THOMAS LARSON

(San Diego Reader January 28, 2015)

Because I’m a writer, I have always thought that among humankind’s most lofty inventions is the printer—the machine, not the person. Be it text or image, how would we know anything about the community we call home without copies of weekly magazines that feature glossy ads for breast enlargement and trend-chasing cover stories? For centuries, print technology has copied text and image onto paper, stone, wood, plastic, or any surface that will receive it. Of course, the copy is flat, sitting on, not rising up from, the surface. But what if we wanted to print something in three dimensions?

We’d have to print the item, in one fell swoop or in parts (with much assembly required), in space—a sippy cup (out of plastic), a pair of Crocs (out of closed-cell resin), a Mercedes (out of steel, fiberglass, leather, and a Bang & Olufsen stereo system).

In the 1980s, at the dawn of the computer age, the idea of three-dimensional printing began light-bulbing a path through the minds of MIT engineers. They discovered that a software program could scan as an “image,” say, the key to your car’s ignition. Designers created a digital model or prototype of that key. They adapted an inkjet printer (replacing the ink with a thermoplastic) and laid down (or built up) the body of that key, layer by layer: two inches long, half-an-inch wide, an eighth of an inch thick, cutting its edges to conform to the exact ridges and valleys of the original.

What’s being called a revolutionary technology, transforming manufacturing and promising paradisiacal health benefits much as stem-cell research did (more on 3-D bioprinting shortly), starts to make sense when I visit David Feeney and Bennett Berger, cofounders of SD3D on Convoy Street. It’s a boot-strapped, two-guys-will-print-it operation, a storefront space the size of a dentist’s waiting room. Over-tabled and over-strewn with wires, needle-nose pliers, gears, laser-light motors, Frappuccinos, and half-a-dozen desktop 3-D printers, whole or in various stages of undress. Four printers are buzzily at work, making robot parts, “26 hours a day,” says Berger. Their nozzles or extrusion tips zip and zigzag a solid object into being: “It’s an additive technology,” Feeney says. “It builds. You’re not cutting anything away.”

Feeney’s just out of SDSU and a quick stint at Solar Turbines. He’s as business savvy as those rapacious millionaires on Shark Tank. He orients me by describing injection-mold printing. You take an object and make a mold, pour in plastic or titanium or cookie batter, let harden, and there’s your copy. (Feeney says the Chinese and the Mexicans are today’s top mold merchants, stamping out Wal-Mart plasticware more cheaply and quickly than anyone.) With 3-D, you don’t need the mold because your computer scans the object—he calls such programs, “infinite digital molds”—and the printer welds it, so to speak, before your eyes.

What’s curious about SD3D is that it’s a startup that keeps starting up because the desktop printers, and their unending small jobs, fail 30 percent of the time. Only those $250,00 printers, used by the defense industry to print the real toys, for example, work all the time. It’s maddening how much Feeney and Berger have to baby their printers.

Feeney and I watch a printer make a large plastic part when, on cue, the nozzle, madly extruding a layer of 220º Celsius plastic, goes rumble-bump, like a dresser drawer pulled open. Feeney calls it: “Right there. That’s a failure. I’ll have to stop this and start over.” He says a mistake-free “complete printer” can calibrate down to five micron-thick layers, but the housing’s temperature remain constant. For this printer, MakerBot, Feeney sticks his hand under the platform on top of which the piece is growing and twists a little gear. “How not sophisticated these machines are!” Can machines, I wonder, be smarter than the error-prone humans who build them?

Majorly frustrated, Feeney and Berger, who often finish one another’s sentences, are erecting their own 3-D printer to augment, or supersede, the stumblebum machines they’re stuck with. Their goal—to build failsafe machines—is a technology, Feeney says, that “everyone has given up on.” Investors with cash to burn? SD3D is on the Web.

The pair were invited here by the building’s owner who’s gathered start-ups into this two-story design center on Convoy called Ansir. He had the 3-D guys put a printer in his Pangea Bakery Café, next door. There, in a “tech corner,” it “prints” little Nutella chocolates or curvy plastic gewgaws, which, charming patrons with their bee-like fussiness, become friendly ads for this new technology. No, it can’t print a copy of your iPhone but it can make an iPhone case.

Out of what? Thermoplastic—a substance that is soft and moldable when heated and quickly turns solid when cooled. One type of thermoplastic, a biodegradable brittle material derived from corn starch and sugarcane, “smells like waffles,” Berber says, when cooked to form. The rubbery or flexible plastics, which some printers use, are carbon composites, “high-strength and low-weight.”

Berger says the beauty of this technology is “location-based manufacturing,” in effect, local companies like theirs “doing just-in-time printing” and “lowering the carbon footprint.” All cheap parts don’t need to be shipped from China. Consumer demand (think 3-D machines under Christmas trees) is a fad, Feeney says. Too few father-son hobbyists can justify a market. As yet. Boom-time will reign when machines are reliable and the material used is “electro-conductive filament.” Such filament can already print the housing for a flashlight with space for batteries.

Could SD3D print a 1962 Corvette? Yes, they could, given the million dollars it would take to buy and run a horde of large and small printers. Hobbyist geeks have scanned every nook and cranny of that Corvette. Given the right material, flexible or stiff as needed, the car is possible to reproduce, though much assembly is required. Feeney’s idea is to get the digital files for the most in-demand parts, put that file in the cloud, and link a print-on-demand website button so SD3D receives an order and makes arm rests and radio knobs in their shop. Simple.

Feeney laments that thousands of things are not made, which can be, because a manufacturer needs ten thousand orders to justify the expense of making the prototype. And yet the “infinite digital mold” idea means that any one-of-a-kind item, say, the cartilage for your aching knee, can be printed once without mass production. Monetizing this—somewhere between the Costco invoice and the one-off body part—is the future. That, he says, should be a “game-changer for the entire economy.”

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It’s true: our 3-D print future arrived last Thursday. Replicator technology already prints gun parts, gold and silver jewelry, fabric, lampshades, dentures (to make a denture is to “creature” it), prosthetic legs and arms, a human jawbone, and food, mostly meltable things like chocolates. (My Neanderthal reaction was, Why print food when you can grow it?) Someone’s printed an electric car from carbon fiber and reinforced thermoplastic. The assembly line car has up to 6000 parts; this one, just 49. And a shout out to my favorite objet méchanique: the self-replicating printer, which prints its own parts and which you assemble into a printer that can, like mirrors mirroring mirrors, copy itself endlessly.

The non-alive stuff Feeney and Berger are printing is called “passive objects.” But now, since bioengineers have crashed the 3-D party, active or living applications have arrived. Nano-technologists have printed a chunk of urinary bladder and successfully implanted it in a child. They’ve made a miniature functional kidney for a lab rat. Skin for grafting. Blood vessels. Capillaries. It’s no surprise, also, that San Diego bio-science labs are leading the charge.

On the UCSD campus, I wander by my old homes, the Music and Literature departments, housed in squat buildings where foliage swallows them like jungle huts. Nothing modest for Structural and Materials Engineering across the street—a gloweringly wide, three-story edifice where today’s device-makers and patent-holders are amassing new nano-matter in corporate-sponsored, group-project labs. The air inside is unwinded, stale, and I note few stare at cellphones.

I find Dr. Shaochen Chen, Berkeley grad, nanotechnologist PhD, and dream-team leader. His bailiwick is the Institute for Bioengineering Medicine where he and his students are printing human tissue. With a background in semi-conductor and laser technology, Chen has steered his passion “to produce something useful. Since I was a child, I’ve always wanted, as an engineer, to improve human health.” He says 3-D bioprinting ignited a desire in him to create “personalized products—not for mass production. Diseases are all individualized. If I can combine 3-D printing and medicine, then I can solve big problems.”

Chen came to UCSD four years ago because of the medical school and his department’s close proximity, intellectually and geographically, a short bike ride apart. Friday casual, he’s wearing a fine grey suit, his dress shirt’s top button unbuttoned. Chen is patient with a non-engineer’s questions. Patient but emphatic: “I do not print cells. I print structures that house cells.” In the past, cells could be grown in a petri dish, but “not in the shape you want.” Voila, a new technology—printing “tissue constructs” in his lab and then, via campus courier, rushing the piece to the school of medicine where, so far, the “patients” receiving the tissue are mice.

His current project is building a “piece of mouse spinal cord,” a four-millimeter thick section, a few centimeters long, to replace the same but defective piece. Alas, the cord section was not hurt from an overload of mouse calisthenics but was “deliberately injured,” the mouse’s health sacrificed for the good of science.

How does it work? Chen creates the scaffold, that is, a structure made of a polymer or a collagen, either organic or inorganic material. The section—the mouse’s spinal cord—has a shape and a mass. (Cell size, Chen says, is measured in nanometers, one thousand millionth of a meter, while tissue, a composite of interlocking cells, is measured in microns, one millionth of a meter.) He calls the mouse section a “tube,” or a nanostructure, cells and the space in between them where blood vessels, neurons, and muscle cells course and connect. (Like the ignition key I discussed earlier, this spinal cord piece is scanned and modeled via a 3-D computer program.)

The scaffold is often made of biodegradable material so it dissolves once the cells of the tissue are added, grow, and take over. Chen’s word is “recruit”—after you place this printed, fledged chunk of spinal cord into the mouse, the cells recruit surrounding cells to bring the new piece in line, in sympathetic order, so to speak, with the environment. As the new piece settles in, the tissue construct dissolves in the same way that after food is digested, it dissolves or turns to waste.

To this end, Chen shows me videos of two printed patches, composed of mouse cardiac cells. First comes the scaffold. This structure comes from a batch of lab-created, differentiated stem cells. Chen calls the scaffold “a micro-architectural environment,” which is built by successive hits from the ultraviolet light of a laser. Layer fuses to layer. As each segment cools, the whole becomes a “solid 3-D structure.” He then extrudes the cardiac cells onto/into the scaffold where they begin to grow.

In the lab, where his institute assembles its own nanotechnology machines—those capable of printing layers five microns thick—one of Chen’s eager graduate students describes the mouse cardiac cells in their micro-architectural environment. Under the microscope, I see the scaffold lines, in parallel array, as cells are added. In a video, later, I watch this tissue construct grow into mouse heart tissue. It’s growing, its cells aligning and pulsing, in harmony, as one.

“They’re alive, right?” I ask. “Yes,” Chen says, “a few days after we inject them” into the scaffold, “they start beating. They beat because that’s their nature. They’re synchronized. They’re talking to each other.” Specific kinds of cells, grouped like a family around dinner table at Thanksgiving, trigger a genetic expression, speak a common language. Heart cells beat in a “cascade of communication,” as if they have a music, in concert, where each one is a member of the choir.

One human application, a life-saving experiment, came in 2008. A bioengineer built a section of windpipe or trachea from a two-year-old girl’s stem cells to repair her faulty trachea. After implantation, she lived only three months. That may be the most complex human surgery yet done using bioprinting.

The difficulty? Living tissue, Chen says, contains a “vascular system.” Vascularization is a network of veins and capillaries that brings oxygen and nutrients, via the blood, to organs and tissue. The networks he creates “can’t be too brittle or too hard.” The challenge is to get them to take, that is, work in the body. To print cell-colonized constructs for the human body requires, before the FDA allows human testing, ten years of experimentation on the vascular systems of animals. Chen and crew are on their way.

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On its way, as well , is Organovo, San Diego’s only bioprinter of human tissue. Its CEO, Keith Murphy, is a chemical engineer who, while at Amgen, developed bio-tech drugs for patients and markets, that is, “everything downstream from the initial R&D.” Murphy, who speaks to me at his Sorrento Valley office, enlisted researchers and investors, as fascinated by the emergent field of bio-physics as he was. The result is Organovo, launched five years ago. Murphy’s explanatory passion feels unrehearsed; his medically savvy fits squarely into crisp paragraphs.

He describes the process of 3-D printing as building an aggregate of “cells in the active space, gel in the negative space.” The gel lasts only until the cells stabilize and begin to multiply, in effect, replacing the gel with their own structure. In 24 hours the cells bind and become self-sufficient, even robust. Once on their own, however, most printed cells die. Within days. It’s presumed that they lack a larger systemic “purpose,” a neurological environment, in which they express their DNA codes. The mystery needs to be uncoded. So far Organovo has built only discrete short-lived “parts”: blood vessels, bio-printed breast and pancreatic cancer tumors, lung and kidney tissue, skin, and the most prevalent, liver tissue.

First, Murphy ticks off tissue applications outside the body. The market for printed liver tissue makes sense, he says, when Big Pharma needs to know whether a drug in development is toxic to the liver. You don’t need a human and a liver to test the toxicity of a drug. In addition, printing petri-dish tumors and bombarding them with drugs is another lab procedure where cell colonies are needed.

What about tissue for use inside the body? Right off, he cautions, no one is building replacement livers. Nor is anyone growing humanoid bodies, like those replicant pods in Invasion of the Body Snatchers, for later-in-life organ exchange. Throw out the idea of “printing whole organs,” a media feast and an industry foolery. (Bioengineers at Wake Forest University have printed and inserted a human bladder, saving one adolescent a lifetime of dialysis.) Instead, Murphy and his 60-person operation are printing surgically transplantable tissue for human livers. “Think of it as a liver patch,” he says. The patch acts as a delay for a patient needing a transplant, a Band-Aid, as it were.

Murphy says that liver cells cluster together like grapes. If you compress the spheroids so the space between them is scrunched, you have an image of liver cells: packed in like those pits full of colored balls children sink in. This compressing creates, via the touch of membranes, a micro-world in which chemical signals are sent and the cells pulse as one. When they quit working, as they do, he says, it’s like Chen’s mouse cardiac cells: they lack the vascular network, that is, the context of the body.

The bioprinters at Organovo are like most: cells and gel material—incubated in a “bio-ink”—drop into a multi-well plate, composed of 24 little cups. The computer-programmed platform on which the plate sits moves up, down, and side-to-side as the material is deposited and baked by laser light, layer by layer of convivial cells. Convivial is a relative term. Liver cells are not “happy,” Murphy says, not until they are companioned with a living liver. Once printed and stored, they last a day. Put into a body, the estimate is, they’ll go for a month, convinced, for a time, that their nativity is real.

One yellow-brick road for Organovo is to build heart muscle tissue to treat heart-attack patients. The coronary victim suffers when the cardiac muscle is deprived of oxygen because his blood flow is temporarily constricted or stopped. It may be possible to replace heart-muscle tissue or add to it by grafting. Either way the heart requires a mostly healthy musculature. Which does last a good three score and ten. Clearly, more heart muscle would mean more life for the aged.

Murphy reminds me that there is such a thing as cell therapy—injecting healthy cells directly into the heart—but the heart is fickle and will accept only five percent of what’s given. The big mystery of cell therapy is identifying the language with which cells of different and neighboring tissues communicate. Organs, remember, are multi-cellular constructs. With the heart, smooth muscle cells speak very actively with fibroblast and endothelial cells, the latter, cells that coat blood vessels and the coronary arteries.

What is the precise chemical language different cell types use for life-sustaining conversations? No one knows. Giving every cell type in an organ a seat at the table won’t insure a fine hand of bridge. One application Murphy would love to discover and print in big batches: a tissue whose signal, a switched-on gene, announces to invading cancer cells that they are surrounded and they will not spread.

Several times in our talk Murphy uses the term “revolutionary.” This technology, moving from 2-D petri dish cell growth and study to 3-D applications, “is very different from what people have worked with before” in the bio-sciences. Its blessing will be to mass produce what he calls automated tissue for research, its chief benefit to forgo “animal models.” He notes that “the right human model will have to be more predictive [of success] than any animal model.” Because, obviously, the intended recipient is not them but us—our cells, tissue, and organs, our inner terra incognita. The hackneyed metaphor of the fish wiggling onto land may apply. More apt is Murphy’s analogy, “an artist who was once stuck modeling clay can now cast bronze.” That’s rather like a Cambrian explosion in the life sciences.

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Here’s a word for the new millennium: morphogenesis. Explored by, among others, Alan Turing, the British mathematician who helped break the Nazi Enigma code, it’s the science of how an organism develops its shape through cellular signaling, stickiness, and differentiation.

As an expression of the morphogenetic, I recognize something like it at an after-school meeting of Patrick Henry High School’s “Patribots.” Kids building robots. I’m watching a dozen of them—buttoned by the two most talkative: one in a Star Trek T-shirt, the other, a dress shirt, tie, and Navy blue sweater—build a computer-controlled robot for a competition run every April at the Sports Arena. The robots, designed by area high school teams, play a soccer-like game as shooters, passers, and defenders. Each machine must pick up a two-foot-diameter exercise ball, move it across a field, pass it to other robots, and bounce, roll, or catapult the ball into a low or a high goal for a score. Extra points go to robots who assist others in scoring. The robot has a few of its mechanical parts made on a 3-D printer, which the kids sketched with computer-assisted design (CAD) programs.

Brown-haired Carolina, team co-president, tells me while describing the upcoming meet that making these machines go is the “hardest fun ever.” (The first robot she helped create picked up ping pong balls and plunked them in a bucket.) At the famously geeky High-Tech High, she says, there’s a whole class devoted to robot-building. “Robotics is at the football level for them.” At Patrick Henry, football remains top dog while their engineering club paws for funds from outside sponsors like Qualcomm.

Harold Mumford is the class advisor. One of his many roles is to enlist those corporate donors and to engage Northrup-Grumman engineers to volunteer as mentors. Mumford’s first calling is to help kids—many would be “blissfully happy” to remain cabled to video games—learn “how to control technology so technology does not control them.” He admits he may have failed at doing just that: “If I let them, they’d stay here all night, working on the robot.”

Mumford says his charges used to be “game heads; now they’re gear heads,” a lateral move but one with more career potential. The complexity of building robots, he notes, taps into what they don’t know and must grok by doing. With video games, they play at the level of their individual expertise. “Here,” Mumford says, whispering, “building a robot together humbles them. As you can see,” he continues, spy-glass sharp but giving little instruction, “we don’t do it for them.”

Sixteen-year-old Josh, Harold’s son, explains to me the 3-D printer’s process, its temperamental nature, its size and material limitations. He lets me hold a few structural gears and balancing wheels the robot needs and the printer has printed. It’s like he’s show-rooming the wonders of a Whirlpool Dishwasher to a house husband. Ah, OK, I see. Amazing.

In addition to the basketball-playing robot itself—it takes the kids time to get the coded signals and electric motors, from computer to device, to talk to each other so the jittery, buzzy catapult rolls itself and arcs the ball and maneuvers past like-minded robots from the other team who are “thinking” how not to let their “opponent” score—I find myself reflecting on how to associate 3-D printing with morphogenesis. One link is that to make a biological shape, cells need to signal one another when to turn on and grow and when to turn off and wait their turn, so to speak. For an organism to shape itself, this kind of cell-to-cell savvy must be known by all participants.

It seems obvious that the Patribots as a team are doing this. If morphogenesis is an interaction among its members toward a goal, which none alone can create, then the organizational plan is already working among these young engineers.

Same with tissue. Cells sort themselves by type—they elongate, separate, fold, and thin into distinct layers where the combinations build structures. What tells them to become what they become? DNA tells cell types to stick to each other and function. That’s when they not only pulse but also live beyond a day. DNA also tells cells when to join other cells that have different adhesive qualities, different biological outcomes. In this way, tissue becomes a shape when the different cell types either stick or stay separate and remain singularly focused.

If one wants to bioengineer anything, it’s safe to say that creating these matrices of cells so they pulse in harmonic alignment, attracting siblings and cousins and the occasional stranger, for a larger, shared purpose—well, that’s it. One is not just printing 3-D objects. One is making life itself. There’s no other way forward, I’m afraid, than adapting to what evolution has selected us for. The Patribots already know this.