Program Me Some Cells, Please

Tempted though I might be to write about Nvidia’s new platform for “physical AI” – aka, robots – I figured plenty of others will do that. What’s another trillion in market cap for Nvidia, anyway?  On the other hand, I don’t see enough excitement about some recent research at Rice University on “smart cells.”

If you want to program cells, Xiaoyu Yang is your man. Credit: Jeff Fitlow/Rice University

The research, published in Science with the matter-of-fact title Engineering synthetic phosphorylation signaling networks in human cells (by contrast, Nvidia’s marketers named their foundation models for humanoid robots “GRooT Blueprint” -- now, that’s catchy), was about how to program human cells to detect and respond to signals in the body. Between synthetic biology and robots. I’ll pick synthetic biology everyday (unless the robots are nanobots, of course).  

“Imagine tiny processors inside cells made of proteins that can ‘decide’ how to respond to specific signals like inflammation, tumor growth markers or blood sugar levels,” said Xiaoyu Yang, a graduate student in the Systems, Synthetic and Physical Biology Ph.D. program at Rice who is the lead author on the study. “This work brings us a whole lot closer to being able to build ‘smart cells’ that can detect signs of disease and immediately release customizable treatments in response.”   

Imagine, indeed.

It turns out that there is a natural process called phosphorylation, which cells use to respond to their environment. As the Rice press release explains: “Phosphorylation is involved in a wide range of cellular functions, including the conversion of extracellular signals into intracellular responses — e.g., moving, secreting a substance, reacting to a pathogen or expressing a gene.”

It goes on to elaborate:

Phosphorylation is a sequential process that unfolds as a series of interconnected cycles leading from cellular input (i.e. something the cell encounters or senses in its environment) to output (what the cell does in response). What the research team realized — and set out to prove — was that each cycle in a cascade can be treated as an elementary unit, and these units can be linked together in new ways to construct entirely novel pathways that link cellular inputs and outputs.

“This opens up the signaling circuit design space dramatically,” said Caleb Bashor, an assistant professor of bioengineering and biosciences and corresponding author on the study. “It turns out, phosphorylation cycles are not just interconnected but interconnectable — this is something that we were not sure could be done with this level of sophistication before. Our design strategy enabled us to engineer synthetic phosphorylation circuits that are not only highly tunable but that can also function in parallel with cells’ own processes without impacting their viability or growth rate.”

The “sense-and-respond” cellular circuit design occurs rapidly – seconds or minutes – which allows it to be used for processes that occur on similar timescales, unlike other previous efforts. For example, the researchers tested it to detect and respond to inflammatory factors, which they believe could be used to control autoimmune flare-ups and reduce immunotherapy-associated toxicity.

Soon-to-be Dr. Yang added: “We didn’t necessarily expect that our synthetic signaling circuits, which are composed entirely of engineered protein parts, would perform with a similar speed and efficiency as natural signaling pathways found in human cells. Needless to say, we were pleasantly surprised to find that to be the case. It took a lot of effort and collaboration to pull it off.”

Professor Bashor concluded: “Our research proves that it is possible to build programmable circuits in human cells that respond to signals quickly and accurately, and it is the first report of a construction kit for engineering synthetic phosphorylation circuits.”

A “construction kit” for “programmable circuits” in human cells.  Tell me that’s not exciting stuff.

Caroline Ajo-Franklin, director of the Rice Synthetic Biology Institute, added: “If in the last 20 years synthetic biologists have learned how to manipulate the way bacteria gradually respond to environmental cues, the Bashor lab’s work vaults us forward to a new frontier — controlling mammalian cells’ immediate response to change.” 

“This is like embedding tiny processors in cells, made entirely of proteins, that can ‘decide’ how to respond to specific signals such as inflammation, tumor growth, or high blood sugar,” Dr. Yang explained to SynBioBeta. “Our work moves us significantly closer to constructing ‘smart cells’ that can detect disease indicators and instantly produce tailor-made treatments.”

You had me at “smart cells.”

I would be remiss if I didn’t mention a couple of other developments that offer to make this kind of advance even more powerful. Last month researchers at University of California San Diego announced a new software package they call SMART: Spatial Modeling Algorithms for Reactions and Transport. “SMART provides a significant advancement in modeling cellular processes,” said Emmet Francis, PhD, lead author of the study and a postdoctoral fellow at UC San Diego

They believe it can realistically simulate cell-signaling networks; it “takes in high-level user specifications about cell signaling networks and then assembles and solves the associated mathematical systems.” This “could help accelerate research in fields across the life sciences, such as systems biology, pharmacology and biomedical engineering.”

If you are not a fan of geometry, much less computational geometries, SMART is not for you, but if you are a biologist it opens up lots of possibilities. Someone such as Blaise Manga Enuh, a Postdoctoral Research Associate in Microbial Genomics and Systems Biology at University of Wisconsin-Madison. He writes in The Conversation about genome-scale metabolic models, or GEMs, which can be used to virtually carry out experiments that would have taken painstaking, time-consuming experiments in the lab.

“With GEMs,” Dr. Enuh says, “researchers cannot only explore the complex network of metabolic pathways that allow living organisms to function, but also tweak, test and predict how microbes would behave in different environments, including on other planets.”

Moreover:

Synthetic biologists can use GEMs to design entirely new organisms or metabolic pathways from scratch. This field could advance biomanufacturing by enabling the creation of organisms that efficiently produce new materials, drugs or even food.

I have a feeling Dr. Yang, Dr. Francis, and Dr. Enuh would have a lot to talk about.

So with GEMs or SMART, you could model out what you want to happen at a cellular level, then use the Rice technique to program cells to accomplish that. That’s 22^nd century medicine – and we’re lucky enough to be catching glimpses of it in 2025.