stick ant as viewed through a microscope. In brushed gold, silver and black, it looked like an artist’s depiction of a cosmic event.

A couple of years before this, at the Hauz Khas reservoir in Delhi, Aatish Bhatia, a physicist and science writer who works at Princeton university’s Council on Science and Technology, imaged a water flea—a Daphnia—under a microscope. It was a brilliant purplish-blue, and had a sac full of eggs.

In Hyderabad, N. Arun, a student in Class IX, was busy imaging cells taken from his own cheek under a microscope. With great wonder, he observed the cell walls, the cytoplasm and the nucleus.

In the Peruvian Amazon, Aaron Pomerantz, an entomologist working on his PhD from University of California, Berkeley, put the wings of a moth—the green Lepidoptera—through a microscope, and found that the green wing scales had shifted colour to a burst of blues, purples and pinks, rendered like watercolour brushstrokes.

Each of these explorers, working thousands of kilometres apart, used not an ordinary microscope, but one made of folded paper, a micro-lens, and a cheap LED light source the size of a small button. The instrument is made of materials that cost less than a hundred rupees. It can fit into a trouser pocket. Yet, it works just like a conventional microscope that’s many times its size and weight, and roughly a thousand times its cost.

It’s called a Foldscope, and it was first made in 2014 by Manu Prakash, an assistant professor of Bioengineering at Stanford University, and his then-student Jim Cybulski. Since then the Foldscope has travelled rapidly around the world, in the hands of scientists, medical workers, students and even people outside the scientific community. The device is in constant evolution: recent improvements allow for dark-field microscopy (visualizing objects against a black background) and fluorescence microscopy (imaging objects that glow under certain lights); it now features focus-locking mechanisms and an ability to map a slide; it can diagnose diseases like leishmaniasis, which is endemic to many parts of Africa, and schistosomiasis, a parasitic disease that affects large numbers of people without access to clean water. At this moment, the Foldscope is undergoing perhaps the most challenging adaptation of its short life—the ability to detect malarial parasites.

What remains the same is how the Foldscope is made, and its miraculous manufacturing cost. More than fifty thousand Foldscopes are in use today. Prakash and Cybulski have now set up a benefit corporation (a type of for-profit corporate entity, recognized in most states in the US, that creates a positive impact on society, the community and the environment) called Foldscope Instruments, with factories in San Francisco and China, that hopes to make and distribute a million instruments by the end of this year. Cybulski is the CEO of Foldscope Instruments. They also plan to set up a manufacturing unit in India, among several other sites.

While the Foldscope is being put through multiple clinical and field trials for use as a research and diagnostic tool, its founders are more excited by deeper, more intangible goals.

“A very simple vision is, what happens when a microscope becomes as common as a pencil?” says Prakash over a phone interview. “Pencils are everywhere. And their presence indicates something very profound—literacy. Microscopes are a way of access to science, and if thousands and thousands of kids around the world can pull out a microscope from their pockets, what that can do is create a society that’s not just aware of science, but truly engaged in it; not just from the top down, but also from the bottom up.”

Prakash doesn’t go anywhere without a Foldscope in his pocket.

Frugal Science

Prakash, who is 37 years old, was born in Mawana, a rural sugar-producing town in Uttar Pradesh. He runs the Prakash Lab at Stanford University, a playground for frenetic inventor prodigies across various disciplines, all engaged in “curiosity-driven science”. They often work, Prakash says, without a set agenda, “working on intuition…we don’t know whether something we are working on will ever be useful, but we think there is something there”.

Prakash has a full head of curly hair and a scraggly, thick beard. He looks and speaks like a folk troubadour: his sentences, steeped in old-world wisdom, reveal a consistent engagement with grass-roots problems, and wonder at the natural world.

Prakash is leading what could be termed, without much exaggeration, a revolution in scientific and medical research. It’s called “frugal science”, and it has a simple premise: Is there a way to build scientific instruments and medical systems that are really, really cheap? Can we then share them with everyone, particularly in resource-poor countries with limited access to technology?

Prakash has infused this core value in the workings of his lab. Since the first Foldscope was made, the laboratory has, in quick succession, created a device that allows smartphones to scan for oral cancer; a method of identifying mosquito species by recording the sound of their wingbeats with a mobile phone; and a “chip” that mosquitoes mistake for human flesh and bite into, depositing their saliva on the chip, which is then sampled for pathogens and DNA. This year, in another major breakthrough, they created a centrifuge made of a paper disc and piece of string—called a “Paperfuge”—that can reach up to 125,000 RPM (revolutions per minute) just by pulling on the string with your hands, and can separate plasma from blood in under 2 minutes, just like a $10,000 centrifuge used by medical labs, spinning at around 16,000 RPM.

“The idea of frugal science is not about hacking something together quickly,” says Prakash. “For each of our tools, there are 10-20 pages of math involved. We are often trying to look at unknown principals.”

The story of how the Paperfuge came into being is a case in point. The Paperfuge is basically a toy—one of mankind’s oldest, as it turns out—popularly called a whirligig. You probably played with it when you were a child. You passed a thread through the holes of a button and then held both ends of the thread and pulled, and the button spun in the middle.

Toys and tools

In 2013, when Prakash and his students were in Uganda, they visited a clinic where they saw an expensive medical centrifuge being used as a doorstop. The centrifuge needed electricity to run, but the clinic rarely received adequate supply.

“I’ve seen this over and over again, in many parts of the world,” says Prakash. “It’s like a graveyard. Expensive medical equipment that lies unused because there is no electricity.”

The challenge was to create a centrifuge that needs no power supply. Prakash started thinking about spinning toys. He first started with yo-yos. The lab bought every kind of yo-yo in the market and built new ones to test. They were fast, but not at all easy to use. A spinning top was subjected to experiments. It took three years of playing around before a solution was found.

In early 2016, Saad Bhamla, a postdoctoral scholar at the lab, and a graduate of Indian Institute of Technology (IIT) Madras, brought in a home-made, button-and-thread, whirligig . Using the toy in front of a high-speed camera, he found that it was spinning between 10,000 and 15,000 RPM, enticingly close to what was needed for medical use. The team dove right in, spending months studying the way the whirligig worked, teasing out the math hidden in the toy.

“No one before us had tried to understand how this toy works,” says Prakash. “We found that the whirligig derives its power from a phenomenon called ‘supercoiling’. Supercoiling has only been described really well in DNA mechanics. So we actually used the same math that’s been used to describe how DNA supercoils to understand how a little toy works. Our calculations show that we have the capacity to go to a million RPM. Think about that. A million RPM will easily break Mach 1.”

The researchers now began building prototypes. They experimented with various materials until they found that to make the disc, the same thing used for Foldscopes—polymer film-coated waterproof paper, commonly used to make currency—worked really well. Next, they devised sealed tubes that can hold blood samples and be taped to the inside of the discs without fear of contamination. Now the Paperfuge, like the Foldscope, is being tested at field trials in Madagascar.

In the last decade, this kind of science, that smashes through economic shackles, creating methodologies and tools aimed at resource-poor settings, has had something of a renaissance. Some of the best minds in elite institutions have dedicated their time and effort to it. Rebecca Richards-Kortum, a bioengineer at Rice University, Houston, and her team of researchers are developing a host of low-cost, high-performance tools for lifesaving medical technology. This includes optical imaging systems to detect molecular signs for cancer-screening, and an integrated system to prevent neonatal deaths that costs a hundred times less than similar systems used in developed countries. This integrated system is in the running for a $100 million grant this year. At Harvard University, George M. Whitesides, one of the most accomplished chemists in the world, has developed a series of intricate paper-based medical tests, that cost next to nothing and require no sample preparation.

Bhamla, the co-inventor of the Paperfuge, starts as assistant professor in the School of Chemical and Biomolecular Engineering at Georgia Tech next month, with the aim of creating “frugal tools for science and global health”.

Origin Stories

The Foldscope and Paperfuge have similar origins. Prakash’s interest in microscopy began in 2011, around the time he joined Stanford. Prakash was at a meeting with doctors and healthcare providers in a village in Madhya Pradesh when he was struck by a photograph of Mahatma Gandhi, sitting cross-legged in his dhoti and peering through a microscope. Soon after, Prakash was in the jungles of Thailand at a research station where fluorescence microscopes lay unused because the researchers there were afraid of damaging such expensive equipment.

“The starting point was actually (the) cost,” says Prakash. “Can you build an instrument for a dollar and still have the range of performance that allows you to collect quality data? We realized we had to start from scratch.”

The first idea was to bring in micro-optics, lenses the size of a grain of salt, used extensively for lasers and optical routers but not for microscopy. The next was to try origami; Prakash is an enthusiast, and had a fair idea of the infinitely complex structures that could be built just by folding a flat sheet of paper.

On the flight back to the US from Thailand, Prakash began to lay out the schematics. Then came the math, the central challenge of which was to derive an equation that would show the best way to make an optical instrument given a restricted number of optical surfaces.

“A normal microscope has between 30 and 40 optical surfaces,” says Prakash, “and when you can bend light 30-40 times, you can do many things that you can’t do when you are allowed to bend it only two or three times.”

By the end of the month, Prakash and Cybulski were ready to make prototypes. It was a Friday, and at Prakash Labs, that means “Friday Experiments” day—“the idea is to do something crazy every Friday when we are not trying to do our normal work,” says Prakash. There were a lot of matchboxes lying around at the lab from a previous project. Cybulski and Prakash made the very first prototype of the Foldscope using these boxes.

It took them 15 minutes. Prakash is not sure what the first thing he saw under the Foldscope was—“I’ve now seen a million things,” he says, and hazards that it was the root of a strand of hair he pulled off his own head—but the feeling of using the Foldscope for the first time has stayed with him.

“It was like seeing a glimmer of hope through an enormous tangle of problems,” he says.

Starting early

This was not Prakash’s first attempt at building a microscope from random, salvaged stuff. That came when he was only seven years old, living in Rampur, a small town in Uttar Pradesh.

Prakash had seen microscopes at school, but did not have access to them, and was gripped by the idea of building his own. He fashioned the body out of discarded cardboard tubes meant to hold badminton shuttle cocks. Prakash’s brother Anurag, two years older, wore thick prescription glasses. Prakash stole them one day when his brother was asleep, using them as lenses.

“My brother was pretty upset,” says Prakash with a laugh, “and of course the microscope did not work because I was a kid and did not know how microscopes work.” He did figure out how to finish the crude instrument later, and found a shop where he could buy discarded lenses.

Prakash and his brother, who is now an engineer in Ottawa, moved to Rampur early in their lives when their mother Sushma took a job in a government college there. While their father, Brij Pal, a building contractor, travelled often for work, the brothers spent much of their childhood outdoors, experimenting with whatever they could get their hands on. They climbed tall trees to look for abandoned birds’ nests and made a collection of nests of 15 different species of birds. They found a used syringe and proceeded to inject plants with a “whole bunch of things” to see if there were any reactions. On reading about the way Faraday made his first set of motors, using a giant vat of mercury to allow power to flow into the motor while it was still spinning, they built their own version, breaking open thermometers to get to the mercury.

“I realize now how dangerous it was to do those things,” says Prakash. “Just think of how stupid an idea it was for a kid to have that much mercury! But at the same time, it taught me safety, and it taught me to be creative; things were not easy, and you had to have a lot of grit. You had to do the best you could with what you had, and you could not give up easily.”

Just as Prakash was entering his teens, he had a unique stroke of luck. They moved house, to a sprawling complex in Rampur belonging to a farmer, who let a small room to Prakash’s mother. The farm started in the backyard, which housed cows, buffaloes, equipment and two abandoned cars. But Prakash was most interested to learn that there was an abandoned chemistry laboratory in one of the rooms. The previous tenant was a chemistry teacher who ran private tutorial classes in the room, and had set up a full-fledged lab. When the teacher failed to pay his rent, the owner evicted him, telling him that he could only have his equipment back if he paid his dues.

“It was a wonderland!” says Prakash. “It was this really quiet room with a leaking roof, with bottles of acids and chemical agents, broken weighing scales, a giant old rheostat. The fact that it was not under the eyes of our parents and we could lie to them and tell them we were going out to play, and sneak into the lab instead, made it all the more special.”

For the brothers, it quickly became a serious pursuit. They did not just play around with the stuff, but actually began taking care of the lab, fixing broken instruments and setting up careful experiments.

“Around five years ago, I visited Rampur again and I went to the house,” says Prakash. “I quite regret that I did not knock on the door. I just passed by.”

At 18, Prakash secured a place at IIT-Kanpur, where he studied computer science, but spent most of his time in the robotics lab. By 2002 he was in MIT (Massachusetts Institute of Technology), researching at the Center for Bits and Atoms, an interdisciplinary programme that specifically nurtures out-of-the-box thinking. Prakash fit right in.

“What I most treasure about my time in MIT is that there were all these fantastic machines, all these absolutely incredible resources, but there was also this idea of freedom, the idea that no one tells you what to do and you can do what you want,” he says. “This was new to me, and it turned out to be very valuable because it gave me the breadth and the freedom to think about things without an agenda and without a goal.”

Prakash’s thesis was on how water droplets can be used to process and carry information the way electrons do in a computer circuit. It was like a return to his childhood wonderland, but with the broken rheostat replaced by nanoscale laser cutters, extreme precision 3D printers and atomic force microscopes, and a lab full of colleagues from wildly different disciplines working on futuristic projects.

Meeting of minds

Prakash lives in San Francisco with his wife Sophie Dumont, an assistant professor at the Department of Cell and Tissue Biology at University of California, San Francisco, and their twin one-year-old daughters. Before the twins were born, Prakash and Dumont’s home used to be one giant lab. Now their equipment has moved to the garage.

Prakash met Dumont while both were junior fellows at Harvard. It was 2008 and MIT was refusing to give Prakash his degree because he had accumulated thousands of dollars in fines at the library. Dumont lent Prakash money and her car so he could return the books and get his PhD. They were married in 2011.

Prakash is a wanderer, zipping around the world the way microscopic organisms zip around under his Foldscope. In the month separating two phone conversations we had, he was in Russia (collecting samples from a pond), on a boat in New Zealand with the members of Plankton Planet, a non-profit organization studying the ecosystem of planktons, and at the Marine Biological Lab at Woods Hole (“a Mecca for biologists”, says Prakash) in Massachusetts, across the country from his West Coast home.

At each of these places Prakash collected specimens, put them through the Foldscope and posted his findings online. Charles Darwin wrote in his diary that the naturalist “suffers a pleasant nuisance in not being able to walk a hundred yards without being fairly tied to the spot by some new & wondrous creature”. It would be an accurate description of Prakash, who lives in a blur of fantastical ideas and constant observation.

“Science is not in the lab,” says Prakash. “It is wherever you are, it is all round us. Right under our noses are thousands of phenomena that no one understands.”

“For example, how does rain form?” he continues. “Now that’s actually quite a profound question. Something has to nucleate the droplets, otherwise the vapour phase is perfectly stable up in the sky. Now it actually turns out that there is bacteria up there that nucleates rain drops! I mean, who would have thought? Bacteria is everywhere. But you ask anywhere, even in a science class, how many people have seen bacteria with their own eyes, and very few hands are raised.”

The discovery that mosquitoes transmit malaria parasites, he points out, was simply because Ronald Ross sat out in a field in a village in Bengal, catching mosquitoes and then watching them through a microscope. “Most discoveries are made by curious people who use a different framework to ask the same questions that others are asking,” he says.

Prakash continues to work on developing the Foldscope. One of the significant improvements pertains to malaria. The Foldscopes being manufactured now have magnifications to the tune of 450x, and a resolution of 700 nanometres (nm). “But to detect malaria, you have to get resolutions of around 400nm,” he says. “Very recently, we’ve converged on a lens that allows us to go down to 400nm, and we will be starting a clinical study in Madagascar now.”

Lab-proven tools do not always make it to the wider market for various reasons: the lack of corporate funding to transform new inventions, especially frugal ones, to usable products that don’t promise robust returns to investment is one; the obvious interests of pharmaceutical and medical companies in keeping at bay technology that may threaten their business model is another.

For Prakash, these are problems to be tackled later. Meanwhile, he continues to work towards a future where the tools of an entire diagnostic chain—drawing a drop of blood, sealing it, running it through a centrifuge, putting it on a slide without fear of infections and observing it through a microscope—will cost less than a McDonald’s burger, and fit into a pocket.