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SCIENTIFIC PAPERS


Personalised Medicine Professor Dr. Robert Hess

Today’s patients demand personalised and individualised medicine. Stereotypes belong to the past. One of the most important tools for an individual integration of the patient into age-related prevention is the determination of genetic risks with the assistance of measuring genetic polymorphisms. This can set the course towards risk recognition and health optimisation at an early stage, which in turn can counteract the development of diseases. The deciphering of the genetic code is owed to the combination of data processing and data technology on the one hand, and biomedical research on the other. Without this upgrade, molecular biology would not have succeeded in identifying the ca. 38,000 genes in our body. Due to the cooperation between electronic data processing and molecular genetics, we are now in a position to recognise the small individual differences in the genome and to associate them with clinical pictures, above all, however, with risk constellations. This makes preventive medicine possible. In recent years, the analysis of the human genome has resulted in an enormous increase in the knowledge of its sequence, organisation and structure. The vision that the knowledge of our genetic makeup would in the end lead to significant progress in human medicine seems to have been fulfilled: the molecular biological and the human genetic sciences will co-determine a new era of “Genomic medicine”. The principle of analysing our genetic information in medicine is therefore not new. For decades,scientists have searched for carriers of classic inherited diseases within the scope of newborn screening, for example, in order to be able to initiate preventive measures even before the first symptoms occur. If, until recently, genetic diagnostics have mainly been used for identifying persons suffering from rare monogenic hereditary diseases, genetic information is now increasingly gaining in importance for determining individual genetic dispositions in the field of major widespread diseases, which are so important for anti-aging medicine. These include arteriosclerosis, hypertony, osteoporosis and diabetes. Unlike monogenic diseases, however, complex diseases are on the one hand influenced by a large number of genes (polygene) and on the other by an equally large number of very different and non-inherited factors such as diet, lifestyle and environment. Today, the human genome has been completely deciphered. On the one hand, the DNA sequence is practically completely known and on the other hand, the knowledge of the structure of the genome is continuously growing. As a result, there is more and more comprehensive knowledge on the organisation of genetic information in coded and non-coded areas, and on number, arrangement and structure of the genes. Genetic diagnostics are able to identify a number of relevant risk factors and to emphasise the requirement for primary preventive measures. In addition, they are a significant help in developing medicinal intervention as a secondary preventive measure. The question what oncologists can learn from cardiologists is very simple. The answer is prevention. Imaging processes are of great importance for preventive examinations. It is, however, even more important, not to let the malignoma develop in the first place. The recognition of risk-collectives and the targeted preventive strategy in medicine will gain more and more in importance. This will not only help the emergence of preventive oncology – preventive cardiology already exists – but also of preventive neurology, preventive urology, preventive dermatology, etc. Small gene changes, which occur differently in different populations, are sometimes responsible for the association with diseases, particularly when functional polymorphisms are concerned.

Genetic Variation An important but in fact somewhat unexpected finding concerns the variability of the genome within the human population. The genome of a variable nucleotide, a so-called “single nucleotide” polymorphism, SNP for short, contains 1,000 bases. The variable in the human genome, however, does not always only concern single nucleotide components. Although less frequent, insertions or deletions (“in/del”) both of short and long DNA sections are also described, just as are variations in the number of repetitive DNS sections. Single Nucleotide Polymorphisms (SNPs) SNPs always assume one of two possible conditions, they are inherited as bi-allelic (e.g. as allele) and occur with a frequency of less than one percent within a specified population. Each person inherits an allele of one gene from the mother and one from the father. Alleles can occur with different prevalence, i.e. with different allele frequency, and determine the genotype of an individual. The “visible” form of the genotype is called the phenotype. To this day, more than two million frequently occurring SNPs (those with an allele frequency of more than 20 percent) are known. Experts, however, work on the assumption that they can find and describe a total of three and a half million such SNPs in the human genome. Hence, SNPs are “variations on a theme” in our genetic makeup and theoretically have neither positive nor negative characteristics. The majority of these variants concern intergenetic regions (DNA sections between genes) and are therefore phenotypically neutral. SNPs, however, can also occur in coded regions of the genes and by changing a codon alter the amino acid sequence of the coded protein. In doing so, SNPs can also affect the function of proteins and modulate or even compromise them. Hence, SNPs in coded regions can have an impact on the phenotype, just like SNPs in the regulated sections of the gene, where they can change the expression of a gene in promoter sequences or the stability of a gene transcript (mRNA) in terminal sectors. Sequence variants are also known which affect or completely hinder the correct “splicing” of a gene transcript in the mature functional form of the mRNA. A significant characteristic of the SNPs is – as already mentioned – that they are inherited as bi-allelic markers, thereby forming both genotypes and so-called haplotypes. This has two important consequences. Firstly, SNPs occur in three possible genotypes: in one of two possible homozygote forms (Allele I /Allele I or Allele 2 /Allele 2) or in a heterozygous “mixed form” (Allele 1/Allele 2). This makes another level of modulation or phenotypical characteristic possible. Many SNPs behave recessively, i.e. they are neutral in a heterozygous state. On the other hand, they form so-called haplotypes with their adjacent SNPs, which can occur as allelic “blocks” within large chromosomal sections. The creation of these haplotype blocks is the responsibility of the coupling of adjacent genetic characteristics on one chromosome, which is referred to as “linkage” in the specialist literature.

Genetic individuality and personalised medicine The entirety of the small million-fold differences (SNPs) in the genome is responsible for the fact that each person in this world with the exception of identical twins has his or her “own” unique genome. Whilst 99.9 percent of the genome is identical, millions of SNPs are responsible for the inherited variety between people; they contribute to their individuality and can explain why the same environmental factors have a different effect on different people. Doctors already have the option of letting detailed knowledge about the individual genetic predisposition flow into the treatment or into the successful prevention of human diseases. The analysis of genetic polymorphisms therefore represents an important pillar within an overall concept for diagnosis, therapy, medication and prevention. If one works on the assumption that preventive examinations are sensible they will indeed be even more sensible the more predicative they become. Research into polyphorphism diagnostics is still in its early stages. However, it has already become apparent that its predictions are becoming more precise from month to month, and more and more association studies are available. However, the knowledge of polyphorphisms, and in particular their interpretation, will have to be integrated into medical training, as the lack of knowledge in this area, even in case of university lecturers, is the most common reason that polyphorphism diagnostics are rejected.
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