Reprogramming Aging Bodies Back to Youth

A little over 15 years ago, scientists at Kyoto University in Japan made a remarkable discovery. When they added just four proteins to a skin cell and waited about two weeks, some of the cells underwent an unexpected and astounding transformation: they became young again. They turned into stem cells almost identical to the kind found in a days-old embryo, just beginning life’s journey.
At least in a petri dish, researchers using the procedure can take withered skin cells from a 101-year-old and rewind them so they act as if they’d never aged at all.

You must be logged in to view this content.

Induced PluriPotent Stem Cells

Some of the first trials to test whether reprogrammed stem cells can repair diseased organs have begun to report positive results. Research teams involved in the studies, all based in Japan, say they provide early hints that the hotly anticipated technology works. But many researchers outside the country are cautious about overstating the significance of the trials, saying they were small and the results have yet to be peer reviewed.

Induced pluripotent stem (iPS) cells are those that have been reprogrammed from mature cells — often taken from the skin — into an embryonic-like state. From there, they can then turn into any cell type and be used to repair damaged organs.

In January, researchers reported in a preprint1 that the first person in Japan given a transplant of heart-muscle cells made from reprogrammed stem cells had experienced improved heart function following the procedure. Then, in April, another group announced that several people’s vision had improved after their diseased corneas were transplanted with corneal cells made from reprogrammed stem cells — a world first.

Ongoing trials are “delivering encouraging first insights into the evolution of iPS-cell-based therapies, from lab to patient”, says Wolfram-Hubertus Zimmermann, a pharmacologist at the University Medical Centre Göttingen in Germany.

The biggest impact of the iPS-cell trials in Japan so far is that they “give people confidence all over the world that it is doable”, says Kapil Bharti, a translational stem-cell researcher at the US National Eye Institute in Bethesda, Maryland.

The iPS-cell field is hugely popular in Japan, in large part because it was a local scientist, Shinya Yamanaka at Kyoto University, who discovered how to make the cells. Expectations for the potential uses of iPS cells soared in 2012, when Yamanaka won the medicine Nobel prize for his 2006 discovery. In 2013, the Japanese government announced that it would pour ¥110 billion (US$814 million today) over the next ten years into regenerative medicine.

In that time, Japanese scientists have launched at least ten trials in people. These have largely shown that the technology is safe, but have yet to establish that it has a beneficial effect. Now, public enthusiasm has waned, which threatens future government funding, says Masayo Takahashi, an ophthalmologist and president of the cell-therapy company Vision Care in Kobe, Japan.

iPS-cell technology has only been around for 16 years. And bringing it into clinical testing has happened unbelievably fast,” says Zimmermann. “The challenge is that this is all happening under high public attention.”


Conscious Artificial Brains

One way in which scientists are studying how the human body grows and ages is by creating artificial organs in the laboratory. The most popular of these organs is currently the organoid, a miniaturized organ made from stem cells. Organoids have been used to model a variety of organs, but brain organoids are the most clouded by controversy.

Current brain organoids are different in size and maturity from normal brains. More importantly, they do not produce any behavioral output, demonstrating they are still aprimitive model of a real brain. However, as research generatesbrain organoids of higher complexity, they will eventually have the ability to feel and think. In response to this anticipation, Associate Professor Takuya Niikawa of Kobe University and Assistant Professor Tsutomu Sawai of Kyoto University’s Institute for the Advanced Study of Human Biology (WPI-ASHBi), in collaboration with other philosophers in Japan and Canada, have written a paper on the ethics of research using conscious brain organoids. The paper can be read in the academic journal Neuroethics.

Working regularly with both bioethicists and neuroscientists who have created brain organoids, the team has been writing extensively about the need to construct guidelines on ethical research. In the new paper, Niikawa, Sawai and their coauthors lay out an ethical framework that assumes brain organoids already have consciousness rather than waiting for the day when we can fully confirm that they do.

We believe a precautionary principle should be taken,” Sawai said. “Neither science nor philosophy can agree on whether something has consciousness. Instead of arguing about whether brain organoids have consciousness, we decided they do as a precaution and for the consideration of moral implications.

To justify this assumption, the paper explains what brain organoids are and examines what different theories of consciousness suggest about brain organoids, inferring that some of the popular theories of consciousness permit them to possess consciousness.

Ultimately, the framework proposed by the study recommends that research on human brain organoids follows the ethical principles similar to those for animal experiments. Therefore, recommendations include using the minimum number of organoids possible and doing the upmost to prevent pain and suffering while considering the interests of the public and patients.


Rejuvenation by Controlled Reprogramming

On 19 January 2022, co-founders Rick Klausner and Hans Bishop publicly launched an aging research initiative called Altos Labs, with $3 billion in initial investment from backers including tech investor Yuri Milner and Amazon founder Jeff Bezos. This is the latest in a recent surge of investment in ventures seeking to build anti-aging interventions on the back of basic research programs looking at epigenetic reprogramming. In December, cryptocurrency company Coinbase’s cofounder Brian Armstrong and venture capitalist Blake Byers founded NewLimit, an aging-focused biotech backed by an initial $105 million investment, with the University of California, San Francisco’s Alex Marson and Stanford’s Mark Davis as advisors.

The discovery of the Yamanaka factors’ — four transcription factors (Oct3/4, Sox2, c-Myc and Klf4) that can reprogram a differentiated somatic cell into a pluripotent embryonic-like state — earned Kyoto University researcher Shinya Yamanaka a share of the Nobel prize in 2012. The finding, described in 2006, transformed stem cell research by providing a new source of embryonic stem cell (ESC)-like cells, induced pluripotent stem cell (iPSCs), that do not require human embryos for their derivation. But in recent years, Yamanaka factors have also become the focus for another burgeoning area: aging research.

So-called partial reprogramming consists in applying Yamanaka factors to cells for long enough to roll back cellular aging and repair tissues but without returning to pluripotency. Several groups, including those headed by Stanford University’s Vittorio Sebastiano, the Salk Institute’s Juan Carlos Izpisúa Belmonte and Harvard Medical School’s David Sinclair, have shown that partial reprogramming can dramatically reverse age-related phenotypes in the eye, muscle and other tissues in cultured mammalian cells and even rodent models by countering epigenetic changes associated with aging. These results have spurred interest in translating insights from animal models into anti-aging interventions. “This is a pursuit that has now become a race,” says Daniel Ives, CEO and founder of Cambridge, UK-based Shift Bioscience.

The Yamanaka factors that can reprogram cells into their embryonic-like state are at the heart of longevity research

We’re investing in this area [because] it is one of the few interventions we know of that can restore youthful function in a diverse set of cell types,” explains Jacob Kimmel, a principal investigator at Alphabet subsidiary Calico Life Sciences in South San Francisco, California. The zeal is shared by Joan Mannick, head of R&D at Life Biosciences, who says partial reprogramming could be potentially “transformative” when it comes to treating or even preventing age-related diseases. Life Biosciences, a startup co-founded by David Sinclair, is exploring the regenerative capacity of three Yamanaka factors (Oct4, Sox2 and Klf4).


Destroying Cancer Cells by Enhancing Radiation Therapy

A new study by researchers at Kyoto University’s Institute for Integrated Cell-Material Sciences (iCeMS) and collaborators in Japan and the United States demonstrates that enhancing radiation therapy using novel iodine nanoparticles can destroy cancer cells.

When X-rays are irradiated onto tumor tissue containing iodine-carrying nanoparticles, the iodine releases electrons that break DNA and kill the cancer cells

X-ray irradiation of high Z elements causes photoelectric effects that include the release of Auger electrons that can induce localized DNA breaks,” wrote the researchers. “We have previously established a tumor spheroid-based assay that used gadolinium containing mesoporous silica nanoparticles and synchrotron-generated monochromatic X-rays. In this work, we focused on iodine and synthesized iodine-containing porous organosilica (IPO) nanoparticles.”

Exposing a metal to light leads to the release of electrons, a phenomenon called the photoelectric effect. An explanation of this phenomenon by Albert Einstein in 1905 heralded the birth of quantum physics,” said iCeMS molecular biologist Fuyuhiko Tamanoi, PhD, who led the study. “Our research provides evidence that suggests it is possible to reproduce this effect inside cancer cells.

The researchers sought to overcome the challenge of effective radiation therapy at the center of tumors where oxygen levels are low due to the lack of blood vessels penetrating deeply into the tissue.

The findings were published in the journal Scientific Reports .