By Justin A. Varholick, Ph.D.
As we grow older theres an impending fear that we will slowly, but surely, begin to lose our vision. This slow loss of vision is clinically dubbed low vision and impacts more than 39 million Americans, costs $68 billion annually in direct health care costs, and is only growing in our population as baby boomers enter the at-risk age of 65 and older. Magnifiers can often be used to help people with acute issues of low vision, but are often inconvenient and frustrating. More serious issues of low vision such as cataracts, age-related macular degeneration, glaucoma, and diabetic retinopathy require advanced treatment and surgery. For example, cataracts can be improved or reversed by removing the cloudy lens and replacing it with an artificial one. Such surgeries are not always ideal, or convenient, and further contribute to the already hefty direct health care costs. But, a recent breakthrough by Japanese scientists, in correcting blurry vision, might reverse this bleak future.
Old cells can become new againOur story begins around the mid-20th century, in 1958. A young and aspiring scientist, named John Gurdon, was studying frogs at the University of Oxford in England. Not everyone thought Gurdon would end up actually becoming a scientist. In his early days his school master thought such a career was far-fetched for Gurdon. Indeed, he ranked last in his Biology class out of 250 students. Yet despite such poor grades, Gurdon found himself studying frogs at Oxford and earning a doctoral degree in Biology. And his studies would surprisingly lead to a breakthrough in vision, and likely many other issues in human health, like Parkinsons Disease, heart disease, and spinal cord injury.
At the time Gurdon was trying to test an age-old theory on cell development. Many scientists before him discovered that cells the smallest unit of life begin without a clear fate in the early stages of an embryo. Then as the cell develops, their fate becomes more clear. They become cells of the heart, of the brain, the kidneys, the stomach, the spinal cord, or the eyes. But they cannot go back to a time when they had no fate, or specialization. The cells can only develop in one direction, from no destiny, to a clear path, then to a mature adult cell; like one found in the heart. But you just cant take a heart cell and start the process over, maybe turning it into a brain cell.
In disagreement with this theory, Gurdon did a simple experiment. He knew that a tadpole has more adult cells than a frog egg. A tadpole has gills, a heart, eyes, etc., while a frog egg simply does not. So, he cut open the tadpole and removed a single cell from the intestine; an intestinal cell. He then cut open the intestinal cell and removed its nucleus; the seed of the cell carrying all the DNA. Very carefully, he did the same with the frog egg, and finally replaced the nucleus of the frog egg with the nucleus of the intestinal cell. According to the age-old theory, the intestinal nucleus should stop normal development of the frog egg. But thats not what happened.
Instead, the new frog egg continued to develop normally, becoming a tadpole that later became an adult frog. Gurdon thought this was unbelievably odd, and so did everyone else in science. After many more experiments doing the exact same procedure (i.e., replication), it seemed that what he saw was a real, replicable fact. For some reason the nucleus of the intestinal cell was able to reverse itself to have no fate and slowly develop into any other adult cell. The seed from the intestine somehow could become the seed of a heart, brain, kidney, or even an eye cell and of course, an intestinal cell too.
After many more experiments testing the same theory, on many more animals, it seemed the theory was true, but it just didnt work for mammals. Given that the same effect could not be repeated in a mammal, some believed this discovery did not apply to humans. But they were wrong.
The discovery of induced pluripotent stem cellsAlmost 45 years later, around the start of the millennium, Shinya Yamanaka and Kazutoshi Takahashi began running experiments that would translate Gurdons findings to humans. Born after Gurdons findings were already published and well known, Yamanaka and Takahashi grew up in a world in which the fact that old cells can become new again was widely knowna solid foundation for further hypotheses, experiments, and discovery. So, the scientists set out to do what no one had before: turn adult skin cells of mice into new cells without a clear fate.
Yamanaka, the lead investigator of the study, shared a similar early history with Gurdon. He first became a medical doctor in Japan but was frustrated by his inability to quickly remove small human tumors taking over an hour rather than the typical 10 minutes. Senior doctors gave him the nickname Jamanaka, a Japanese pun for the word jama meaning obstacle. He then found himself earning a PhD in pharmacology and becoming a post-doctoral scientist, but spent more time caring for mice than doing actual research. Frustrated again, his wife suggested he just become a practicing physician. Despite her advice, Yamanaka applied to become an Assistant Professor at Nara Institute of Science and Technology, in Japan, and won everyone over with his fantastical ideas of investigating embryonic stem cells; the cells without a clear fate.
Then the persistence paid off when Yamanaka with his assistant, Takahashi discovered how to induce adult skin cells from mice to return to an embryonic, or stem cell, state without a clear fate. They began their experiments knowing that gene transcription factors proteins that turn genes on and off were responsible for keeping embryonic cells in a state without a clear fate. They thought that by turning specific genes on and off with these factors, they could turn back time and make an adult cell embryonic again. So, they tried many different combinations of gene transcription factors and ultimately discovered that 4 specific ones were enough to induce an adult skin cell to a mouse to become an embryonic cell. Because these re-newed embryonic cells, or stem cells, originally came from adult cells they came up with a new name, induced pluripotent stem cell. Broken down, induced pluripotent stem cells means that the cell was induced to become pluripotent pluri meaning several, like plural, and potent meaning very powerful (and stem meaning to have the ability to turn into any cell in the body).
These induced pluripotent cells were thought to be very powerful indeed and scientists across the globe were excited by this great discovery. They had visions of taking a persons skin or blood, forming them into induced pluripotent cells, and then using them to grow a new liver or new parts of the brain. Laboratories across the world confirmed the results by repeating the experiment.
Human stem cells Just repeating the experiments in mice, or frogs, was not enough. They needed to begin making induced pluripotent stem cells from humans. Enter scientists from the University of Wisconsin-Madison. The lead scientist, James Thomson was already well known for deriving primate embryonic cells from rhesus monkeys in 1995 and the first human embryonic cell line in 1998. In fact, Thomsons accomplishment of isolating embryonic cells from monkeys was the first sound evidence that it was possible to do the same for humans. Such discoveries placed him on the forefront in ethical considerations for research using human embryos and the most obvious scientist to lead the path toward making induced pluripotent stem cells from humans.
Thomsons team made the first human derived induced pluripotent stem cells from adult skin, with Yamanaka as a co-scientist. They followed the same general principles set by Yamanaka, who did the procedure with mouse skin cells. Importantly to Thomson, this discovery helped to relieve some ethical controversy with using human embryos to make human stem cells. By being able to induce adult human skin to become pluripotent stem cells, much research on human stem cells could be done without human embryos albeit research with human embryos remains necessary.
Yet more important to the discussion at hand, the ability to induce human skin to become pluripotent stem cells placed us on the edge of a breakthrough. With some clinical trials in humans, the fantasy of growing a new liver, heart, or eye was more a reality than ever before.
The start of human trials In 2012, around the time both Gurdon and Yamanaka were presented with the Nobel Prize in Physiology and Medicine for their work leading to induced pluripotent stem cells, human clinical trials were beginning in Japan. The first clinical trial was for age-related macular degeneration, an eye condition leading to blindness. Unfortunately, this trial was quickly terminated when Yamanaka and his team identified small gene mutations in the transplanted induced pluripotent stem cells from the first patient. Although the procedure did cure the patient of macular degeneration, these small gene mutations worried the scientists because they could lead to tumor development.
But recently with the introduction of an inducible suicide gene that can signal cells with abnormal growth to die, human trials are starting up again. In October of 2018, Japanese scientists began trials with Parkinsons disease, a brain disease related to a shortage of neurons producing dopamine. Scientists took cells from the patients, made them into induced pluripotent stem cells, guided them to develop into dopamine producing cells, and then deposited them in the dopamine centers of the brain through surgery. The outcome is promising since similar procedures in monkeys have been successful.
Other trials in Japan have also started, including spinal cord injury and one for replacing the cornea of the eye. Early results replacing damaged corneas with induced pluripotent stem cells, thereby correcting blurry vision, were just announced at the end of August. Although it will take more patients and safety checks before all humans can get induced pluripotent cells to correct their damaged eyes, malfunctioning brains, or broken spinal cords, Takahashi the post-doctoral scientist working with Yamanaka thinks it might happen as early as 2023. So, it looks like that in our lifetime we just might be able to stay young and enjoy retirement because of great breakthroughs in animal research.Note, EuroStemCell is a great resource for learning more about the ethics and research currently being done with stem cells derived from human embryos.
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