Our cells have abilities that go far beyond the fastest, smartest computer. They generate mechanical forces to propel themselves around the body and sense their local surroundings through a myriad of channels, constantly recalibrating their actions.
The idea of using cells as medicine emerged with bone marrow transplants, and then CAR-T therapy for blood cancers. Now, scientists are beginning to engineer much more complex living therapeutics by tapping into the innate capabilities of living cells to treat a growing list of diseases.
That includes solid tumours like cancers of the brain, breast, lung, or prostate, and also inflammatory diseases like diabetes, Crohn’s, and multiple sclerosis. One day, this work may extend to regenerating tissues outside or even inside the body.
Taking a page from computer engineers, biologists are trying their hands at programming cells – by building DNA circuits to guide their protein-making machinery and behaviour.
“We need cells with GPS that never make mistakes in where they need to go, and with sensors that give them real-time information before they deliver their payload,” said Hana El-Samad, PhD, a professor of biochemistry and biophysics. “Maybe they kill a little bit and then deliver a therapeutic payload that cleans up. And the next program over encourages the rejuvenation of healthy cells.”
These engineered cell therapies would be a huge leap from traditional therapies, like small molecules and biologics, which can only be controlled through dose, or combination, or by knowing the time it takes for the body to get rid of it.
“If you put in drugs, you can block things and push things one way or the other, but you can't read and monitor what’s going on,” said Wendell Lim, PhD, a professor of cellular and molecular pharmacology who directs the Cell Design Institute at UCSF. “A living cell can get into the disease ecosystem and sense what's going on, and then actually try to restore that ecosystem.”
Like people, cells live in communities and share duties. They even take on new identities when the need arises, operating through unseen forces that biologists term, “self-organizing.”
Some living cell therapies could be controlled even after they enter the body.
Lim and others say it is possible to begin adapting cells into therapy, even when so much has yet to be learned about human biology, because cells already know so much.
Their built-in power includes dormant embryonic abilities, so a genetic nudge in the right place could enable a cell to assume a new function, even something it has never done before.
“When a cell, a building block that’s 10 microns in diameter can do that, and you have 10 trillion of them in your body, it’s a whole new ballgame,” said Zev Gartner, PhD, a professor of pharmaceutical chemistry who studies how tissues form. “We’re not talking about engineering in the same way that somebody working at Ford or Intel or Apple or anywhere else thinks about engineering. It’s a whole new way of thinking about engineering and construction.”
For several years now, synthetic biologists have been building rudimentary feedback circuits in model organisms like yeast by inserting engineered DNA programs. Recently, Lim and El-Samad put these circuits into mice to see if they could tamp down the excess inflammation from traumatic brain injury.
They demonstrated that engineered T-cells could get into the sites of injury in the brain and perform an immune-modulating function. But it’s just a prototype of what synthetic circuits could do.
“You can imagine all kinds of scenarios of therapies that don’t cause any side effects, and do not have any collateral damage,” said El-Samad.
UCSF researchers are building ever more complex circuits to move cells around the body and sense their surroundings. They hope to load them with DNA programs that trigger the cell’s protein-making machinery to do things like remove cancerous cells, then repair the damage caused by the tumor’s haphazard growth.
Or they could make cells that send signals to finetune the immune system when it overreacts to a threat or mistakenly attacks healthy cells. Or build new tissue and organs from our body’s own cells to repair damage associated with trauma, disease, or aging.
“The fact that biological systems and cellular systems can self-organize is a huge part of biology, and that’s something we’re starting to program,” Lim said. “Then we can make cells that do the functions that we want. We aspire to not only have immune cells be better at killing and detecting cancer but also to suppress the immune system for autoimmunity and inflammation or go to the brain to fight degeneration.”
SOurce: UCSF