FANCY a liver that works a little harder? Synthetic DNA circuits inserted into human stem cells could soon allow us to build new organs with unprecedented precision and speed. The circuits can be designed on a computer and assembled from ready-made parts ordered online. The technique could prove an efficient way of making organs for transplant without the worry of rejection, and raises the tantalising possibility that it might one day be possible to upgrade the organs we were born with. Human cells have already been used to create a tiny liver and a set of neurons.
“At the moment, the aim is to normalise cells, but in future, enhancement has to be on the menu,” says , a professor of regenerative medicine at University College London, who wasn’t involved in the work.
“Everything we have in our bodies is hardwired,” says synthetic biologist at the Massachusetts Institute of Technology, part of the team pioneering the new approach. Apart from egg and sperm cells, all our cells contain exactly the same genetic instructions. They develop into different kinds of cell because “epigenetic” switches turn some genes on and others off. By hijacking this mechanism, we can rewind adult cells to an embryonic-like state and make them develop into different tissues.
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To turn these induced pluripotent stem (iPS) cells into a specific tissue type, they are typically placed in a soup of DNA and signalling molecules. These enter the cells and flick certain epigenetic switches. What gets turned on or off depends on the ingredients in the soup. “The problem is that there are tens of thousands of these switches that all need to be set in the right way,” says Mason. Another hurdle is that all cells in the soup are influenced in the same way and grow into the same tissue type. But a piece of liver tissue, say, is not the same as a functioning liver. The issue is even more apparent with complex organs such as hearts, says Guye.
What would be more helpful is an instruction manual that each individual stem cell can follow during its development. And this is exactly what Guye’s team has provided. They started by looking at what happens in neurons and liver cells during natural embryonic development – which genes are switched on and when. They then designed and built artificial DNA control circuits to reproduce this switching in iPS cells. The circuits are slotted together using a combination of standard DNA parts – such as sequences that code for different proteins – available from online repositories and newly synthesised genetic material. These circuits were then chemically inserted into thousands of iPS cells (Nucleic Acids Research, ).
Control from inside
“You assemble it into one large logic circuit and put it into the cell,” Guye says. “It’s interfacing with the natural system. We’re not replacing anything, we’re putting a control layer on top.”
Once in the cell, the circuitry kicks into action. “The idea is that the circuit is pretty much autonomous,” says Guye. It can measure activity – such as levels of gene expression in the cell – and react to it. When the circuit detects that an iPS cell has turned into a precursor cell, for example, it can initiate the next stage of development.
As yet unpublished results suggest that the technique is faster and more reliable than existing methods of creating tissues from iPS cells (see Programming a new liver). In one study, his team turned iPS cells into neurons in just four days with almost 100 per cent success. “If true, it’s incredibly rapid,” says Mason. “Normally it takes weeks.”
Another advantage of Guye’s approach is that it only requires cells from one person. “You get an organ that really corresponds to an individual,” he says.
But before the technique can be used to grow organs for transplant, Guye’s team needs to find a way to get rid of the artificial DNA once it has done its job. It currently lasts inside the cells for a few weeks, and is passed on when they replicate – it “becomes physically part of the genome”. Although the artificial DNA is unlikely to cause any harm, people will have legitimate concerns about long-term implications, says Guye. One solution would be to build circuits out of messenger RNA, which would survive long enough to push the cells in one developmental direction and then degrade after a few days.
“We are overriding the natural programming with our gene circuit,” says Guye, who presented the work at the at Imperial College London earlier this month. “The cells already have the knowledge. We are just helping them get on their way.” For many, however, the ideal is to create tissues and organs with added extras such as resistance to parasites (see “Designer organs to order“).
“The logical end point is to create organs with added extras, such as resistance to parasites”
“This is what we are going to do,” says Mason, although he admits we’re not there yet and the regulators certainly aren’t. Takanori Takebe at Yokohama City University in Japan agrees. “I think it is theoretically possible to improve the functions of generated organs,” says Takebe, whose group recently got three cell types to self-assemble into a tiny liver similar to the one Guye has made. Ethical discussions will be needed though, he adds.
“At the moment, it exceeds our knowledge,” says Guye. “We would need to re-engineer much more than our gene circuit.” But in the long term, he thinks the limitations will be conceptual rather than technical. “What type of new organ or function would one wish for?”
Designer organs to order
If you could build body parts from scratch with exquisite control (see main story), why not improve on what nature gave us?
“One quickly gets into an area of science-fiction-like speculation,” says Patrick Guye of the Massachusetts Institute of Technology, whose team is laying the foundations for this to become a reality. In theory, he says, we can imagine creating a human organ for detecting magnetic fields – birds have such things, for example. But augmenting organs, rather than making entirely new ones, is within closer reach. Synthetic biology provides a rapidly increasing number of biological sensors that react to different stimuli. These could be inserted into tissues so that gene expression could be controlled by light alone, say, which may allow less invasive treatments.
People with brain disorders like Parkinson’s, caused by the loss of nerve cells that produce dopamine, could benefit from neurons that release an extra hit. Growing 1000 more-potent brain cells instead of 100,000 normal cells would make cell therapies more affordable and quick to implement, says Chris Mason of University College London.
Other ideas suggested by researchers contacted by Â鶹´«Ă˝ include organs that can release drugs on demand, that are resistant to parasites or that break down toxins we can’t deal with.
This article appeared in print under the headline “Better than nature”