Limb Regeneration Becker

Abridged and edited from the original version washingtonpost Aug 6, 1978

Transfer the treasure trove of capacity of the remaining natural world for human enhancement. Restoring damaged organs - whole, perfect and in situ.

The salamander regenerates its severed limbs. In the 70's, scientists grew back a frog's leg from elbow to toes and a rat's leg from shoulder to the top half of the elbow, with cartilage and bone, muscle, nerves and veins. Dr. Robert Becker, applied the newly found healing mechanism to broken human bones, successfully knitting fractures that previously had failed to heal even after extensive surgical procedures. He and his colleagues have now reached the point where they can confidently predict that regeneration of human parts will be achieved, in the next few decades.

The body of every animal, from the flatworm on up the evolutionary scale, possesses primitive, undifferentiated cells. When a creature which can regenerate loses a limb, these cells migrate to the injury, forming a mass called a blastema. Some of the mature, specialized cells at the site of the injury dedifferentiate, reverting to primitive form, and add further to the blastema. The blastema then respecializes, transforming itself into whatever types of cells are needed to replace the missing part - bone cells, cartilage cells and so forth. Somehow, the blastema absorbs information about what to produce along the way, so that at the appropriate moment, it creates an elbow joint or a tibia or a fibula, a left leg or a right one.

Two Important Clues

The first formal paper on regeneration was written by the Italian physiologist Luigi Spallanzani and appeared in 1768. Spallanzani's experiments: The younger the animal, the greater its capacity for regeneration; and the lower an animal is on the evolutionary scale, the greater its capacity for regeneration.

This latter finding was especially interesting, the lower orders that regenerate are biologically just as complicated as man; their parts are just as difficult to replace. The main difference is that animals in the lower orders have comparatively more nerves in their extremities.

A third clue in the writings of the late 1700s. Every time a creature is injured, an electrical charge is generated at the site of the injury. This phenomenon is called the current of injury, and it is proportionate to the severity of the wound.

180 years later, in 1945, the biologist Meryl Rose amputated the forelegs of some frogs below the elbows. Thinking he could perhaps promote growth by preventing the injuries from scarring over, he bathed the stumps of the frogs' limbs in a strong salt solution.

About half of each amputated limb regenerated, developing new bone and muscle and in some case even showing the beginnings of digital growth. Thus, Rose became the first to prove that an animal which cannot regenerate naturally can be made to do so artificially.

The next year, a Russian named Vladimirovic Polezhaev amputated frogs' legs in a similar fashion and then irritated the stumps by repeatedly jabbing them with needles. The result? Astonishingly, he regenerated about the same amount of growth that Rose had with the salt solution. It was possible that the salt not only had prevented scarring but, like the needle punctures, had actually exacerbated the injuries and thereby stimulated growth. Now there was another clue: Regeneration may somehow be connected to the severity of injury.

In the early 1950s, Marcus Singer, transferred nerves from a frog's healthy hind legs to the stump of its foreleg; his frog also regenerated about the same amount of growth that Rose's had. The nerve tissue required for regeneration must constitute at least 30 percent of the total tissue at the site of the injury.

In 1958, a Russian named A.V. Zhirmunskii discovered that the current of injury is proportionate not just to the severity of the injury but also to the amount of nerve tissue in the area.

Becker in 1958: Injury is related to regeneration; nerve tissue is related to regeneration, and both injury and nerve tissue are related to the current of injury.

He measured the current of injury in a salamander's regenerating leg and in a frog's scarring stump. On the day the legs were amputated, both creatures generated the same current of injury - a positive voltage. But there the similarity ended: As the frog's stump scarred over, the current of injury in its leg declined to zero; but the current of injury in the salamander's leg switched from a positive to a negative polarity and only then began to decline, reaching zero when regeneration was complete.

Becker had definitely discovered a connection between the current of injury and regeneration. The way the current of injury worked in those limbs was simply not concurrent with the way nerves are supposed to produce electricity.

Nerve fibers have traditionally been thought to respond to stimulation in only one way: Sodium penetrates into the nerve cell and potassium leaks out, creating a chemical reaction that generates a charge called an action potential. Whatever the stimulus - a gentle touch or an injury - the action potential is exactly the same. Moreover, each nerve fiber can create only one of these potentials at a time. Becker compares the system to that of a digital computer, which transmits single impulses in rapid succession.

Herein lay Becker's problem: How could the action potential - a constant - account for the switch from positive to negative polarity that he had seen in the salamander's current of injury? How could the action potential account for the fact that the current of injury lasted many days after the stimulated nerve cells should have either died or repaired themselves and ceased their impulses? How could the action potential, which responds in the same way to every stimulus, account for the fact that creatures feel intensities of pain?

Becker guessed that in additin to its digital-computer impulses, the central nervous system can carry steady currents and potentials - in the way an analog computer can. he further theorized that the body's analog computer system has an input signal - could it be pain? - that triggers an output signal which switches on the healing function.

Becker measured the electrical potentials of different points on the skin of humans and other animals. He found an electrical field that roughly parallels the nervous system. A disturbance in that field, such as an injury, might stimulate cells to begin repairs.

Becker's theory ran counter even to basic textbook explanations of the nervous system. "That cells are capable of sensing and responding to levels of electrical current is hardly universally accepted," he wrote in one medical journal. But he stuck to his convictions. Today, his work is largely buried.

Bone Regeneration

The experiments that Becker based on his unorthodox vision of the nervous system produced remarkable results. First, in 1964, Becker began to examine the spontaneous regeneration of human bone. Given the fact that bone is not well innervated, the theories about electrical stimulation would not apply - unless none could generate its own electricity. Becker knew that bone accommodates automatically to mechanical stress. When he measured the currents around a stressed bone, he discovered that it generated a positive charge on the stretched side (which dissolved some bone) and a negative charge on the other side (which built up bone and provided the necessary added support). Then Becker administered a negative charge to a mouse's broken leg bone to see if he could artificially stimulate bone growth. It did.

In 1964, Steven Smith, then a student of Meryl Rose, studied Becker's findings and got the idea of implanting a simple electrode right into the muscle tissue of the stump of a frog's leg. He soldered together a piece of platinum wire, which has a positive charge, and a piece of silver wire, which has a negative charge, and embedded the metal into the animal tissue - with the negative end at the stump - thus improvising a crude battery. It worked. He regenerated about as much growth as Rose, Polezhaev and Singer experiments had the decade before.

Becker examined his healing frog bones under a microscope and saw that the blastema around the regenerating bone was coming from a blood clot that had formed there. (A frog's red blood cells are prime candidates for blastema, unlike the red blood cells of mammals, they have nuclei and thus can easily divide and dedifferentiate.)

He had a student expose frog blood to various levels of electrical current in order to find out exactly how much of a charge is needed to turn blood cells into blastema. The student administered smaller and smaller currents to the blood (high ones either did nothing or began to cook the cells), he saw no evidence of change. Finally, he found that blood cells revert to blastema at a few billionths of an ampere.

In 1973, armed with this knowledge of how much current produces a blastema, Becker decided to have the step from regenrating amphibians to regenerating mammals. He amputated a rat's foreleg below the shoulder and implanted the platinum-silver electrode device at the stump. Again, success. The animal regenerated nerves and tissue and even formed the humerus, the upper-arm bone, complete with the rounded end that fits into the elbow joint. Other parts of the elbow joint began to take shape, including cartilage and two bony structures that Becker surmissed were the forerunners of the radius and ulna bones of the lower leg. Everything about the new growth was precisely as it had been in the original limb. And all this growth took place in just three days.

But then the growth ended; for the electrode remained implanted in the shoulder tissue, while the end of the stump, where regeneration was taking place, had grown beyond the reach of its vital current.

The rat's growth, though incomplete, was nevertheless significant, particularly in one respect: The fact that the rat, whose red blood cells have no nuclei, could form a blastema - probably from bone marrow - indicated that in all probability humans could do so as well.

About this time in London, two newborn infants lost their fingers, and the fingers regenerated naturally. The explanation, in Becker's view, Spallanzani's early finding that the younger the creature, the better its ability to regenerate. But what was most significant about the babies' growth was that it indicated that the human body contains its capacity for regeneration.

Later in 1973, Smith devised an electrode that would travel with the regenerating stump. Again he amputated a frog's leg below the elbow: With the new device, the frog's entire leg grew back.

The year 1973 marked a third triumph as well: Becker began using his findings about the body's electricity in experiments on human bone. A patient who had fractured his ankle two years earlier suffered from a mild diabetic condition that was interfering with the bone's ability to regenerate. The ankle had failed to mend despite two corrective operations; and the bone on both sides of the break had deteriorated.

Under normal circumstances, Becker would have had to amputate the leg. Instead, he implanted an electrode into the fracture and administered the same current that he found had divided the frog's red blood cells. He waited three months, the time an ankle fracture would normally take to heal, and the fracture regenerated. A sample of the new bone showed it to be normal in every respect.

Clue in the Nerves

The next year, during the course of routine experiments, Becker stumbled on another clue that finally shed considerable light on his nervous system theory. With the intention of impeding growth, he and his staff broke the tibia in a rat's leg and then cut the nerve that led to the broken limb, assuming that without a nerve supply the rat's bone would heal poorly, if at all. But the fracture healed well; the only drawback was that it took twice the normal time. Perhaps the severed end of the nerve needed time to degenerate, they thought. So they cut the nerve six days before breaking the bone. To their astonishment, the bone healed in the normal amount of time, as if the nerve had never been cut at all.

They opened up the leg, only to discover that the nerve fiber had not healed. What had healed was the nerve's sheath of Schwann cells - one of a dozen types of cells that make up the "perineural group" - traditionally thought to serve no purpose other than the insulation of the nerve fiber. The perineural cells in the brain were known to carry a steady current - for what reason, no one knew. It now seemed apparent that Schwann cells also carry a steady current. This was proof enough for Becker that the analog computer system he had theorized was indeed contained in the perineural cells - cells that sheathe the entire central nervous system.

The perineural discovery is by no means the end of the tale. Experiments must still be conducted to determine if electrical regeneration is entirely safe. Could applications of electricity to the peripheral nervous system, for example, induce some sort of behavorial disorder? Or damage our cognitive powers? Every human body contains dormant cancer cells. Could an implanted electrode shock them into fatal multiplication?

Nevertheless, much of the mystery has been solved. Could damaged human parts grow back properly.

We may also someday regenerate a damage heart. Becker has discovered that salamanders replace some 50 percent of their cardiac muscles by regeneration. And Polezhaev has cut away the scar tissue on the hearts of dogs which had suffered severe heart attacks; all of the hearts regenerated and less than 5 percent of the dogs died. We may even replace parts defective at birth, given that damaged genes do not garble the instructions given to the blastema.

Becker himself is hesitant to herald regeneration as an immediate cure for amputees. The replacement of severed parts, he says, is still pretty far off. Why not aim for more immediate uses? Severing the spinal cord in man produces paraplegia because man's spinal cord does not regenerate. Becker, however, thinks that since salamanders regenerate their spinal cords, man's spinal cord could perhaps be electrically stimulated to do the same thing. It would take only a year to see whether electrical stimulation works without complications in a paraplegic.

Unanswered Questions

Animals that regenerate don't get cancer. If a tumor is implanted in a lizard's body, which does not regenerate, it grows to fatal proportions. But if it is implanted in the tail, which does regenerate, the tumor disappears.

Hormones play an important role in regeneration. A chopped-up adrenal gland when implanted in a frog will generate some growth. Moreover, if the adrenal gland is removed from a lizard, the creature will lose its ability to regenerate its tail. If the hormone prolactin is then injected, the lizard will regain its regenerative potential. It has also been hypothesized that hormones secreted during stress can cause cancer. Prolactin is secreted during stress. Is there a connection? Do carcinogens impose a stress on the body, which then triggers a hormonal release that oversensitizes the body to its own electrical forces, thus sparking wild division of cells?

If a negative charge builds up bone and a positive charge dissolves bone, could positive charges have an effect on malignancies?

If pain is the input signal needed by the brain to trigger healing, does anesthesia - the muffling of the pain signal - impede healing?

Does the body's sensitivity to electricity explain why the earth's magnetic field is a communication system for certain animals?

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I don't get it, how does this relate to aging? Mortality and immortality is relative to the ability of an organism to regenerate, as suggested by model organisms like the Planaria.

As mentioned in the article, salt improved regeneration of a wound, not consumed orally but to change the action potentials of the cells. Sodium, crucial for action potentials in nerves and may play a role in neuronal regeneration. Calcium, triggers various cellular processes, including cell growth and differentiation, modulating these channels could be relevant for bone regeneration, wound healing, and even hair follicle regeneration. Potassium, these channels regulate membrane potential and cell excitability, targeting specific types could influence stem cell activity and guide their differentiation. Chloride, these channels are involved in cell volume regulation and migration, mediators influencing their activity could potentially be used to promote tissue remodeling and accelerate wound healing.

BioDome and drug cocktails: A recent study by Michael Levin at Tufts University (2020) utilized a silicone cap (BioDome) loaded with a five-drug cocktail, applied for just 24 hours after amputation. Triggering limb regeneration in adult African clawed frogs, even exceeding the capabilities of tadpoles. No electricity was used.

The BioDome and Five-Drug Cocktail: the five specific drugs (prozac, a histone deacetylase inhibitor, a ROCK inhibitor, a glucocorticoid receptor agonist, and a β-adrenergic receptor agonist) applied for 24 hours.

  1. Prozac: Enhances neural activity and potentially stem cell activity.
  2. Histone deacetylase inhibitor: Modifies chromatin structure, potentially increasing gene accessibility for regeneration.
  3. ROCK inhibitor: Promotes cell migration and proliferation.
  4. Glucocorticoid receptor agonist: Balances inflammatory responses and cell differentiation.
  5. β-adrenergic receptor agonist: Stimulates cell growth and metabolism.

Perhaps the current of injury identical to the salamander would be artificially induced into an area of the body. After heavily removing damaged tissue.

Tissue Regeneration: Becker's research demonstrated that applying weak electrical currents could stimulate tissue regeneration in wounds and even induce limb regrowth in some amphibians. This suggests the potential for using electrical stimulation to promote cellular repair and regeneration, which could slow down or even reverse some aspects of aging.

Cellular Function: Becker proposed that the decline in electrical potential across cell membranes is a key factor in aging. His work with pulsed electromagnetic field therapy aimed to restore this potential, potentially improving cellular function and overall health.

Wound Healing: Studies have shown that electrical stimulation can enhance wound healing, which is often impaired with age. This could contribute to improved recovery and prevent age-related complications.

Since then, many groups have done many experiments from which to read on.

  

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