Regeneration of limbs and organs is not science fiction

The Morphoceuticals co-founder believes that regeneration research conducted in frogs can eventually be recreated in humans – it’s only a matter of time.

Last month, we told you the story of Morphoceuticals Inc and its successful regeneration of the hind leg of an African clawed frog – a species that does not naturally regenerate complex limbs in adulthood. Incredibly, the Juvenescence-backed start-up was able to boost overall regeneration with just one 24-hour treatment using a multi-drug cocktail. The company is now set to test some of its drug cocktails in mouse models as it seeks to create a “regenerative medicine platform”.

Longevity.Technology: The prospect of regenerating human limbs and organs may seem like science fiction, but recent work from Morphoceuticals shows that we are closer than you think to making it a reality. Although we would have liked to share with you the thoughts of the frog who benefited from the procedure, she was unfortunately too busy swimming to jump to discuss. We did, however, manage to speak to Dr. Michael Levin, professor of biology at Tufts University and co-founder of Morphoceuticals, who shared insight into how the company was founded.

The basic concept behind what Morphoceuticals does, Levin says, is the idea that if we could control which cells cooperate to build, we could solve almost any problem in biomedicine, with the possible exception of infectious diseases.

“Birth defects, traumatic injuries, aging, degenerative diseases, even cancer – all of these could be completely solved if we knew how cells decide what to build and how to manage those decisions,” he says. .

In nature, some animals are already extremely good at this. Salamanders, for example, regenerate many organs as adults, and the planarian flatworm appears to be essentially ageless and immortal, thanks to its ability to continually regenerate.

“We know it’s possible to be a complex animal and regenerate throughout your life,” Levin says. “And we know there are major gaps in understanding the algorithms by which cells decide to do things – this collective cellular intelligence that knows the difference between building a leg and an eye.

“But the most amazing thing about regeneration in salamanders, for example, is that they know when to stop regenerating. How do cells know how to stop when a correct salamander arm has been done, and how do they even know what a decent salamander arm is? Most people would say it’s genetic, but we can read genomes now, and there’s nothing in there about the size and shape of your arm.

Regeneration is about software, not hardware

This concept of cellular intelligence is key to Levin’s area of ​​interest. With a computer background, he sees the problem as a software and hardware problem.

“All the exciting things that happen in molecular medicine – gene editing, rewiring pathways, promoters, protein engineering – it all happens at the hardware level. And that’s fine – we have to understand the hardware. But when you’re on your laptop and want to switch between programs, you don’t pull out your soldering iron and start resoldering the computer. The future of biomedicine is in understanding the software of life – it’s much easier to push all the complexity onto the hardware and work at a higher level.

Accordingly, Levin’s lab has focused on trying to understand how individual cells, with very basic roles, link together into a collective intelligence that has much larger and more complex goals, such as building a member or organ.

“I’m interested in information, decision-making, and how we can manipulate those collective intelligences to build the kinds of structures we want to build,” Levin says. “And that means understanding evolution – how did it get there in the first place, how do cells know what to do?

“Part of what we’ve done in my group is to look at how the electrical communication in our body allows this to happen. Evolution understood early on that our power grids are fantastic for increasing activity, so for 20 years we have studied how groups of cells store information in power grids. How do they communicate electrically and what can we do with it? »

A nudge from evolution

The second area of ​​interest in Levin’s lab is how to control and manage these collective cellular actions. Rather than trying to “micromanage” this at the cellular level, the approach is to try to take advantage of evolution.

“Everything was already generated during embryonic development, so all of that information is still there,” Levin says. “So what we’re looking for is a set of triggers that activate a modular set of steps. You don’t have to rediscover or recreate all those steps every time you want to use it, you trigger a module and then it all happens on its own.

“Our goal for short-term regenerative medicine is not to try to micromanage this stuff, which will take a long time to learn, but rather to understand how the animal’s body knows where things are going, identifies the triggers and then intervenes at a very high level.

Levin and his Morphoceuticals co-founder, David Kaplan, professor of engineering at Tufts, launched the frog experiment in 2019. Activation of the specific triggers needed to induce regeneration was carried out using a cocktail of “ion channel drugs”, which are drugs that open and close ion channels to establish specific bioelectrical states.

Kaplan’s lab expertise in materials science was key to developing the tiny bioreactors needed to provide the controlled environment needed to stimulate regeneration in a specific area, such as a frog’s hind leg.

The Morphoceuticals bioreactor used to treat the frog.

“These are engineering devices that you place on the stump,” Levin explains. “There’s a gel in there that contains the different drugs we’ve invented.”

What really amazed the researchers, however, was that the initial treatment was so effective.

“We put this stuff on for just 24 hours, and then we had a year and a half of leg growth,” says Levin, who says the regrown limb was 100 percent functional. “So it’s a very short initial decision that is made, and then these modules unfold on their own. The second thing is that there is nothing leg-specific about the cocktail we used. We just asked the body to build everything that normally goes there.

“We think this is a very interesting strategy for regenerative medicine because once you know what the trigger is, you don’t need to already have all the pathways that are going to be involved. That’s ultimately what I hope for Morphoceuticals – we started with a leg, but I want this company to be the first in a wave of regenerative medicine that’s going to come at the information level.

The path of human regeneration

Morphoceuticals are now moving forward on several fronts, testing new drug combinations and trying to understand their impact on bioelectrical signaling. The company is also done with frogs and moving into new animal models, in what Levin calls “an active growth phase.”

“There’s a whole pipeline of different things that now need to be tested,” he says. “I think we’ve shown what can be done in the frog model, so it’s time to move on to mammals. So that’s what we’re doing now – testing previous bioelectric cocktails and our new cocktail sets in mice.

Levin’s hope is that the new work in mice will lead to early successes in areas such as improved strain health, innovation and skin repair. But, as hands-on work in animal models progresses, Morphoceuticals is also working on a discovery engine platform to crack the bioelectrical code needed to achieve a particular outcome.

“We are assembling the beginnings of a turnkey regenerative medicine platform where ultimately you will identify the tissues you wish to regenerate, and this will provide a computational path, showing you the ion channels you need to open and close to get to the correct bioelectric state, then you can just choose the drugs after that.

So, does Levin see a clear path to human applications of this work?

“People often make a lot of distinction between mammals and so-called lower animals,” he says. “Of course there are physiological differences, but once you get past yeast and into multicellular organisms, we’re all fundamentally very similar. Evolution solves the same problem in all of us – and once we understand these principles, everything else is just engineering details. This is the software we have to crack and which extends throughout evolution, we are no different from any other creature in this respect.

“I have no doubt that this is possible in humans, the question is when. I would be lying if I could tell you what the timeline of all of this will be. I am hopeful that we will see this in my lifetime. , but who knows, it’s science!

Photography: Morphoceuticals Inc.
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