How human cells can be reprogrammed to renew our bodies

The human body is composed of about 37 trillion tiny units called cells, and there are about 200 different types of cells corresponding to the many different tissues and organs of the body, such as muscle, nerve etc.

In addition to these differentiated cell types the body also contains stem cells. These are undifferentiated cells that can renew themselves through cell division and under certain circumstances can develop into differentiated organ-specific cells.

Stem cells present in the early embryo have the remarkable ability to develop into all the specialised cells types found in the body. Embryonic stem sells (ESC) are said to be pluripotent. Human pluripotent stem cells can be grown in a laboratory, and are of great interest both medically and scientifically, e.g. for growing new human organs to replace organs that have failed (regenerative medicine).

Human ESC can be isolated from human embryos, but the embryo is killed in the process and many people object to this process on ethical grounds. To get around this problem a method of inducing differentiated human cells to transform into pluripotent stem cells (IPSC) that behave like ESC was devised in 2006. An improved method of preparing IPSC, ensuring that they closely resemble human ESC (the gold standard), has just been published.

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A human life begins at conception when a sperm cell from the father fuses with an egg cell from the mother. Both the sperm and the egg are genetically haploid, containing only one copy of each of the 23 different human chromosomes in the cell nucleus. When they fuse to form the zygote, the resulting human embryo now contains 23 pairs of chromosomes (diploid).

Two daughter cells

The zygote divides into two daughter cells, each daughter next divides in two and so the process goes on as the embryo grows and develops. Every time a cell divides a copy of the chromosomes is passed to each daughter. So all human body cells have the full human genome of 46 chromosomes. But, under normal circumstances, only in the early embryo can the genetic instructions be played out to allow all the human differentiated cell types to emerge.

However, in 1962, John Gurdon, Cambridge University, demonstrated that, in the right environment, the genetic material even in a mature cell can be reprogrammed to form all types of cells. Gurdon removed the nucleus of a fertilised frog egg cell and replaced it with a nucleus of a cell from the frog's intestine. This modified egg cell developed into a whole new frog.

In 2006, Shinya Yamanaka of Kyoto University took matters further, revealing that inserting just four genes (Yamanaka factors) into adult mouse cells can transform them into ESC-like IPSC. Human IPSC were created in 2007. Yamanaka and Gurdon were jointly awarded the 2012 Nobel Prize in physiology or medicine for demonstrating that adult cells can be reprogrammed.

The latest development in the IPSC story was reported by Jere Weitner and others in Nature Communications on July 6th. These workers developed a protocol for reprogramming human adult skin cells into IPSC without the need to add any Yamanaka factors. They activated these inactive but naturally occurring factors in the fibroblast genome using the gene editing technology CRISPR.

One of the authors, Prof Timo Otonkoski said, "Reprogramming based on activation of endogenous genes rather than overexpression of transgenes is theoretically a more physiological way of controlling cell fate and may result in more normal cells" – ie IPSC that very closely resemble ESC.

New drugs

IPSC are proving very useful in many areas e.g. discovering new drugs. This approach makes IPSC from a patient who has a particular disease and induces them to grow in the laboratory into the particular tissue afflicted by the disease. Large numbers of potential new drugs can be screened quickly by observing their effects on the tissue.

Yet progress in regenerative medicine using stem cells has been slow, with only one clinical trial reported to date, in 2014. IPSC-derived sheets of retinal epithelium were used to treat a degenerate eye condition. The trial ended in 2015 when mutations were detected in the IPSC.

However, we can confidently expect that success will be attained in regenerative medicine using IPSC. IPSC were only discovered in 2006 and it takes about 20 years to move a laboratory discovery to clinical use.

William Reville is an emeritus professor of biochemistry at UCC