The Nobel Prize in Medicine: From Hercules' Hydra, to Human Eternal Life

Hercules' Hydra: The Road to Eternal Life?

"Enjoy the little things, because one day you may look back and realize they were the big things." Robert Brault, blogger.

In Western culture we usually count the years since the birth of Jesus of Nazareth. Indeed, there is no doubt that the Christian faith changed the face of human history in the generations that followed it. But a thousand years or more before the Christian Messiah emerged from the womb of his more or less virgin mother, various legends dictated the nature of culture in the world in general and in the Greek islands in particular. Tales, tales of heroism and great exploits fed the storytellers who sat around the fire and hearth. They passed from word of mouth, through singing, playing and rhythmic recitation, and over the years have been preserved and developed into writings and theater plays in ancient Greece. All of these are now recognized as part of Greek mythology, which left its mark on Western culture until these years.

One of the most famous heroes - for good or bad - in Greek mythology is Hercules. Like Jesus in turn, Hercules too was the product of the union between a mortal woman and the king of the gods Zeus (Jove in Latin, reminiscent of the Hebrew Jehovah). Pairings of this type were common at the time, so much so that a Greek hero did not prove his worth unless he could boast of an immortal father. To the relief of the heroes and their mothers, the gods never denied these claims of dubious parentage.

Already in the cradle Hercules demonstrated his divine virtues. While he was lying next to his brother, who came from a more carnal lineage, the two were attacked by two giant venomous snakes sent by the goddess Hera to kill him. When the children's nanny approached the crib, she found the whelp smiling and laughing loudly as he strangled another snake with each of his hands. This was only the first of the attempted molestations initiated by the lawful wife of Zeus to take revenge on her husband's bastard son. Like most of them, it didn't work out for her either.

The enormous strength of Hercules, inherited from his father the king of lightning and thunder, continued to serve him faithfully throughout his life and during the many journeys in which he took part. He participated in the Argonauts' quest for the famous Golden Fleece, saved the Titan Prometheus who gave fire to humans and conquered an entire island of warring Amazons. His bravery knew no bounds, and so did his self-confidence. He believed in his ability to perform any heroic deed he thought of, and was usually right, as his strength equaled that of the gods themselves. His confidence in his power was excessive to the point of parody (some would say stupidity) and during his plots these qualities are sometimes emphasized to the point of ridiculousness. When the hero felt that the sun was weighing him down with a wall, he threatened her that he would send half of it into her if she did not stop. When his boat rocked on the sea waves, he roared that he would unleash his wrath on them if they did not stop.

From all this it is clear that although Hercules' strength was greater than that of any mortal, his mind was far from meeting the same standards. The goddess Hera, who unreasonably accused him of adultery with her husband Zeus, was not able to face the most powerful man on earth, but she did not need to either. As the ancient Greeks said, "Those whom the gods want to destroy, they drive out of their minds first." Indeed, Hera waited patiently like a coiled snake for Hercules' moment of weakness. Only when he returned from his many wars, shed his armor and embraced his wife and three children, Hera used her magic and shattered his sanity. In a fit of furious madness, Hercules slaughtered his children and also killed his wife when she tried to protect their eldest son.

When Hera's hold on his soul was broken, Hercules came to his senses and found himself standing among the corpses of his loved ones with his hands covered in blood. He begged those around him to reveal to him who was committing the heinous act, and they revealed with a shudder that he was the culprit. Hercules, consumed by pangs of conscience, ends by telling him to atone for his crime in any way possible. To accomplish this goal he agreed to serve his distant cousin Eurystheus, who reigned in the city of Mycenae in Greece. Eurystheos, who was a hard and cold man, did not spare his relative his tribe. He sent Hercules to accomplish twelve tasks, each and every one of which was beyond the capabilities of an ordinary mortal. Among other things, Hercules ordered to kill a huge lion immune to any weapon forged by human hands, to clean stables containing thousands of horses in one day and to capture Cerberus, the three-headed dog guarding the gates of the underworld. Hercules did not flinch. He could no longer find a purpose for his life, and chose to devote himself to the difficult tasks, hoping that one of them would bring his life to an end to the pain.

As Job said, "Those who wait for death, and are not;" – Death to whom even Hercules refused to come. One by one, the tasks were completed. He strangled the lion with his own hands, diverted an entire river that washed away the stables, overcame the hound of the underworld and carried him all the way to Mycenae - where Eurystheus took a quick look at the beast, and ordered Hercules to return him to the abyss from which he came. These were only three of the dozen tasks that the hero completed, and it seems that they are dwarfed by one other task that Eurystheus assigned to him: to slay the hydra, a wild and nightmarish creature that boasted nine deadly and poisonous snake heads. It was a clearly impossible task, because it was known all over Greece that one of those heads was immortal, like the gods, and could never die.

Hercules found the hydra in the marsh near Lake Lerna and challenged it armed with his sharp sword. The serpent's heads cowered at the threat, but Hercules did not hesitate to charge forward and managed to cut off one of the mortal heads. He jumped back to escape the mist of poisonous blood that emanated from the stump, and when he looked up at his opponent again, he discovered to his astonishment that two new heads had grown from the stump, each as large and menacing as the original head. The Hydra, it turns out, allowed itself to ignore the law of conservation of mass when it didn't suit its needs. The desperate Hercules continued to cut off the heads, and the halos continued to grow as fast as he cut them off. After a few dozen new heads were created for him, even the slow mind of Hercules saw the realization that this way might not be optimal for killing the hydra.

Fortunately for Hercules, not all of his relatives were estranged like Eurystheus. Hercules' nephew, a young man named Aeolus, was present nearby and joined his sharp wits to his uncle's muscles. Aeolus carried a burning torch in his hands, and with it he scorched each fresh stump so that the new heads could not sprout and grow from the wound. After many hours, when all the snake's heads were cut off and their necks were set on fire, only the immortal head remained alive. Although Hercules could not kill him, he chose to bury him under a huge rock and thus forever eliminated the threat of the Hydra from the Greek islands. At least, until a bulldozer arrives that can lift the rock and expose the Hydra to the world again.

The hydra is revealed in reality

How grounded is the Hydra story?

During the thousands of years that have passed since the first myths about Hercules were told, the culture of Greece spread throughout Europe, and the spiritual descendants of the Greeks explored the continents and waters of the earth throughout their length and width. Many different species of animals were discovered and recorded on those dangerous journeys. Many of the educated explorers tried to gain world fame and locate the relatives of the legendary hydra, or at least its only head that remained buried. Despite all their efforts, until the 18th century no hint of the existence of the original Hydra from the legends was discovered. Even when the duplicate of the Hydra was rediscovered, in a puddle of stale water, no one suspected for the first time that it resembled the legendary Hydra. In fact, if the hydra from the legends was more similar to the one that exists in reality, most likely the battle between her and Hercules would have ended in a few seconds, since her entire length reaches three centimeters. And despite her smallness, she is as immortal as the mythological hydra.

The modern-day hero who located the Hydra was not the strongest man in the world, or even born of a god. His name was Avraham Tremblay, and despite the notable lack of his lineage and his muscles, he is remembered to this day as an important naturalist and one of the fathers of biology. Tremblay dived into the recesses of fresh water pools, and there he found a creature that had escaped the eyes of many until that time. The shape of the tiny creature resembled a fork, with multiple hunting arms instead of teeth. At the rear end of its elongated body the strange creature boasted a suction pad with which it could stick to surfaces, jump or crawl along them. At its front end, the creature is endowed with a mouth surrounded by 'fork teeth' - long hunting arms that are sent into the water similar to those of the jellyfish. The food of the little spoonbill was mainly based on other tiny creatures like tiny insects. The hunting arms are endowed with the ability to secrete a nerve toxin that paralyzes the prey and allows them to lure it safely into the mouth.

As you can see in the picture, the creature resembles a tiny aquatic plant more than an animal. Tremblay also recognized the problem, and tried to decide whether it was a plant or an animal. For this he cut the fork into several parts, believing that only a plant could survive after such a crude operation. To his surprise, the creature remained alive after the operation, regrowed the parts that were cut from its body and returned in no time to hunt prey in the lab jars. The creature refused to die, but Tremblay decided it was an animal after all, mainly due to its ability to move independently. However, the surprises did not end here for the daring researcher, because when he continued to follow the parts he cut out of the hydra's body, he saw that each of them continued to live on its own - and even regrowed the rest of the body! Each of the parts that Tremblay removed from the animal's body created a new whole organism in itself. Relying on the incredible ability to regenerate, and on the creature's resemblance to the ancient Hydra, Tremblay's finale says to perpetuate Greek mythology, and he named the falcon the Hydra, by which it is known to this day. And in Tremblay's own words -

"I created hydras with seven and eight heads, by cutting parts of the head along the body. So I did the deed of Hercules. I bravely cut off the seven heads from one hydra. The seven heads are back, and what's more, each of the seven severed heads will soon become a hydra. For this reason I am careful and careful to manage them well. I have a polyp [Hydra] that has already been cut into 36 parts, and most of those 36 are multiplying and will continue to multiply if I want them to.”

Tremblay's discovery caused a revolution in the scientific and religious world, because until that day the belief that each body contained one soul adapted only for it was particularly widespread. The modern hydra was a real breakthrough for the philosophy of the life sciences, because it required religious and scientific people to find an explanation for the hydra's ability to create more hydras by simple cutting. If the Hydra really only has one soul, what is the fate of that soul when the Hydra splits into two new Hydras, or even thirty-six new Hydras? And is it even possible to divide and separate the solitary soul? After many disagreements, the naturalist and philosopher Charles Bonnet proposed an initial solution to the mystery. Bonnet claimed that animals contain cells in their bodies that are capable of replicating and performing actions on their own, and each of the cells has its own little 'soul'. Thus the little hydra produced the conceptual nucleus for the fact known today, that every living being is composed of a large number of tiny cells, each of which is endowed with life and the ability to reproduce itself.

The secret of regeneration and eternal life

At first glance it seems that the most impressive feature of the hydra is its ability to regenerate its organs. This is a false position, as the hydra is not the only one in the animal world capable of healing from injuries, or even making copies of itself. If we take one flatworm, cut it into hundreds of pieces and give them two weeks to regrow, each one will complete itself into a whole new worm. Not only microscopic creatures are capable of regeneration. In the decades after the discovery of the hydra, naturalists have shown that salamanders are also able to regrow their limbs, and newts can regenerate their dislocated eyes. The snails beat the last two without thinking twice, or even once. They are able to regrow their heads even after being cut off, as Lazaro Spallanzani discovered in 1769. Paradoxically, this discovery led to a deterioration in the living conditions of the snails, because that year thousands of naturalists and ordinary people went out into the fields to verify for themselves the truth of the miracle. Humans are also gifted with a limited capacity for regeneration, and our muscles and bones are in many cases capable of recovering from serious injuries. And yet, we cannot regenerate whole severed limbs, and neither can most of the advanced animals on the planet. What makes the hydra unique compared to humans, allowing it to regenerate where other living creatures would have died?

One of the snail species in France is able to regrow its head if it is cut off. Many residents of France went to the fields armed with a knife to test for themselves the correctness of the discovery. Definitive proof that there are insights that are better kept to yourself. The source of the image is Wikipedia.

The difference between the bodies

"What is a person? A miserable little pile of secrets.” Andrey Malraux, 1901-1976

Every tissue in our body consists of many different types of cells, which integrate with each other in a variety of architectures. Even blood vessels, which resemble tubes, are not simple. They are lined from the inside with cells that are close to each other, which do not allow the blood to leave the blood vessels. Above them there is a layer of muscle cells, which are capable of exerting force and constricting the blood vessels, thus reducing the amount of blood passing through them. The smooth muscle cells are surrounded by cells called fibroblasts, which create an elastic and strong layer that surrounds the blood vessel and gives it strength so that it does not collapse in on itself. And if one blood vessel is a complex structure, containing several different types of cells, compare in your mind how complicated a whole hand is, which includes many blood vessels, nerves, muscles, tendons, bones, cartilage, fatty tissue and skin! In order for an amputee to be able to regrow the limb from the stump, he must regenerate all those specialized cells, each of which knows how to perform exactly the role defined for him and make them organize themselves in space in the same exact arrangement that prevailed in the lost hand. He must reproduce, in fact, the embryonic stage in which the hand grew as part of the complete embryo.

Every person begins his life as a single cell - the fertilized egg. At this point, one of the father's sperm has already managed to sneak its genetic load into the mother's egg and fertilize it. The supplied egg takes some time to digest the new situation, and then begins one of the most wonderful engineering processes in nature - the creation of an entire baby, whose body contains one hundred thousand billion cells, from one single cell. It is a long journey of nine months, and as journeys do, it also begins with one small and incredibly simple step: the fertilized egg splits into two cells. Each of the two new cells itself divides into two cells, and each of the four new cells also divides into two cells, and again and again and again.

After several such divisions, a hollow globule is obtained consisting of approximately one hundred cells. The shell of the ball is made of cells, but the content of the ball is the truly important treasure: the hollow ball contains several dozen embryonic stem cells, capable of creating the baby's body on their own. In the next nine months, these cells divide many times, build the body of the fetus inside the womb and produce the types of cells suitable for each tissue: here a heart, there an intestine and elsewhere a liver, kidney, lung, or any of the many other tissues that make up the body. Like a surge guided by the hand of an artisan, over many months the embryonic cells flow and flock to their destinations and assemble the embryo in all its parts. It is an arduous building process, which also affects the builders themselves, because during it the embryonic cells also undergo a radical change and become mature body cells.

What distinguishes an adult body cell from an embryonic cell? The embryonic cells can be thought of as school children. When they are young, they can acquire any profession they want. If they receive the appropriate instructions, these cells can mature and become skin cells, heart, liver, or any other tissue present in the body. But from the moment the cells received their new occupation, they are considered mature cells, and they cannot turn back the clock. The profession they chose will remain theirs forever, and they will not be able to change it until the day they die. The second difference lies in the ability of the embryonic cells to divide and multiply without limitation. They are young, that's clear. But from the moment they grow up and acquire a profession for themselves, they usually lose the ability to divide. These cells will carry out the role they assumed until their last day, without allowing them to bring offspring into the world - that is, to reproduce and create more copies of themselves.

Allegedly, this sounds a hideous absurdity. Why wouldn't we want our body cells to keep dividing? After all, in this way, we could recover from any injury and accident! The bones and nerves would restore themselves and amputated limbs would grow to their full length. But the ways of the body are smart. If all the cells in the body were able to divide uncontrollably, the delicate balance between the tissues would quickly go wrong, and the complex system that is the body would collapse. Sooner or later the whole body would turn into one big cancerous tissue, unstoppable or restrained. The bones, nerves and muscles would fight against each other, instead of cooperating and resulting in the creation of a functioning tissue. It is certainly difficult for a crippled or crippled person to be encouraged by the fact that his limbs do not regenerate by themselves, but he can take solace in the knowledge that if the adult cells were able to continue dividing without limit, then every child would have cancer already in the first years of his life.

The body of the hydra is also composed of mature cells, which are mostly unable to divide. And at the same time, every cell that spends its life inside the body of the hydra is replaced by another cell that takes over the role of its predecessor. To carry out this operation, the hydra uses an unusual mechanism: Her body is full and saturated with embryonic stem cells, which are able to respond quickly to any injury, to divide and make up for the lack of damaged cells. Every nerve cell that ages and dies in the hydra's body is immediately replaced by the power of the stem cells. Any injury, scratch or amputation of a hunting arm will be repaired by regenerating the missing cells. The hydra is in fact an eternal embryo, whose growth process is stopped in the pattern that was marked for its body. Since it was shaped by the forces of evolution, the hydra is able to constantly repair its body and complete the body pattern coded in its DNA, or even recreate itself according to the same pattern. If ever there was an animal worthy of the title of immortal, the modern hydra is it. She obeys, in her way, the picturesque saying of Doris Lessing - "The great secret that all the elderly share is that you haven't really changed in seventy or eighty years. Your body has changed, but you haven't changed at all. And that, of course, causes great confusion."

Unfortunately, humans are not immortal embryos. The embryonic stem cells that were present in our bodies in the embryonic stage disappear from the tissues until birth. Their job was to create and shape the baby's body, and after that is over they are no longer needed. For better or worse, we cannot revert to the embryonic stage as the hydra does.

Hope for the future?

Although embryonic stem cells no longer exist in the adult body, we are now able to extract them from embryos a few days old. At this stage, the embryo is no more than a ball of cells the size of a dot on a page, and has not yet developed tissues. From any practical point of view, the fetus is not human at this stage - no more than a cancerous growth is human. At most we can define it as having the potential to create a person. But on the other hand, so are the millions of sperm cells emitted in every male ejaculation. The Catholic Christian Church forbids the collection of human embryonic stem cells (Judaism actually permits the act), but the question must be asked: will humans also be able to regenerate their limbs in the future, by using the embryonic stem cells? It may be so.

In the last two decades, a lot of research has been invested in human embryonic stem cells, and various ways have been demonstrated that make it possible to communicate with the cells in their language and instruct them to divide or differentiate into different types of cells. These innovations would give hope that embryonic stem cells could supplement missing human tissues, if not for one problem: the immune system. Since the embryonic stem cells are extracted from human embryos, they are endowed with their own immune markers, and any tissue produced from them will be rejected by the transplanted body, whose immune system only knows how to recognize its own tissues and not the foreign implants. Any solution that relies on embryonic stem cells, therefore, will require the use of the injured person's own embryonic stem cells - but these, as you remember, no longer exist in the adult body. It was only in 2006 that a solution to the problem was found for the first time, which may one day provide a tip for copying the eternal life of the hydra to man. Last week one of the researchers facing the discovery won the Nobel Prize.

Restoring the youth of the cells

In 2006, Shinya Yamanaka bought his world and his place in the history of science, in an experiment whose ink continues to reverberate to this day in the scientific community, and for which he won the Nobel Prize for Medicine together with John Gordon in 2012. Yamanaka extracted fibroblast cells from the skin of a mouse, grew them in a petri dish and through engineering Sophisticated genetics managed to give them back their youth and return them to the embryonic state. The fibroblasts, which up until that moment had behaved like any adult cell with a way of life and lived their lives without dividing, responded to the renewal of youth with excessive enthusiasm. They divided uncontrollably and filled entire petri dishes with their offspring. These offspring, exact copies of their parents, also had all the properties of embryonic stem cells. In principle, these cells were supposed to start the process of creating mouse embryos inside the petri dish. And indeed it happened. The cells began to mature at a dizzying pace, while each of them re-chooses their profession in life. Within a few weeks, the petri dishes were filled with mature, beating heart cells, active kidney and liver cells, and even nerve cells that tried to connect with the other cells and send them messages. These were not real mouse embryos, whose tissues are well organized in the body. Perhaps it is more correct to define them as a terribly messy fetus. what went wrong? Everything - and nothing.

When the egg is fertilized inside the woman's body and begins to divide and become an embryo, it receives messages and instructions from the cells around it. Each of the young cells in the embryo's body also receives instructions from the cells around it, and thus it knows what it must do where it is and what profession it must acquire. The instructions that the cells receive are not just instructions for choosing a profession - in many cases, the cells receive instructions to migrate to distant places in the body of the fetus and only there to acquire their new profession.

In slow-motion photography, the process looks almost chaotic: millions of cells migrate in simulated randomness from place to place in the fetal body, displacing other cells and sending conflicting instructions to their environment. The embryo, at the beginning of its journey, is like a puzzle with millions of parts, each part of which changes its shape and its adaptation to the overall picture hour by hour. Millions of cells dance in perfect synchronization with each other, on the smallest dance floor in the world.

Some embryos will not survive the extreme creation and design process. In fact, there are estimates that a third of pregnancies end in the first months as a result of an error in the assembly of the fetus. But even though the process seems completely random to an outside observer, the embryonic cells manage to understand the messages they receive from their friends and differentiate accordingly. As evidence, most of the young embryos survive the self-assembly process, and even finish it when they are perfect and without any flaw (especially according to the proud parents).

Yamanaka's fibroblasts, when they regained their youth, returned to the embryonic stage. At this stage they were supposed to assist in the creation of the embryo's body through division, controlled migration and the acquisition of a profession. They were surely expecting instructions to be passed on to them from their environment, instructions from their relatives and close associates that would signal to them how they should behave. If they were inside an existing embryo, they would have received such instructions. But while imprisoned in the petri dish, without a guiding and guiding hand, they lost control and obeyed every fleeting and ephemeral message they received from the cells around them, which were just as confused and embarrassed as they were. Within the plates, cells and tissues of all types existing in the embryo grew and developed, as the products of the desperate attempts of the young stem cells to fulfill their role and create the embryo from scratch. Without guidance, they failed in their role, and instead of creating an organism with all its tissues organized and communicating with each other, they created a jumble of mature cells, without clear order or organization.

Although Shimanaka was not able to properly direct the young cells he created from the mature fibroblasts, he realized that the cells in the plates could be sorted out and some of them into groups - heart cells, liver cells, nerve cells and so on. These selected cells did not encounter immune rejection when injected into the mice from which the original fibroblasts were taken, because they still carried the markers indicating that they originated from the same mouse's body. In at least one study it was proven that nerve cells created from those fibroblasts can be absorbed well into the brain of the mouse from which the original cells were taken, and take the place of nerve cells that died as a result of Parkinson's disease.

This advanced experiment raises an interesting question: can we restore the hydra's self-renewability through technological means? After all, if we can cause adult body cells to turn back into embryonic stem cells, it seems that we are not that far from the place of the hydra. And if we can genetically engineer the cells in our body, so that a small number of them can become stem cells in an area of ​​injury or damage and restore the injured cells, then the abilities of the hydra will be seen in our eyes as a part of everyday life. Unfortunately, the technologies we have are not yet able to reach such a level of subtlety and sophistication in genetic engineering. The road is still long, but the end is already in sight. If we just keep walking down the path of science, we may discover what awaits us at the end of the path.

Note: The article is very reminiscent of some of the lectures in the courses I give on demand, in biology, genetic engineering and the future - between myths and scientific truths. You can refer toThe courses page On the "Other Science" website for more details.