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. Two immunotherapies, Kymriah developed by Novartis Pharma Inc. for and Yescarta, a spinoff of Kite Pharma, are Chimeric-antigen- access to their receptor therapies (CAR-T) designed to encourage the body’s proprietary gene immune system to attack aggressive hematological mutations. therapy. CAR-T begins with the removal of the patient’s own T cells. T cells play a central role in the immune system. After leaving the thymus gland, T cells have the ability to morph into other key lymphocytes, such as cytotoxic cells that destroy virus-infected cells, cancer cells, or other malignancies. CAR-T therapy produces a genetically re-engineered T cell with an artificial T cell receptor. Using the patient’s own reengineered T cells to produce a protein specific to that patient’s cancer cells. Re-engineered cells are injected into the patient, then seek out the corresponding protein, (antigen) that resides on the surface of the cancer cell and bind with it. Normally antibodies recognize antigens that the body produces as “self,” part of the body. Antigens that originate outside the body are recognized as “non-self.” Antibodies that recognize “non-self” antigens, such as those produced by the re-engineered cells, bind to them and solicit a response from the body’s immune system. Like a key in a lock, CAR-T cells recognize the cancer as “non-self” and send out a call for a response from the patient’s immune

Genomics 7 system.

To combat cancer among other diseases, an antisense gene therapy is being tested. It seeks to shut down gene expression, attacking the disease at its origin. For example Luxturna, developed by Spark Therapeutics in partnership with Children’s Hospital in Philadelphia, treats a rare form of inherited vision loss. After receiving pediatric disease priority status, it became the first FDA-approved DNA gene therapy. Since then, several antisense drugs have been approved. Antisense therapies prevent the production of non-functioning, disease-causing proteins by preventing the gene’s translation—in effect silencing it. It does this with oligonucleotides, short sequences of DNA or RNA, made in the lab that compliment a chosen sequence in the mutated gene. This snip of synthetic mRNA binds with the disease-causing gene and shuts down expression. Sarapta Therapeutics has developed an antisense therapy that shows promise in the treatment of Duchennes’s Muscular Dystrophy and is undergoing tests for use against viruses including West Nile, SARS, Hepatitis C, Dengue fever, and Ebola.

As reported on December 13, 2019 by Dow Jones Research, Sarepta Therapeutics Inc. (Ticker SRPT) shares rose 30% to $130.54 after the company said the U.S. Food and Drug Administration has approved Vyondys53 golodirsen, an antisense drug for the treatment of Duchenne muscular dystrophy. According to the National Organization for Rare Disorders, approximately 250,000 Americans live with a muscular dystrophy disorder.

Biotechnology is almost entirely about altering genes so the cell will stop producing a faulty protein or to produce a desirable protein by removing a gene and replacing it with new genes so that the organism produces synthetic proteins. For example, Recombinant DNA is combining or fusing two strands of DNA so the cell will produce proteins known to interfere with the mechanisms that lead to disease. Another example, Enbrel (Etanercept) is a fusion protein developed at the University of Texas Southwestern Medical Center in Dallas. Rights to this patented protein were sold to Immunex, which was later acquired by Amgen. Enbrel became Amgen’s largest selling drug and has improved thousands of lives. This protein binds to a targeted receptor on the antibody, preventing it from signaling the immune system to attack.

Antibodies are proteins that bind to antigens on the surface of pathogens. Antibodies recognize pathogens by their unique molecular surface and “tag” it for destruction by macrophages. Sometimes they mistake the body’s healthy tissue as a pathogen, which is expressed as an autoimmune disease. Examples of autoimmune diseases include rheumatic arthritis, psoriasis, and colitis. A similar reaction occurs when the immune

Genomics 8 system overreacts to a bee sting or a peanut.

When you consider that the immune system has to recognize and dispatch an almost infinite variety of invaders, and recognize and Biology is self- protect healthy tissue, it’s a wonder that more of us do not suffer assembling from autoimmune diseases. nanotechnology All of the scientific benefits mentioned above – the creation of with a built-in specific drugs to enhance the body’s immune reactions and mute programming genetic errors - is made possible through the study and practice of language. genomics. To better understand the intricacies of genomics, it is important to understand the role of proteins and basic cell function. SingularityU, TO UNDERSTAND GENOMICS, UNDERSTAND PROTEINS Andrew Hessel, Germany Summit “A gene encodes a message to build a protein to enable form and 2017 function that regulates a gene that encodes a message to build a protein and so on…Although there are seemingly 1,000s of drugs in human usage, the number of molecular reactions targeted by these drugs is a minuscule fraction of the total number of reactions. Of the several million variants of biological molecules in the human body, enzymes, receptors, hormones, and so forth, only about 250 (0.025%) are therapeutically modulated by our current pharmacopeia. If our human body is visualized as a vast global telephone network with interacting nodes and networks, then our current medicinal chemistry touches only a fraction of a fraction of its complexity.” The Gene, Siddhartha Mukherjee

What scientists have learned about cells in the human body in the last half century is beyond anything our ancestors could have imagined. According to NOVA, the long running PBS science television show, the elements that make up the human body can be purchased for about $168. Despite the low cost, the assembly of the human body is so complex that creating a single cell from these elements is beyond even the world’s best scientific minds.

Most of what is known about genetics today was unknown at the turn of the century. In just the last few decades, scientists have learned that the 200 varieties of human cells are not the torpid hollow balloon-like structures as portrayed in old medical textbooks.

Genomics 9 Each cell contains thousands of complicated pieces. Every second of every day the activity inside each cell is equivalent to that of a large city. This activity is an intricate dance of chemical messengers traveling between subcellular machines called organelles. Organelles include mitochondria, endoplasmic reticulum, Golgi apparatus, ribosomes, peroxisomes, lysosomes, and proteins—each one has a unique function. Organelles communicate by exchange of molecules, like supply ships at sea. At work 24/7 in every cell in your body, these machines are dedicated to building proteins.

All life is based on polymers (multiple molecules) and linked monomers (single molecules). Schematic of the relationship between the human genome, DNA, RNA Amino acids are one kind of and protein. monomer. When linked, amino acids become proteins. Most proteins consist of about 20 amino acids. Proteins perform the vast array of functions that make life possible. Essential polymers (large molecules) are DNA (deoxyribonucleic acid) and RNA (ribonucleic acid). These are polynucleotides (many bio nucleotides). These three— DNA, RNA, and proteins—are responsible for cell replication, response to stimuli, cellular structure, and transport.

Since the beginning of the last century, scientists knew that DNA was involved in passing down characteristics from parent to child, but the mechanism remained a mystery. Francis Crick, an Englishman, and James Watson, an American, discovered how the code for life was written in the structure of DNA. At Cambridge University in 1953 they discovered that in the sequence of just four amino acids held the instructions for the reproduction, organization, and development of all known plants, animals, bacteria and some viruses. Written in DNA is the difference and the similarity between all humans and all living things.

At the time, it was not known that DNA contained the instructions for all of life or that it was such a stable molecule. It has now been found intact in fossils of animals that lived hundreds of thousands of years ago. Like plants and animals, prokaryotic cells (bacteria) and viruses Mitochondria

Genomics 10 also contain genetic information, but lack organelles. Because of this genetic information or DNA, scientists are able to say all life on earth evolved from the same organism. Sixty percent of the DNA in every cell in a fruit fly is found in every human cell. Every cell of every organism carries this code. The code for life is written with four monomers, or four molecules. They are the nucleotides Guanine, Thymine, Cytosine, Adenine. Linked together they make the polynucleotide DNA (deoxyribonucleic acid). Like the rungs of a ladder, C always pairs with T and G with A. Famously pictured as a twisted double helix, like a spiral staircase, human DNA has three billion base pairs that are linked to other pairs with a sugar phosphate backbone. This chain of DNA is two molecules wide and up to six feet in length. Portions of the strands are occasionally wrapped around protein molecules called histones. Most of this code does nothing. It is what biologists call “junk” DNA. However, there are short sequences of base pairs that do something very important. These are called genes. Cramming this much genetic material inside the cell nucleus requires the chain to be very tightly coiled. In this coiled state, the genes are called chromosomes.

The human genome is the sum of all of the genes inside the chromosomes. Humans have twenty-three pairs of chromosomes, twenty-three from the mother and twenty-three from the father. Containing the instructions for life, genes are protein blueprints. The variety of protein designs include enzymes, which are important for speeding up chemical reactions. Some proteins are chemical messengers called hormones. Other proteins are antibodies that attack pathogens.

When a gene is “turned on” it creates a protein. This process is called expression. Expression occurs in two stages, transcription and translation. Transcription occurs when RNA polymerase, an enzyme, synthesizes RNA from a DNA template. RNA is identical to DNA but with Uracil in place of Thymine and there are other variations of RNA. During transcription, RNA polymerase attaches itself to a segment of DNA near the beginning of a gene. The enzyme then moves along the strand of DNA unzipping the two sides to allow other bases, C, T, A, and G floating in the cell’s cytoplasm to attach to their exposed compliment; G with Source: Wikipedia A, and C with T. The product is mRNA.

Genomics 11 Importantly, messenger RNA (mRNA) contains sections called exons and introns. Before mRNA can be used as a template, it is processed through the removal of unneeded introns and the attachment of needed introns. The necessary introns act as the head or tail of the gene.

During the second stage, called translation, ribosomes in the cytoplasm attach themselves to a strand of mRNA and begin synthesizing proteins. Transfer RNA (tRNA) shepherd free- floating amino acids to the ribosomes, like parts to a factory. The mRNA “reads” segments that consist of three base pairs called codons. If the individual bases can be thought of as letters, codons are words. As the words are read, amino acid molecules are delivered to the corresponding codon. After delivery, the next codon read, and the next, and the next each time an amino acid is linked to the previous one.

TRANSLATION When the last amino acid is delivered, translation is complete and the chain detaches from the ribosome as an unfolded sequence called a polypeptide. This polypeptide folds, origami-like, into a very specific 3D shape and is now a protein. Both the sequence of amino acids and the folded shape inform the protein’s purpose. The folding process takes just a couple of seconds.

Shape determines function, so correct folding is essential to proper function. If something goes wrong within the process, the cell cannot function properly. Image source: Nature Education

This chain of amino acids grows at a rate of 200 amino acids per minute and grows until a stop codon is read. In this process, one can see the sequence of codons determines the sequence of the amino acids in the chain. When the last amino acid is delivered, translation is complete and the chain detaches from the ribosome as an unfolded sequence called a polypeptide. This polypeptide folds, origami-like, into a very specific 3D shape and is now a protein. Both the sequence of amino acids and the folded shape inform the protein’s purpose. The folding process takes just a couple of seconds.

Genomics 12 Shape determines function, so correct folding is essential to proper function. If something goes wrong within the process, the cell cannot function properly.

There are 64 codons including the start and stop codons. The resulting peptides, short chains of amino acids, have the ability to convey information via a 20 amino acid alphabet (remember that DNA and RNA only have a four-letter alphabet). A larger alphabet allows proteins to convey more information than DNA. The result is that there are over 200,000 different kinds of proteins in the human body. Scientists understand the purpose of just 2% of the proteins and very little about the folding process.

There are multiple reasons for malfunctions. Most errors occur when there are incorrect genetic instructions from mutated genes or a disrupted folding process. Proteins that are folded incorrectly can cause minor problems—like allergies—or major problems. Major problems occur if the damage sets off a chain reaction that leads to a whole series of incorrectly folded genes. Such a cascade can make the body vulnerable to life- destroying pathogens or result in conditions such as sickle cell, Alzheimer’s, cystic fibrosis, Huntington’s, or Parkinson’s disease. Mutated genes also play a role in cancer. Proper genetic instructions are critical, especially early in life. According to the gene sequencing machinery company, Illumina, mutated genes from inherited genetic disorders collectively account for one in five infant mortalities and over 25% of sudden cardiac arrest in adults.

When one considers that billions of translations happen every minute, the process is incredibly reliable. When mistakes happen, mutant proteins are destroyed while inside the cell. When mistakes result in mutated cells, they are destroyed by the organism’s immune system. Occasionally, some mutations survive. Illumina and others have developed targeted gene panels, microarrays, and next-generation sequencing tools to help identify causative genetic variants. Their tools are critical to understanding the genetic basis of cancer and other genetic diseases.

BIG PHARMA AND THE ERA OF PERSONALIZED MEDICINE

Medical science turned a corner at the beginning of the 20th century. Thanks to the general acceptance of germ theory, personal hygiene, clean hospitals, and improved sanitation our exposure to pathogens declined and our disease-resistance improved. The result was fewer diseases and longer average life spans. In the second half of the century, thanks to vaccines, anti-bacterial solutions, and new drugs, average life expectancy improved exponentially.

The drug development process is lengthy, expensive, laborious, and inefficient. Historically, drugs have been discovered by identifying the active ingredients in traditional remedies

Genomics 13 or simply stumbling upon a solution through trial and error. During the late 20th century, chemical libraries of synthetic compounds or small molecules were created where compounds could be screened for molecules with desirable traits.

“The introduction of genomic based medicine is the most ambitious project I have ever been involved in and the one with the most far reaching impact. It’s also one of the few areas where the UK has the ability to legitimately lead the world in the introduction of personalized medicine at a national scale. It represents a true confluence of biology, physics, computing power and data analytics on a huge scale. We now need to move from a project to an operational organization in partnership with the NHS as we move from 100,000 genomes to up to 5 million…global health is about security, sustainability and equity.” Professor Dame Sally Davies, Financial Times, March 22, 2019

Although its hopeful that our increasing knowledge of genetics will speed up and lower the cost of drug discovery, modern drug discovery remains a capital-intensive process because drug candidates must survive a gauntlet of clinical trials before they are approved for use on humans; most fail. According to the industry, a billion in today’s dollars would have resulted in 90 new drugs in the early 1950s. Today, it requires $3 billion to develop just one drug, and that does not include the basic research funded by government and philanthropic organizations. These same challenges have increased the lab-to-market time line to 12 years, while 90% of drugs washing out in one of the phases of human trials. CREATING NEW ANTIBIOTICS The time, expense, and risk of drug According to the industry, a billion in today’s discovery has convinced most large dollars would have resulted in 90 new pharmaceuticals to concentrate their drugs in the early 1950s. Today, it requires $3 billion to develop just one drug, and efforts on low-risk, profitable drugs that that does not include the basic research can be taken frequently and for long funded by government and philanthropic periods—like statins. Consequently, the organizations. The time, expense, and risk of drug discovery has convinced most large pharmaceutical industry has retreated pharmaceuticals to concentrate their efforts from developing new antibiotics at a on low-risk, profitable drugs... time when they are desperately needed. Today, common bacterial infections that were once easily treated with simple antibiotics have evolved resistance. Evolved diseases such as methicillin-resistant Staphylococcus aureus (MRSA) have become virtually untreatable due to overuse of

Genomics 14 prescription antibiotics in humans and livestock. With the exception of the United States, most western countries have outlawed overuse in livestock.

HUMAN LIFE EXPECTANCY INCREASES

Medical science turned a corner at the beginning of the 20th century. Thanks to the general acceptance of germ theory, personal hygiene, clean hospitals, and improved sanitation our exposure to pathogens declined and our disease-resistance improved. The result was fewer diseases and longer average life spans. In the second half of the century, thanks to vaccines, anti-bacterial solutions, and new drugs, average life expectancy improved exponentially.

Filling the research and development void are smaller companies that now play a critical role in the development of new drugs. Cash flow negative for most of their life, startups and small biotechs monetize their discoveries by selling the rights to their drugs to larger companies with the financial resources to run the clinical trials.

Although the genomes of two people are 99.9% the same, it is the remaining 0.1% of the genome that explains why no two people are exactly alike. The 0.1% leaves almost 1 million single-nucleotide polymorphisms (SNPs), places where individual genomes routinely differ. Individually, most differences have little effect. Add many variances together and, with time, they change your phenotype; your height, eye color, personality or risk of disease, etc.

Cell therapy and gene therapy are advancing rapidly. The former transfers live cells into a patient and the latter modifies a person’s existing cells to treat or cure disease. These therapies begin with sequencing. The SNPs that are known to be related to disease can be discovered by comparing a single genome from the patient with a library of genomes taken from the general population.

Obviously, the larger and more diverse the sample population, the better the chances

Genomics 15 for a match, but building libraries of genetic data has not been easy. To determine if the prevalence of a disease is affecting 10% of the general population, approximately 10,000 volunteers must be screened. For this reason, genome-wide association studies (GWAS) are prohibitively expensive. Therefore, researchers have turned to smaller arrays to search among only the most common SNPs.

Even today, most drugs are initially tested on animals. One of the drawbacks to animal studies, however, is that animals do not have the same diseases, nor do they respond to the treatment in the same way as humans. This can be a problem for human studies. Genome variances, SNPs, and our unique phenotypes cause some medicines to affect individuals differently. Cold medicines, for example, keep some people awake and make others drowsy. Men and women are known to react differently to aspirin and some insomnia medications. The differences are written in our genes.

GWAS help scientists discover which genomic differences will affect drug efficacy. Discovery is done with automated sequencers with reagents supplied by companies like Agilent, Roche, and Illumina. The results are stored in freely accessible data bases. ClinVar is a U.S. based public database funded by the NIH that routinely asks companies like Myriad Genetics to share valuable data, but has not been successful. These resisters will hamstring basic research.

“All genomes contain arrangements of genes that make psychological disorders, cancers, dementias, or circulatory disease either more of a problem or less of one. Everyone has genes that either make them better or worse at metabolizing drug, more or less likely to benefit from specific forms of exercise, better able to digest some foods than others.” The Economist, March 14, 2020

One of the largest biobanks, UK Biobank, holds digitized samples from more than 100,000 donors. The UK is promoting itself as the upcoming world leader in biology. Their massive database has already lead to more precise and personal medicines. Around 2,700 studies using SNP sequencing show that on average, the population in the UK has a 50% chance of inheriting any one phenotype, or trait, from parents and 50% chance from the environment. For example, they have determined that the genetic marker for heart disease is about 44% heritable, meaning having the genetic marker does not mean the disease is inevitable. Lifestyle plays a significant role in determining the outcome. According to The Economist, Nasim Mavaddat of the University of Cambridge, a 47-year-old British woman’s chances of inherited breast cancer before age 57 is only 2.6%. Lives can be saved if knowing one’s genetic profile shows a predisposition to diabetes, and preventative steps should be taken at an early age. (www.economist.com).

Genomics 16 One of artificial intelligence’s greatest contributions to drug discovery is its ability to find patterns in very large data sets. Google’s AI tool, DeepVariant is able to distinguish between random genetic errors and mutations faster, cheaper and more accurate than humans. Pfizer, GlaxcoSmithKlien and Novartis are among the pharma companies said to have also built AI expertise in-house, and it is likely that others are in the process of doing the same. AI-based drug discovery applications can be programmed to learn to recognize the different features of the cell and biologic compounds after being shown tens of thousands of labeled samples.

According to Scientific American in February 2020, scientists think artificial intelligence will improve drug development in three ways: by identifying more promising drug candidates; by raising the hit rate; and by speeding up the overall process. AI-based drug discovery startups raised more than $1 billion in funding in 2018 and over $1.9 billion in 2019 but only a few AI-discovered drugs are actually undergoing human trials and none have begun phase 3 human trials. A British firm, Genomics, offers screening for 16 diseases, and the data from these screens aids in the development of “personalized” medicine. Pharmacogenetics studies the role of the genome in drug response. They correlate gene expression with pharmacokinetics, drug absorption, distribution, metabolism, and elimination. As this knowledge expands, doctors will be able to personalize the medicines patients take, matching them with the patient’s own genetic information to create an optimized therapeutic protocol.

“It was part of our evolution to forge a symbiotic relationship with bacteria. The science of understanding the microbiome is still in its infancy, but I

expect it will explode in the coming decade. We’ll soon begin to understand how different microbiotic profiles, much like genetic profiles, are related to certain diseases or to optimal health. And we will begin to learn how we can leverage the microbiome to prevent and treat a variety of ailments, from neurodevelopmental challenges in early life to neurodegenerative problems and chronic illnesses in later life. You’ll be able to figure out whether your gut is harboring tribes that code for wellness or, conversely, sickness. And you will be able to make targeted tweaks to your diet and daily habits to support the growth and maintenance of the right kind of microbes for you. You may think that you’re doomed to have X, Y, and Z due to your genetics, but in the Lucky Years your fate will hinge more on how you play the cards you’ve been dealt through how you live than on solely which cards you hold.”

David Argus, author of The Lucky Years: How to Thrive in the Brave New Years of Health

Genomics 17 THE HUMAN MICROBIOME

The earth is estimated to be roughly 4 billion years old. For the last two billion years bacteria and viruses have been the dominate branches of life, both in terms of numbers and by sheer weight. Therefore, it should be no surprise that all plants and animals today harbor millions of bacteria. So humans really are two biomes, human and bacterial. It estimated that each of us harbor ten times more non-human cells than human cells, equating nearly two pounds of non-human cells for the average human.

Bacteria is a common epigenetic influence. Most of the species we share our bodies with are benign, some helpful and some harmful. Our microbiota differs by location and differs greatly between one individual and another.

Disease can breakout when normal levels of microbiota move beyond normal ranges. This can happen with injury or poor hygiene. The immune system can defeat most bacterial infections. When it cannot, doctors supplement with an antibiotic drug that destroys both bad and good bacteria. It’s like using a shotgun to kill mice in the house. The immune system sometimes damages healthy tissue in the fight, like an overzealous police force, causing collateral damage in the form of an autoimmune response. Examples of autoimmune diseases include Crohn’s Disease, rheumatoid arthritis, and irritable bowel syndrome. Other times the immune system doesn’t recognize the intruder. In the case of non-Hodgkin’s lymphoma, the cancerous blood cells actually trick the immune system into thinking they are a normal part of the body while they are killing the host.

Our bacteria also contain their own viruses. We are just learning about ANTIBIOTICS - NOT FOR VIRUSES our relationship with bacteria, but what we learn will dramatically Antibiotics are useless against viruses. alter our health care in the coming For example, there is still no cure for the decades and likely change our common cold, which is an infection of the current antibacterial solutions. Rhinovirus. However, mapping the genomes of infectious bacteria and viruses is paying Viruses were discovered in the dividends. 1930s. Since then we have learned that, like bacteria, some viruses inhabit our genome. Like bacteria, viruses contain DNA and in some cases RNA. Unlike bacteria and us, viruses possess only a few genes. Because of their genetic diversity, they are so very hard to kill.

Genomics 18 Antibiotics are useless against viruses. For example, there is still no cure for the common cold, which is an infection of the Rhinovirus. However, mapping the genomes of infectious bacteria and viruses is paying dividends. For example, approximately 3% of the world’s population has Hepatitis C with 3 to 4 million additional victims infected each year, contributing to the estimated 160,000 deaths from liver cancer. The insidious hepatitis C virus (HCV) is a single strand RNA which causes severe liver damage and eventually cirrhosis. Gilead, one of the largest biotechnology companies, developed a nucleotide analog of the HCV virus that acts like a defective protein and inhibits RNA protein synthesis, preventing the virus from replicating. This drug, Sofosbuvir, sold under the brand name Sovaldi, has a much higher cure rate than previous treatments, which involved injections of an interferon-based drug over six to twelve months with severe side effects. Sovaldi has fewer side effects, is taken orally, and has drastically shorter therapy time. Gilead received the FDAs coveted Breakthrough Therapy Designation for Sovaldi.

EPIGENETICS AND DISEASE

There are 200 types of cells in the human body. Each one contains the same DNA. So how is it that some become skin cells, while others become kidney cells? Epigenetics is the study of how gene expression is influenced, turned on or off, from outside the cell. It is the job of biologists to discover the mechanics of nature and the technologists GENE EXPRESSION IMPACTS to manipulate life with that knowledge. GENERATIONS

As has been shown, it is easy to assume Epigenetic factors include poor genetics—nature—is fate, but it is not nutrition and stress. Both can leave an that simple because DNA is not a static epigenetic mark on our DNA that can compound. When astronaut Scott Kelly be passed to future generations. returned to earth after a year in orbit, researchers at NASA discovered that his DNA had changed. A year later it was back to its previous state. Oxygen-deprivation stress, increased inflammation, and dramatic nutrient shifts associated with space flight were responsible for altering 7% of Kelly’s genes.

Environmental factors can alter DNA. Indeed, the longer someone lives, the less likely the DNA is the same as at the start. The reason cancer is primarily a disease of old age is because DNA over time succumbs to the sling and arrows of mutagens like oxidizing agents, ultraviolet light, X-Rays, and the benzopyrenes found in smoke. Even non-chemical influences like mental and physical trauma cause genetic changes.

Genomics 19 Epi, which means above, refers to the factors that influence the genetics someone is born with. Outside factors may cause the DNA strand to uncoil from a histone, exposing a gene that might otherwise would have remained dormant or never expressed. Alternatively, epigenetic influences may cause the DNA to wrap more tightly to the histone making it less likely that the RNA does its job.

Epigenetic factors include poor nutrition and stress. Both can leave an epigenetic mark on our DNA that can be passed to future generations. For example, known as the Dutch Famine, the 1944-45 German-occupation of the Netherlands resulted in 18,000–22,000 deaths from starvation. This resulted in changes to the DNA of survivors and their children. The children of mothers who were pregnant at the time were smaller than the previous generation and so were their grandchildren. The famine left an epigenetic mark passed down to future generations. Audrey Hepburn lived through this episode as a child. To survive, her family was forced to make flour out of tulip bulbs. As an adult, she suffered from anemia, respiratory illness, and edema. In addition, she had five miscarriages. Tragically, she died of colon cancer after decades working to eliminate childhood

EPIGENETICS MECHANISMS

Source: Wikipedia

Genomics 20 malnutrition.

A person’s collection of genes is a kitchen pantry of ingredients that can be combined in many different ways. Chemical tags can attach themselves to DNA. The set of all of these attachments is called the epigenome. Although each of the 200 types of human cells contains identical DNA, each type of cell has its own epigenome. Methylation is an organic process that occurs when methyl groups are added to the DNA. Without changing the sequence of base pairs, some chemical tags, such as methyl groups, can cause the strand of DNA wrapped around a histone protein to change its grip, turning the gene on or off. In this way, epigenetics can contribute to cancer, depression, and other diseases.

“Autopsies suggest that individuals who committed suicide showed epigenetic changes that switch off the SKA2 gene, which controls the brain’s response to cortisol and stress.” Juan Enriquez and Steve Gullans, authors of Evolving Ourselves.

GENOMICS AND CANCER

“Gene by gene, and now pathway by pathway, we have an extraordinary glimpse into the biology of cancer. The complete map of mutations in many tumor types will soon be complete, and the core pathways that are mutated, fully defined.” The Emperor of all Maladies, Siddhartha Mukherjee

“Synthetic biology will make it possible to go beyond standard practices in at least two ways. One by providing entirely novel methods of treating exisiting diseases. Mostly, this involves genomically engineering microorgansims or nonhuman mamalian species for the purpose of performing specific medical interventions. The other is by reengineering the human genome itself for the purpose of preventing diseases from occurring in the first place.” Regenesis: How Synthetic Biology will Reinvent Nature and Ourselves, George Church

Cancer is one of the most feared diseases today. Until the 18th century, cancer was untreatable, though most did not live long enough to get cancer and feared diseases like influenza and tuberculosis instead. Sufferers had to live with a growing and sometimes open wound that was grotesque and putrid until they died. Today, almost 40% of Americans will have some brush with cancer during their lifetime. In 2018, there were over 10 million cancer deaths worldwide. It is estimated that over 100 million people are currently living with cancer. Unfortunately, those numbers will rise as the world’s populations grow older as age increases cancer risk.

Genomics 21 Cancer is the uncontrolled growth of mutated cells that do not die. Healthy cells die when they wear out; for example, red blood cells live only for about 40 days. Cell death (apoptosis) is normal, programed, routine and necessary. Cancer cells continue to grow, form tumors, and metastasize. Lysosomes, part of our immune system, will destroy a mutant cell as if it were a pathogen, however, sometimes the sheer number of mutations can overwhelm the body’s defenses, and some cancers have adapted with a disguise to avoid detection.

Cancer treatments today typically involve a sledge-hammer protocol of chemicals and radiation. A disfiguring surgery and ever-increasing levels of radiation and chemo are applied until either the cancer or the patent dies. Scientists have learned how to balance these treatments so that survival rates are increasing sharply.

Most cancers are related to unhealthy lifestyle choices that include smoking, drinking alcohol in excess, and obesity. Viruses and bacteria like Hepatitis B and C also cause cancers. Cervical cancer can be caused by an infection of the Papillomavirus (HPV)— discovered in 1983 and related to viruses that cause common warts. The protein produced by an HPV infected cell alters the cell’s reproductive cycle, causing it to rapidly accelerate growth just like other cancers. Some cancers quietly accrete in the body for decades before forming a tumor large enough to be detected.

As reported in the journal Nature, in some cancer types, a substantial proportion of somatic mutations are known to be generated by environmental exposures. For example, tobacco smoking promotes mutations associated with lung cancers and ultraviolet light increases the odds for skin cancers. Abnormalities in DNA maintenance can also cause mutations. For example, colorectal cancers result from the body’s attempt to repair a defective DNA mismatch. However, our understanding of the mutational process that cause somatic mutations is remarkably limited, but we do know that mutagens like ultraviolet light leave a mark on the DNA found in melanoma related tumors (www.nature.com).

Cancer is not a single disease. Scientists have identified over 200 variations in 6 billion different individuals, therefore, a one-size-fits-all protocol no longer makes sense. Furthermore, the genomes of people and the genomes of cancer vary. That is, both have different morphologies, physiologies, and temperament. Increasingly, cancer treatment protocols begin by sequencing the patient’s genome and the cancer’s genome. The cancer’s phenotype must be understood before an appropriate therapy is selected. Biopsies provide the genetic material, which is sequenced to find the mutations responsible for uncontrolled cellular growth. This approach is called “precision oncology.”

Genomics 22 Early detection is the key to survival, but some cancers quietly grow for decades without displaying any signs. For example, less than 20% of colon and liver cancers are detected at a curable stage. It is hoped that soon routine tests will be available to detect cancer before it shows up as a tumor on an MRI scan. “John Hopkins School of Medicine, has developed a blood test that can measure eight types of cancer related proteins and 16 genetic mutations from just the DNA in a blood sample.” (www.wsj.com). Indeed, recent improvements in genomics and mass spectrometry have made it practical and economical to comprehensively examine tissues for cancer biomarkers. Scientists are close to a blood or urine test to detect cancer in its earliest stage. There are diagnostic tests for proteins present with prostate cancer (PSA), influenzas, strep throat, even pregnancy. Startups like SomaLogic are advancing diagnostic screening technology to detect the chemical fingerprints of more elusive proteins.

Genotyping specific cancers is changing the taxonomy of cancer research and how we think about cancer as a disease. When viewed through the lens of genetics, cancer’s genome is gradually exposing its secrets. Just as there are genes for height, eye color, and personality, there are genes for skin cancer, lung cancer, etc. To date, 50 or more genes that have the potential to cause cancer—oncogenes—have been identified. Patients may have more than one oncogene; some might contribute to the disease while others might not. For example, breast and colon cancer cells contain up to 80 genetic mutations while some types of leukemia cells may contain as few as five. The challenge is to understand which mutated genes are oncogenes. Finding the causative agent is like looking for a needle in a haystack. Cancer scientists are using gene sequencing to find which genetic changes cause tumors to spread. According to The Economist, the Pan-Cancer Analysis of Whole Meticulous Research says the Genomes study of 2,658 samples of 38 different DNA sequencing market will be tumor types comparing those with the genomes worth of healthy donors to look for the genetic $10.35 billion by signatures of cancer cells. As of mid-October 2019, Invitae Inc. has sequenced over 800,000 2025 people. They believe that this rapidly expanding as patients push for deeper genomic database screened with applied insights into their genetic risks artificial intelligence using pattern recognition for disease. algorithms, will lead to clues for a cure.

Investor’s Business Daily, Genetically “simple” tumors can be targeted December 9, 2019 with chemo or monoclonal therapies to interrupt their growth. Sometimes called “magic bullets” monoclonal antibodies bind to monospecific

Genomics 23 cells or proteins. For example, signal blocking drugs such as Herceptin (Trastuzumab) treat breast cancer by targeting the HER2 gene, a gene that normally promotes cell growth, to prevent the gene from overexpression. Trastuzumab binds to a receptor on the outside of the cell inducing an immune response that encourages antibodies to recognize the tumor as dangerous and attack. These monoclonal antibodies are clones from identical parent antibodies and therefore mimic the parental behavior. Simple antibodies can be used effectively against simple, homogeneous oncogenes because they are clones of an immune cell so behave predictably.

Drugs that employ monoclonal antibodies usually end with the letters mAb. Example include Emtuzumab, Bevacizumab, Ipilimumab, and Rituximab. Predictably, mab’s bind to the same epitope, the part of the antigen that is recognized by the antibody. First developed in the 1970s, there are now several monoclonal antibody therapies that can block the target and shut down gene expression. Another therapy uses anti-cancer monoclonal antibodies. These work by signaling the body’s immune system to attack the cancer. Other monoclonal antibodies are being developed for autoimmune diseases and some are being tested to treat neurological diseases such as Alzheimer’s.

Illumina’s next generation sequencing (NGS) tools help researchers perform whole-genome studies on a patient’s healthy and cancerous cells. Artificial intelligence has joined the fight. With its ability to rapidly scan through large data bases, it can compare tens of thousands of genomes from healthy people and cancer patients. The difference is written in their genes. Precision Oncology is still experimental and to date results have been mixed.

According to the American Enterprise Institute, the FDA has approved four gene therapies in the last three years. However, the industry has another 800 similar products in various stages of development. At this rate, it is likely that by 2025 the FDA will approve 10 to 20 gene therapy drugs a year, most for oncology.

The National Cancer Institute is running a trial called MATCH that involves sending tumor biopsies to gene-testing labs that scan them for one or more of 4,000 possible variants of 143 cancer causing oncogenes. Today 29% of health-care providers in America use genetic testing. In the near future all doctors will require a routine test for cancer’s precursors.

Genomics 24 VIRUSES, VACCINES AND CURES

The most likely source of the latest coronavirus SARS-COV-2, a close relative of SARS, the virus “The world needs to linked to an epidemic from 2002-2004, was a live prepare for pandemics the animal market in Wuhan, China. Naturally occurring way it prepares for war.” viruses are more deadly than those made by man because they are everywhere. The mechanism for Bill Gates, Business Insider transmission from animal to human was through 2018 consumption of an infected wild animal. From human to human the virus is transmitted through breathing, sneezing or touching. The virus is small enough to ride on expelled droplets. On surfaces, some coronaviruses can stay active for days and some viruses are more contagious than others. Coronaviruses, in particular, are more contagious than Ebola but are not as contagious as the measles.

While biology has advanced since the last outbreak of SARS, there is still no cure for the pathogen labeled COVID-19. It’s dangerous because it attacks mucous and cilia cells preventing the lungs from ejecting debris allowing fluid in the lung to accumulate.

In some people the immune system overreacts and damages the healthy tissue in the lungs and other vital organs. Proteins called Cytokines, part of the immune system’s alarm system, can grow into a cytokine storm, making it hard for blood and oxygen to reach vital organs and the heart, causing permanent damage or death. This has happened with this current outbreak.

As it became a pandemic, the World Health Organization has coordinated a global search for a vaccine. The WHO will ultimately be responsible for choosing which vaccine will be tested in humans. Although influenza viruses kill over 250,000 people each year, this particular virus is new or “novel”, meaning we have no prior immunity, and seems to be especially contagious.

To understand what we are facing quickly, Chinese scientists sequenced the virus from a sample obtained from one of the first victims, and within ten days its genetic code was shared with the world’s medical community. This information allowed the world’s scientists to immediately start work on a vaccine. “Once China had provided the DNA sequence of this virus, we were able to put it through our lab’s computer technology and designed a vaccine within three hours,” said Kate Broderick, Senior Vice President of Research and Development at Inovo in an interview with BBC News published on January 30, 2020. She

Genomics 25 added, “Our DNA medical vaccines are novel in that they use DNA sequences from the virus to target specific parts of the pathogen, which we believe the body will mount the strongest response to. We then use the patient’s own cells to become a factory for the vaccine, strengthening the body’s own natural response mechanisms.” BBC News, January 30, 2020. However, vaccines must be put through a gauntlet of tests for efficacy and safety. Only then can production begin in large quantities. It’s likely we will not see a vaccine before mid-2020.

Viruses have always been with us. They dominated the CREATING A COVID-19 planet before plants and animals. Human born viruses VACCINE have been known to hide out of sight for decades “Our DNA medical only to reappear as long as a century later. Smallpox vaccines are novel pustules have been found on Egyptian mummies. in that they use DNA Smallpox plagues occurred regularly in ancient China, sequences from the virus India, and Greece. Crusaders brought it back from the to target specific parts Middle East during the middle ages where it established of the pathogen, which itself and killed an estimated 500 million people we believe the body will between 1400 and 1800. Columbus extended its range mount the strongest to the new world. response to. We then use It wasn’t until the 1700s that a British physician, the patient’s own cells to Edward Jenner, discovered that English milkmaids become a factory for the rarely got infected. Cowpox, a cousin of smallpox, had vaccine, strengthening inadvertently inoculated the maids against the pox. the body’s own natural When he applied a small amount of the animal’s pus to response mechanisms.” a scratch on a healthy person, the individual became Kate Broderick, Senior slightly ill but recovered quickly. He called it vaccination Vice President of after the Latin name for cowpox. As vaccinations Research Development at became widely accepted, the incidence of smallpox Inovo, BBC News interview declined. Scientists have since sequenced and have January 2020 a complete map of the smallpox genome, and have engineered more effective vaccines.

The Spanish flu infected one-third of the world’s population in 1918 and killed an estimated 50 million. Today somewhere between a quarter and a half a million people die of the flu each year. Viruses spread in water droplets from a sneeze or cough. Viruses lack the ability to reproduce on their own, but evolved a way to take over the reproductive mechanisms inside bacterial, plant, and animal cells. They are not technically alive since they cannot reproduce on their own but have genes. Viruses have less than 1,000 genes compared to

Genomics 26 22,000 in humans.

After finding a host cell, with S glycoprotein a virus latches onto a specific protein on the surface of the cell. This convinces the cell the virus is not a threat. Then, like a key in a lock, the virus injects its own RNA through the cell’s membrane and appropriates the cell’s resources, proteins, and reproductive organelles to reproduce itself. Inside a host cell, viral RNA reproduces itself over and over again until the host cell dies and its membrane bursts, releasing throngs of viral RNA to find new host cells and continue the cycle.

Viruses are not bacteria. Antibacterial drugs are ineffective against viruses, so viruses are more difficult to treat. A healthy individual can resist an infection long enough for a few days until their immune system can mount a defense. Those antibodies created will remain after recovery as a natural vaccine or defense within the body to fight future invasions, effective for a year or two in older people and longer if they are young.

Research continues but future remedies will likely come in the form of a drug that can locate and block the proteins that the virus uses to attach itself to the cell, like breaking a key off in a lock. Still another class of drugs called “protease inhibitors” block the virus’s ability to use the cells resources by preventing viral enzymes from cutting long strands of nonfunctional proteins into usable smaller pieces. Research and testing will take time.

Unlike most pathogens, viruses can jump species. Indeed, the source of HIV was traced to butchered African monkeys. SARS originated in camels that had been infected by bats. Moreover, scientists in New York discovered 18 new viruses in 133 rats they trapped for research, none of which were present in humans. The source of future epidemics will undoubtedly be wild animal vectors and possibly unsanitary meat processing.

According to David Quammen in his book Spillover, “Human-caused ecological pressures and disruptions are bringing animal pathogens ever more in contact with human populations, while human technology and behavior are spreading those pathogens ever more quickly and more widely.”

HIV accounts for most of the worldwide AIDS pandemic. It has already killed 30 million humans since the disease was noticed three decades ago; roughly 34 million other humans are presently infected. Despite the breadth of its impact, most people are unaware of its source; a remote region in African forest where its precursor looked as a seemingly harmless infection of chimpanzees in the headwaters of a jungle river called the Sangha, in southeastern Cameroon, in the 1930’s. The zoonotic spillover is a lesson few know or understand. Misinformation abounds regarding the HIV/AIDS crisis, a sickness for which we still do not have a vaccine and have only recently developed drug regimens to manage.

Genomics 27 “Will the next one come out of the rainforest or a market in China?” wrote Quammen in 2012.

Will we be better prepared for the next epidemic? While humans can be infected with viruses from animals, the ease of contagion and the more it spreads through the body determines how deadly it is. The more that humans expand their footprint on the planet, the more often we will come across pathogens like COVID-19. Epidemiologists have been warning about this for decades. This science is important.

The Bush administration wisely developed an early warning system and a rule book for a Federal response to such an outbreak in 2005. The Obama administration expanded the document and put in place an epidemic response team with a seat on the National Security Council. As part of the pre-pandemic planning, the U.S. government had purchased and stockpiled 50 million treatment courses of antiviral drugs, and states had purchased 23 million regimens.

During the 2009 H1N1 outbreak the government added another 13 million treatment courses of antiviral drugs and the CDC decided against closing schools, suggesting instead that staying at home when ill, avoiding large gatherings and telecommuting along with vaccinations would flatten the curve. Within a week of the warnings in April 2009, the CDC was developing a virus that could be used as a vaccine and was shipping it to drug stores before CDC GUIDANCE DURING the year ended. The FDA issued an emergency H1N1 OUTBREAK authorization to allow diagnostic labs to use a real- time test that the CDC had developed and began shipping to states. Within weeks, 40 states had been During the 2009 H1N1 validated to conduct their own tests. Having learned outbreak ... the CDC lessons from the H1N1 experience and their respect decided against closing for scientific institutions, Taiwan and South Korea saw schools, suggesting far fewer deaths per capita than the U.S. during the instead that staying at current pandemic. home when ill, avoiding large gatherings and In 2017, the incoming Trump administration disbanded telecommuting along with and dismissed the pandemic response team and cut vaccinations would flatten funding for the CDC. When the COVID-19 outbreak the curve. began in the U.S. the government did not have enough PPE (personal protective equipment) supplies for healthcare workers and no antivirals in the stockpile that might fight COVID-19. COVID-19 testing capacity

Genomics 28 ramped up slowly after China shared the pathogen’s genetic sequences on January 10, 2020. The test was approved February 4, though it was flawed and so restrictions on testing were not lifted until February 29, but then the President immediately called the threat a hoax. The challenges in testing and a rational message from leadership meant lost time, death and economic collapse. Furthermore, America’s psyche was wasted on fighting each other rather than the virus.

By April 26, 2020 the U.S. government was shipping tests to states. Currently Moderna is in a Phase 1 study for a COVID-19 vaccine, expecting Phases 2 and 3 this summer. A vaccine could be ready for approval in 2021 if all goes well. Moderna says it will have the ability to produce millions of doses per month.

READING AND WRITING THE GENETIC CODE

We have known about DNA since its discovery a century ago. We learned how it worked a half century ago. But two breakthroughs in this century have changed the science of genetics and our lives irrevocably. They are the completed map of the human genome and CRISPR.

The English alphabet contains 24 letters. Computer code has just two digits. The instructions for life is written with just four nucleotides assembled as DNA in all human and living things.

As scientists learned how to sequence or read DNA, they discovered which sequences were genes and which were merely spacers or junk DNA. The pioneering method was developed by Frederick Sanger. For this he was awarded his second Nobel Prize and remains the only person to win two Nobel prizes for chemistry. The Sanger Method was effective, but excruciatingly slow and laborious. It involved many man-hours studying radioactive Simple illustration of composition of phosphorous slides and X-rays hunched over a light DNA base pairs. box. It would be decades before the entire human genome, with its 3 billion bases, could be read.

With this tool, however, biochemists tinkered with ways to re-engineer the genetic code in the 1970s and by the 80s they had mapped the DNA of a simple bacteria. Some biochemists saw the potential to grow large colonies of re-engineered bacteria that would

Genomics 29 express large quantities of desirable proteins, such as insulin, which was in short supply. For two biochemists in south San Francisco, Herbert Boyer and Robert Swanson, this goal required a faster sequencing process. So, backed by venture capitalist Stanley Cohen, they developed a new process that would become the foundation for the giant biotech Genentech. Wall Street saw the potential immediately. Genentech went public at $38 per share. The stock climbed to $89 within the first minutes of trading and set a Wall Street record. Today Genentech’s annual sales exceed $13 billion.

THE BLUEPRINT FOR LIFE

Every cell in your body contains the same DNA. Half you inherited randomly from your mother, and half from your father. Siblings have a 50/50 chance of inheriting the same chromosomes, shuffled from the same deck. This is why siblings are similar, in appearance, personality and other traits, but not exactly alike.

For humans, ninety nine percent of our genome is identical. That leaves three million rungs that are different. Yet, as much as 75% to 98% of the DNA in our chromosomes is believed to be junk DNA, so called because it does not code for any amino acids (building blocks for proteins) and has no apparent purpose other than acting as spacers between genes. The purpose of junk DNA is an area of intense debate. New research shows that some of these non-coding DNA sequences might contain clues to why some cancers resist treatment.

DNA AND RNA

Components of RNA and DNA depicted in the traditional double- helix visualization. DNA is being explored as an effective data storage mechanism and is an extremely stable molecule.

Source: Wikipedia

Genomics 30 Robert Polin, PhD Kings College London, believes the non-coding genes are important in regulating genetic expression. According to Dr. Dan Graur, an evolutionary biologist, most of the junk DNA plays a role in protecting the coding DNA from mutation.

Not all junk, it turns out that between the genes are sequences of DNA that regularly repeat. These special sequences are called palindromes because they read the same forwards and backwards, like the words “racecar” and “kayak”. Also there are extra-long series of base pairs that are not palindromes, whose only function is to be spacers. These are called introns.

Finally, at both ends of each chromosome is yet another long, coded sequence called a telomere, whose function is similar to that of shoelace tips. It is believed that telomeres help prevent the chromosome from fraying at the end and therefore help prevent miscoding during DNA transcription. Note that telomeres shorten with each cell division and wear out as we age, increasing the chances of genetic mistakes. Telomeres are involved with the timing of cell death and therefore aging. There is evidence that stress is a factor in shortening telomeres.

More people now die from lifestyle choices—overeating, smoking, excessive drinking, drugs, etc. than from unpreventable disease. According to Bryson’s book The Body, the problem is acute in America, but strangely although Puerto Ricans tend to be more overweight, poor, and have less access to healthcare, on average they live longer. It is believed that social relationships play a role in this discrepancy. Puerto Ricans tend to have tighter social bonds. It has also been noted that Puerto Ricans who live alone and don’t see a child at least once a week tend to have shorter telomeres. It’s an extraordinary fact having good and loving relationships alters your DNA. A similar study in the U.S. showed that not having such relationships doubles your chances of dying from any cause.

Genomics 31 THE RACE TO MAP THE HUMAN GENOME

“I’m fascinated by the idea that genetics is digital. A gene is a long sequence of coded letters. Modern biology is becoming very much a branch of information technology.” Richard Dawkins

The first computer-automated DNA sequencer was invented by Lloyd M. Smith and introduced by Applied Biosystems in 1987, later acquired by Thermo Fisher Scientific around the time that the Human Genome Project received funding from the Reagan administration. Computer aided automation sped up the process and jump started the human genome project in 2001.

Using this new process, researchers began sequencing the genome of a simple bacteria and later mapped the genome of a worm. But for one young frustrated researcher at the National Institutes of Health (NIH), this process was still too slow if they ever hoped to map the human genome. Dr. Craig Ventner, who was already credited with being the first person to sequence the entire genome of a living creature, a bacterium in 1995, wanted to combine computers with robotics to move fast and break things. The great noble laureate James Watson scoffed at such a reckless proposal. So Ventner lifted 30 colleagues out of the NIH and with financial backing from the Institute for Genomic Research created a team to design a supercomputer and linked it to hundreds of state-of-the-art, $300,000 sequencing machines. Ventner’s strategy was to sequence fast and fill in the details later as opposed to the more conservative NIH, which refused to stray from a careful, slower approach. The faster, cheaper, automated process became the foundation for Venter’s new company, named Celera—Latin for quick. Celera went public, and like Genetech, the stock price soared from its IPO price at $15 until it peaked at over $300 per share some months later.

Meanwhile, back at the NIH, Project Chief Dr. Francis Collins continued to painstakingly tease out each genome, one at a time. But worried that Ventner was onto something, he changed course. He convinced Celera’s original sponsor to sell them the advanced sequencers. This war between rivals continued until the spring of 2000 when both teams claimed to have mapped the entire genome. The bitter race ended in a tie. The Clinton administration forced the reluctant rivals to share their news with the world, in person, together, on the White House lawn with President Clinton and Prime Minister Tony Blair attending.

With the conclusion of the Human Genome Project, 20,000 genes within the 3 billion base pairs of the human genome had been sequenced at a cost of $3 billion. The map

Genomics 32 was made public in 2004. However, a genome sequenced is not a genome understood. Researchers quickly staked out the portions on the genome they intended to study. Yet to date, researchers know the function of less than half of the genes mapped.

In 2001, a start-up biotech called Illumina began offering genotyping services for individuals. At first the service was incredibly expensive and took weeks to complete—much too long for practical application. However, with time and dollars, Illumina succeeded in reducing the time and the price.

By 2009, the cost dropped to a mere $50,000 per genome. The cost continues to decline. Illumina released their NovaSeq 6000 system in 2017. With a price tag of $1 million this device can sequence an entire genome in a few hours for less than $1,000 per sequence. Put to practical use, Grail, a division of Illumina, in partnership with the Mayo clinic, received funding from Bill Gates and Jeff Bezos in 2017 to develop a blood test to detect breast cancer. The goal is for the test to cost less than $500. Illumina’s devices remain in high demand. It now has 70% market share and sales exceed $3.3 billion. Illumina is worth $40 billion today.

Today it is possible to read, sequence, store, copy, and digitally alter DNA. Removing, redesigning and replacing genomes is common using tools designed by Stephen Turner of Pacific Biosciences (PACB), a competitor to Illumina. He invented a prototype that became the fastest DNA decoder ever built. When finished, it should be capable of sequencing millions of DNA letters in as little as 15 minutes. Pacific Biosystems, like Google, Apple, and Intel, is a disrupter.

Researchers at Stanford have taken the PacBio machines beyond DNA and are using them to look at the protein making machinery inside the cell, turning the PacBios sequencer into the most powerful molecular microscope on earth. With it, researchers will witness the cellular machinery as it performs its ballet for the first time in real time to see (among other processes) how some drugs block enzymes. The information gathered will be used to build better drugs.

It will take decades to understand everything about genetics. In the process scientists will open the door to gene therapy, personalized medicine, and predictive medicine. It will become possible to prevent maladies including birth defects, dysmorphology, mental retardation, autism, mitochondrial disorders, skeletal dysplasia, connective tissue disorders, and cancer teratogens.

“Almost all human traits are heritable. That’s been known for decades but, until a few years ago no one knew what specific bits of DNA code determined any given trait.

Genomics 33 Now, however, geneticists have identified at least a few hundred variants in the DNA code that are statistically associated with important traits such as intelligence, depression, and risk tolerance. Over the next decade, they are on track to identify thousands of variants associated with dozens of traits. That achievement will open up the ability to score genetic potential on those traits and thereby revolutionize the social sciences.”

Wall Street Journal, American Enterprise Institute, Charles Murray, January 28, 2020

THEN THERE WAS CRISPR

“No one saw CRISPR coming.” The Economist, April 6, 2019

Victoria Gray was the first patient who volunteered to receive a CRISPR edited cell therapy developed by Vertex Pharmaceuticals and CRISPR Therapeutics. It is designed to treat the incurable genetic disease, sickle cell anemia. CRISPR is a molecule that makes it possible to edit genes. “The preliminary data shows for the first time that gene editing has actually helped a patient with sickle cell disease. This is definitely a huge deal,” indicated Dr. Haydar Frangoul at the Sarah Cannon Research Institute in Nashville, Tennessee. The CRISPR edited cells produce a crucial protein at levels needed to alleviate the excruciating pain and life-threatening complications of the disease.

To cure a genetic disease, researchers must first determine which gene is responsible. Correcting or altering gene function requires a tool that did not exist until CRISPR. Known by the acronym, CRISPR, which stands for, Clustered Regularly Interspaced Short Palindromic Repeats will change humanity, literally. Many contributed to its discovery, but two professors, Jennifer Doudna and Jill Banfield of the University of California, Berkley, will likely soon share the Nobel Prize.

One version of CRISPR, known as CRISPR-Cas9, is the most efficient gene editing tool to date. Scientists are deploying it in promising experiments. A number of companies are already using it to develop drugs to treat genetic diseases including cancer along with sickle-cell anemia. The U.S. has recently approved the first clinical human trial using T cell genes edited using CRISPR.

CRISPR/Cas9 can integrate CAR genes into specific sites in the genome so that modified T cells recognize cancer as foreign. First responders in the body’s immune system, T cells roam around looking for cells that don’t look like they belong to “me” the body and once found, T cells signal other lymphocytes to come and destroy the abnormal cancerous or infected cells.

Genomics 34 HOW AND WHY CRISPR?

When asked what the dominant species on the planet is, most people will say humans, although both by weight and number, our planet is and always has been dominated by bacteria and viruses. In 1987 biologists discovered that bacteria had evolved an ingenious way of protecting themselves in their 3-billion-year battle with viruses.

CRISPR, a series of DNA sequences, is part of the bacterial immune response mechanism. Viruses attack cells by landing on their surface and injecting their genetic code, hijacking the cell’s reproductive system to create more viruses. Copies burst from the bacteria cells destroying it before moving on to other cells. Scientists discovered that some DNA sequences in bacteria matched the virus’ genetic code from a previous viral attack. In effect, the viral attack left behind a fingerprint. Bacteria with those sequences became immune to that virus. Once its immune system recognized the intruder, the bacteria issued an enzyme to destroy the virus. The target virus was chopped, scissor-like, at the exact point where the bacteria recognized the sequence from the earlier attack. In some cases, the destroyed sequence was replaced with another sequence. If scientists could harness this ability, they had the tool they needed.

Within a decade of its discovery, CRISPR became a gene editing tool. They did this by creating a “template,” as bacteria do, and attached it to a customized pair of molecular “scissors” that can be used to remove targeted genes. CRISPR will effectively cut out any harmful DNA sequence so it can replace it with a new code or spacer. If the new code is beneficial, its progeny will inherit the corrected version.

Bacterial microbes make thousands of forms of CRISPR, most of which scientists are just starting to investigate. Unsurprisingly, as The Economist reported last year, the firms using CRISPR have on hand more revolutionary-looking projects than they can pursue. Not all forms of CRISPR alter DNA. Scientists have discovered a human mouth bacterium with a form of CRISPR that breaks apart RNA—the molecular messenger used by cells to turn genes into proteins. Using this form of CRISPR, genes within RNA can be edited. Designer cells with this edited RNA can be created to target specific cancer cells related to types of malignancies unrelated to mistakes in DNA, opening a new front in the battle.

“The groundbreaking thing about this work is that it now opens up the RNA world to CRISPR,” said Oliver Rackham, a synthetic biologist at the University of Western Australia, The New York Times.

Genomics 35 “Human genes are the most contentious. In the U.S., a 2013 U.S. Supreme Court decision invalidated thousands of DNA patent claims. That ruling - that human genes cannot be patended in the U.S. because DNA is a “product of nature” - wiped over $500 million off the market value of defendant Myriad Genetics. It opened the door to companies like 23andMe, now owned by UK pharma group GKS, to offer breast cancer tests.

The U.S. biotech industry supports beefing up the patent regime, to underpin the incentives for research. Two senators introduced the bi-partisan “stronger patents act” this summer for the third year running. Patients and civil rights groups worry it could allow genes to be patented, blocking medical research and access to genomic tests. Lawmakers should treat carefully. Patients before patents is a potent rallying cry.” The Financial Times, 10 December 2019

THE NEED FOR FASTER SEQUENCING

At the turn of the century, mapping your genome took weeks—a tragically long time for a critically ill baby with an undefined genetic disease. To find a solution, Rady’s Children’s Institute for Genomic Medicine combined sequencing technologies. According to MIT Technology Review, the rapid sequencing technique researchers built mapped the genomes of 340 children, most of them newborns. In a third of these cases the information led doctors to change their course of treatment. Continuing the quest, Dr. Kingsmore at Rady plans to reduce the time it takes to less than 24 hours, as reported by Technologyreview. com.

Nanopore sequencers are hybrid tools. Part biologic and part semiconductor these tools now cost less than one thousand dollars. By simply placing a drop of organic material on a chip, a genetic code is read, digitized, and stored. These tools allow researchers to sequence DNA in the field.

In addition to saving lives, faster and cheaper sequencing is also accelerating the pace of discovery. In turn, the explosion of new discoveries are stimulating investment in start-up biotechs. In just the first quarter of 2018, biotech venture capitalists raised $2.8 billion. Indeed, five biotech start-ups raised more than $1 billion each according to Biotechnology Review.

Most start-ups will fail and survivors will sell the rights to discoveries to others to bigger companies, while some will go public. As any biotech portfolio manager will attest,

Genomics 36 investing in biotech is not for the faint of heart. On any given day, the stocks with the largest moves, up and down, are usually biotechs. Drug discovery is capricious and patents are elusive.

Agillent, a $3 billion public life science company, is investing heavily in nucleic acid-based science.

HACKING THE HUMAN GENOME

“Well, all information looks like noise until you break the code.” Author Neal Stephenson, Snow Crash

With the mapping of the human genome completed in 2000, the possibility to alter and correct genetic errors before they are expressed, via in vitro medicine, has been realized. This capability opens new facets of philosophical discussions, including whether or not science should make these genetic alterations, if newborn screening for genetic diseases should be mandated by law, and more.

About 1.5% of babies in America started with in vitro fertilization; 5% in Japan. The process is safe and common. Genetic tests on embryos for heritable diseases have been around since the mid-20th century for a limited number of diseases such as Down syndrome. Now it is possible to screen fertilized human eggs, preimplantation, for genetic abnormalities. Each genetic variant has a version associated with a small boost to the trait in question. Called alleles, if you add up these small boosts, you have polygenic score for that trait. The company Genomic Prediction offers parents a test to determine the polygenic risk score, a measure of the susceptibility to a trait or disease for embryos prior to in vitro fertilization. It allows parents to choose one with the least risk and/or preferred traits among a dozen or more embryos.

The test is carried out on a few cells plucked from a day’s old IVF embryo. Then Genomic Prediction measures its DNA at several hundred thousand genetic positions, from which it says it can create a statistical estimate, called a “polgygenic score,” of the chance of disease later in life.

In the last two decades, scientists have discovered an alphabet soup of genes that may help us. Alzheimers, a terrifying disease with no cure, begins by robbing the victim of their short-term, then long-term memory, their personality fades and finally the brain forgets how to manage the body and it dies. Although intellectual and social interaction along with a lean diet have shown to slow its progress, there is no cure. However, it may soon be possible to ensure against it by inserting the CEPT gene which is associated with a 69%

Genomics 37 reduction in Alzheimer’s.

Want to sleep less? You may want the DEC2 gene which is found in people who normally only need six hours of sleep. A rare APOC3 gene has been found to lower fat in the blood by 65%. The HERC2 gene codes for blue eyes. Most Tibetans have a variant of the EPAS1 gene that enhances oxygen-carrying capacity in the blood. Mice with the PEPCK-C gene run twenty times faster. Those who have the long version of 5-HTTPLR, the gene that codes for the serotonin transporter, tend to be happier, more cheerful, and optimistic. Arrowhead Pharmaceuticals develops medicines that treat intractable diseases by silencing the genes that cause them. For example, the AAT gene expresses itself by creating an Alpha-1 Antirypsin protein, normally secreted by the liver that protects the lungs. On the other hand, an abnormal AAT gene, when expressed, can result in misfolded protein that damages the liver as it accumulates and fails to protect the lungs. RNA interference or RNAi is already present in living cells. Arrowhead’s therapies employ this natural pathway to silence the gene, preventing it from expressing itself and creating the offending protein.

Medical professionals will soon be able to alter DNA in vitro to obtain these and other desired traits. For example, parents will be able to select for appearance, intelligence, even personality. Who among us does not want their child to have the best possible advantages? How might a child feel if these advantages were not provided? Just because advantages can be provided, should they be? Where would the less fortunate fit in the world? Will

SYNTHESIZING BIGGER GENOMES With the possibility to synthesize Scientists have progressed to manufacturing single genes in the lab to entire genomes for some species. the entire human genome on the horizon, and the inheritability of Size of genome synthesized successful traits, transgenerational Year Type (base pairs) genetic engineering is no longer 1970 Individual gene 77 science fiction. 2000 Hepatitis C virus 9,600

2010 Mycoplasma bactiera 1 million Ethical constraints can be legislated, though some will argue In progress E. Coli 4.6 million there are too many benefits to be In progress Baker’s yeast 12.5 million ignored. Proposed Human 3 billion

Genomics 38 totalitarian regimes create a race of super soldiers? These questions are being hotly debated in scientific circles. Society will have to decide on limits.

As noted, simply injecting the desired genes is no guarantee of obtaining the desired traits. Genotypes predispose phenotypes. Having a ‘G’ instead of a ‘T’ might increase the odds of a particular trait. Genes predispose us to an outcome, but genes are not immutable destiny. For example, the gene for red hair does not always produce a redhead. Having the gene for breast cancer increases one’s chances, but only by 10%. Those with the gene related to obesity have a 70% chance of being overweight, after controlling for exercise and diet. To these factors add the fact that there is a strong environmental component of a person’s genetic destiny. Epigenetics play a powerful role in determining phenotype. Each has the power to change the probability, whatever the predisposition.

Scientists now believe it is possible and probable to synthesize the entire human genome. They synthesized the entire genome of a bacteria with 1 million base pairs using its molecular precursors in 2010. Scientists regularly synthesize new whole genomes, creating genes and microorganisms that never existed. In the near future, the number of alterations to the human body and the number of possible species we can create based on the human genome is only limited by the imagination. Indeed, because successful traits can be inherited, transgenerational genetic engineering is no longer science fiction. Ethical constraints can be legislated, but in democratic countries some will argue that there are simply too many benefits to be ignored. For example, the UK has just approved transgenerational genetic engineering. In closed societies, ethical constraints are limited.

THE LIFE SCIENCE INDUSTRY - MERGERS AND ACQUISITIONS

“The concentration and the sexiness started in discovery but the digital health world has grown exponentially in the past year,” says Niven Narian, co-founder of biotech group Berg. “18 months ago if I sat here I couldn’t even tell you what a chief digital officer was,” he adds, reeling off the names of big pharma companies, such as Novartis, Pfizer and Sanofi, that now have digital experts on their leadership teams.” Financial Times, January 29, 2020

The number of mergers and acquisitions in the life science industry is also gaining momentum. These transactions and their associated costs and benefits have been sprinkled throughout this paper.

Danaher, a serial acquirer, has purchased several life science entities including the BioPharma division of General Electric for $21.4 billion, approximately 19 times EBITDA. This will allow Danaher to increase its presence in the high-growth bioproduction market.

Genomics 39 Agilent, which spun off from Hewlett Packard in 1999, has also been busy acquiring companies in the life sciences industry, as has Illumina. In 2019, Novartis bought biotech ARTIFICIAL INTELLIGENCE AND BIG DATA Avexis for “Digitizing patients’ medical histories, lab results and $8.7 billion, diagnoses has created a booming market in which tech thereby acquiring companies are looking to store and crunch data, with potential a gene therapy for groundbreaking discoveries and lucrative products.” Wall for spinal Street Journal, January 21, 2020 muscular atrophy called Investors are pouring billions of dollars into companies that offer access to the clinical insights contained in vast troves of Zolgensma. anonymized patient records. Combined with artificial intelligence, digital studies are advancing our discoveries in pharmacology and genetic medicine. The American Recovery and Investment Act allocated $20 billion to health care technology in 2010. It fostered the collection of electronic patient records. Three years ago, the Twenty First Century Cures Act included an endorsement for the use of real- world clinical data in drug approvals.

Besides adding to the world’s digital databases, other genetic databases are opening a window to the past. Ancestry.com operates a network of genealogical, historic records and genealogy websites. Its subsidiary, Ancestry DNA, offers direct-to-consumer genealogical DNA tests that infer family relationships and provide an ethnicity estimate from saliva samples sequenced by Quest Diagnostics with Illumina’s sequencers. In October, the AncestryHealth division introduced two products that guide individuals to the proactive steps required to head-off potential health risks. Based on the blind studies of genomic data from millions of volunteers, it will be an invaluable asset in human efforts to understand diseases along with large-scale population genomic initiatives like the Australia’s Genomics Health Futures Mission, the French Plan for Genomic Medicine 2025, and the Singapore 10k Project.

“While genotyping is equivalent to reading one word in a novel, whole genome sequencing is like reading the whole novel dozens of times…when 23andMe launched its genetic tests in 2006, the cost to sequence a whole human genome was about $10 million. Today, thanks to advances in software, hardware and artificial intelligence, that price tag has come down to the $10,000 mark. Most credit Illumina for this paradigm shift.” Investor’s Business Daily, December 9, 2019

With the help of companies like Britain’s DNA and 23andMe, the world’s database of genetic

Genomics 40 information is growing. After the sample of your DNA in your saliva is read, the data is digitized and compared with other samples and their SNP sites. Some researchers see DNA and RNA as libraries and books full of engineering schematics. One way to simplify is to think of the chromosomal DNA strand as the hard drive and RNA as RAM—temporary or random-access memory. Data stored in DNA as a data storage medium has many advantages over traditional data storage devices, but DNA is a superior storage device. For example, the world produces enough data each day to fill a basketball court full of magnetic tape, the most-dense digital storage device. According to Dr. Carlson of BioEconomy, the equivalent amount of data could be stored in just 20 grams of DNA and it could remain stable for more than a thousand years. In fact, Carlson is working with Microsoft to develop a code that can be written and read in DNA.

“Meanwhile DNA is already being used to manage data in different ways, by researchers who grapple with making sense of tremendous volumes of data. Recent advancements in next-generation sequencing technology allow for billions of DNA sequences to be read easily and simultaneously. With this ability, investigators can employ bar coding–use of DNA sequences as molecular identification “tags” –to keep track of experimental results. DNA bar coding is now being used to dramatically accelerate the pace of research in fields such as chemical engineering, materials science, and nanotechnology. At the Georgia Institute of Technology, for example James E Dahlman’s laboratory is rapidly identifying safer gene therapies, others are figuring out how to combat drug resistance and prevent cancer metastases.” Scientific American, December 2019

(Len Mitchell has authored a more thorough investigation of Artificial Intelligence and its impact on global culture and business, which can be accessed online at www.meritageportfolio.com.)

BIOENGINEERING

AGRICULTURAL ENGINEERING

The Financial Times reported in February 2019 that the world’s banana crop was in jeopardy. Something was threatening a major food source along with several tropical economies. A strain of Panama fungus was shutting down banana plantations around the globe. Because bananas are a monoculture, they could not be bred to resist the disease. All fungicides and chemical treatments failed to stop the disease. The most effective tool was gene modification. Gene modification involves changing the existing gene as opposed to introducing foreign DNA. CRISPR was used to remove a portion of the gene. No new genes were introduced, but the new plants resisted the fungus.

Genomics 41 Gene editing techniques have been used to modify and enhance the flavor of foods and vitamins and even increase their shelf life. Several startups are banking on the public’s eventual acceptance of gene edited foods. Today, many consider gene modified foods to be “franken-foods.”

INDUSTRIAL SCALE BIO-MANUFACTURING

“It’s hard to overstate how much digital technology, based on ones and zeroes, has changed every aspect of our lives. It’s even harder to take an elevator, open a hotel room, turn on a car, get music, take a picture or communicate with friends, without digital code. Most of the wealth and jobs created over the last few decades come from this transition into the digital world.”

“In parallel to the development of digital code, we have been learning how the code of all life is spelled out. Once you can understand these instructions and create blocks of DNA to your specifications, then you can ‘program’ DNA to execute life code. The cell becomes the equivalent of a computer chip….the cell can be programmed to make cells that produce a lot of things, including foods, chemicals, fuels.” Evolving Ourselves, Enriquez and Gullens

Millions of dollars are now flowing into synthetic biology research. Synthetic biology, the application of engineering principals to biology, involves modifying DNA in bacteria, yeast or algae, to excrete bioproducts such as biofuels, pharmaceuticals, food ingredients, and more. Closely related is bioengineering, the design of medical instruments, diagnostic equipment, biocompatible materials, agricultural engineering, renewable energy, disease diagnosis, and tissue engineered organs. Start-ups like Arzenda’s only source of revenue is the design of new proteins.

The Craig Ventner Institute scientists have created new life forms. The tool they have developed is software that includes rules governing DNA replication. The initial stage was to create digital DNA by translating each nucleotide—CTAG—into its own digital binary code, then using the software to design new DNA models. These new life codes could then be written, debugged, and tested virtually. If successful, the code could be translated back to DNA. The final test would be to place the synthetic DNA into a living host cell. If the cell survived to reproduce, the result would be a new life form. E. Coli and brewer’s yeast are very good at reassembling DNA and were initially the hosts of choice. The protein synthesized must then be compatible with the living cell. Most living cells with altered DNA stop reproducing. Even simple organisms, such as yeast, were not designed to host radically different proteins. However, if the injected cell remains viable, thrives and reproduces, products can be produced in quantity.

Genomics 42 The world’s first synthetic organism, created at the Venter Institute, M.mycoides, was the first living organism to have a computer as its parent. As the process improves, increasingly complex organisms will be synthesized. With backing from major organizations, Microsoft and the University of Washington have demonstrated the first fully-automated technology to store and retrieve data in manufactured DNA. Unsurprisingly, the DNA models and the necessary components—both organic and synthetic—are available to anyone with a credit card, creating a new cottage industry. E. Coli bacteria have been programed by students at MIT to produce hemoglobin. After publishing the results of the first synthetic organism, Venter received a letter from both the president and the Pope. How far should we take this new technology?

Gene synthesis is the production of artificial genes. This usually starts with building a onglionucleotides that are 50–60 base pairs long, much shorter that the thousand or millions of base pairs required for life. It is currently possible to email a design for an artficial gene to a nucleotide production facility, like GeneArt in Germany, that will sequence, verify its viability and produce it using a state-of-the-art DNA/RNA Synthesizer. Synthetically produced genetic material placed in compliant organsisms such a yeast or E. Coli bacteria, to excrete the desired amino acids and combine them to make the desired proteins. The process is getting easier and cheaper every year. As much as the computer chip was a game changer, the synthetic cell will be as also.

Synthetic biology enhanced with AI powered pattern recognition, will continue to reduce both the time and cost of drug discovery. Drugs and other products will be designed and tested virtually and produced biochemically.

The French pharmaceutical giant Sanofi recently announced their offer to purchase California biotech company Synthorx at a 170% premium to its market price. Amazingly Synthorx created a semi-synthetic organism by adding a third rung to the DNA ladder. In addition to the two well known C-G and A-T rungs, they added an X-Y to the DNA of the a bacteria E. Coli. This new life form, having never before existed, expresses a coumpound called THOR-707. In clinical trials, the compound helps the human body’s own immune system to more effectively attack tumors.

“Our ability to trace states of disease and health to their atomic underpinnings is a manifestation of the fifth industrial revolution, which focused on atoms…The information- genomics revolution is the sixth.” Regenesis, How Synthetic Biology will Reinvent Nature and Ourselves, George Church

In 2018, Google’s alpha fold AI program—written by the team that created Deep Mind—is

Genomics 43 working on the protein folding mystery. Alpha fold has correctly guessed the structure of 25 out of 40 proteins it was shown. Its closest competitor only correctly guessed three. “It’s never been about cracking Go or Atari, it’s about developing algorithms for problems exactly like protein folding,” team leader Hassabis said.

Synthetic cells could be programmed to produce biofuels, IT storage devices, nonmaterial, and antibiotics. Researchers are learning how to put a gene in a cell that will express itself only under certain conditions. The result is a gene that can be turned on to produce a desired protein then turned off. Genetically designed microorganisms containing the blueprints for synthetic compounds in giant fermentation tanks—think microbrewery and yogurt creamery—will produce gallons or barrels of product. Start-ups like Arzenda’s only source of revenue is the design of new proteins.

Some bioengineers envision microorganisms designed to “You generally start produce computer chips and difficult to manufacture micro- with something electrical-mechanical products. This is currently a $20 billion that exists, and industry that includes devices for motion detection in cell phones, then create a new cars, and switches for optical circuits. Other biotech startups are product or creature, competing to design genes for microorganisms that may one day one that would manufacture computer chips. not exist but for deliberate human Bio-engineering will employ specialists in biocatalysts, invention.” biomechanics, heat transfer, surface science, renewable bio energy, purification science, fluid dynamics. The growth rate for Enriquez and these synthetic biological tools is expected to exceed 20% a year Gullens, Evolving for the next decade. Venture capitalists are investing in a web of Ourselves related biotech startups. Other biotech startups are partnering with major pharmaceuticals to produce synthetic biochemicals. Bayer recently partnered with Joyn Bio to create microbes that produce fertilizer inside a plant’s root system.

Ginkgo Biowork’s founder, Tom Knight, started his career as a software engineer before switching to biology. Gingko sources thousands of organisms from Twist Bioscience a start- up that creates biosynthetic tools, including silicon-based DNA synthesis platforms that enable production of high-quality synthetic DNA. Essentially, Twist produces a 3D printer for DNA. Bioengineers can design it and then insert it into a cell. Ginko expects to produce a billion new base pairs over the next few years.

Other examples of bioengineering companies include Impossible Foods, a west coast company that engineered microbes to produce plant-based proteins such as leghemoglobin.

Genomics 44 Their products mimic the taste and texture of meat; try one at Burger King. Impossible raised $300 million in its debut IPO.

CONCLUSION AND RISKS

“Dr. Hsu, who in 2014 predicted that reproductive technologies would soon be used to select for more intelligent offspring, estimates that an IQ gain of 10 to 15 points would be possible if couples were allowed to choose between ten embryos.” The Economist, November 9, 2019

Biotechnology risk is a form of existential risk that could come from biological sources, such as genetically engineered biological agents. These can come either intentionally (in the form of bioterrorism/biological weapons) or unintentionally (through the accidental release of planned viruses). A chapter in biotechnology and biosecurity was published in Nick Bostrom’s Global Catastrophic Risks, which covered risks such as viral agents. Since then, new technologies like CRISPR and gene drives have been introduced.

While the ability to deliberately engineer pathogens has been constrained to high-end labs run by top researchers, the technology to achieve this (and other astonishing feats of bioengineering) is rapidly becoming cheaper and more widespread. Such examples include the diminishing cost of sequencing the human genome (from $10M USD to $1000), the accumulation of large datasets of genetic information, the discovery of gene drives, and the discovery of CRISPR. The pace of discovery is rapid and accelerating.

Humans will soon create new classes of plants and animals that could not have evolved naturally. We will design new DNA for microorganisms so they produce products on an industrial scale. We can grow human skin and will soon grow human organs. Growing body parts in a lab will be controversial, but that controversy will pale in comparison to our evolving ability to design our progeny. On the other hand, we are learning how to correct nature’s genetic mistakes to improve the lives of those affected. The choices we make regarding genetics will determine the future of our species.

Could CRISPR be made into a weapon? Could someone design a gene to wipe out a basic food source, such as corn? Dr. Doudna in a letter to DARPA, proposed research into such a possibility and to fund development of an antidote. Fortunately, in a proof of concept, scientists at Kansas State have discovered a new class of “anti-CRISPR.”

Since then, Doudna’s lab has discovered more than 40 anti-CRISPR proteins. This might not only provide an antidote to a weaponized CRISPR, it may give biologists more precise control of gene therapies. “I get these questions all the time and I am no more worried about it than other things. Someone could synthesize the smallpox virus,” Doudna reported to MIT’s Technology Review.

Genomics 45 In the early 1960s NASA said, “we already have the tools we need to take us to the moon.” But only a brave few went there. Every human on the planet will in some way be affected by bioengineering. Will society be ready for genetically enhanced humans? Will some countries allow it while others ban it? Will the countries that outlaw genetic enhancements have to prevent its citizens from genetic tourism?

Cellular function is complicated and altering its function frequently comes with unintended consequences. This has always been the price of progress and these genetic developments are certainly not without risk. But the wide-ranging opportunity to further our knowledge and improve so many aspects of our life is not only enticing, it is inescapable.

Genomics 46 LEONARD C. MITCHELL, CFA

Len is a Principal and serves as the lead manager of the Meritage Growth Equity, Small Cap Growth Equity and Strategic Trends strategies. Len has over 35 years of investment experience. Len began his investment career as an oil and energy analyst.

Len serves as a primary contact on many of the firm’s private and institutional relationships. He received his B.A. in Accounting and M.B.A. from Texas Christian University with Honors.

Len’s interests outside of investing include painting and reading scientific journals.

ADDITIONAL TECHNOLOGY WHITE PAPERS BY LEN MITCHELL

The Expanding Presence of Technology (June 2018)

An introduction to this white paper series authored by James M. Klein, CFA

Artificial Intellligence (AI) (September 2018)

Blockchain - truly transformational in its potential (March 2019)

Genomics 47 Sources

Agus, David B. The Lucky Years: How to Thrive in the Brave New Years of Health. New York. Simon and Schuster. 3 January 2017.

Bryson, Bill. The Body. New York. Doubleday. 15 October 2019.

Church, George. Regenesis, How Synthetic Biology will Reinvent Nature and Ourselves. New York. Basic Books. 8 April 2014.

Davies, Sally Professor Dame. “The Power of Genomics.” The Financial Times. 22 March 2019. www.ft.com.

Enriquez, Juan and Gullans, Steve. “Evolving Ourselves: Redesigning the Future of Humanity—One Gene at a Time.” New York. Portfolio. 15 November 2016.

Gatlin, Allison. “Genetic Testing Companies Take DNA Tests to a New Level.” Investor’s Business Daily. December 2019. www.investors.com.

Hessel, Andrew. “Biotechnology/Nanotechnology SingularityU Germany Summit 2017.” Online video clip. YouTube. 8 August 2017.

Specter, MIchael. “A Life of its Own - Where will synthetic biology lead us?” The New Yorker. September 2009.

Lee, Sang Yup. “DNA Data Storage Is Closer Than You Think.” Scientific American. July 2019. www.scientificamerican.com.

“Modern genetics will improve health and usher in ‘designer’ children.” The Economist. November 2019. www.economist.com.

Mukherjee, Siddhartha. The Emperor of All Maladies: A Biography of Cancer. New York. Scribner. 9 August 2011.

Mukherjee, Siddhartha. The Gene: An Intimate History. New York. Scribner. 17 May 2016.

Mullin, Emily. “Fast genome tests are diagnosing some of the sickest babies in time to save them.” MIT Technology Review. 8 March 2018. www.technologyreview.com.

Genomics 48 Neville, Sarah. “Why big pharma sees a remedy in data and AI.” The Financial Times. January 2020 www.ft.com.

NOVA. “Cracking the Code of Life.” NOVA website. https://www.pbs.org/wgbh/nova/ genome/program.html. February 2020.

“Pan-cancer analysis of whole genomes.” Nature. 5 February 2020. www.nature.com.

Terrazono, Emiko, and Clive Cookson. “Gene Editing: How Agritech Is Fighting to Shape the Food We Eat.” The Financial Times, 9 Feb. 2019, www.ft.com

“The engineering of living organisms could soon start changing everything.” The Economist. April 2019. www.economist.com.

“Yuval Noah Harari & Steven Pinker in Conversation.” Online video clip. YouTube. 7 October 2019.

Zimmer, Carl. “Scientists Find Form of Crispr Gene Editing With New Capabilities.” The New York Times. June 2016. www.nytimes.com.

Genomics 49