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Dr Kaushik D Deb
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Genomics is going to play an important role in all the areas of healthcare, namely Prediction, Prevention and Cure.
Genomics in prediction and diagnostics
Prediction is the forecast or possibility of a normal person acquiring a disease or medical condition and diagnostics is a method to confirm what a patient might be suffering from. Current age genomics has interesting tools and roles to revolutionise both these areas of healthcare.
Genetics is the study of inheritance or the way traits are passed down from one generation to another. Genes have the information to make proteins which direct cell activities and functions as well as influence traits like hair and eye colour. Approximately, there are 30,000 genes in the human DNA. Genomics is a newer term describing the study of all of a person’s genes and the interactions of those genes with each other and the environment. Genomics plays a role in nine of 10 leading causes of death, including:
- Heart disease
- Cancer
- Stroke
- Diabetes
- Alzheimer’s disease
For people who are at increased risk for hereditary breast and ovarian cancer, or hereditary colorectal cancer, genetic tests may reduce their risk by guiding evidence-based interventions.
Genome studies are rapidly unravelling the role of genetic factors in the pathogeneses of common diseases in which preventive and therapeutic interventions for complex diseases are related to individuals based on their genetic profiles.
Personalised medicine already exists for disorders such as Huntington disease, phenylketonuria (PKU) and hereditary forms of cancer, in which genetic testing is the basis for informing individuals about their future health status and for deciding upon specific, often radical interventions such as lifetime dietary restrictions and preventive surgery.
An essential prerequisite for personalised medicine to become feasible is a predictive test or prediction model that can discriminate between individuals who will develop the disease of interest and those who will not. The level of discrimination that is required in clinical care and public health applications depends, among other things, on the goal of testing, the burden of disease, the costs of disease, availability of (preventive) treatment and the adverse effects of false-positive and false-negative test results.
Today, more than 900 genetic prediction tests are available. There are also susceptibility tests which can determine an estimated risk for developing the disease. Some of them are:
Carrier screening: Identifies unaffected individuals who carry one copy of the gene that needs two to express the disease. This helps in making the right choice of partners before marriage, so that defective genes are not inherited by the children. One example could be the thalassemia trait.
Preimplantation genetic diagnosis: Embryo from in vitro fertilisation is tested before it is implanted in the uterus. Timely diagnosis could help in medical elected termination of the pregnancy.
Parental diagnostic testing and newborn screening: Point-of-care genetic testing incorporates the newest most sophisticated techniques to identify variations in the genetic sequence at the bedside – enabling clinicians to react and alter therapy based upon the results.
Traditional genetic testing involves the analysis of DNA in order to detect genotypes related to a heritable disease or phenotype of interest for clinical purposes. Point-of-care tests (POCT) are designed to be used at or near the site where the patient is located. They do not require permanent dedicated space, and are performed outside the physical facilities of the clinical laboratories. POCT can be used for diagnosis and also find the stage of different diseases.
Single nucleotide polymorphisms, frequently called SNPs (pronounced ‘snips’), are the most common type of genetic variation among people. SNPs occur normally throughout a person’s DNA. Researchers have found SNPs that may help predict an individual’s response to certain drugs, susceptibility to environmental factors such as toxins, and risk of developing particular diseases. SNPs can also be used to track the inheritance of disease genes within families. Future studies will work to identify SNPs associated with complex diseases such as heart disease, diabetes, and cancer. These also help in detection of occupational hazards, inheritable genetic disorders.
Reduced costs and increased speed and accuracy of sequencing can bring the genome-based evaluation of individual disease risk to the bedside.
Parental conflicts: Conflicts among fathers, mothers to know their offspring can be detected by genomic detection. The data on genomic configuration of an individual would be important to maintain in the coming years to solve disputed parenting issues. This will be particularly important in issues related to same sex marriages, improvement and empowerment in IVF/ ARTs for infertility and surrogacy related affairs.
Genomics in preventive healthcare
Gene tests look for signs of a disease or disorder in DNA or RNA taken from a person’s blood, other body fluids like saliva, or tissues. These tests can look for large changes, such as a gene that has a section missing or added, or small changes, such as a missing, added, or altered chemical base (subunit) within the DNA strand. Gene tests may also detect genes with too many copies, individual genes that are too active, genes that are turned off, or genes that are lost entirely.
Prevention genetics performs genotyping of human DNA polymorphisms in support of biomedical research. We type Single Nucleotide Polymorphisms (SNPs), Diallelic Insertion/ Deletion Polymorphisms (INDELS) and Short Tandem Repeat Polymorphisms (STRPs) (also called microsatellites). A powerful panel of Ancestry Informative Markers (AIMs), based on SNPs is excellent for determining geoancestry. In addition, whole genome scans and fine mapping can also be done for disease prevention and prediction.
Genomics in dry screening
Overall interest in having future newborns undergo whole-genome sequencing was generally high among parents. If whole-genome sequencing were offered through a state’s newborn-screening programme, 74 per cent of parents were either definitely or somewhat interested in utilising this technology. If offered in a paediatrician’s office, 70 per cent of parents were either definitely or somewhat interested. Parents in both groups most frequently identified test accuracy and the ability to prevent a child from developing a disease as “very important” in making a decision to have a newborn’s whole genome sequenced.
Genomics in treatment and drug development
Regenerative medicine is a new and expanding area that aims to replace lost or damaged tissues in the human body through either cellular transplantation or endogenous repair. Adult stem cells infused into the circulation are currently leading the clinical front of regenerative medicine. However, in various genetic diseases like hemophilia, or cardiac diseases, scientists are trying stem cells transplants which have the defective genome corrected with the right genetic sequences.
One recent development in regenerative medicine is the genetic reprogramming of adult somatic cells into stem cells, now known as the induced pluripotent stem cells (iPSC). This landmark cellular reprogramming technology was developed by Dr Shinya Yamanaka, at Kyoto University Japan. The findings led to a Nobel prize in physiology and medicine for Dr Yamanaka in 2012. iPSCs are an important advance in stem cell research, as they may allow researchers to obtain pluripotent stem cells, which are important in research and potential therapeutic uses. Human pluripotent cells such as human embryonic stem cells (hESCs) have ethical limitations in their application in therapy or drug discovery research. However, induced pluripotent stem cells (iPSCs) created from genetical reprogramming of an individual’s adult skin cells and their in vitro differentiation models (say in creation of disease specific cell lines, or hepatocytes , cardiomyocytes etc) provide effective models for investigating drug toxicity, metabolism and mechanisms underlying human diseases and as potential source of replacement cells in cellular transplantation approaches. For e.g.; with the iPSC technology skin biopsy of a patient who is suffering from metabolic disorders can be collected and converted into the iPSC cells, these cells could be undifferentiated into genetically defective cadiomyocytes and hepatocytes. These cells which carries the inherent genetic defect/mutation can be used to screen drugs or do drug metabolism studies.
Personalised drug prescriptions: Pharmacogenomics is the study how a person’s genetic makeup affects their body’s response to drugs. These are drugs which are designed to work mostly with people who have a particular gene functioning in a particular way. Genetic factors may account for between 20 to 95 per cent of the observed variation in drug response between individuals.
One important aspect of personalised medicine is patient-to-patient variation in drug response. Pharmacogenomics addresses this issue by seeking to identify genetic contributors to human variation in drug efficacy and toxicity. Here, we present a summary of the current status of this field, which has evolved from studies of single candidate genes to comprehensive genome-wide analyses.
Examples of using genetic information in the treatment of disease
A person’s genetic makeup affects how their body breaks down certain medicines. Genetic testing can examine certain liver enzymes in a person to find out how their body breaks down and removes medicines from the body. Because these liver enzymes are less active in some people, they are less able to break down and get rid of some medicines. This can lead to serious side effects. This type of testing is being used to find the right dose of certain medicines, such as antidepressants that are used to treat some mental illnesses.
There is now a test to find out whether a medicine called Herceptin will be an effective treatment in breast cancer. This test looks for ‘estrogen receptors’ in tumours.
Children with a common type of leukaemia can be tested to find the right doses of chemotherapy treatment.
Today, family history is the best genomic tool available, and compared with other genetic tests, it can be relatively inexpensively collected. A genetic analyses of the genome of a person can tell a doctor if the patient will respond well to some of the following blockbuster drugs Simvastatin, Atrovastatin, Pravastatin, Warfarin, Clopidogrel, Carbamazepine, 5 Fluorouracil, Metfromin, Abacavir, Floxacillin etc.
Gene therapy involves changing or replacing faulty genes by inserting a normal gene into the body of a person with a serious illness. The approach is used either to disrupt the function of a gene or to replace it with a new one. To replace the gene, we must also add a DNA template for the new gene, which would be copied into the genome after the DNA is cut. The various ways to achieve this includes nanoparticle-based gene deliveries, and other viral vector based genomic integrations. Techniques are being developed to edit the genome with high precision. Complexes known as transcription activator-like effector nucleases (TALENs) can also cut the genome in specific locations, but these complexes can also be expensive and difficult to assemble. Other more precise and user friendly technologies are also being developed. Among other possible applications, these systems can be employed in designing new therapies for diseases such as Huntington’s disease, which appears to be caused by a single abnormal gene. Clinical trials, in which zinc finger nucleases to disable genes, are now under way in the Western countries and may offer a more efficient alternative.
The technology would be useful for treating HIV by removing patients’ lymphocytes and mutating the CCR5 receptor, through which the virus enters the cells. After being put back in the patient, such cells would resist infection. The genetically modified hematopoietic stem cell transplant to reconstitute the patient with normal blood and immune system is a futuristic application too.