John Gurdon‘s initial ground-breaking work is over 50 years old now. He cloned a first animal, which was a frog: by taking a nucleus out from a frog’s gut cell and putting it into a frog’s egg, which had its own nucleus removed, Gurdon observed this new egg living, dividing , growing first into an embryo and eventually becoming a tadpole. In 1997 a similar technique was used to clone the famous sheep Dolly.
Initially, Gurdon’s work was met sceptically because of the common view that the cell commitment to a specific function in the body was irrevocable. For years, until the onset of genomic era, it was impossible to understand how components of the egg would reprogram the nucleus of the somatic cell to make it work like a nucleus of a developing egg. But then the molecular biology came into view.
The cell nucleus is a tiny room where the whole genome in the form of chromosomes is tightly packed. In my post on immortality I’ve mentioned that chromosomes are single extremely long DNA molecules, containing thousands of genes. Because of their length they need to be tightly packed in an orderly manner by specialised proteins, and they need to be accessible to other proteins, which transcribe genes into gene products required for various cellular functions.
What is the difference between chromosomes of an egg and a gut cell? The chromosomes of the developing egg are far more open and accessible to proteins to enable the egg to divide and differentiate into embryonic cells, which would give rise to all the tissues. Such cells are called pluripotent stem cells, they can turn into any cell type. The chromosomal DNA of the gut cell is only accessible in a way that ensures it to stay a gut cell and renders it unable to turn into another cell type. In layman’s terms the gut cell’s nucleus has many genes closed and the specific genes open to keep the gut cell identity under bay.
This is controlled by a chemical modification of DNA called methylation: if a particular part of the chromosomal DNA is methylated, it gets closed, inaccessible, by being associated with special proteins marking it for storage and not for use. Of course, this is an oversimplification, the special proteins I’ve mentioned are chemically modified too. The biological discipline studying all these modifications of DNA and the associated proteins and how they affect the cell processes and inheritance is called epigenetics. I shall definitely blog about it another time.
For now the question is – so what? Okay, we found what makes cells different from each other, what’s the use?
In 2006 Shinya Yamanaka published a study showing how to transform a regular committed cell from the body into a pluripotent cell able to give rise to any other cell types. He called these cells induced pluripotent stem (iPS) cells. To get an iPS, he introduced a minimal set of four genes, encoding DNA-binding proteins called transcription factors, into a somatic cell.
The benefits of iPS are obvious, – regenerative medicine. If one needs transplantation, the required tissue or organ can be produced out of such iPS cells coming from the patient’s own skin cells. This way one would avoid a transplant rejection by the immune system and there would be no need to use the health-wrecking immuno-suppressive drugs.
However, my rambling about open/close genes wasn’t just for the show-off effect. The first iPS cell line Yamanaka created showed wrong DNA methylation patterns (meaning the pattern of Openness/Closedness of the chromatin) compared to normal embryonic stem cells, and these iPS stem cells were not fully functional. There were other complications with these iPS cells, which you can read about in here.
Still, the iPS research moves forward quickly, these cells are becoming better and the therapeutic application is hopefully not beyond the horizon anymore.
To me, the most important contribution Gurdon and Yamanaka made is that they advanced our understanding of how cells commit to their fate (how they become mortal as opposed to immortal stem cells) at the level of chromosomal DNA.
P.S. It’s Friday, it’s my birthday and I can choose not to proofread my post, ho ho ho!
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