Do old and damaged cells know how to become younger and healthier? Who doesn’t like to be young, energetic and disease resistant even in their old days of life? Well, a group of researchers of Harvard Medical School(HMS) demonstrated that the age of complex tissues such as the retina can be reversed into its youthful biological function.
Ageing, quite simply, is a loss of information.
David A. Sinclair (Senior Author, professor of Genetics in the Blavatnik Institute at HMS)
In the study published in ‘Nature’ on December 2,
Firstly, the researchers have successfully restored the vision loss due to ageing in mice through reprogramming the complex tissues (nerve cells of the eye).
Secondly, their attempt to reverse vision loss in animals with a condition mimicking human Glaucoma became successful. And glaucoma is the gradual loss of sight due to the increase in pressure within the eyeball.
Thirdly, damaged optic nerves in mice restored through promoted nerve regeneration.
New Theory of Ageing:
Most cells in the body consist of the same DNA molecules with various functions. For achieving the degree of specialization, these cells should read the genes that are specific to their type. This regulatory function is the responsibility of Epigenome. This is a system of turning genes on and off in certain patterns. And this system will not change the basic DNA sequence of the gene. With this gene expression can alter and is heritable.
On the passage of time, the changes on the epigenome will cause cells to read wrong genes and thereby leads to malfunction.
Role of DNA Methylation in Epigenome:
In DNA Methylation, the methyl groups tack onto DNA sequence. During the development of embryos, the DNA methylation patterns lay down for producing different cell types. As the useful patterns of DNA methylation are lost over time, the switching of genes on or off gets into trouble. This trouble further results in impaired cellular function. Some changes in patterns of DNA methylation are predictable and thereby help in the determination of the age of the cell.
From the current study, the researchers hypothesized that if DNA methylation controls ageing in living organisms then some of its footprints may reverse the age of cells through erasing. Thereby restoring damaged and old cells to a more youthful state.
Gene therapy for Optic Nerve Regeneration:
The researchers chose the cells of the Central Nervous System (CNS) in the current study. Ageing process firstly affects the cells in CNS. Also the ability of CNS to regenerate declines in a fast manner after birth. The researchers made a modification for testing whether the regenerative ability of younger ones can be passed onto the adult mice.
In their work, they used an Adeno-associated virus (AAV- small replication-defective, non enveloped virus with linear strand DNA). AAV is used as a vehicle for delivering three-youth restoring genes into retinas of mice. And the three genes are Oct4, Sox2 and Klf4. Yamanaka factors comprise a fourth gene c-Myc in addition to the above three genes. Shinya Yamanaka, a Japanese stem cell researcher and is a Nobel prize winner for the discovery of the Yamanaka factors (transcription factors). These factors remove the epigenetic markers on cells. Also, the old cells can restore into its embryonic stage. This can further develop into another type of cell.
The passage of gene combination into retinal ganglion cells treats the adult mice with optic nerve injury. The result showed a two-fold increase in the number of surviving retinal ganglion cells and a fivefold increase in nerve regrowth.
Overcoming an important barrier:
The major issues faced by the researchers are:
Firstly when four Yamanaka factors were used in adult mice it could induce tumor growth. The chances of tumor growth makes the technique unsafe.
Secondly, these factors could restore the cellular state to the primitive state (embryonic state). Through this, the identity of the cell can erase completely.
Yuancheng Lu (Lead study author, research fellow in Genetics at HMS) and his colleagues modified their approach to research. They decided to deliver only three Yamanaka factors and dropped the c-Myc gene. Thereby resolving the major issues.
Reversal of Age related Vision Loss and Glaucoma:
For further experimentation, the team collaborated with Bruce Ksander and Meredith Gregory-Ksander who are HMS Assistant professors of Ophthalmology at Schepens Eye Research Institute of Massachusetts Eye and Ear. Two sets of experiments conducted:
(1) whether the vision loss due to normal ageing can be reversed with an approach of three gene combinations.
(2) whether this approach reverses the vision loss due to glaucoma.
The treatment showed an increase in nerve cell electrical activity and visual sharpness in mice in both sets of experiments. According to Ksander, the new approach leads to a new treatment manner in regenerative medicine. And various causes of vision loss in mice can reverse without any retinal transplantation. After treatment researchers found a reverse pattern of DNA methylation in cells. And thereby confirming it is an active driving agent in the ageing process.
Also, the researchers could initiate clinical trials within two years in people with glaucoma if their findings are confirmed in further animal work. With the three-gene approach treatment in mice shows no negative side effects.
Let’s hope that this approach will be a good cause for humanity and not for evil deeds.
Sources:
Also Read, One of our recent article: How does our brain remember time and place accurately?
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