Reprogramming Cells and Building Limbs: The Role of Pattern Memories in Living Systems

Two-headed Planarian

Credit to Jeremy Guay of Peregrine Creative

Making decisions is hard, but it is something we all have to do. Even cells and tissues need to make decisions to function, and Dr. Michael Levin’s research lab at Tufts focuses on the mechanism by which cells do this. He also looks at how these decisions impact medically important outcomes, including regeneration, embryonic development and cancer.

Dr. Levin’s computer science background impacts the way he approaches studying living systems. A computer is reprogrammable, meaning that it can “contain different types of information in the same hardware.” The computer can store different information and perform different types of activities without physically rewiring the machine. For this reason, when you switch from Photoshop to Microsoft Word, for example, you do not need to physically move around the chips in the computer. While we normally think of biology in terms of the genome dictating exactly what living systems are going to do, the Levin lab’s research “has shown this amazing plasticity – that biological hardware is just as reprogrammable, and maybe more so, than the hardware we’re used to in engineering.” We can make use of living systems’ reprogrammability to change how cells and tissues act, rather than re-wiring them at the level of the genome through genomic editing.

Dr. Levin’s lab sought to understand the mechanism which underlies anatomical control in living systems, and predicted that once they did this, they could reprogram that set point and change organisms’ anatomy. Living systems maintain what is called anatomical homeostasis, which we can better understand through the analogy of a thermostat. A thermostat has a set point for temperature and a homeostatic loop which maintains the thermostat in that range. Anatomical homeostasis is analogous to this, except with respect to anatomical structure rather than temperature. For example, if an organism’s eye is not the right size, the organism will re-shape the eye until it reaches the right size, and then it will stop. The fact that the system knows when to stop building “means that the system knows what a correct [limb] looks like.”

The concept of anatomical homeostasis also illustrates the idea of separation of data from the machine, or the ability for the same machine to perform many different functions–you can change the set point of the temperature on the thermostat, rather than rewiring the entire thermostat. Similarly, in anatomical homeostasis, you do not need to edit the cells’ genome, but instead alter the set point.

Dr. Levin’s lab decided “to find the internal representation these cells were using to decide what a correct [organisms] looks like and edit it.” They found that in the bioelectric circuit. The bioelectric circuit “acts as a kind of tissue memory, in the same way your brain holds memories, and [it] holds these pattern memories.” Levin’s lab predicted years ago that if they could figure out how a living organism encodes the set point, then they can change the set point, so that the cell builds to a new set point.

For example, when a flatworm is cut into pieces, each piece grows a single head and a single tail at each end, creating a new worm. The Levin lab “rewrote the pattern memory” in the flatworm’s tissue to say that a normal worm should have two heads, not one. Then, when they cut the worm, the cells built a worm with two heads. The cells will continue to build a worm with two heads because it is effectively a memory. All of this requires no genomic editing. The fact that the worms were able to do this means that “there are mechanisms in the tissue that store memories that are not genetic... and that the hardware of a worm can store multiple different ideas of what a worm is supposed to look like.”

The Levin lab has many exciting works in progress in the field of limb regeneration. They are trying to make animals regenerate limbs after damage, which clearly has many implications for the field of regenerative medicine. Additionally, understanding how to control what cells build is important for solutions to birth defects, cancer, traumatic injury and degenerative disease. The Levin lab currently has cancer projects in which they are trying to make cancer cells build good tissues instead of creating a tumor. They also do work in synthetic morphology–“making novel living creatures that never existed before out of cells, like frog cells.”

One exciting direction Dr. Levin sees his field heading is in synthetic morphology. In creating organisms that have never existed before, “[we] can learn about plasticity of cells in a way that does not have millions of years of evolution behind them to tell them what they’re supposed to be.” In the future, an open question will be further understanding cellular collectives’ plasticity to perform new functions “on a much faster time scale that doesn’t require eons of selection pressure.”

Dr. Levin’s work is changing the way we think about cellular behavior and information processing in living systems. I think it’s fascinating that Dr. Levin’s lab has found a way to alter what cells build and to create novel organisms without any genomic editing, and I’m excited to see the all the work they have coming up in the future.