"A flatworm, a cancer cell, and a lump of intelligent frog skin walk into a bar. The bartender asks, what's the deal? The flatworm chirps: Why, we're all model organisms in the works of the scientist Dr. Michael Levin!"
(the bartender then promptly starts to dissociate and have a panic attack)
Try answering the following questions to the best of your ability.
Take your time, they're meant to be tricky! Close your eyes if you need to visualize :)
- What is a "self"? Is it a whole person? A brain? The brain cells that make up a brain?!
- Do you think individual cells have goals they try to achieve, akin to humans pursuing their own goals?
- Are humans and animals the only creatures that can "remember"?
More specifically, the idea that cells, organs, and organisms can be sovereign, individual "selves". This is kind of a revolutionary idea, and it is a central theme to the research of accoladed Tufts scientist Michael Levin.
What is electricity?
What is an ion channel?
- Ion pumps - proteins that use chemical energy to pump ions against their concentration gradients (e.g. pushing positive ions towards a crowded space of other positive ions).
- Ion translocators - proteins local to each cell that stabilize the resting potential/ground voltage of that respective cell
- Gap junctions - will talk more about this in depth further down :)
Bioelectricity is responsible for many cell behaviors and functions. In addition to the several vital biological processes listed in the previous sections, bioelectricity is a fundamental impetus for morphogenesis, growth, and development of all multicellular life. It is an ancient property of living things, tracing its inception back to bacterial biofilms.
Morphogenesis and metamorphosis
Planaria, a model organism
- Signals (either nervous, metabolic, or immune) from the site of injury begin to build up in the body
- Pluripotent stem cell reserves (making up about 30% of a planaria's body!) flock to the site of injury
- Stem cells proliferate into a blastema, a bud of tissue which differentiates into the structures needed
- The missing structures fully form into their target morphology, as in the structures that were prior injured. Cellular proliferation, differentiation then stops. Regeneration is complete!!
|Looks... suspiciously familiar, doesn't it?|
Gap junctions are an ancient ancestor of synapses. Neurons take advantage of these mini information highways to form our central nervous system! And these gap junctions have been at it for way longer too.
With the power of bioelectric voltage gradients, by manipulating ion channels and gap junctions, we can now change the target morphologies– the "homeostatic setpoints"– of living organisms. We can do this in a permanent way, too. If you kept the gap junctions of this two headed planarian off some more and cut them in half again, you would have two pairs of two headed worms. And just as simply, you could turn them back on, amputate them once more, and have one headed worms again.
"One view of cancer (distinct from the current paradigm of intrinsically "cancerous" cells resulting from specific DNA modifications) is as a problem of organization within a "society of cells". Cancer is, in some sense, a disease of geometry - a failure of cells to attend to the signals that normally organize their behavior towards the patterning needs of the host"
|The bioelectricity they don't want you to know about! :p|
|Figure B here shows the abnormal, tumor like lesions caused by malignant melanocyte cells. This was caused by the misexpression of a potassium channel gene called KCNQ1.|
When a cell becomes cancerous, it develops its own goal states and starts behaving like an individual organism, reverting back to an “ancient” unicellular past. It treats the rest of the body around it as a farm of resources to grow and flourish off of. Cancer grows well in hypoxic conditions, not much unlike our own ancient unicellular ancestors.
|(the two guys who uploaded these videos, Sam Kreigman and Josh Bongard from UVM were also crucial to the development of these things. they deserve big credit for this too)|
So what are xenobots? In a broad sense, they are the first unique living organisms not designed by natural selection but by algorithm. Levin, Kriegman, Blackiston, and Bongard prodded together skin and heart muscle cells of Xenopus laevis (a model organism of frog) embryos to from into the shapes shown below.
More specifically, the skin cells they used are called epithelial cells, which were used to create structural integrity and protection for the xenobots. The heart muscle cells were used for motility, because tissues that could contract (like muscles do in animals) allow for movement. Using Kriegman's computer evolved xenobots as a template, the skin and muscle tissue is able to be modeled into shapes ideal for different tasks
|Above, a digitally evolved xenobot (in silico) moving in virtual space. Below, an in vivo xenobot modeled after its digital counterpart moving around physical space.|
Because xenobots are designed algorithmically in a virtual environment (where the conditions of fitness can be changed on a whim), they can possess different qualities which can solve different tasks. Some xenobots evolved leglike appendages which allow them to "walk" around, others grew cilia (hairlike protrusions) that give them the ability to "swim" around. Most awesomely, some xenobots were even evolved to be able to mop up loose particles around the petri dish it lived in.
|Xenobots have been evolved digitally into all sorts of shapes! Try spotting the Among Us xenobot|
Another incredible capability that xenobots possess is their capacity for regeneration. Xenopus embryonic cells (which xenobots are made out of) are highly regenerative, meaning if you cut a xenobot half it will reform. Take a look!
|After the forceps mess up the structure of the xenobot, it heals itself back to ship-shape.|
Very recently, Levin, Kriegman, Blackiston, and Bongard showed that xenobots can kinematically reproduce. New xenobots have been designed to be able to push together Xenopus cells into shapes and structures that resemble xenobots themselves.
So, when are these things going to take over the world?
I'm glad you asked. Right now, we have every right to feel concerned about gain of function research. There is significant evidence that the SARS-COV2 virus was created in a Wuhan lab, and look where that got us. When I first heard that xenobots could replicate, I even made a joke on my Twitter that they could destroy the world by making paperclips.
Mazel tov to Sam and team!!! As long as we don't let them make paperclips I think we'll be OK https://t.co/fXDBPuP4L2— Alex Kesin (@alexkesin) November 30, 2021
But the creation of xenobots is not dangerous. Fortunately, they:
1) can't do many bad things right now. I don't even know if they can survive out of petri dishes, and I'm sure that cytotoxic compounds can kill them just fine
2) have a conveniently programmed time to die. Because there is no way for them to currently consume food, the individual Xenopus cells survive off the yolk that they are "born" with. This means it takes about a week before the xenobots cells starve and die.
3) The "reproduction" of xenobots is not quite like mitosis, where heredity is involved. As of now, the xenobots need fresh, lonely frog cells floating about to be able to push around into new xenobots. Its not like they can "bud" off new xenobots.
And as Levin had noted, frogs shed their skin cells into lakes all day... yet we don't see xenobot swarms destroying power grids or turning into some crazy hivemind monster.
While I'm definitely more convinced than not whether they're safe, the public seems to be wary of their existence. Especially people in YouTube comment sections (whose wisdom is obviously some of the most impartial, empirical, and rigorous).
|Three commenters in a row cowering in fear of the ferocious frog cells|
"The vertebrate body plan is basically bilaterally-symmetrical; however, consistent and well-conserved asymmetries of the brain and visceral organs are superimposed upon the fundamental structure. Strikingly, it is now known that even single mammalian cells in culture maintain a consistent left-right axis. We are working to understand the mechanisms by which the embryo aligns the left-right axis with respect to the other two axes, and imposes this spatial information on macroscopic cell fields prior to the morphogenesis of the asymmetric organs. In contrast to popular models of asymmetry initiation by extracellular fluid flow during gastrulation, our lab studies much earlier, intracellular events that break symmetry and establish consistent asymmetry as a form of planar cell polarity, using physiological mechanisms to amplify cytoskeletal chirality across cell fields."
At first glance, this reads confusingly. So let's break it down a bit.
"The vertebrate body plan is basically bilaterally-symmetrical; however, consistent and well-conserved asymmetries of the brain and visceral organs are superimposed upon the fundamental structure."
Interestingly, all vertebrate animals (basically any animal with lots of bones) are always left-right symmetrical. Have you ever seen a creature that look exactly like it does upside down? How about back and front? If you split a person in half (very sorry for the graphic image), the two halves are perfectly chiral (mirrored).
"We are working to understand the mechanisms by which the embryo aligns the left-right axis with respect to the other two axes, and imposes this spatial information on macroscopic cell fields prior to the morphogenesis of the asymmetric organs."
Embryos too are like this– and makes sense, because our chirality needs to start at some point. By "macroscopic cell fields", I think what they're trying to say is that individual cells create more complicated structures that are symmetrical in their own right (emergent symmetry).
Remember gap junctions? Well, they seem to be an important reason for why this symmetry occurs. Again, in their own words:
"We identified a dependence of asymmetric gene expression on early communication between left and right sides in the chick and frog. For example, expression of left-sided markers depends on events occurring on the right side, during very early stages, suggesting that the two sides need to coordinate their decision with respect to the L-R identity of each. One mechanism for communicating between cells and tissues involves gap junctions: multimers of connexin proteins form channels between cells and pass small molecules, subject to complex regulation by various signals."
It makes perfect sense– for such a complicated aspect of morphogenesis, gap junctions play a crucial role in determining that at scale, the organism that it's forming into is symmetrical. There is no other way to coordinate the left and right sides in unison without gap junctions working well (which is possibly a reason why congenital deformities happen– they could be interpreted as disorders of symmetry).
Plasticity of the "self"
- What is a "self"? Is it a whole person? A brain? The brain cells that make up a brain?!
- the capability to pursue tasks/goals
- it is reinforced to generate positive behaviors for survival (its bad traits get it punished, its good traits have it rewarded)
- it can hold complex information/memory
Okay, still not convinced about the plasticity of the self? I will give you two more bizarre examples that Levin mentions in the TAME paper.
- see what the other is seeing (they tested them by blindfolding one and asking her what the other sister was looking at)
- taste what the other sister is eating
- feel what the other sister is feeling (they tickled one sister and the other would get jumpy!)
The promising future we have ahead
- Levin's lab has found ways to manipulate voltage channels and bioelectrically surpress the cancer causing effects of oncogenes. They were able to shrink and eliminate tumors this way!
- Through causing deformities in tadpoles (dubbed Picasso tadpoles, since their facial features were put in all the wrong places), Levin was able to show that as the tadpole becomes a frog, an "electric face" is cast onto the facial tissue, reorganizing it into a proper frog face without any deformities.
- By manipulating ion channels in tadpole gut cells to emulate behaviors of an eye, the gut cells developed into... well... an eye. A fully functional one, in fact! This means we can develop new organs by manipulating bioelectric networks in our bodies– imagine if we could grow new eyes for the blind, or repair old ones.
- Xenobots have many amazing use cases– cleaning up ocean waste, scraping up cholesterol in arteries, and delivering drugs are a few of many possible ways they can perform tasks that current technologies have great difficulty performing precisely.
- Regrowing limbs!!! Levin's lab has been able to regrow Xenopus frog legs by coaxing them to regrow with bioelectricity manipulating hormones.
Levin is actually working on a company called Morphoceuticals that has the goal of regrowing limbs in mice. You can check it out here!