G&H Week 12 Lecture Notes PDF

GENETICS & HEALTH WEEK 12 Future therapies & technologies Lecture Dr Craig McFarlane WEEK 12 LEARNING OUTCOMES By the end of this week you should be able to: § Explain what is meant by risk in terms of genetic analysis. § Evaluate sources and reliability of genetic information. § Explain new gen...

GENETICS & HEALTH WEEK 12 Future therapies & technologies Lecture Dr Craig McFarlane WEEK 12 LEARNING OUTCOMES By the end of this week you should be able to: § Explain what is meant by risk in terms of genetic analysis. § Evaluate sources and reliability of genetic information. § Explain new genetic tools and applications that affect medicine and how Australia legislates for new genetic technologies. § Describe the main ethical issues associated with the use of novel genetic technologies. § Consider what novel technologies should be considered when dealing with patients. SCIENCE, TECHNOLOGY AND MEDICINE – THE EVER-INCREASING KNOWLEDGE GAP § Science and the human genome project gave humanity many answers about who we are, and it is still revealing more information everyday. § Technology is rapidly evolving. § The nexus of both is causing a widening of the knowledge gap between “average person” and “educated professionals.” LODOX System Full 6 foot image in 13 seconds using 10X less dose than regular X-ray. § Medical doctors need to understand both the technology and the science of medicine to explain new developments to your patients in a way they can understand. PROGRESS OF TECHNOLOGY We are at a point where there is exponential growth in technology: § Estimates indicated that between 2000 and 2014 we would make 20 years of progress, when measured by the rate of progress in 2000. § This is equivalent to the advancements of the entire 20th century. § And then we'll do the same again in only seven years. § We won't experience 100 years of technological advance in the 21st century. § But ~20,000 years of progress when measured by the rate of progress in 2000, or about 1000 times that achieved in the 20th century DESIGN APPROACHES USING GENETICS When we think about genetics and genetic disorders, we have to consider the fundamentals: 1) 2) 3) 4) What is the disorder? Recessive? Dominant? X-linked? Mitochondrial or Epigenetic (perhaps in the future)? How can we cure/prevent outcome? In the person (improve quality of life) or in their offspring (Germ-line; don’t want to pass the condition on)? What technology can we use and where? Gene therapy (gene level), chromosome therapy, new technologies like CRISPR, which option is the best approach (Ex vivo, in vivo or in situ). Is it a permanent or transient outcome? Is the cure, once in a lifetime or do you need regular treatments (monthly/yearly). REPLACEMENT PARTS - TISSUE ENGINEERING § Replacing damaged or defective parts in the body, an old idea brought into the future § Tissues made to order with your own stem cells. § Genetically identical to you, thus, no rejection problems. National Institute of Biomedical Imaging and Bioengineering TISSUE ENGINEERING iPSC – induced pluripotent stem cells; HDACi – histone deacetylase inhibitors. Tissue Engineering.jpg iPSCs Figure.jpg FDA Approved To treat diabetic foot ulcers Bioprinting – Using patients cells as ‘ink’. “The cells are rendered into a printable living ink, or bioink, “The bioink is loaded into syringes and squeezed out of a nozzle, tissue built up layer-by-layer. 3D-printed-organs-may-soon-be-a-reality Preparation-begins-for-first-clinical-trial-of-a-bioprinted-skin-330971 For knee cartilage defects 2022 GENE THERAPY FOR GENETIC DISEASES Instead of replacing whole parts, we can also look at the gene and DNA level. Lewis Fig 19.4 / 20.4 SOMATIC VS GERMLINE GENE THERAPY § Recessive disorders like Haemophilia & Cystic Fibrosis have excellent potential to be treated by Gene Therapy. § Disorders that are dominant, involving a gain-of-function mutation are more difficult to treat using Gene Therapy. WHY? We don’t want to give the patient more of that gene or gene product to make the condition worse. (e.g. FGFR3 & Achondroplasia). § Somatic Cell Gene Therapy involves inserting a “normal” gene into somatic (adult) cells in such a way that these cells will then make the missing gene product in sufficient quantities to alleviate or eliminate the symptoms of the disorder. § Germline Gene Therapy, where corrections are made or extra genes added to the germ cells; currently ethically unacceptable to most societies. § There are two main methods being developed to introduce ‘foreign’ genes into somatic cells for Gene Therapy. § Mechanical/chemical introduction of DNA (Give working copy of gene) § Viral Vectors (Take advantage of viral insertion of DNA into host) MECHANICAL VECTORS FOR GENE THERAPY Mechanical/Chemical methods of introducing genes into cells fall into 2 basic categories § Liposomes (or ‘soap bubbles’) § Microprojectiles LIPOSOMES MICROPROJECTILES • Liposomes are small membrane like microspheres that are manufactured to contain the gene to be expressed. • Small Gold or Platinum spheres are coated in DNA containing the gene to be introduced to cells. • Exposure of cells to Liposomes causes them to fuse with the cell membrane and deliver their contents into the target cell or tissue. • Using a variety or mechanisms, these spheres are mechanically ‘shot’ into living cells/tissues. • Some of the nucleic acid delivered will be randomly integrated into a chromosome and expressed to varying degrees. • Some of the nucleic acid delivered will be randomly integrated into a chromosome and expressed to varying degrees. VIRAL VECTORS FOR GENE THERAPY § Viruses by there very nature introduce ‘foreign’ DNA into cells and express their genes with high efficiency § Commonly used viruses are Adenovirus (AV) Adeno-associated virus (AAV), Herpes virus and Retroviruses § Gene Therapy using viral vector methodology involves inserting a ‘normal’ CFTR or factor VIII gene (or whatever!) into a virus, and infecting a CF or Haemophilia affected individual with that virus. VIRAL VECTORS PROBLEMS § Prevention of an immune response to the virus following repeated administration. § Recombination with related endogenous viruses: thereby producing hybrid viruses with unknown properties. § Spread of virus to ‘Healthy’ individuals. § Viral insertion into oncogene or tumour suppressor gene causing oncogenesis (recently documented to occur in mice). § Identifying viruses with appropriate tissue / cell-specificities for each particular genetic disease. GENE THERAPY APPROACHES Three main approaches related to gene therapy. Ex vivo § target cells are removed from the body. § cultured in the laboratory with a vector. § and re-inserted into the body. In situ In vivo § affected tissue is directly exposed to the Gene Therapy Vector. § vector is introduced into the body, typically via the blood stream. § Vector is targeted to site in the body. § Useful for disorders where only one tissue affected or causes symptoms. APPROVED GENE THERAPIES The first gene therapy approved by the European Medicines Agency (EMA) in 2012 was Glybera. Was designed to treat lipoprotein lipase deficiency (LPLD), lack an enzyme required to break down triglycerides. § Cost: USD$1 million for one-off treatment, as such was withdrawn from the market. Several other gene therapy products have been approved by the FDA, some examples below: Name Disease How it works Genetically modified herpes simplex virus type 1, which is engineered to produce GMCSF protein that causes rupturing and killing of the tumour cells Patient’s T cells are genetically modified (viral) to make a protein called chimeric antigen Large B-cell KYMRIAH receptor (CAR). CAR can attach to another protein on the surface of cancer cells called lymphoma CD19, which kills the cancer cells, thereby helping to clear the cancer from the body. A functional copy of RPE65 gene is introduced to patients via a subretinal injection of LUXTURNA Retinal Dystrophy Adeno-associated viral vector solution. Hematopoietic Stem Cells (HSCs) are collected from the patient, then treated with a BetaZYNTEGLO lentiviral vector to introduce functional Beta-globin gene. HSCs are then re-introduced Thalassemia to the patient. Spinal Muscular Utilizes Adeno-associated virus (AAV9) to deliver functional copies of the SMN1 gene ZOLGENSMA Atrophy (survival of motor neuron 1) to neurons. IMLYGIC Melanoma https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-products GENE THERAPY FOR MULTIFACTORIAL TRAITS? § Most common genetic disorders involve more than one gene. § Most diseases involve the interaction of several genes and the environment (epigenetics). § It MIGHT be possible to modulate epigenetic effects directly. § Epigenetic therapies for complex multifactorial traits, such has cancer have been developed. Important regulators of the Epigenome: § Enzymes that add acetyl or methyl groups to the histone or DNA are ‘writers’ § Enzymes associated with the removal of histone marks are ‘erasers’ § Enzymes that recognize histone and DNA modifications are chromatin ‘readers’ § Therapies targeting the various functions of theses enzymes have been developed…. GENE THERAPY FOR MULTIFACTORIAL TRAITS? Subhankar Biswas, C. Mallikarjuna Rao, Epigenetic tools (The Writers, The Readers and The Erasers) and their implications in cancer therapy, European Journal of Pharmacology, Volume 837, 2018 GENE THERAPY FOR MULTIFACTORIAL TRAITS? § Current FDA approved Epigenetic therapies for cancer. Jin, N., George, T.L., Otterson, G.A. et al. Advances in epigenetic therapeutics with focus on solid tumors. Clin Epigenet 13, 83 (2021). 2006 NOBEL PRIZE E (MEDICINE & PHYSIOLOGY) • So, one key treatment for dominant disorders is RNA interference. Craig Mello and Andrew Fire Their discovery, RNA interference (RNAi), can be used to specifically block a protein from being produced within any living cell. GENE THERAPY FOR DOMINANT TRAITS? Antisense RNA, complimentary to target region Forms a complex that recognizes mRNA target region § First discovered in the Nematode worm (C. elegans) in 1995. § antisense RNA known to inhibit gene expression. § Introducing 21-23 bp small interfering RNA molecules (siRNAs) leads to cleavage of the target mRNA and specific loss of protein synthesis. § Silences the expression of target genes! mRNA is cleaved, protein is not made. Mechanism video: https://youtu.be/cK-OGB1_ELE FDA APPROVED RNAI THERAPIES Five (5) RNAi-based therapies for metabolic conditions have FDA approval: Name Disease How it works Acute hepatic porphyria Breaks down aminolevulinate synthase 1 (ALAS1) mRNA, decreases (AHP) aminolevulinic acid (ALA) and porphobilinogen (PBG) levels in blood Hereditary transthyretin Breaks down transthyretin (TTR) mRNA, decreases production of Patisiran amyloidosis (hATTR) TTR protein in circulation and its deposition in tissues and organs. heterozygous familial Breaks down proprotein convertase subtilisin/kexin type 9 (PCSK9) Inclisiran hypercholesterolemia mRNA. Raises uptake of low-density lipoprotein cholesterol (LDL-C) (HeFH) and reduces its levels in the blood Breaks down hydroxy acid oxidase 1 (HAO1) mRNA. HAO1 produces Primary hyperoxaluria glycolate oxidase (GO). Reduces the production of the enzyme Lumasiran type 1 (PH1) alanine glyoxylate aminotransferase (AGT) that is mutated in PH1. Hereditary transthyretin Breaks down transthyretin (TTR) mRNA, decreases production of Vutrisiran amyloidosis (hATTR) TTR protein in circulation and its deposition in tissues and organs. Givosiran https://www.fda.gov/news-events/press-announcements/fda-approves-first-its-kind-targeted-rna-based-therapy-treat-rare-disease https://www.ncbi.nlm.nih.gov/books/NBK580472/#:~:text=Patisiran%2C%20givosiran%2C%20lumasiran%2C%20and,RNAi)%20of%20their %20target%20mRNA. CHROMOSOME THERAPY? We also have chromosome therapies under development STABLE HETEROCHROMATIN MODIFICATIONS + CHROMOSOME-WIDE TRANSCRIPTIONAL SILENCING + DNA METHYLATION = ‘CHROMOSOME 21 BARR BODY’ Genome editing integrates XIST into chromosome 21 in trisomic iPS cells. Provided proof-of-concept that we could target & switch off extra chromosomes. Jiang J, et al., Translating dosage compensation to trisomy 21. Nature. 2013 Aug 15;500(7462):296-300, 2013. PMID: 23863942 2018 https://www.nature.com/articles/s41467-018-07630-y Individuals with Down Syndrome have hematopoietic abnormalities including high risk of leukaemia. Transcriptional silencing of one chromosome 21 by XIST effectively corrects cell function and development to prevent excessive production of megakaryocytes and erythroids, in human iPSCs in culture. CHROMOSOME TRANSPLANTATION (CT) • • • Chromosome transplantation (CT) – The perfect substitution of an endogenous defective chromosome with an exogenous normal one. CT can re-establish a normal diploid cell. In this study: A normal exogenous X chromosome was first transferred into cells from Lesch-Nyhan syndrome (LNS) patients, an X-linked recessive disease caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). Transfer resulted in the extra sex chromosome being spontaneously lost. • • • • Been shown that cells acquiring an extra chromosome are prone to spontaneously lose the additional one. Thought to be due to abnormalities in nuclear morphology and the decreased cellular fitness associated with trisomy. They selected for cells that contained corrected X chromosome. Important: Any of the three sex chromosomes can be lost, but only cells maintaining the normal (donor) X chromosome would survive selection! HUMAN ARTIFICIAL CHROMOSOMES (HACS) § Human artificial chromosomes (HACs) are being developed to treat specific genetic conditions. Restore missing parts of chromosomes, e.g. Prader-Willi Angelman Syndromes. § No danger of insertional inactivation of other genes, and will be stably passed down during cell division. § Currently they can only be introduced into human cells with low efficiency (however, is improving). § HACs show great promise for off-the-shelf (somatic) gene therapy. § Technically could also be used for germline gene therapy. § Additional work has been done looking at HACs for Hemophilia treatment in mice. § Used a HACs to reintroduce functional FVIII. 2020 THREE PERSON BABIES § On February 3rd 2015, the House of Lords approved the creation of babies from three people and began the road towards legislation. § March 2017 - first license to create three-person baby was granted. § In Australia, on March 30th 2022, the Australian Senate passed the Mitochondrial Donation Law Reform Bill, also known as Maeve’s Law, named after a 6-year-old Australian girl with a mitochondrial disorder called Leigh syndrome. § Mitochondrial donation will be offered at just one fertility clinic as part of a clinical trial. The trial likely won’t begin for another 1-2 years. Australian Government will invest up to $15 million over four years to fund the clinical trial. § An estimated 1 in 5,000 children are born with diseases caused by mitochondrial mutations. § There are two (2) methods used to produce a threeperson baby – embryo or egg repair. WebMD Link. Bioedge Article link Wired News Article METHOD 1: EMBRYO REPAIR Step 1) Two eggs are fertilised with sperm, creating an embryo from the intended parents and another from the donors. Step 2) The pronuclei, which contain genetic information, are removed from both embryos but only the parents' are kept. Step 3) A healthy embryo is created by adding the parents' pronuclei to the donor embryo, which is finally implanted into the womb. http://m.bbc.com/news/health-31594856 METHOD 2: EGG REPAIR Step 1) Eggs from a mother with damaged mitochondria and a donor with healthy mitochondria are collected. Step 2) The majority of the genetic material is removed from both eggs. Step 3) The mother's genetic material is inserted into the donor egg, which can be fertilised by sperm. http://m.bbc.com/news/health-31594856 § Mother carries mutations for Leigh Syndrome. § The family had already experienced the heartache of four miscarriages as well as the death of two children - one at eight months and the other at six years of age. § The US team, who travelled to Mexico to carry out the procedure because there are no laws there that prohibit it, used a method that takes all the vital DNA from the mother's egg plus healthy mitochondria from a donor egg to create a healthy new egg (method 2) that can be fertilised with the father's sperm. http://www.bbc.com/news/health-37485263 First ‘three-person baby’ born using new method CRISPR-CAS9 – EDITING THE GENOME Clustered regularly interspaced short palindromic repeats Huge news in 2015, seen as a major step forward for disease cure/prevention by many people! https://www.nature.com/articles/d41586-020-02765-9 2020 Through correcting and replacing defective genes in the genome we can potentially treat all genetic disorder/disease types. http://www.yourgenome.org/facts/what-is-crispr-cas9 SCIENCE FACT: DNA EDITING Problems with the CRISPR-Cas9 system u An example: Cystic fibrosis u Mutations in CFTR gene Cytogenetic Location: 7q31.2 u Most common mutation: ΔF508 - a deletion of one amino acid at position 508 u Amino acid sequence: K E N I I F G V S Y D u DNA Sequence: 5’AAA GAA AAT ATC ATC TTT GGT GTT TCC TAT GAT TTT GTT TTA TAG TAG AAA CCA CAA AGG ATA CTA 3’ u CRISPR targets are between 20 - 30 base-pairs long u How many hits do you think match that sequence in the human genome? http://www.nature.com/news/ethics-of-embryo-editing-divides-scientists-1.17131 THERE WERE OVER 200 100% MATCHES THROUGHOUT THE HUMAN GENOME § Off-target cleavage and modifications. § This sequence exists in the following genes: § Homo sapiens phosphate cytidylyltransferase 1, choline, beta (PCYT1B) gene: § Starch and sugar metabolism. § Homo sapiens zinc finger protein, FOG family member 2 (ZFPM2), § Transcription factor for hematopoiesis and cardiogenesis. § There were many matches in introns and “junk DNA”. § At this stage we don’t know what a lot of the so called ‘junk DNA’ does. § Is it important for us? HUMAN GENOME EDITING – THE CRISPR-BABY SCANDAL CCR5 – HIV (Fathers had HIV) https://www.nature.com/articles/d41586-018-07545-0 Original YouTube Video from He lab • Three babies were born that had been genetically engineered (the twins Lulu, Nana & Amy) • Several problems noted in his manuscript: • Neither Lulu nor Nana possessed the 32-base pair deletion in the CCR5 gene, & each embryo instead expressed variants of various lengths. • Off-target edits but were dismissed as the ones he saw were not in genes. • Noted mosaicism between different cells. • Served 3 years in prison for “illegal medical practice” & Fined $430,000 USD & Released April 2022 Make People Better Documentary YouTube Trailer 2023 • • Chinese scientist - He Jiankui • He appears intent on relaunching his career and has set up a lab in Beijing to work on affordable gene therapies for rare diseases such as DMD. Has obtained funding through charitable donors to rent lab space, employ five scientists and begin animal studies He does not view the scandal as an insurmountable barrier to running clinical trials again in future. CRISPR CLINICAL TRIAL LAUNCHED 2018 § Vertex and CRISPR Therapeutics Collaboration § Drug cleaves the gene called BCL11A, which has been shown to repress the production of Fetal haemoglobin (HbF, α2γ2). § BCL11A directly represses the γ-globin gene promoter, which is the process that underlies haemoglobin switching. § Ex vivo approach - blood cells (CD34+ Human Hematopoietic Stem & Progenitor Cells (hHSPCs) removed from the patient, edited, & replaced. § Can be used for 𝛽-thalassemia (TBT) & Sickle cell disease (SCD) § Now in phase 3 trials. § Anticipated to be approved this year (2023), making it the 1st approval of a CRISPR-based therapy for use in humans and is a “landmark moment in realizing the potential of CRISPR to improve human health.” Therapy is called CTX001 https://innovativegenomics.org/multimedia-library/meet-victoria-gray/ https://www.bbc.com/news/health-60348497 https://innovativegenomics.org/news/crispr-clinical-trials-2023/ https://www.npr.org/sections/healthshots/2021/12/31/1067400512/first-sickle-cell-patient-treatedwith-crispr-gene-editing-still-thriving L E • Results from over 40 individuals with TBT and over 30 with SCD have been shared. • 42 of 44 individuals with TBT were no longer transfusion dependent 3yrs post-treatment. • All of the participants with SCD are free of the vasoocclusive crises following treatment. • Even without directly repairing the mutations, this treatment seems to be a functional cure for SCD & TBT. AUSTRALIA’S POSITION Prohibition of Human Cloning for Reproduction Act 2002 13 Offence—creating or developing a human embryo by fertilisation that contains genetic material provided by more than 2 persons offence if: A person commits an (a) the person intentionally creates or develops a human embryo by a process of the fertilisation of a human egg by a human sperm outside the body of a woman; and (b) the human embryo contains genetic material provided by more than 2 persons. Maximum penalty: Imprisonment for 15 years. 15 Offence—heritable alterations to genome (1) A person commits an offence if: (a) the person alters the genome of a human cell in such a way that the alteration is heritable by descendants of the human whose cell was altered; and (b) in altering the genome, the person intended the alteration to be heritable by descendants of the human whose cell was altered. Maximum penalty: Imprisonment for 15 years. STEM CELLS Potential to be used to regenerate and repair diseased and damaged cells and tissues in the body. § Stem cells have two (2) essential properties – 1) self-renewal and they can 2) differentiate into different cell types. Three (3) main categories: 1. Embryonic stem cells form as a normal part of development. § Can become any cell type in the body. § Promising source of cells to treat many diseases. 2. Adult (somatic) stem cells exist naturally in the body & function to maintain and repair tissues in the body. § Can normally only become a small subset of cells (multipotent). 3. Induced pluripotent stem cells (iPSCs) are made through reprogramming and individuals own differentiated cells. § e.g. Skin cells, adipose cells & fibroblasts. § Have the potential to become any cell in the body. § Could be useful for multiple diseases including genetic ones. STEM CELL TRANSPLANT § Kristy Cruise had relapsing, remitting multiple sclerosis. § On August 20th 2013, she went to Russia to have a haematopoietic stem cell transplant. § She chronicles her journey on a Facebook community page Moving Mountains to Defeat MS. https://www.facebook.com/Movi ngMountainsForKristy/ § The talk she gave to MD1020 in 2013 is on LearnJCU. § MS is now in complete remission. AHSCT is thought to ‘reset’ the immune system to a less inflammatory or injurious state, reducing the autoimmune attack on the central nervous system. A PIONEER OF HSCT 60 minutes documentary Video available at: https://www.youtube.com/watch?v=51gJJO0UJ2Q Update video at: https://www.youtube.com/watch?v=_0hekaFdmD0 STEM CELL TOURISM § Stem cell technology has given rise to unregulated clinics all around the world offering stem cell treatments to cure every incurable disease documented. § Many GPs report people asking for recommendations for stem cell treatments for muscular dystrophy, Alzheimer’s, Parkinson’s, etc. § Many are told that they are part of legitimate clinical trials and have testimonials from patients (which actually have a financial conflict of interest in the clinic) § Need to educate patients to check if a clinical trial exists via ClinicalTrials.gov before agreeing and that there will never be fees to be a part of a trial. Jim Gass – Stem cell therapy for stroke. http://www.nejm.org/doi/full/10.1056/NEJMc1600188 http://www.nytimes.com/2016/06/23/health/a-cautionary-tale-of-stem-cell-tourism.html?_r=0 PREVENTION BETTER THAN CURE KNOW YOUR OWN GENETIC CODE! § New concept of personalised medicine and/or genomics (Week 0). § In less than a decade, people will be able to get their own genomes sequenced for an affordable price ($100 genome, Week 1). § Personalized genome readings will indicate how genetic variation and lifestyle affect our chances of disease. § When that happens (perhaps during your career), a whole new industry of personal genomics will take off. § This will allow therapies to be exquisitely tailored to the biology of the individual - for maximal effect. § Remember that every single therapy and drug you will learn about (or use) in your career was once an experimental drug or treatment. ILLUMINA Inc is now selling an automatic sequencer using pyrosequencing technology that can generate 1 million reads (~400bp each) in a single 10 hour instrument run PREVENTION BETTER THAN CURE IDENTIFYING DISEASE PREDISPOSITION GENES § So, where are we headed in the future? § All diseases have a genetic component, whether it be an inherited defect or the way a body responds to environmental stresses like viruses or toxins. § Predisposition alleles (SNPs) for almost any trait will be identified and the genotype correlated with response to pharmaceutical therapies. § The more predisposition alleles we find, for example for Schizophrenia, the better our predictive capabilities will be, including therapy response. e.g. Genome wide association studies (GWAS) for T1D, Week 10 Lecture PREVENTION BETTER THAN CURE MICROARRAY TECHNOLOGIES How do we identify mutations (SNPs) associated with certain diseases? § DNA Microarray (also called gene chips) has been developed for many different biological applications. § Physically, DNA chips are squares (typically made of glass, nylon or silicon) whose surface can be covered with hundreds or thousands of short pieces of immobilized DNA, laid out in rows and columns (array). § Principle of microarray is DNA hybridization between two DNA strands. § Where complementary nucleic acids specifically pair with each other. § Use of a fluorescent probe to identify target sequence. § Signal will only be produced with 100% match between the probe and the test DNA. § Two main applications: § Expression profiling (Allows us to evaluate the expression of thousands of genes at a time). § Mutation profiling (Allows us to determine the sequence of many genes simultaneously, e.g. SNPs for 23andMe). MICROARRAY – MUTATION (SNP) PROFILING Mutation arrays: can be used to detect polymorphisms, such as single nucleotide polymorphisms (SNPs) in genes. These microarrays use an immobilized fluorescent probe for various single nucleotide polymorphisms linked to different diseases. Each spot has multiple copies of DNA containing each SNP, GG or TT, for example. For example: SNP = G/T Red = GG (homozygous) Green = TT (homozygous) Yellow = G/T (heterozygous) 23ANDME TODAY USA ONLY Illumina Infinium Global Screening Array (GSA): ~640K SNPs across the entire genome. 3+ Reports including: CYP2C19 Drug Metabolism DPYD Drug Metabolism SLCO1B1 Drug Transport 23ANDME TODAY USA ONLY WHAT ABOUT AUSTRALIA? Therapeutic Goods (Excluded Purposes) Specification 2010 § Section 41BEA, Therapeutic Goods Act 1989 “IVD medical device for self-testing may not be used for: (a) to test specimens from the human body for the purposes of, or exposure to, pathogenic organisms or transmissible agents, including agents that cause notifiable infectious diseases; (b) genetic testing to determine the presence of, or predict susceptibility to diseases in humans; (c) to diagnose, aid in diagnosis or indicate the presence of a serious disease or condition, such as cancer or myocardial infarction; (d) to test for the presence of markers that are precursors to a serious disease or condition such as Pap smear tests (marker for cervical cancer) or prostate specific antigen tests (marker for prostate cancer).” IVD = in vitro diagnostic GLS Activity 1: Future Therapies and Technologies Questions to Tackle Activity 2: Personal Genomics Exercise Explore the PDF that has the 23andMe outputs for 12 patients and answer the questions. Decide for yourself; If this information was available for each person would it be useful for: • Lifestyle choices? • Ongoing medical advice? • The healthcare system as a whole? • Insurance companies?