Better Nature

By Gregory Mone

Discover04.2013

© 2013 by Discover Media LLC. This PDF is authorized for electronic distribution and limited print distribution through March 18, 2014.

Better Nature

At Harvard, researchers absorb the lessons of

the natural world, from the human immune system to an

insect-trapping plant, thentweak them to create bold, new

technologies for health.

BY GREGORY MONE

04.2013

Donald Ingber, founding director of

the Wyss Institute for Biologically Inspired

Engineering, has made a career of

bridging disciplines.

PHOTO BY SAM OGDEN

Inside the Boston headquarters of Harvard University’s Wyss Institute for Biologically Inspired Engineering, an exuberant Don Ingber weaves through a maze of chlorine-scented laboratories,

glass-walled offices, and darkened rooms. In less than five minutes, Ingber, the institute’s 56-year-old director, has pointed out a mattress that could prevent life-threatening sleep apnea in newborns; simulated lungs, intestines, and hearts made of silicone rubber using microchip manufacturing technology; and a machine that forces mutations in bacteria, directing their evolution so they can produce low-cost biofuels and drugs. More than once, he stops to revel in the scope of the research. “There’s so much,” he says. “It’s just ridiculous.”

The 4-year-old institute consists of six core research areas focused on a wide range of technologies, from cancer vaccines to robotic bees that will pollinate plants. Most of the institute’s 18 core faculty members split their time between other academic departments and the Wyss, where they share multidisciplinary lab space that forces roboticists and biologists, chemists and computer scientists, clinicians and engineers to put their heads together and see their projects through.

What most distinguishes the Wyss is

that its scientists treat the natural world as their inspirational springboard. It isn’t just a matter of parroting nature’s methods, but of absorbing lessons from nature and then tweaking them to create something entirely new. Wyss chemist Joanna Aizenberg, for example, borrowed the concept for a new nonstick material from the slick surface of the insect-trapping pitcher plant. But Aizenberg didn’t just copy the plant’s tech-nique—she improved upon it, then spun out prototypes for use in the real world (see “Super Sliders,” page 37).

A New SensibilitySome scientists are content to publish their ideas in journals and then move on to the next experiment. But for Wyss researchers,

translation has always been the major point. In 2005, when Harvard convened a commit-tee to envision the future of bioengineering, Ingber (along with Harvard bioengineer David Mooney) was chosen to lead the charge. Ingber was no stranger to discipline-hopping. His first major scientific insight had its roots in a sculpture class he took while a junior at Yale University. The profes-sor showed the class an abstract sculpture made of wooden dowels and elastic strings. It was built according to the principles of an architectural concept known as tensegrity, in which an object’s structural stability arises from the tension among its parts.

Ingber watched as the instructor pushed down on the sculpture, flattening it out. The energy he exerted was stored in the structure, and as he let go, the sculpture popped back to its normal upright form. A few days earlier, Ingber, a biochemistry major, had seen something similar happen to cells in the cancer research lab where he worked: Cells would adhere to the bottom of culture dishes, flattening underneath and then popping back to a more rounded shape when released. Ingber became convinced that tensegrity applied to cells as well. When he theorized that pushing or squeezing them might affect their function, “people thought I was crazy,” Ingber says. But in the

The Wyss Institute, located in Boston and Cambridge, Massachusetts, supports the work of about 750 researchers. T

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34DISCOVER

Inside the Boston headquarters of Harvard University’s Wyss Institute for Biologically Inspired Engineering, an exuberant Don Ingber weaves through a maze of chlorine-scented laboratories,

glass-walled offices, and darkened rooms. In less than five minutes, Ingber, the institute’s 56-year-old director, has pointed out a mattress that could prevent life-threatening sleep apnea in newborns; simulated lungs, intestines, and hearts made of silicone rubber using microchip manufacturing technology; and a machine that forces mutations in bacteria, directing their evolution so they can produce low-cost biofuels and drugs. More than once, he stops to revel in the scope of the research. “There’s so much,” he says. “It’s just ridiculous.”

The 4-year-old institute consists of six core research areas focused on a wide range of technologies, from cancer vaccines to robotic bees that will pollinate plants. Most of the institute’s 18 core faculty members split their time between other academic departments and the Wyss, where they share multidisciplinary lab space that forces roboticists and biologists, chemists and computer scientists, clinicians and engineers to put their heads together and see their projects through.

What most distinguishes the Wyss is

that its scientists treat the natural world as their inspirational springboard. It isn’t just a matter of parroting nature’s methods, but of absorbing lessons from nature and then tweaking them to create something entirely new. Wyss chemist Joanna Aizenberg, for example, borrowed the concept for a new nonstick material from the slick surface of the insect-trapping pitcher plant. But Aizenberg didn’t just copy the plant’s tech-nique—she improved upon it, then spun out prototypes for use in the real world (see “Super Sliders,” page 37).

A New SensibilitySome scientists are content to publish their ideas in journals and then move on to the next experiment. But for Wyss researchers,

translation has always been the major point. In 2005, when Harvard convened a commit-tee to envision the future of bioengineering, Ingber (along with Harvard bioengineer David Mooney) was chosen to lead the charge. Ingber was no stranger to discipline-hopping. His first major scientific insight had its roots in a sculpture class he took while a junior at Yale University. The profes-sor showed the class an abstract sculpture made of wooden dowels and elastic strings. It was built according to the principles of an architectural concept known as tensegrity, in which an object’s structural stability arises from the tension among its parts.

Ingber watched as the instructor pushed down on the sculpture, flattening it out. The energy he exerted was stored in the structure, and as he let go, the sculpture popped back to its normal upright form. A few days earlier, Ingber, a biochemistry major, had seen something similar happen to cells in the cancer research lab where he worked: Cells would adhere to the bottom of culture dishes, flattening underneath and then popping back to a more rounded shape when released. Ingber became convinced that tensegrity applied to cells as well. When he theorized that pushing or squeezing them might affect their function, “people thought I was crazy,” Ingber says. But in the

The Wyss Institute, located in Boston and Cambridge, Massachusetts, supports the work of about 750 researchers. T

HIS

PA

GE,

FR

OM

TO

P: R

ICK

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AU

, WYS

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AM

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34DISCOVER

Inside the Boston headquarters of Harvard University’s Wyss Institute for Biologically Inspired Engineering, an exuberant Don Ingber weaves through a maze of chlorine-scented laboratories,

glass-walled offices, and darkened rooms. In less than five minutes, Ingber, the institute’s 56-year-old director, has pointed out a mattress that could prevent life-threatening sleep apnea in newborns; simulated lungs, intestines, and hearts made of silicone rubber using microchip manufacturing technology; and a machine that forces mutations in bacteria, directing their evolution so they can produce low-cost biofuels and drugs. More than once, he stops to revel in the scope of the research. “There’s so much,” he says. “It’s just ridiculous.”

The 4-year-old institute consists of six core research areas focused on a wide range of technologies, from cancer vaccines to robotic bees that will pollinate plants. Most of the institute’s 18 core faculty members split their time between other academic departments and the Wyss, where they share multidisciplinary lab space that forces roboticists and biologists, chemists and computer scientists, clinicians and engineers to put their heads together and see their projects through.

What most distinguishes the Wyss is

that its scientists treat the natural world as their inspirational springboard. It isn’t just a matter of parroting nature’s methods, but of absorbing lessons from nature and then tweaking them to create something entirely new. Wyss chemist Joanna Aizenberg, for example, borrowed the concept for a new nonstick material from the slick surface of the insect-trapping pitcher plant. But Aizenberg didn’t just copy the plant’s tech-nique—she improved upon it, then spun out prototypes for use in the real world (see “Super Sliders,” page 37).

A New SensibilitySome scientists are content to publish their ideas in journals and then move on to the next experiment. But for Wyss researchers,

translation has always been the major point. In 2005, when Harvard convened a commit-tee to envision the future of bioengineering, Ingber (along with Harvard bioengineer David Mooney) was chosen to lead the charge. Ingber was no stranger to discipline-hopping. His first major scientific insight had its roots in a sculpture class he took while a junior at Yale University. The profes-sor showed the class an abstract sculpture made of wooden dowels and elastic strings. It was built according to the principles of an architectural concept known as tensegrity, in which an object’s structural stability arises from the tension among its parts.

Ingber watched as the instructor pushed down on the sculpture, flattening it out. The energy he exerted was stored in the structure, and as he let go, the sculpture popped back to its normal upright form. A few days earlier, Ingber, a biochemistry major, had seen something similar happen to cells in the cancer research lab where he worked: Cells would adhere to the bottom of culture dishes, flattening underneath and then popping back to a more rounded shape when released. Ingber became convinced that tensegrity applied to cells as well. When he theorized that pushing or squeezing them might affect their function, “people thought I was crazy,” Ingber says. But in the

The Wyss Institute, located in Boston and Cambridge, Massachusetts, supports the work of about 750 researchers. T

HIS

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34DISCOVER

The Wyss Institute’s suite of machining tools includes 3-D printers (one of which is shown at far right) that make three-dimensional objects based on computer-generated drawings. This wide view is a composite of seven photos.

decades since, his work has proven otherwise. He has demonstrated, for example, that exerting a mechanical force on a cell can activate cell signaling.

At the fi rst committee meeting in Cam-bridge, Massachusetts, Ingber found himself surrounded by other scientists breaking boundaries—physicists publishing in biology journals, biologists in physics publications. Th e group resolved to form a research center that not only tolerated but also encouraged the same kind of interdisci-plinary sensibility, and whose ideas would be inspired by the now-burgeoning knowledge about how nature builds.

Swiss-born billionaire Hansjörg Wyss, a Harvard Business School graduate, liked the idea so much that he donated the single largest gift in Harvard history, $125 million, to make it happen. Th e school tapped Ingber to run the show.

Sole SearchingIngber and I stop inside a gleaming, 500-square-foot laboratory space with airy, high ceilings. Standing at a black counter-

Bioengineer David Mooney has packed a cancer-fighting factory into what looks like a tablet of aspirin. With this new technology, he aims to improve treatment of melanoma, a deadly skin cancer that can claim up to 85 percent of patients diagnosed after metastasis. To start, Mooney’s team members biopsied a mouse tumor, isolated some of its proteins, and loaded them into the tablet, a biodegradable plastic device so porous that it is 90 percent air. They also filled the tablet with GMC-SF (granulocyte macrophage colony-stimulating factor), an inflammatory protein known to attract immune cells.

Then they implanted the tablet under the mouse’s skin. As expected, GMC-SF triggered a red alert, attracting immune cells that flooded the tiny device. Once inside, these immune cells came in contact with the tumor proteins and learned to recognize them as well. Before too long, contents of the tablet, including the trained immune cells, were trafficked to the lymph nodes, biological garrisons that help the body recognize and fight germs. Once ensconced inside, the trained immune cells taught naïve counterparts to recognize the tumor and attack. “We’re able to shuttle millions of cells through this device, generating a very potent immune response against the cancer cells,” Mooney says.

In 2009, Mooney reported that the device ledto a complete regression in 40 percent of micewith metastatic melanoma. Yet the projectmight have stalled if not for the Wyss, whereMooney has been working with collabora-tors to develop efficient and low-costmanufacturing techniques and to preparethe cancer-fighting factory for human trials. The first tests, in fewer than a dozen patients, will take place at the Dana-Farber Cancer Institute this year.

Cancer-Fighting Factory

Filled with tumor-specific proteins and implanted under the skin, the porous plastic disk David Mooney developed reprograms the body’s immune system to attack tumors.

04.2013

The Wyss Institute’s suite of machining tools includes 3-D printers (one of which is shown at far right) that make three-dimensional objects based on computer-generated drawings. This wide view is a composite of seven photos.

decades since, his work has proven otherwise. He has demonstrated, for example, that exerting a mechanical force on a cell can activate cell signaling.

At the fi rst committee meeting in Cam-bridge, Massachusetts, Ingber found himself surrounded by other scientists breaking boundaries—physicists publishing in biology journals, biologists in physics publications. Th e group resolved to form a research center that not only tolerated but also encouraged the same kind of interdisci-plinary sensibility, and whose ideas would be inspired by the now-burgeoning knowledge about how nature builds.

Swiss-born billionaire Hansjörg Wyss, a Harvard Business School graduate, liked the idea so much that he donated the single largest gift in Harvard history, $125 million, to make it happen. Th e school tapped Ingber to run the show.

Sole SearchingIngber and I stop inside a gleaming, 500-square-foot laboratory space with airy, high ceilings. Standing at a black counter-

Bioengineer David Mooney has packed a cancer-fighting factory into what looks like a tablet of aspirin. With this new technology, he aims to improve treatment of melanoma, a deadly skin cancer that can claim up to 85 percent of patients diagnosed after metastasis. To start, Mooney’s team members biopsied a mouse tumor, isolated some of its proteins, and loaded them into the tablet, a biodegradable plastic device so porous that it is 90 percent air. They also filled the tablet with GMC-SF (granulocyte macrophage colony-stimulating factor), an inflammatory protein known to attract immune cells.

Then they implanted the tablet under the mouse’s skin. As expected, GMC-SF triggered a red alert, attracting immune cells that flooded the tiny device. Once inside, these immune cells came in contact with the tumor proteins and learned to recognize them as well. Before too long, contents of the tablet, including the trained immune cells, were trafficked to the lymph nodes, biological garrisons that help the body recognize and fight germs. Once ensconced inside, the trained immune cells taught naïve counterparts to recognize the tumor and attack. “We’re able to shuttle millions of cells through this device, generating a very potent immune response against the cancer cells,” Mooney says.

In 2009, Mooney reported that the device ledto a complete regression in 40 percent of micewith metastatic melanoma. Yet the projectmight have stalled if not for the Wyss, whereMooney has been working with collabora-tors to develop efficient and low-costmanufacturing techniques and to preparethe cancer-fighting factory for human trials. The first tests, in fewer than a dozen patients, will take place at the Dana-Farber Cancer Institute this year.

Cancer-Fighting Factory

Filled with tumor-specific proteins and implanted under the skin, the porous plastic disk David Mooney developed reprograms the body’s immune system to attack tumors.

DISCOVER

Bioengineer Kit Parker, a major in the U.S. Army, was on duty in Afghanistan in 2009 when an explosive struck the lead vehicle in his convoy. The driver and vehicle commander suffered major concussions in the crash. Their behavior suggested the soldiers had suffered traumatic brain injuries, or TBIs, which can have devastating long-term effects, including cognitive and psychiatric disorders, seizures, and early-onset Alzheimer’s disease. “I thought to myself, ‘There’s no first aid for this,’ ” Parker says. If the men had suffered a broken limb, he could have tied a splint, but he knew there was no way to immediately stop the cascade of damaging chemical events happening in those soldiers’ brains. So he went back to his lab to find one himself.

The solution Parker hit upon is a “brain on a chip,” a model of the traumatized brain that is a first step toward understanding the effects of TBIs and how to halt them. To replicate the brain in miniature, Parker and his team started with an elastic substrate about the size of a fingernail, then added a layer of cells on top to mimic networks of blood vessels in the brain. To replicate the traumatic effects on vascular tissue from an improvised explosive device, Parker and his team used a high-speed motor to stretch the elastic substrate by one-fifth of an inch in just a few microseconds, then release it. When they analyzed the samples of the substrate about 90 minutes later, they found no evidence of increased cell death or even simple tearing. But they did find that the stretched cells were hypersensitive to a protein that promotes constriction of blood vessels. To Parker, the results suggest that head trauma kick-starts a chemical chain of events leading to a narrowing and reshaping of blood vessels in the brain. Over time, Parker speculates, the effect contributes to longer-term consequences such as depression and a wide variety of neurodegenerative diseases.

Parker hopes to eventually use the “brain on a chip” to test drugs that can halt the process. If a compound administered immediately after the simulated explosion were to stop the cascade of chemical events, then it could be used at the site of an injury, just as a soldier would tie a splint on a broken limb.

Concussion in Miniature

Wyss bioengineer Kit Parker (left, with Harvard graduate student Borna Dabiri) is studying how pressure waves from explosive blasts affect brain tissue.

top, Ingber picks up a pair of oversize shoe insoles wired to small battery packs. He explains that elderly people often suff er from poor balance when the nerves in their feet lose sensitivity. Th e insoles produce vibrations that override those eff ects.

Th e key to making them work was not searching for an ideal vibration frequency, but recognizing how complex systems in nature—like weather, for example—respond to random signals in the environment. Biomedical engineer James Collins, who invented the insoles, knew that the act of walking is itself a complex system—a dynamic interplay of the ground, the walker’s footwear, the countless nerves that enervate the feet, and the brain that governs the process. Suspecting that a person’s gait could be just as responsive to random signals as the weather, Collins tried delivering random pulses to elderly subjects’ feet. Sure enough, the signals worked. Th e sensitivity of the nerves in the subjects’ feet was so thoroughly restored that they were able to walk with the balance of a typical 20-year-old.

Yet the shoe inserts almost didn’t happen. Collins developed the basic technology over a decade ago and started a company to turn his prototype into an actual product. But by 2009, a foundering economy had left the project in the fl edgling prototype stage. Th at might have been the end of it—one more idea in the boneyard of promising

James Niemi, lead senior staff engineer at the Wyss Institute, demonstrates James Collins’s vibrating shoe insoles, which help people with balance and walking problems.

In Parker’s “brain on a chip” (top), brain cells cultured on silicone form neural networks (bottom). Rapidly stretching the cells at high speed mimics mechanical blast forces.

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36DISCOVER

The Wyss Institute’s suite of machining tools includes 3-D printers (one of which is shown at far right) that make three-dimensional objects based on computer-generated drawings. This wide view is a composite of seven photos.

decades since, his work has proven otherwise. He has demonstrated, for example, that exerting a mechanical force on a cell can activate cell signaling.

At the fi rst committee meeting in Cam-bridge, Massachusetts, Ingber found himself surrounded by other scientists breaking boundaries—physicists publishing in biology journals, biologists in physics publications. Th e group resolved to form a research center that not only tolerated but also encouraged the same kind of interdisci-plinary sensibility, and whose ideas would be inspired by the now-burgeoning knowledge about how nature builds.

Swiss-born billionaire Hansjörg Wyss, a Harvard Business School graduate, liked the idea so much that he donated the single largest gift in Harvard history, $125 million, to make it happen. Th e school tapped Ingber to run the show.

Sole SearchingIngber and I stop inside a gleaming, 500-square-foot laboratory space with airy, high ceilings. Standing at a black counter-

Bioengineer David Mooney has packed a cancer-fighting factory into what looks like a tablet of aspirin. With this new technology, he aims to improve treatment of melanoma, a deadly skin cancer that can claim up to 85 percent of patients diagnosed after metastasis. To start, Mooney’s team members biopsied a mouse tumor, isolated some of its proteins, and loaded them into the tablet, a biodegradable plastic device so porous that it is 90 percent air. They also filled the tablet with GMC-SF (granulocyte macrophage colony-stimulating factor), an inflammatory protein known to attract immune cells.

Then they implanted the tablet under the mouse’s skin. As expected, GMC-SF triggered a red alert, attracting immune cells that flooded the tiny device. Once inside, these immune cells came in contact with the tumor proteins and learned to recognize them as well. Before too long, contents of the tablet, including the trained immune cells, were trafficked to the lymph nodes, biological garrisons that help the body recognize and fight germs. Once ensconced inside, the trained immune cells taught naïve counterparts to recognize the tumor and attack. “We’re able to shuttle millions of cells through this device, generating a very potent immune response against the cancer cells,” Mooney says.

In 2009, Mooney reported that the device ledto a complete regression in 40 percent of micewith metastatic melanoma. Yet the projectmight have stalled if not for the Wyss, whereMooney has been working with collabora-tors to develop efficient and low-costmanufacturing techniques and to preparethe cancer-fighting factory for human trials. The first tests, in fewer than a dozen patients, will take place at the Dana-Farber Cancer Institute this year.

Cancer-Fighting Factory

Filled with tumor-specific proteins and implanted under the skin, the porous plastic disk David Mooney developed reprograms the body’s immune system to attack tumors.

04.2013

Chemist Joanna Aizenberg found the inspiration for her latest innovation in the ultra-slippery leaves of the carnivorous pitcher plant. Then she improved on nature to create permanent nonstick surfaces that could keep artificial walls free of insect infestations, prevent ice from adhering to airplane wings, and deter bacterial growth on medical devices continually in contact with body fluids.

When wet, the leaves of the pitcher plant are essentially friction-free: Insects slide down the surface into the interior, where the plant slowly digests them. The technique works in nature because rain regularly replenishes the moisture needed to keep the surface slick. Aizenberg knew there was no use replicating that trick: An artificial material that needs to be refreshed with new liquid to remain friction-free would have limited value. Instead, Aizenberg needed to find a way to lock lubricants in place.

Toward that end, she tested several candidate materials and finally selected two: a Teflon and an epoxy resin, both highly porous. She then poured a series of sample lubricants onto small sheets of each of the porous materials. The lubricants seeped in, with a bead of liquid clinging to the surface of each pore. Next, she used an air gun to blow away the excess liquid, leaving a smooth, liquid surface. Lab tests revealed that blood, grime, oil, and ice all rushed freely off each locked-in liquid without displacing any of it. The particular lubricant did not matter, and neither did her choice of substrate. The surfaces also self-healed: When Aizenberg cut through the center, the remaining lubricant rushed in and filled the new gap.

Aizenberg is now working with the Wyss Advanced Technology Team to find the first applications for her invention, dubbed slippery-liquid-infused porous surfaces, or SLIPS. One of the lubricants they tested is FDA-approved for contact with blood, so they are exploring the possibility of using the material in blood transfusions and medical devices—including Ingber’s sepsis device.

Super Sliders

The slippery-liquid-infused porous surfaces (SLIPS, right) was inspired by the pitcher plant (inset), whose slick leaves capture insects and escort them to a watery demise.

but unfulfilled inventions. But when Collins joined the Wyss in 2010, Ingber encouraged him to revive the project. Working with the institute’s Advanced Technology Team, composed of industry veterans, Collins improved the inserts’ comfort and reined in manufacturing costs. Now, the inserts have morphed from monstrosities resembling orthotics for Andre the Giant into a sleek, small form. They are about to enter a clinical trial, and if successful, they could be sold soon afterward.

Not all Wyss inventions are so readily identifiable. The next contraption that stops Ingber looks mundane enough, with a square base, a smartphone-size LCD screen, a pair of red plastic knobs, and a few docks for blood collection tubes. He removes half of the rounded, plastic top to reveal a far more complicated interior structure filled with valves, motors, and electronics. This invention magnetically pulls pathogens out of a sample of blood to diagnose sepsis, a deadly inflammatory condition caused by a

range of bacteria but also fungi and viruses. Sepsis infections kill more than 1,400 people worldwide every day. Normally it takes days for doctors to identify the causative patho-gen by growing it in culture. And until they know the precise cause of the problem, they can’t choose the appropriate treatment.

The device in front of us borrows a tool of the human immune system: molecules known as opsonins, which bind to patho-gens, marking them for destruction. The opsonins inside this device are genetically modified variants of naturally occurring ones, each one stuck to the surface of a microscopic magnetic bead. When infected blood courses through the machine, the opsonins latch onto pathogens. Magnets built into the device then pull on the beads, washing them out of the blood, pathogens in tow. Finally, an internal microscope scans the filtered pathogens, enabling scientists to identify the culprit or culprits so they can provide speedy treatment.

The magnetic beads were Ingber’s idea,

a remnant of work he’d begun at Yale. A member of the Advanced Technology Team, Michael Super, is an expert in opsonins, so he took charge of genetically modifying the molecule to make it more efficient. Even the nuts and bolts of the machine can be traced back to Wyss production lines. Ingber snaps out a chamber that holds the blood and other fluids, explaining that it was manufac-tured on a 3-D printer a few steps away.

The device excites Ingber not only because it is his brainchild. From the tour, it is clear that he is proudest of the inventions that are edging out of the lab and into the world: The institute’s true measure of success, he says, will be the companies started and tech-nologies licensed over the next five years. Ingber is confident the Wyss will succeed. “We’ve built a new model for innovation,” he declares, that should produce technology solutions “at an unprecedented rate.”

Gregory Mone is a regular contributor to DISCOVER and author of the novel Dangerous Waters (2012).

(#76190) Copyright 2013 by Discover Media LLC. Reprinted with permission from the April 2013 issue of Discover.This PDF is authorized for electronic distribution and limited print distribution through March 18, 2014.