The man who built organs on chips

Does Donald Ingber have the best job in science? He thinks so. He directs the Wyss Institute, a biomedical research centre set up at Harvard with the largest single donation in the university’s history: a $125million gift from Swiss entrepreneur-philanthropist Hansjorg Wyss. The conditions were that the director had to take risks with the money entrusted to him – and he had to be Ingber.

Ingber has a record of kick-starting scientific revolutions. A one-time cancer researcher, he’s a founder of  “biologically inspired engineering” – a new field that emulates nature’s design principles to find new ways to tackle problems ranging from cardiovascular disease and cancer to energy efficient windows.

He was the first to realise that cells sense and respond to their physical environment via an internal network of tensioned fibres, similar to the way a spider detects a fly in its web. His team was also the first to marry electronics to biology to make living “organs on chips” – tiny automated bits of human organs that promise to revolutionise the pace of drug discovery.

At the Wyss, if any of his team comes up with an equally revolutionary idea Ingber has the funds to make it reality. “I sometimes feel like Santa Claus,” he says, with a twinkle in his eye to match. Ingber keeps his beard more neatly trimmed – and himself far more trim – than Santa. But he radiates the kind of energetic, creative, can-do attitude that you’d want around the North Pole in the pre-Christmas rush.

The Wyss Institute started in 2009 but didn’t get its physical lab space up and running for another year. But it already boasts a remarkable track record – close to 1,000 patent filings and nearly 800 journal papers published. For 58 months running Wyss researchers, comprising 375 staff led by 31 academics, have had at least one paper published each month in Science or Nature.

These feats have been achieved even though the academics effectively work at the Wyss in their spare time. Each has a full time position in their home faculty at Harvard as well as leading teams of researchers at the Wyss. Ingber himself holds two Harvard positions – an endowed chair at Harvard Medical School and the Boston Children’s Hospital; and a professorship at Harvard’s School of Engineering.

The Wyss’s academic achievements tell only half the story. Hansjörg Wyss is a Harvard Business School alumnus who made a fortune with a medical implants business specialising in plates and screws for fixing broken bones. He funded the institute specifically to carry out “translational research” – to bridge the chasm between academic research and useful products.

So Ingber’s success is also measured in commercial terms – in patents gained (28 so far); products licensed (34); start-up companies formed (17 incorporated or being discussed); and products on the market (one). The process is going so well that last year Wyss doubled his donation, giving the institute a second $125 million gift. Again, the cash was contingent on Ingber staying on as director for the next five years.

Don Ingber grew up on Long Island in one of New York’s first modern suburbs, built in the early 1950s. It left a lasting impression. “Every house identical,” he recalls with a shudder. “Same refrigerator, dishwasher, ovens – everything was identical. I was so bored. That was the driving force for me to work as hard as I did for the rest of my life.”

Science wasn’t part of Ingber’s escape plan. At school he excelled at mathematics, and that’s what he chose to study at Yale. “When I got to Yale it was a dream come true,” he says. Everything except maths class, that is. “I got turned off. I went to such advanced courses that everybody was like Poindexters (nerds) with thick glasses and serious, and I just walked out and never went back.”

The switch to science came naturally. Ingber ended up majoring in molecular biophysics and biochemistry. “I never thought I wanted to be a scientist, but I always had a natural sense of how things worked and a wonder for how things worked – and that to me is the essence of science,” he says.

But others had seen the scientist in him early on. “When I was a kid all my friends’ parents gave me science toys for my birthday. But I wanted to build with building blocks.”

Today, Ingber can indulge both interests at the interface of biology and engineering. An appreciation for the mechanical has been at the heart of the insights he has brought to cellular biology. But he was set on this path in an undergraduate sculpture class.

“I always really wanted to get into an art class. It was so competitive at Yale they had interviews through the night. I was turned down. But then I saw these students walking around campus carrying geodesic sculptures that looked just like the viruses I was studying.”

Intrigued, Ingber tracked down the course, which as luck would have it, was taught by his girlfriend’s lecturer, an Austrian sculptor called Erwin Hauer. Hauer let Ingber into the class.

The career-shaping day came early in the course. Ingber and his classmates were making rigid, three-dimensional structures from wooden dowels and fishing line, built so none of the sticks touched each other. It’s a construction concept called “tensegrity”, a term coined by the architect and inventor Buckminster Fuller. The way it works, Ingber explains – the sentences flying from his tongue – is that the wire is tensioned against the rigid wood dowels, holding the structure up. “It’s really how our bodies are built. If you go to an anatomy lab and see a human skeleton, it has to be wired together and hung from a stick to look like us.” In the living body, our muscles, tendons and ligaments pull against our rigid bones to hold us upright.191015 ingber 4

Back in the mid-1970s, Hauer introduced the concept to his class while playing with a small tensegrity model held together by elastic. He’d squash it flat then let it go and the structure would ping back into its roughly spherical shape, bouncing up off the table. That motion resonated with Ingber. He’d seen it before. “About three days earlier I had just started to do research in a cancer lab where I was culturing cells for the first time,” he recalls. “To do that, you grow cells on a dish, where they stick and stretch out, holding themselves down with tiny molecular anchors. To move them to another dish you add an enzyme called trypsin that clips their molecular anchors – and the cells retract and leap up off the dish.”

At the time, cell biology was at a pivotal point. The first papers showing that cells had an internal “cytoskeleton” scaffold were appearing. “And I saw this thing bounce up off the table in my sculpture course and thought, ‘oh, that must be how cells work’.”

The insight was original. The more Ingber discovered about cells, the more important it appeared to be. The first time-lapse movies of cells forming an embryo were starting to appear. “You saw this incredible physicality of cells in the embryo, the cells are all pushing and pulling, moulding the organs,” he says.

Also at that time, a Harvard professor called Judah Folkman, who demonstrated that cancers rely on blood vessels to feed their growth, published a paper in Nature suggesting a cell’s shape can also control its growth. When cells could stretch out they grew, and when they were round they didn’t.

All these strands of research started to coalesce in Ingber’s mind. “So I had this idea there was mechanical control of growth,” he says. Cells were using their internal tensegrity to sense and take developmental cues from their physical environment, he realised. In the developing foetus, that’s how organs form, and when this process goes awry in adults, it can lead to cancer.

As Ingber came to the end of his PhD, “the one person I wanted to work with was Judah Folkman”, he recalls. Folkman liked Ingber’s ideas and invited him to Harvard. “I showed him my tensegrity model and he was showing everybody – ‘look at this, he’s figured it out!’ ” Ingber joined Folkman’s lab. His goal was to prove that mechanical forces affect cell shape, which in turn controls how those cells behave.

Harvard isn’t short of creative minds. A conversation over a beer led to Ingber finding a way to prove his theory. One of Ingber’s students was chatting to a student from Harvard chemist George Whitesides’s lab. Whitesides, now in his mid-70s but as active as ever, is the world’s most highly cited chemist. In the 1990s Whitesides’s group had been experimenting with simpler, cheaper ways to make computer chips. They found a way to do this by stamping out tiny patterns. The researchers thought the technique might also be useful for biology, but weren’t sure how it could be used.

Ingber and his student realised they now had the means to stamp out different sized footholds for cells. Cells normally attach themselves to a substance they produce called the extracellular matrix. Whitesides’s and Ingber’s groups got together and stamped out different-sized dot patterns of extracellular matrix. Each patch of extracellular matrix was identical, apart from their sizes. And yet cells behaved differently on each: on wide dots the cells would stretch out and start to grow; cells on medium-sized dots stopped growing and started to differentiate; and cells on tiny dots no bigger than themselves died.

It was final, conclusive proof that cells are mechanical structures, sensing and responding to the physical nature of their environments.

Ingber’s research still revolves around his discovery of the physical interaction between cells and their environment. His rich collaboration with Whitesides – now one of the core faculty members at the Wyss – led Ingber down the path to creating “organs on chips”, which promises to revolutionise drug discovery.

Before being tested on people, experimental medicines are tested on cell cultures in petri dishes. But as Ingber has established, our cells are attuned to their environment, and so behave differently in a dish than they do inside the body. Ingber’s idea was to engineer environments to make different cell types feel at home. He created a lung on a chip, which uses air pumps to continually stretch and release lung cells as they would in a living, breathing lung. He’s made a kidney on a chip through which liquid flows like urine in the real organ; and an intestine on a chip in which intestinal cells are pulled and released in the same Mexican wave motion our bodies use.

The idea is they will experience the same forces as they would inside the body. This should make organs on chips the perfect platform on which to develop new drugs, replacing animal testing which is frequently fallible. In 2010, Ingber published a paper on his lung-on-a-chip in Science, quickly winning funding support from the US Food and Drug Administration, the National Institutes of Health and the Defense Advanced Research Projects Agency. The team has now developed more than 10 organ-on-a-chip models, and has developed an automated instrument to allow these organs to work together to make what is effectively a whole body on a chip. This July the team announced a start-up company to drive the idea towards commercialisation.

The Wyss Institute is unique, and not only because of the money its benefactor has pumped in. Its focus on research with near-term potential to transform society is itself a new experiment. In a traditional university department every academic has their own patch of lab space to rule over. Not at the Wyss. There, lab space is allocated not to people but to projects, which involve many academics. And then there’s the unusual make-up of the staff. More than 40 members have been recruited from industry for their experience in developing products for market. These skills are embedded into every project.

Ingber recalls the pivotal conversation with Hansjörg Wyss that kick-started this vision. “Wyss said: ‘I know big companies, they’re great at product development but they can’t innovate – I can’t make my own company change direction, it’s like a tanker. And I know academia, you guys do creative innovative things but you publish papers and nothing ever happens. I want to see a start-up in the midst of the world’s greatest academic environment that’s going to have near-term impact, that’s going to work with industry, do high-risk stuff, and span the academic interface’.”

One example is the cancer vaccine, developed by Wyss faculty member David Mooney, that the Wyss is putting through early stage human clinical trials. Vaccines are usually made in a lab but this one is made in a patient’s body. A “boot camp” for immune cells, it takes the form of a finger-nail sized sponge that is impregnated with bits of the patient’s tumour plus factors that rile immune cells. In the preclinical study reported in Science Translational Medicine in 2009, 50% of mice treated with two doses of the vaccine showed complete tumour regression. All would have otherwise died from melanoma within about 25 days.

And yet no company was willing to test this unconventional treatment on people. So Ingber stepped in, dipping into his risk fund to pay for the initial human clinical trials. “I thought: ‘We’re supposed to take risks – let’s do it!’”. So far a handful of patients have received the therapy, and having human results should be enough to persuade a pharmaceutical company to step in, license the implant and put it through final clinical trials.

Ingber has always been driven towards translational research. “When I was a kid my grandmother had heart disease. I would give her oxygen and do her blood pressure and watch the doctors come in to do her bloods. A part of me wanted to have an impact on healthcare, and I felt I could have more impact by doing science that was transformative rather than taking a gall bladder out every hour.”

Folkman was one of the first academics to work closely with industry to try to get their ideas out into the real world – to the horror of his contemporaries. “He got a $23 million grant from Monsanto in the 1970s, and there was a four-page article in Science saying he had sold out,” Ingber recalls. “But he got the support of the [university] president, and it funded his cancer research for 10 years.”

The hostility to industry collaboration may have died, but ambivalence often lives on. “I once met with a guy who was showing me his work, he was so excited, he’d found this chemical that looked like it inhibited cancer, and I said, ‘Did you patent it?’ He said, ‘Oh no, I wouldn’t do that, I’m not interested in money. I just published it.’ And I said, ‘Well, it’s never going to see a patient, you just killed that technology’.” Without the protection of a patent, no company would invest the vast sums needed to develop a promising chemical into a licensed drug.

Not long after Ingber arrived at Harvard he became involved in consulting work for industry. In the 1980s he launched his first start-up company with fellow Folkman protégé Bob Langer, the biochemical engineer based nearby at MIT who has 1,250 scientific publications to his name, holds more than 1,000 patents, and has launched two dozen start-ups. “So I started to get into that world, and started to see people could be creative from a business perspective as much as from a science perspective – and that you don’t have impact unless you commercialise it.”

What aspect of the Wyss Institute’s growing reputation is Ingber most proud of? The model for translational research that he and his team have developed, Ingber says. It’s a model he hopes other institutes will be able to adopt, at least in part.

And yet there’s something unique about the Wyss, both in its generous funding and its geographic location at the heart of the world’s leading academic institute – and in its driven and visionary leader.

“I’ve been at Harvard for 30 years, and you are always playing tennis with somebody that’s better than you. And it’s good, it keeps all of us trying to play the game, keeps us swinging.”

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