Scientists Grew An Eye In The Wrong Place. Then Things Got Stranger.

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0:03On a quiet afternoon in 2011,

0:05an American scientist was staring closely

0:07as an eye was beginning to grow on the back of a frog.

0:10His name is Professor Michael Levin,

0:12and for the past several decades,

0:14his experiments have continued to challenge some of our most basic assumptions about how biology actually works.

0:20Now, you're probably familiar with the saying that DNA is the blueprint of life.

0:24And as important as it is,

0:26Professor Levin's research suggests that there may be a more subtle layer involved in deciding how our body actually forms,

0:32a layer known as bioelectricity.

0:35Over the past 30 years, his experiments would come to produce animals with extra organs in unusual places

0:40organisms with two functioning heads,

0:42and even regenerate limbs in adult animals that we had long thought to be incapable of doing so.

0:48And all of this happened without rewriting their DNA.

0:51And slowly, these experiments began leading him towards a much bigger revelation.

0:56That there may still be something fundamentally missing from our understanding of life itself.

1:01To truly appreciate why Professor Levin came to see life this way,

1:04let us take a moment to introduce how all of this even began.

1:12Michael says he's always been fascinated by the world of engineering.

1:16As a child, his dad would sometimes take the back of an old television set as a way to distract him during asthma attacks.

1:22And the two of them would sit together to look at the intricate wiring inside.

1:26He was captivated by the idea that someone knew how to put all those individual parts together

1:31in just the right way to make a picture appear on the other side.

1:35His dad told him this was something called engineering.

1:38But to Michael, what he heard was magic.

1:42As he grew older, he would spend time with his friends collecting insects,

1:46and they would marvel at how these tiny creatures interacted with the world around them.

1:50That curiosity followed him into university, where he would take two seemingly unrelated degrees

1:55that would come to define his entire career.

1:58In developmental biology, he saw as entire organisms developed from a single cell.

2:03This fascinated him and he began to ponder how millions of cells which are identical

2:07with the exact same DNA knew which of them would develop into an arm, or a heart, or to stop growing altogether.

2:15While in computer science, he learned about programming

2:17and how to get computers to do complex things simply by providing it with the correct inputs.

2:22It taught him that the same machinery could behave in completely different ways depending on the instructions it received.

2:29And over time, he began to wonder whether biology might work in a similar way.

2:34After his PhD, Michael devoted himself to understanding how cells work together during development

2:39He noticed that by manipulating the electrical signals between cells,

2:43it was possible to influence how an animal developed

2:45like which side of the body their heart grew on all without making any changes to their DNA.

2:51Over the next 10 years, Michael would conduct experiments to try and understand how far this really went.

2:57And the longer he studied this,

2:59the harder it became to believe that DNA alone

3:01could explain how millions of cells knew what they were supposed to build.

3:05And eventually, his work during these years would lead to an experiment

3:08that would come to reshape the way he thought about biology itself.

3:17The experiment he was conducting was about a creature that fascinated him to no end.

3:22Something he called a Picasso tadpole.

3:25His team had disrupted the earliest development of these tadpoles

3:28leaving their facial structures in completely abnormal positions.

3:31And this captivated him because the obvious expectation was that these deformities would only become worse as these animals grew.

3:38And yet, in his lab, he found that these tadpoles would later grow up and become frogs with fairly normal frog faces.

3:45These tadpoles have to become a frog.

3:48In order to become a frog, they have to rearrange their face.

3:50So, the jaws have to move forward, the eyes have to come in, various things like that.

3:54And it was thought that this is a hardwired process.

3:57Basically, every organ in the face moves in a certain direction a certain amount.

4:01We made the hypothesis that this was actually a more intelligent process than that.

4:06And so, what we did was we created what we call Picasso tadpoles.

4:09So, um the eye is off to the side, the jaws are on top of the head, everything is kind of scrambled.

4:15And what we found is that even those animals generally make pretty normal frogs

4:19because all of these organs move in novel, unnatural paths to get to where they're going, and then they stop.

4:26But, all of these things move around until they get to a pretty normal frog face.

4:31This raised an extraordinary question.

4:34How did the body know what a correct frog face look like?

4:38Michael's research over the years have been pointing him towards one possible answer.

4:42Electricity.

4:44See, every cell in our body maintains a tiny electrical voltage across its membrane.

4:48That voltage is produced by charged particles moving through microscopic gates called ion channels.

4:54In previous experiments, Michael had found that by manipulating these channels,

4:58he could alter the electrical state of cells,

5:00and that doing so would often cause abnormalities in how animals developed.

5:04And that gave him an idea.

5:06What if these electrical signals weren't simply influencing development,

5:10but actually carried information about what the cells were supposed to build?

5:14So, he began designing an experiment to try and test this.

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6:17Now, let's get back to Michael's research.

6:20First, he would place early frog embryos in a fluorescent dye that allowed him to see differences in the electrical states of their cells.

6:27As he watched the embryos develop, he noticed two distinct patches of cells appearing where the eyes would later form.

6:33These cells had a different electrical state from those surrounding them.

6:37Next, he had two different groups of frog embryos.

6:39In one group, he would alter the ion channels in these cells and this changed the electrical state before the eyes had formed,

6:46while the second group was left alone and served as the control.

6:49Michael wanted to see whether the electrical pattern in these cells

6:52were actually helping to build the eyes

6:54or if they were instead simply a byproduct of the eyes forming.

6:58And what he found was that while the control group formed perfectly normal eyes,

7:02this wasn't the case in the group where he had disrupted the electrical patterns.

7:06These tadpoles would instead end up with deformed eyes or in some instances,

7:10no eye at all and all of this happened without any changes being made to their DNA.

7:15In the coming weeks, Michael thought about what all of this really meant.

7:20If the electrical pattern really was responsible for what the body built,

7:23what would happen if you recreated that same pattern on another part of the body?

7:29For his next experiment, he would begin by injecting a particular form of mRNA into a frog embryo

7:34during its earlier stages of development.

7:37This caused some of the cells to produce a new ion channel,

7:39which helped to the same electrical pattern they had observed in the developing eye.

7:43As the embryos continued developing,

7:46they noticed the pattern spread across different parts of the body,

7:48and before long, patches of eye tissue began appearing all across the body,

7:52with some developing on the head, while others appeared on the side of the body, and even on the tail.

7:57And in a small number of tadpoles, these cells didn't merely produce fragments of eye tissue,

8:02they assembled an entire eye, complete with a lens, retinal tissue, rods, and many of the same specialized cells found in the normal eye.

8:09And in a later experiment, Michael found that they were even able to see out of these eyes.

8:15If we make a tadpole with no primary eyes, but we put an eye on its tail,

8:19what happens is that that eye makes a single optic nerve.

8:21The optic nerve does not go to the brain, sometimes it synapses on the spinal cord here, sometimes to the gut, sometimes nowhere at all.

8:27And these animals can see perfectly well.

8:29How do we know?

8:30Because we built a device that trains them,

8:32automatically trains them on visual cues,

8:35and we can show that they learn from visual assays.

8:37And this is amazing. Why do you not need

8:39additional rounds of evolutionary adaptation here?

8:42You've got an animal with a radically different sensory motor architecture.

8:46The eye's connected to the spinal cord or some other organ.

8:50Why does this just work?

8:52Over the next several months, Michael began testing how far this really went.

8:57He would try replicating this process with other organs,

9:00something he called decoding the bioelectric code.

9:03And in doing so, he was able to create frogs not only with extra eyes and limbs, but even a complete beating heart.

9:10We've never succeeded in making an eye that's bigger than a normal eye.

9:14I tried at first, I wanted to have one giant eyeball. I wanted the whole thing to be one giant eyeball.

9:19And if you do that...

9:25So what I would do is I would go in and inject like an eight cell embryo,

9:29I would inject every single cell.

9:31Like okay, this thing's going to be a giant eye.

9:32No, you can get multiple eyes, but you will never get a bigger eye.

9:35The eye, there's something that we haven't cracked yet that's that where they (the cells) know what the size is.

9:40When this footage aired, it attracted attention from researchers and skeptics all around the world.

9:45Michael's work had not only been a revolutionary experiment on frogs,

9:49but came to reveal that our body might be controlled by far more than the genetic material inside each cell.

9:56And for Michael, his work over these years would slowly begin to shape his belief around how life itself worked.

10:02More and more, he began to think about biology in much the same way he once thought about computers.

10:07That our DNA contained the instructions to form the molecular hardware like proteins in our bodies,

10:12but how those instructions could be used was controlled by the electrical networks in our body, which he called the software.

10:19So, if electrical signals really could control what the body built,

10:22is it possible to even build something as complex as an entirely new head?

10:27Well let's take a look at that next.

10:33To answer this question,

10:35Michael would turn his attention to a rather unique life form.

10:38A Planarian.

10:39These were flatworms that had an incredible ability for regeneration.

10:43When cut, both ends of the worm will regenerate and form entirely new functioning bodies.

10:48In fact, their regeneration is so powerful that they can be cut into over 200 pieces

10:53and each individual piece knows how to regenerate the full-bodied worm.

10:57And one day, as Michael was watching these worms swim around in his lab,

11:01a question began to surface in his mind.

11:04How exactly did the pieces know when to grow a head and when to grow a tail?

11:09So, most textbooks, what you'll see is they show the worm being cut into thirds.

11:13Okay? And then they draw this like gradient.

11:16And they say, "Well, this is how you know where the head and tail is."

11:18That's all well and good.

11:20But, what they're neglecting to show you is the simpler but much more challenging version of one cut.

11:26Because if you make one cut in the middle, just cut it down the middle.

11:29The cells on the left side of the cut are going to make a tail.

11:32The cells on the right side of that cut are going to make a head.

11:35Their positional information is exactly the same. They were neighbors until you came with your scalpel and cut them apart.

11:40As he thought about how they were able to do this,

11:42he felt there must be some kind of collective signal that the cells were using to communicate between them.

11:47Michael hypothesized that when cut, the cells would notice the breakage and try to form something new.

11:53But before doing so, they would first send out a signal to the rest of the body

11:57through structures known as gap junctions,

11:59which would help determine what it needed to form.

12:01So, what happens when you block that signal?

12:04To test this, Michael would first place the worm in a specific drug solution

12:08that temporarily blocked the gap junctions between the cells.

12:12Next, he removed both the head and tail of the worm before waiting several days to see what would happen.

12:17And one morning, when Michael returned to his lab, he laid eyes on the creature that was almost alien.

12:24In some of the worms, instead of regenerating a head at one end and a tail at the other,

12:28both ends had grown entirely new heads.

12:32In the following weeks, Michael would spend his days mesmerized by these creatures.

12:36He found that these two-headed worms were fully functional,

12:39although having two brains trying to control the body would sometimes lead to rather confused behavior.

12:44Later on, he found that through altering the electrical signals in different ways,

12:48he was even able to create a worm with no heads.

12:51But as Michael watched these two-headed creatures move around in his lab,

12:55another question began to bother him.

12:57The first two-headed worms were seen around 1903,

13:01made by a completely different process.

13:03Nobody had thought to recut them for over 100 years.

13:07Why? Because everyone thought it was obvious what would happen.

13:10Their genetics are unchanged. If you just get rid of that that ectopic secondary head,

13:13of course they're going to regenerate normally. Like, why would you even do this?

13:16We said, "Well, yeah, the genetics are the same,"

13:19but I didn't really believe that the genetics were, you know, were storing all this stuff, anyway.

13:23And so, I said, "Well, why won't we recut them and see what happens?"

13:25This time, rather than an octanol solution, (Sorry the image is meant to show a two-headed worm here).

13:28the two-headed worms would simply be placed in plain water.

13:31And yet, when Michael cut the worms, both ends always end up forming new heads.

13:37For Michael, this experiment revealed something remarkable.

13:40That tissue itself seemed to retain a kind of memory of what it was supposed to build.

13:45Michael compared this to a programmable calculator,

13:48where you may start with a default setting, but that setting can be changed.

13:52And once it changes, it remembers the new state.

13:55He believed that living tissue might behave in a similar way.

13:59And what's even stranger is that when Michael decided to cut the worms from the first experiment,

14:04which only regenerated one head, around a quarter of them ended up regenerating two heads this time around.

14:11That worm, if you look at it anatomically, one head.

14:15If you look at molecular markers, perfectly normal,

14:17anterior markers in the head, posterior in the tail,

14:20you wouldn't know anything was wrong until you looked at voltage.

14:23And it's kind of like um the decoding that neuroscientists try to do.

14:27You look at the voltage, you go, "Wait a minute, this thing this thing has a false memory. It thinks that it thinks that it should have two heads."

14:31But you won't know that, it's a late memory until you injure it.

14:33As soon as you cut it, now you get two heads.

14:36In 2017, Michael published these findings in a groundbreaking paper in the Biophysical Journal.

14:42His findings revealed that the temporary intervention at the bioelectric level

14:45could produce lasting changes in the body,

14:48almost as if the tissue itself could be reprogrammed with a new anatomical goal.

14:52Now, this is pretty amazing, right?

14:55But at this point, you might be thinking, "What can we actually do with this research?"

15:00Well, let's take a look at that next.

15:06As Michael continued his research,

15:08he became increasingly interested in what these discoveries might enable us to do in the future.

15:14One field that particularly fascinated him was that of biomedicine and regeneration.

15:19See, one of the greatest challenges in regenerative medicine has been trying to grow entire functional organs.

15:24And traditionally, scientists have tried to tackle this by painstakingly guiding cells through each stage of development.

15:31However, if bioelectricity really did hold the key to what our cells built,

15:35then we may be able to go around this problem entirely.

15:39This time, he wanted to see whether a brief intervention

15:42could prompt an adult animal's own cells to rebuild a limb they would normally be unable to regenerate.

15:49To test this, he would first remove a leg from two different groups of adult African clawed frogs.

15:55These animals largely lose their regenerative abilities once they reach adulthood.

15:59The first group was allowed to recover naturally, and they served as the control.

16:03While the second group was immediately fitted with a wearable bioreactor,

16:07which contained a hormone that aided with wound healing and altered the electrical state of the cells.

16:12And there's an important detail here.

16:14This capsule was only fitted for 24 hours before being removed entirely.

16:19Michael would then observe how each group recovered over the next several months.

16:23And he found that the control group would regrow a single spike-like structure.

16:27In comparison, the group fitted with the biodome seemed to regenerate much thicker, paddle-like structures over the same period of time.

16:35The most recent work had to do with very large adult frogs

16:40which have never been shown to be able to regenerate anything like this.

16:43Using a bioreactor, we were able to induce very significant regeneration.

16:48But maybe the most amazing thing about it is that

16:51we only interacted with the wound for 24 hours.

16:54So, it's a wearable bioreactor. 24 hours of treatment gives you 18 months of growth, during which time we don't touch it at all.

17:01This experiment taught Michael a very important lesson.

17:05That our bodies may already be capable of far more regeneration than we believed.

17:09And the real challenge might be finding the right signals to trigger that ability.

17:13Because just several years later, Michael would try to tackle this problem again.

17:18This time, he wanted to see whether he could improve the degree of regeneration

17:22using what Michael called a "chemical cocktail".

17:25This was a biodome consisting of five different compounds,

17:28each of which had previously shown promise in a different aspect of regeneration.

17:33First, he removed a leg from three different groups of frogs.

17:36A control group with no treatment,

17:38a sham group which had a wearable biodome with no actual solution,

17:42and finally, the test group which was fitted with the biodome containing the chemical cocktail.

17:47Similar to the previous experiment, the capsule was only fitted for 24 hours before being removed entirely.

17:54Michael would then observe how each group recovered over the next 18 months,

17:57and what he found was fascinating.

18:00Compared to the control group, which again formed a spike-like structure,

18:03the group which had the biodome with no solution still seemed to have slightly greater regeneration over an 18-month period.

18:10This suggested that simply changing the environment around the wound

18:13during those first crucial hours was enough to lead to more regeneration and could influence what happened much later.

18:20But the biggest difference came from the chemical cocktail itself.

18:24These frogs regenerated much larger and more complex limb structures

18:27with greater amounts of nerves and blood vessels, and some were even able to regrow parts of their toes.

18:33And in a later experiment, Michael found that these new legs were even sensitive to touch.

18:39They turn on immediately these pro-regenerative genes. They begin to make a leg. You've got some toes.

18:44By 45 days, you've already got a toenail and some toes.

18:46Eventually, very nice leg. The leg is touch sensitive and motile.

18:51And all of this happens from a brief modulation.

18:55In fact, in the recent work on adult frogs,

18:57we show that just 1 day, 24 hours of application of our ion channel cocktail,

19:02you get a year and a half of leg growth.

19:04So, this is not 3D printing. This is not scaffolds. This is not us telling stem cells where to go or what tissues go next to what tissues.

19:11We have no idea how to build a frog leg.

19:12It'll be a really long time before anybody can micromanage that process,

19:17But you don't need to.

19:17Because the cells already know how to do it.

19:19What you do need to do is to convince them that that's what they should do instead of scarring.

19:24Regeneration, however, was only one side of the problem.

19:27Across all of these experiments, Michael had been trying to direct a group of cells to work together towards a larger goal.

19:34And eventually, he began to wonder whether it may even be possible to use this

19:38to tackle one of biomedicine's greatest challenges.

19:41Cancer.

19:42See, cancer occurs when cells that were once part of a larger collective

19:46begin behaving increasingly for themselves and multiplying uncontrollably.

19:51And that raised one final question.

19:53If changing the signals around normal cells could redirect what they built,

19:57could the same approach persuade cancer cells to behave normally again?

20:02It turns out, Michael's lab had already began testing that idea.

20:06Years earlier, his team had introduced a powerful cancer-causing genes in frog embryos,

20:11causing some of their cells to begin developing tumors.

20:14But when they altered the electrical state of those same cells,

20:17many of the tumors were suppressed even though the cancer-causing genes were still active.

20:23And in 2016, Michael decided to take this even further.

20:27This time, they would introduce a human oncogene in a frog embryo and allow the tumors to mature before intervening.

20:34And yet, when they altered the electrical state of those very cells,

20:38many of the tumors began to shrink or return to behaving like normal cells.

20:43If you inject a human oncogene, you will get tumors,

20:46but if you also co-inject a channel that forces the cells into the appropriate bioelectrical state

20:52and keeps them in coupled to their neighbors,

20:55then you won't get a tumor in a good chunk of the cases.

20:57And so, the oncoprotein is blazingly expressed, but there's no tumor

21:01because it isn't the genetics that drives. It's the physiology.

21:04And once these cells are connected to their neighbors,

21:06they're basically going to keep working on you know, the skin and muscle and everything else that they were doing.

21:16Michael's research reveals something much deeper than strange experiments on frogs or planaria.

21:22They challenge a belief that has shaped biology for decades,

21:25that our DNA alone could give us the key to understanding how our bodies are built.

21:30For decades, he had watched as these experiments played out in his lab.

21:34Time and time again, they suggested that our cells are not simply following a rigid set of instructions,

21:39but instead are actively communicating with one another and can even be tuned to work towards entirely new goals.

21:46And slowly, the world around him began to pay attention.

21:50Researchers who had once seen his ideas as speculative were beginning to recognize just how important they might be.

21:56And in 2016, Michael was chosen to lead one of the first Allen Discovery Centers,

22:02bringing together researchers from biology, engineering, and computer science to pursue these ideas further.

22:07His team would even go on to create self-replicating biological robots known as Xenobots.

22:13But perhaps that's a story for another time.

22:16For some people, Michael's work may seem unsettling

22:19or raise difficult questions about how far we should really go in reshaping life.

22:24But behind all of it is something much more human.

22:28He speaks about the countless emails he receives every day from people all around the world.

22:33From those living with cancer or birth defects to parents writing about their children.

22:38And what pains him most is that science still can't give many of them the answers they need.

22:43When Michael looks into the future,

22:45he imagines a world when children will look back at many of the diseases and injuries we simply accept today

22:51and wonder why we were ever unable to repair them.

22:54He hopes they will look at us with the same disbelief we feel

22:57when looking at the limitations faced by generations before us.

23:01And perhaps in some ways, Michael is still chasing the same idea that fascinated him as a child.

23:07Back then, he would stare into the wiring of an old television and marvel at something so magical could emerge from so many individual parts working together.

23:16And perhaps after all these years, he still approaches biology with much the same sense of wonder.

23:21Only now, he's working at the frontiers of science,

23:24helping bring us closer to a future that not so long ago...

23:28Might have seemed like magic.