Hailed a “game changer”, and an “incredible discovery”, the process of transforming blood cells back into their embryonic “stem cell” state merely by bathing them in acidic solution for up to thirty minutes, is so simple that even Haruko Obokata, who made the breakthrough, could not at first believe her own results…
A stem cell is an undifferentiated cell with the potential to transform into any of the highly specialised cells in the human body. Their potential uses range from cancer treatment to “personalised medicine” where a patient’s own healthy skin or blood cells can be used to repair damaged tissues, such as heart disease or brain injury.
However, until now, stem cells brought about several dilemmas. The traditional method of extracting stem cells from embryos for use in regenerative medicine resulted in the destruction of human embryos and thus, a plethora of ethical concerns. In 2012, Cambridge University scientist Sir John Gurdon and Japanese colleague Shinya Yamanaka circumvented this problem by working out how to genetically reprogram mature cells to become induced pluripotent stem cells (iPSCs): a feat which won them the Nobel Prize. However, their work involved introducing four genes that are normally found in pluripotent cells using a harmless virus, which raised questions about the dangers of genetic manipulation and the possibility of genetic mutation potentially causing the formation of cancerous cells.
But now Japanese scientists in collaboration with Charles Vacanti of Harvard Medical School, have found a cheaper, simpler and more effective way to rewind adult cells – without manipulating the DNA and without destroying any living embryo. Simply bathe the cells in a weak acidic solution – stronger than milk and weaker than juice – for up to 30 mins and voila! – they revert to their embroyonic, pluripotent form – free from conditioning, and thus able to be inserted into the body anywhere needed.
Professor Austin Smith of Cambridge University, writing in the journal Nature, where the results were published on Wednesday, said the the new cells could be seen as a ‘blank slate’ from which any cell could emerge depending on its environment.
They have called the technique “stimulus-triggered acquisition of pluripotency” or STAP. It is so simple it could be done in any lab without the need for special equipment, dramatically reducing expense and opening doors to all kinds of personalised cell regeneration therapies, which could be developed into effective treatments for cancer, as well as many other diseases.
Haruko Obokata began work on the procedure 5 years ago when studying at the Harvard Medical School in Boston. She decided to study the effects of different types of stress upon cells after noticing that, when squeezed through a small tube, they shrank to the size of stem cells.
The breakthrough discovery took place when she and colleagues at the Riken Centre for Developmental Biology in Kobe, Japan cultivated a gene that glows green in the presence of Oct-4, a protein that is only found in pluripotent cells, within a groups of mice. They then isolated white blood cells called lymphocytes which carried this gene, and exposed them to various strong but fleeting physical and chemical stresses.
One batch of cells was exposed to a “sub-lethal” acidic environment, with a pH of 5.7, for 30 minutes. The team then tried to grow the cells in the lab. Despite having no results on day 1, on day 2, a number of cells began to glow green, meaning they were producing Oct-4. By day 7, two-thirds of the surviving cells showed this pluripotent marker, together with other genetic markers of pluripotency – many of which are also seen in embryonic stem cells.
To make sure these STAP cells were pluripotent, they subjected them to a number of tests, including injecting them into a mouse embryo. Once inserted, the STAP cells seemed to integrate themselves into the structure, and the embryo went on to form the three “germ layers” that eventually give rise to all cell types in the body. The embryos developed into pups that incorporated STAP cells into every tissue in their body. These pups subsequently gave birth to offspring that also contained STAP cells – showing that the cells incorporated themselves into the animal’s sperm or eggs, and were inherited. When inserted into an adult mouse, the cells demonstrated their pluripotency by forming into an embryonic but benign tumour called a teratoma.
Haruko Obokata has said she was “really surprised” at the way the cells reacted to the acid and had a hard time convincing other scientists her results were not a mistake.
Indeed, as the New Scientist reports “the method is striking for its simplicity”. The scientists cannot yet be sure whether the reprogramming is initiated by the low pH or by some other type of stress, such as chemical changes happening further down the line. But they think they are tapping into a fundamental body-repair process and believe other types of “stressful scenarios” would produce similar results.
This could happen in all tissues throughout the body, Vacanti says. “Perhaps injuries like a bump on the arm or a burn cause mature cells to revert back to stem cells.”
With the right environmental cues, these stem cells then specialise into healthy new cells to repair the damage. “We think that the more significant the injury, the further back down the tree these cells revert,” says Vacanti. “It’s mother nature’s repair process.”
The acid-bath process has also been enacted on brain, skin, bone marrow, fat, muscle, lung and liver tissue to varying degrees of success, but success none the less. The same technique is now being tried with human blood cells.
“If it works in man, this could be the game changer that ultimately makes a wide range of cell therapies available using the patient’s own cells as starting material – the age of personalised medicine would have finally arrived,” Professor Chris Mason, an expert in regenerative medicine at University College London said.
While the results are undeniably staggering, there may still be some glitches. Why did a mouse fetus formed of these cells ceased to develop normally half-way through? Indeed, Prof Lovell-Badge of the Medical Research Council said: “It is going to be a while before the nature of these cells are understood, and whether they might prove to be useful for developing therapies, but the really intriguing thing to discover will be the mechanism underlying how a low pH shock triggers reprogramming – and why it does not happen when we eat lemon or vinegar or drink cola?”
Why not watch Haruko Obokata talk about her project here: http://www.bbc.co.uk/news/science-environment-25967136
Sources include: The Independent; New Scientist; BBC News; The Telegraph
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