Prenatal Diagnosis & Designer Babies Lecture Notes PDF

Prenatal diagnosis Expected Learning outcomes Define Prenatal diagnosis Identify the methods and applications of prenatal diagnosis Understand IVF and its applications Explain the process of gene editing Understand the process, benefits and challenges of designing babies What is Prenatal diagnosis ?...

Prenatal diagnosis Expected Learning outcomes Define Prenatal diagnosis Identify the methods and applications of prenatal diagnosis Understand IVF and its applications Explain the process of gene editing Understand the process, benefits and challenges of designing babies What is Prenatal diagnosis ? Procedures undertaken to diagnose genetic abnormalities and structural anomalies in early embryo and fetus in order to undertake timely prenatal counselling and appropriate interventions. It allows timely termination of pregnancy thereby preventing perinatal mortality. Prenatal diagnosis allows : timely medical treatment of a condition before or after birth parents to make decisions regarding whether to abort a fetus with a diagnosed condition parents to prepare psychologically, socially, financially, and medically for a baby with a health problem or disability. determine the outcome of pregnancy. Indications for prenatal diagnosis Advanced maternal age Previous child with a chromosome abnormality Women who are pregnant with multiples (twins or more) Family history of single gene disorder Family history of a neural tube defect Family history of other congenital structural abnormalities Abnormalities identified in pregnancy Women who have previously had miscarriages Other high-risk factors (Maternal illnesses) Different methods of sampling for Prenatal Diagnosis Applications of prenatal diagnosis Maternal serum screening:- Fetoprotein, estriol and HCG estimation Ultrasonography:- Structural abnormalities Amniocentesis:- Fetoprotein and acetylcholinesterase Chromosomal analysis Biochemical analysis Chorionic villus sampling:- DNA analysis Chromosomal analysis Biochemical analysis Fetal blood sampling:- Chromosomal analysis DNA analysis In vitro fertilisation (IVF) In vitro fertilisation (IVF) is a process by which an egg is fertilised by sperm outside the body, in vitro. Evolved as a major treatment protocol for infertility. The term in vitro, from the Latin meaning in glass, is used, as early biological experiments involving cultivation of tissues outside the living organism were carried out in glass containers such as beakers, test tubes, or petri dishes. A colloquial term for babies conceived as the result of IVF, is "test tube babies“. IVF is most clearly indicated when infertility results from one or more causes having no other effective treatment Tubal disease - In women with blocked fallopian tubes, IVF has largely replaced surgery as the treatment of choice. Endometriosis - Patients with endometriosis, often have tubal involvement and ovarian cysts (endometrioma). Ovulatory dysfunction - In patients with polycystic ovarian disease (PCOS) and other ovulatory problems. Age Related Infertility - In normal reproductive life, a woman's ovarian function is diminished with age. In many cases, this reduced function can be overcome through the use of IVF Male Factor Infertility - Azoospermia, oligozoospermia, asthenozoospermia, anti-sperm antibody etc. Preimplantation Genetic Testing (PGT) Genetic testing on pre- implantation embryos may be indicated for patients who are at risk for genetic disorders such as Cystic fibrosis and Thalassemia What are designer babies ? Babies who are “designed” through a genetic modification process are called designer babies. Genes play a major role in our life. If the genes of an embryo are altered using technology, adding in desired characteristics and taking away the undesired ones, then the resulting embryo will have a genetic makeup that has been engineered through gene therapy. Reasons for the formation of designer babies The specific genetic disease will be screened beforehand. By editing the DNA of these cells or the embryo itself (germline engineering), it could be possible to correct disease genes and pass those genetic fixes on to future generations. Such a technology could be used to rid of genetic diseases like cystic fibrosis and muscular dystrophy. Methods of Designing Babies Germline engineering Germline genetic modification is a form of genetic engineering which involves changing genes in eggs, sperm, or very early embryos. This type of engineering is inheritable, meaning that the modified genes would appear not only in any children that resulted from the procedure, but in all succeeding generations. Pre-implantation Genetic Diagnosis Pre-implantation genetic diagnosis (PGD or PIGD) is the genetic profiling of embryos prior to implantation (as a form of embryo profiling), and sometimes even of oocytes prior to fertilization. PGD is considered in a similar fashion to prenatal diagnosis. Gene Editing by CRISPR/CAS9 CRISPR: CRISPR stands for clustered, regularly interspaced, short palindromic repeats. Cas9 stands for CRISPR-associated protein 9 (Cas9). It is a revolutionary technique for germ line gene editing that has made gene editing cheaper and more accessible to scientists and laboratories. CRISPR-Cas9 technology allows to cut-and-paste a desired ‘code’ in the gene. The specific location of the genetic code that is required to be altered is identified on the DNA strand, and then, using the Cas9 protein, which acts like a pair of scissors, that location is cut off from the strand. A DNA strand, when broken, has a natural tendency to repair itself. This auto-repair process is intervened by supplying the desired sequence that binds itself with the broken DNA strand. The most popular way to edit genes relies on a system called CRISPR–Cas9. It uses an enzyme called Cas9 to make cuts to DNA. A snippet of RNA can guide Cas9 to a specific site in the genome. Cas9 have been known to cut DNA at other sites, too, particularly when there are DNA sequences in the genome similar to the target (see ‘Off-target effects’). Such ‘off target’ cuts could result in health problems: a change to a gene that suppresses tumour growth, for example, might lead to cancer. On-target, but wrong: how precise does gene editing need to be? A bigger problem than off-target effects might be DNA changes that are on-target but unwanted. After Cas9 cuts DNA, it is up to the cell to heal the wound. But the cell’s repair processes are unpredictable. One form of repair, called non-homologous end joining, often deletes some DNA letters at the cut site — a process that could be useful if the goal of the edit is to shut down expression of a mutant gene. Another form of repair, called homology-directed repair, allows to rewrite a DNA sequence, by supplying a template that gets copied in at the site of the cut. This could be used to correct a disease such as cystic fibrosis, which is generally caused by short deletions in the CFTR gene (see ‘On-target effects’). Wanted, but dangerous: which edits are safe? Even if the targeting and precision of changes in genome editing were perfect, there would still be a question about what kinds of changes to the human germ line are likely to be safe. Creation of Designer Babies Because of the Human Genome Project, it is possible to read all the base pairs (about 3.2 billion for one DNA copy), which are the basic modules in the blueprint of life. After Cas9 has successfully found and cut the target region, the defective part of the DNA needs to be changed. For this step, body’s repair mechanism called HDR (homology directed repair) is triggered. Each cell uses the HDR mechanism to repair breaks in its DNA. HDR uses a protein complex similar to Cas9. This protein complex is kind of a DNA glue. However, it not only glues together the free ends of the DNA strands but also replaces the adjacent area in the DNA based on an intact template of the whole region. The reason for this is that the area around the breakage could also be damaged and is safer to replace it at the same time. Many DNA strand fragments that exactly match the area around the breakage are generated. But some parts are different containing new or altered information. These altered DNA fragments are then transferred into the cell. When HDR looks for a template to fix the cut in the DNA strand, it will most certainly take one of these matching but modified fragments because the area around the breakage is surrounded by them. Patchwork babies: how to prevent mosaics? Sometimes genes differ not only between individuals in a population, but also among the cells of an individual. Mosaicism might pose problems for gene editing. An embryo tweaked to correct a gene that causes Huntington’s disease could contain a mix of corrected and uncorrected cells. How that affects the health of the resulting child would depend on which cells were edited and which were not — something that could be difficult to predict in advance. Methods to assay the DNA sequence in an embryo rely on removing a small number of cells for testing, and then destroying them. One approach used by researchers is injecting the CRISPR–Cas9 machinery into embryos at very early stages of development, when they are still only a single cell. This technique eliminated mosaicism. Genome editing so early in development creates a new problem: there is no way to distinguish embryos that carry the genetic disease from those that do not at the single-cell stage. Benefits of designer babies Longer life: When a baby is genetically modified, it means that the defective genes are been taken out. Theoretically these babies live a healthier life with fewer chances of illness. According to studies, this can add up to 30 years to a child’s life expectancy. No genetic disorders: There are a number of illness caused due to genetic disorders. These include Alzheimer’s disease, muscular atrophy, Down syndrome etc. Genetic modification reduces the chances of child being impacted by many such genetic problems. No hereditary disorders: Often, many health conditions such as diabetes, cancer, obesity, heart ailments are inherited from either of the parents’ families. Knowing the family history in advance will help genetic scientists to remove the problematic genes in question from the embryo. Problems associated with designer babies Possibility of damage to the gene pool. Genes often have more than one use. Most of the work done are still in experimental stages. Very Expensive. Termination of embryos. Disadvantages Some people want to have designer babies for non-medical reasons. They can decide the hair color, sex, intelligence, athletic ability and cosmetic traits by having the proposed application of pre- implantation. It has been possible for the parents to select the sex of the baby since it involves with the X and Y chromosomes. Ethics related to designer babies Religious leaders have raised objections over physicians and others “playing God.” The Catholic Church insists that human beings are — or must be — “begotten, not made.” Secular thinkers also worry that technology is giving some decision makers a degree of control over human lives, and indeed the human future for which they are not adequately prepared. Governments could engineer children to win Olympic medals, be better soldiers, be compliant workers or be brilliant scientists. Designing favorable traits in babies is very challenging DNA generally differs between people in two ways: There are DNA mutations and DNA variations. Mutations cause rare diseases like Huntington’s disease and cystic fibrosis, which are caused by a single gene. Mutations in the BRCA genes substantially increase the risk of breast and ovarian cancer. Women who don’t have BRCA mutations can still develop breast cancer through other causes Fatal conditions with a strong, clear-cut genetic contribution — such as Huntington’s disease, which is almost inevitable when the mutation is present and are good candidates for gene editing. Selecting embryos that do not have these mutations removes the entire or main cause of disease. Variations are changes in the genetic code that are more common than mutations and associated with common traits and diseases. DNA variants increase the likelihood that you may have a trait or develop a disease but do not determine or cause it In several large study populations, a DNA variant was more frequent among people with the trait than those without. These variants don’t determine a trait but increase its likelihood by interacting with other DNA variants and nongenetic influences such as upbringing, lifestyle and environment. To design such traits in embryos would require multiple DNA changes in multiple genes and orchestrating or controlling relevant environment and lifestyle influences too. The DNA sequence created by the edit should carry no known risk of disease. It is not only difficult to predict the precise sequence of an edit, but also hard to know with certainty that a variant will not increase the risk of disease. Some mutations in a gene called PCSK9, are associated with lower cholesterol levels and therefore a reduced risk of heart disease. The gene is sometimes suggested as a candidate for editing. But only a small number of people have these protective mutations. The first known attempt at heritable gene editing in humans was an effort to disable a gene called CCR5, which produces an immune-cell receptor that allows HIV to infect humans. Break the gene, and the children should be resistant to the virus, But a study from the UK Biobank found that the deletion might also shorten lifespan. The effects of some genetic variants can also depend on the environment and on other variants present in the genome. The CCR5 mutation, for example, is very rare in Chinese populations, raising concerns that the gene could be important for protection against viruses that people would be more likely to encounter in Asia. Most DNA mutations do nothing else other than cause the disease, but DNA variations may play a role in many diseases and traits. Take variations in the MC1R “red hair” gene, which not only increases the chance that the child will have red hair, but also increases their risk of skin cancer. Or variations in the OCA2 and HERC2 “eye color” genes that are also associated with the risk of various cancers, Parkinson’s and Alzheimer’s disease. Editing DNA variations for “desirable” traits may have adverse consequences, still unknown. To be sure, even though complex traits such as intelligence, athletics and musicality cannot be selected or designed, there will be opportunists who will try to offer these traits, even if totally premature and unsupported by science. People need to be protected against this irresponsible and unethical use of DNA testing and editing. The creation of designer babies is not limited by technology, but by biology. The origins of common traits and diseases are too complex and intertwined to modify the DNA without introducing unwanted effects. Any Questions ?