In June 2011, an Eritrean man entered an operating theatre with a cancer-ridden windpipe, but left with a brand new one. People had received windpipe transplants before, but Andemariam Teklesenbet Beyene’s was different. His was the first organ of its kind to be completely grown in a lab using the patient’s own cells.
Beyene’s windpipe is one of the latest successes in the ongoing quest to grow artificial organs in a lab. The goal is deceptively simple: build bespoke organs for individual patients by sculpting them from living flesh on demand. No-one will have to wait on lengthy transplant lists for donor organs and no-one will have to take powerful and debilitating drugs to prevent their immune systems from rejecting new body parts.
The practicalities are, as you can imagine, less straightforward. Take the example I have already described. The process began with researchers taking 3D scans of Beyene’s windpipe, and from these scans Alexander Seifalian at University College London built an exact replica from a special polymer and a glass mould. This was flown to Sweden, where surgeon Paolo Macchiarini seeded this scaffold with stem cells taken from Beyene’s bone marrow. These stem cells, which can develop into every type of cell in the body, soaked into the structure and slowly recreated the man’s own tissues. The team at Stockholm’s Karolinska University Hospital incubated the growing windpipe in a bioreactor – a vat designed to mimic the conditions inside the human body.
Two days later, Macchiarini transplanted the windpipe during a 12-hour operation, and after a month, Beyene was discharged from the hospital, cancer-free. A few months later, the team repeated the trick with another cancer patient, an American man called Christopher Lyles.
Macchiarini’s success shows how far we have advanced towards the goal of bespoke organs. But even researchers at the cutting edge of this area admit that decades of research lie ahead to overcome all obstacles.
“A good way to think about it is that there are four levels of complexity,” says Anthony Atala from the Wake Forest Institute for Regenerative Medicine, one of the leaders of the field. The first level includes flat organs like skin, which comprise just a few types of cells. Next up are tubes, like windpipes or blood vessels, with slightly more complex shapes and more varied collections of cells. The third level includes hollow sac-like organs, like the bladder or stomach. Unlike the tubes, which just act as pipes for fluid, these organs have to perform on demand – secreting, expanding or filtering as the situation arises.
Grow your own
Scientists have fashioned lab-grown organs from all three of these categories. Surgeons have implanted artificial skin and cartilage into thousands of patients. Synthetic windpipes are now a reality. Artificial blood vessels are going through clinical trials for patients on dialysis and children with congenital heart problems. Atala himself has transplanted lab-grown bladders into several patients, the first of whom has now been living with her new organ for over a decade.
It is the fourth level that presents the greatest challenge: the solid organs like the kidneys, heart, lungs and liver. They are thicker than most of the others, and each has a complicated architecture, featuring many different types of cells and an extensive network of blood vessels to provide them with oxygen and nutrients. Incorporating these vessels into growing organs, especially at the microscopic scale required, is a particularly vexing problem. Without cracking it, lab-grown organs will always stay small and simple.
But whether it is “level one” or “level four” organs, the basic premise is the same. You need a source of the patients’ own cells, and you need to coax them into growing in the right way. The cells can come from a patient’s own organs – even a sample the size of a postage stamp can be expanded to seed an entire scaffold. Stem cells, as used for Beyene’s windpipe transplant, provide an even more efficient source. And since 2006, scientists have been rapidly developing ways of reprogramming adult cells back into a stem-like state, providing a ready supply for aspiring organ-builders.
Once you have the cells, you need to steer the way they grow and specialise. That means getting the right balance of temperature, pH, hormones, and more. It also means exposing growing tissues to the forces they would normally experience inside the body. Engineered arteries need to experience pulses of pressure that simulate the blood that normally pumps through them. Engineered muscle needs to be stretched. Engineered lungs need to feel a regular flow of air. “Every cell has the right genetic information to create the organ. You just need to put them in the right environment,” says Atala.
We can build you
The cells also need to grow along the right shapes, so getting the right scaffold is essential. For simple organs, like Beyene’s windpipe, it is possible to fabricate the whole scaffold from scratch. But solid organs have more complex shapes, so some teams start with existing organs, taken either from cadavers or from animals. They use detergents to strip away the cells, leaving behind a natural scaffold of connective tissues and blood vessels, which can then be seeded with a patient’s stem cells. It is the equivalent of stripping a building down to its frame and filling the walls back in. Scientists have made livers, lungs and even beating hearts in this way, and some have started to transplant their organs into animals.
Some researchers are excited by the potential organ-building capabilities of three-dimensional (3-D) printers. These devices are modified versions of everyday inkjet printers that squirt living cells rather than drops of ink. Layer by layer, they can make three-dimensional structures such as organs and, as of September last year, the blood vessels they contain. Atala is developing this technique – he wowed the audience at a TED conference last year by printing a kidney on stage (although not a functional one). He says, “For the level four organs, it’s just a matter of time,” says Atala. “We’re still a long way from full replacement, but I do believe that these technologies are achievable.”
Even after scientists successfully devise ways of growing organs, there are many logistical challenges to overcome before these isolated success stories can become everyday medical reality. “Can you manufacture them and grow them on large scales?” asks Robert Langer, a pioneer in the field. “Can you create them reproducibly? Can you preserve them [in the cold] so they have a reasonable shelf-life? There are a lot of very important engineering challenges to overcome.”
Doing so will take time, perhaps decades. Laura Niklason from Yale University first described how to engineer an artery in 1999, but these lab-grown vessels are only now ready for clinical trials in humans. If these simple tubes – just level two in Atala’s hierarchy – took a dozen years to advance, it is a fair bet that solid organs will take much longer.
But advance they will, driven in part by a substantial and growing medical need. “We’re doing a better job of keeping people alive longer, and the more you age, the more your organs tend to fail,” says Atala. “The number of patients on our transplant lists continues to increase, but the number of transplants performed remains flat. The need is only going to become more prominent as time goes on.”