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A Biological Primer for Multiple Sclerosis

 

Before I get into too much detail about specific subjects, I'd like to go through some basic biology to be sure that we're all reading from the same page of the same prayer book. In this section, I want to look at genes, proteins and cells because they are important to the understanding of what multiple sclerosis is doing at the microscopic level. Hopefully, it will help you to read medical papers and take a proactive role in the management of your own disease.

Genes

Genes and microchips have been the buzz-words of the second half of the 20th century. At the end of World War II, the former had not been discovered and the latter had not been invented. The impact that these two concepts have had on our lives cannot be understated. Needless to say, I have no intention of discussing microchips here.

Let's go back almost 150 years to an Austrian monk named Gregor Mendel. Mendel is one of the least recognised of the truly great biological scientists. Everyone has heard of Darwin and Crick and Watson and can describe what their work was about. Gregor Mendel, on the other hand, was unsung in his own lifetime and, outside biological circles, remains largely so, even today. Everybody has heard of genes and yet the person who first described them is often overlooked.

What Mendel did was to experimentally observe the effects of genes in action, propose their existence (although he didn't call them genes) and to describe the broad mechanisms of their behaviour.

In 1856, he began working in a monastry flower garden and performed a number of carefully controlled breeding experiments with sweet-peas. His methods were extremely rigorous. He proposed that the existence of characteristics such as blossom colour is due to the occurrence of paired elementary units of heredity. Mendel presented his work in 1865 and it was only really noticed and validated in 1900 some years after he had died.

We now know that what Mendel found out applies to most multi-celled organisms – including all plants and animals. Though they don’t always obey Mendel’s rules of inheritance, we now know that genes, in combination with the environment, determine the appearance, constitution and behaviour of all life on earth from the tiniest virus to the great blue whale.

For most inherited traits, there are two underlying genes. These two genes can be the same as eachother or slightly different but only one version will be expressed in the animal. Mendel proposed that certain genes were dominant over others. If an organism had both a gene for a dominant characteristic and a gene for a recessive one, then only the dominant gene would be expressed to the exclusion of the recessive one. Genes that behave in this manner are known as Mendelian genes. Different possible variations for any trait are known as alelles of eachother.

Without directly observing them, Mendel had inferred the existence of genes and showed that the phenotype (the external character of an organism) is distinct from, but causally related to, its genotype (the genes that an organism carries). Subsequently, however, only the minority of characteristics have been found to follow the simple dominant-recessive pattern that Mendel described. Some genes are only partially dominant over others and both alleles (the alternative genes) can be expressed. Most characteristics are the product of several genes acting together but often, each of these operates in a Mendelian way.

DNA and genes

Nearly one hundred years later, Francis Crick and James Watson, working in Cambridge University, England, mapped out both the chemical and physical structure of DNA. This fascinating molecule contained the ingredients that explain all of Mendel's observations.

DNA has two remarkable features. It holds chemical codes for the manufacture of cellular chemicals and it is able to make near perfect copies of itself - to replicate itself. It is even more remarkable because these two functions are not performed by different parts of the DNA: they are rolled into one - the codes themselves are capable of self-replication. Both these processes are astonishingly elegant, astonishingly sophisticated and just plain astonishing. I'll try to convey the basics of them both although I won't go into much detail as cellular biochemistry is extremely complex (even the experts don't fully understand what is going on).

DNA is double stranded helix rather like a twisted rope ladder (see figures 1 above and 2 below). Each of the two parallel rope uprights is kept apart from and connected to the other by the wooden steps. All of the steps are the same width but are made of two parts joined at the middle. There are four different kinds of half step which are called “bases” because of their chemical nature. The four bases are, Adenine (A), Thymine (T), Cytosine (C) and Guanine (G). Adenine always joins to Thymine and Cytosine always joins to Guanine giving the ladder four possible types of step – called “base pairs” - AT, TA, CG and GC.

Along the beams of the ladder, the bases are organised in groups of three known as triplets or codons. Because there are four possible bases, there are 64 possible codons, all but three of which act as codes for the production of a type of chemical known as an amino acid. The three exceptions behave as 'stop' codes that terminate the production of these amino acids. In animals, there are 20 different amino acids most of which are coded for by more than one codon. A group of codons terminated by a stop code is known as a gene.

At a time appropriate to the biochemistry of the cell that contains the DNA, a gene will be transcribed from the DNA into a similar chemical called ribonucleic acid (RNA). From the RNA, amino acids are produced and are joined together to form something called a protein. Other chemicals are often combined with the protein - for example, iron in haemoglobin. You will often see proteins called peptides, polypeptides and oligopeptides. Technically, an oligopeptide has fewer than 10 amino acids, a polypeptide has between 10 and 50 amino acids and a protein has more than 50 amino acids. They are all peptides. In lay speak, oligopeptides and polypeptides are often simply called small proteins.

Almost every cell in our bodies has a nucleus which holds our genetic material strung into long tight-wound lengths called chromosomes. Every chromosome has an equivalent pair which holds the equivalent genes (alleles) that we discussed above. Human beings have 23 pairs of chromosomes - other animals and plants have a different number. Bacteria and viruses have but a single copy of each of their genes.

Proteins

As we have seen, proteins are not just a dietary food-group. They are the things that make us who we are. Our skin, hair, nails, haemoglobin, blood-factors, cell walls, cell signalling messages, bones - in fact, the key constituents of our bodies are proteins. Most of your proteins are identical to mine. Most of a chimpanzee's and a fair proportion of a cabbage's proteins are also identical. However, what makes me different to you and both of us totally different to a cabbage comes from the difference in our proteins and, as a consequence, the difference in our genes.

Proteins can get very big indeed and fold up into complex bundles like tangled string. The example shown in Figure 3 is a protein called Human Leukocyte Antigen (HLA). In fact, it is comprised of more than one component protein and is important to the functioning of the immune system. Some of the genes that code for HLA are believed to confer a susceptibility to multiple sclerosis. I shall explain more about HLA in the section on the immune system.
 
 

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