It’s a good day to study transgenics

By the lakeside on campus on this rather fine day, revising various methods of generating transgenic animals. The goose and the fly decided they wanted in on this knowledge too. 

Age is just a number?

(Picture from J.D. Boer et al, Premature ageing in mice deficient in DNA repair and transcription, Science, 2002)

In the above picture a specific gene has been mutated. Mouse A and Mouse B are both 3 months old. Mouse C is Mouse A, at 15 months old. Mouse D is Mouse B at 15 months old.

Mouse A is your regular laboratory mouse. Known as a wild type. This means it’s just not been genetically modified in anyway, so is just a healthy mouse. Mouse B, however, is of the same age as Mouse A - and has pretty much the same genetics - except for one gene. Mouse B is a mutant of the Xpd gene. As a result, Mouse B has exhibited accelarated ageing. Simply from looking at it at 15months old, you can see that it has grey fur, emaciated structure and its’ skeletal structure looks abnormal. Other defects of the mouse which correlate with its’ accelarated ageing are infertility, osteoporosis, and a reduced lifespan. As it is evident, mutating this gene has caused premature ageing. This premature ageing is known as trichothiodystrophy. It is also known to affect humans, though it is very rare.

(Picture from J.D. Boer et al, Premature ageing in mice deficient in DNA repair and transcription, Science, 2002)

X-Rays to show skeletal differences in the mice described earlier.

The gene codes for a protein called a helicase. There are many types of helicase, and this particular helicase is involved in DNA repair and DNA transcription to RNA. All helicases unwind the DNA double helix to produce 2 single strands, which can then be accessed by an enzyme known as a polymerase. Polymerases access the single strands and create copies of DNA, or create RNA from the DNA template. In this particular case, the helicase is involved in repair.

Helicase unwinding DNA doubles strands

DNA is damaged by oxidation from free radicals within the cell, and from ultraviolet light from the sun. This experiment done on these mice shows that a lot of the processes of ageing are the result of an accumulation of DNA damage. As you get older, you are exposed to more sunlight, and your cells undergo more oxidative damage. Oxidative damage from freee radicals is caused by your mitochondria. So the very components of your cells which keep you alive, also contribute to your ageing in the long run.  As mitochondria release energy from sugars, oxygen radicals are released every now and again. These are single oxygen atoms with a free electron. This is highly reactive and when it binds in DNA, it can cause chemical changes to the Nucleic Acids that build up DNA, which means they may not be copied accurately by polymerases. This can be repaired by cells’ own repair mechanisms and most times, they are. However, every now and again, one damaged nucleic acid makes it through the repair process and is replicated as a mutation, becoming part of that cells (and all subsequent cells it may produce) DNA.

A mitochondrion

Ultraviolet radiation from the sun is the same type of energy as gamma radiation (only it has less energy so the cancer risk is lower). However, prolonged exposure to UV rays can lead to cancer as the high energies involved in UV radiation can cause damage to the DNA. As iterated earlier, this can be repaired. But prolonged exposure means some damages make it through the repair process and are embedded as mutations. If a mutation occurs in a gene that controls cell growth, then the cell may not be able to regulate its own growth. As a result, it may proliferate uncontrollably, producing a mass of cells - i.e. a tumour.

Another contributor to ageing is the fact that whenever DNA is replicated, some of the end of the DNA is lost. DNA is replicated when a cell is about to divide, so the new cell that is produced has a full set of DNA. So, just before cell division, the DNA content of a cell doubles. Trouble is, the new chromosomes in the new cell are slightly shorter than the original cell. This is because the ends of the DNA cannot be replicated efficiently (due to okazaki fragments and inadequate primer placement). Eventually, after many divisions, chromosomes will be significantly shorter than the original cell. Cells get round this by adding lots of non coding DNA at the end of chromosomes which is designed to be lost. These are known as telomeres. They are only added once, when the cell is a stem cell. After than telomeres cannot be regenerated. So you live most of your life, with your cells dividing, losing bits of telomere. Eventually, if you live long enough, the telomeres run out and you may start losing bits of coding DNA. This leads to cell damage etc. Thus contributing to ageing.

The red ends on this Computer generated image indicate where telomeres occur

Cancer cells and sex cells are the only cells which can regenerate telomeres with an enzyme called telomerase. These cells are known as immortal cells, as they can divide indefinitely, without loss of genetic information. Telomerases could be used to slow down the ageing process, and research is being done in utilising them, but it is a hard process, tampering with the very genetic mechanisms that define us. So who knows what lies in wait for our life expectancy and the way we age? (See more on ageing on a post I wrote some time back… here )

So, as we can see, the process involved in ageing and cancer have similarities. This also explains why as you get older, you are at more risk of developing cancer. Indeed, you may just develop random cancer due to mitochondrial damage. It’s why there’s all this rage in the commercial world about anti-oxidants. But I’m not going to endorse any of those products. However, grapes are a good source of anti-oxidants.

Grapes are goooooood.