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Next Generation Genomics the DNA Revolution

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Next Generation Genomics the DNA Revolution June 2020 Next Generation Genomics The DNA Revolution Leonard C. Mitchell, CFA Table of Contents Introduction 3 Precedents for Hyperbolic Change 4 The Promise of Genetic Engineering to Reduce Human Suffering 5 To Understand Genomics, Understand Proteins 8 Big Pharma and The Era of Personalized Medicine 12 The Human Microbiome 16 Epigenetics and Disease 18 Genomics and Cancer 20 Viruses, Vaccines and Cures 24 Reading and Writing the Genetic Code 28 The Blueprint for Life 29 The Race to Map the Human Genome 31 Then There Was CRISPR 33 How and Why CRISPR? 34 The Need for Faster Sequencing 35 Hacking the Human Genome 36 The Life Science Industry - Mergers and Acquisitions 38 Artificial Intelligence and Big Data 39 Bioengineering Agricultural Engineering 40 Industrial Scale Bio-Manufacturing 41 Conclusion and Risks 44 About the Author 46-47 This is the third in a series on developing technologies that will drive our economy and soon change our lives. Two technologies in particular, Artificial Intelligence, covered earlier, and Genomics, will be the most impactful in shaping life in the 21st century. Leonard C. Mitchell, CFA “We are running on the last ounces of gas in the philosophical gas tank, we are facing philosophical bankruptcy, the new challenges, especially for the new technologies. Climate change and nuclear war are kind of easy challenges, because we know what to do about them, we need to prevent them, it’s very easy. Not all agree on what to do, but nobody says in principal, we should have more of these. But with AI and genomic engineering there are no agreed goals. The dream of some people are the nightmares of others. We don’t even have the philosophical basis to discuss it.” Yuval Noah Harari (author of Sapiens) and Steven Pinker (psychologist, author) in conversation. Genomics 3 INTRODUCTION “We have got to the point in human history where we simply do not have to accept what nature has given us.” Jay Keasling, professor of biochemical engineering, UC Berkeley in The New Yorker, 2009 The study of genomics is rapidly changing the medical field. George Church, Harvard professor of genetics, and author of Regenesis: How Synthetic Biology Will Reinvent Nature and Ourselves, tells the story of a child named Nic in Madison, Wisconsin who began having intestinal problems before the age of two. The physicians at Children’s Hospital in Milwaukee failed to find the cause. After more than 100 surgeries before he turned four, Nic’s chief physician determined that the symptoms were so severe and uncontrolled that the problem had to be genetic. Four months after Nic’s genome was sequenced, they identified the gene responsible for his illness. Nic had a rare disease that required a bone marrow transplant. The transplanted stem cells from cord blood of a matched healthy donor replaced his defective immune system with a functioning one. Thanks to genetic science, Nic is healthy today. Advancements in genetics means we can now read, remove, copy, and replace defective genes. As unimaginable today as iPads and smart phones would have been to our grandparents 100 years ago, our understanding of genomics means that we are on the verge of being able to engineer disease resistance in our cells, grow molecular computers, and program bacteria to produce any chemical humans need. A diagnosis of a genetic disease or cancer will soon no longer be a death sentence. It will be possible for pharmaceutical companies to customize drugs for your unique biome. New drugs will be formulated in half the time and at half the cost. Personalized medicine will replace the one- size-fits-all pharmacology of today. Human cells will be reconfigured to resist common viruses; no more colds or flus. The descendants of today’s humans will be stronger, smarter, more beautiful, and healthier while living well into their 100s. Farmers will have crops that fertilize themselves in less than a decade. Domestic animals and pets will be creatures that do not exist today. The largest databases will be stored on DNA chips. The precursors for all of these advancements are found in modern laboratories today. Genomics 4 PRECEDENTS FOR HYPERBOLIC CHANGE “Our forebears expected the future to be pretty much like their present, which had been pretty much like their past. Although exponential trends did exist a thousand years ago, they were at that very early stage where an exponential trend is so flat that it looks like no trend at all. So their lack of expectations was largely fulfilled. Today, in accordance with the common wisdom, everyone expects continuous technological progress and the social repercussions that follow. But the future will be far more surprising than most observers realize: few have truly internalized the implications of the fact that the rate of change itself is accelerating. Most long-range forecasts of technical feasibility in future time periods dramatically underestimate the power of future technology because they are based on what I call the “intuitive linear” view of technological progress rather than the “historical exponential view.” To express this another way, it is not the case that we will experience a hundred years of progress in the twenty-first century; rather we will witness on the order of twenty thousand years of progress at today’s rate of progress, that is.” Ray Kurzweil, American inventor, author, and futurist HYPERBOLIC CHANGE - A VISUAL Human existence remained pretty much the same from one generation to the next. Changes wrought by the introduction of steel and later petroleum along with advancements in science and engineering changed life forever. These charts show that the rate of change can at first be gradual and then suddenly hyperbolic. The combination of artificial Intelligence and genomics in this century will change us as rapidly and shake the foundations of society. Later sections of this paper will explain why this change is upon us and which companies and industries will be affected. Genomics 5 THE PROMISE OF GENETIC ENGINEERING TO REDUCE HUMAN SUFFERING “Computer science is going to evolve rapidly, and medicine will evolve with it. This is coevolution.” Larry Norton, cancer specialist at Memorial Sloan- Kettering Cancer Center working with IBM’s Watson DNA is remarkable chemical. It is both so extremely stable and dependable it is found in fossils that are hundreds of thousands of years old. DNA exists only to reproduce itself and does so with remarkable accuracy, on average with only one error or mutation for every billion letters copied. When they occur, genetic errors can create mutant proteins, most of which are benign and quickly dispatched by the body’s immune cells; however, some mutant proteins survive to cause problems. If there are too many errors, the cell dies; too few and the organism cannot adapt to changes in its environment. Genetic errors are the price organisms pay for evolution. When mutations are beneficial, such as when they result in stronger muscles or regenerative liver tissue, the organism is more likely to live longer and pass these improvements to offspring. Tragically, genetic errors are the most common reason for infant death. Genetic errors are also responsible for 19% of deaths in hospital pediatric intensive care units, half of all pediatric long-term care, and over half of all end of life admissions. Genetic errors, abnormalities in the genome, come in several varieties. Genetic errors are monogenic when it is a single mutated gene and polygenic when it involves more than one complete chromosomal abnormality. Errors can take the form of an extra codon (duplication), a codon where it should not be, a missing codon (deletion), or a codon that repeats too many times. Other genetic abnormalities include missing genes and extra (translocation) or missing chromosomes. Genetic mutations can be inherited or can occur spontaneously. Most of us are familiar with one or two genetic diseases. In fact, there are over 6,000 known genetic disorders. Around 65% of people are affected by one or more disorders that affect health. Well known genetic diseases include Huntington’s, Crohn’s, Down syndrome, Fabry, Gaucher, hemophilia, Marfan syndrome, microcephaly, cystic fibrosis, albinism, Alzheimer’s, muscular dystrophy, Tay-Sachs, primary pulmonary hypertension, mental retardation, and sickle cell anemia. It is the deletion of just three bases from the CFTR gene on chromosome 7 that is sufficient to cause cystic fibrosis (CF). CF patients have difficulty breathing, constantly cough up mucus, and have frequent lung infections. So far there is no known cure. Sickle cell anemia causes frequent severely painful attacks when misshapen red blood cells become trapped in veins. Its source is the substitution of just one letter in the HBB gene sequence that codes for hemoglobin. Genomics 6 Some biomedical platforms have developed new DNA-, RNA-, and cell-based therapies with broad potential applications that offer a glimmer of hope for treating life-threatening diseases that just a few decades ago, had no cure. The Japanese pharmaceutical platform, Astellas Pharma Inc., recently announced plans to buy Audentes Therapeutics for $3 billion, a 110% premium to its Audentes market value. Astellas believed it was worth it to access gene Therapeutics therapy that included three compounds that cause mutated valued at sections of the genetic code to be ignored during the translation phase, ignoring the mutation that leads to Duchenne Muscular $3 billion Dystrophy. - a 110% premium to its There has also been some success in the battle against another market value monstrous genetic disease Lymphomas. Lymphoma is a group - by Japanese of blood cancers sourced from lymphocytes. The most common is non-Hodgkin’s lymphoma. With immunotherapies designed to pharmaceutical combat the disease recently receiving regulatory approval, help is company Astellas on the way.
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