ED Guidebook2020_21Digital

2020-2021 GUIDEBOOK CONTENTS

About HudsonAlpha Institute for Biotechnology . ...............................2–3 Shareable Science/Beyond the Blog . ......................................................4 Educator Professional Learning ..............................................................5 Executive Summary ..................................................................................6 Science Snapshots ....................................................................................7 New Findings . .....................................................................................8–17

Recent research findings provide a quick update on the genetics, genomics, and biotechnology field. This section represents discoveries, treatments or applications that have been announced during the past year.

Infographic on Infectious Disease . ..................................................18–19 HudsonAlpha Digital Applications .........................................................20 Snapshot References and Image Credits . .............................................21

ONLINE BIOTECH BASICS

Looking for a place to start? HudsonAlpha offers easy-to-understand explanations of foundational concepts at hudsonalpha.org/biotech-basics. Twenty-four key technologies or concepts are described in detail.

Language and concepts are intentionally geared to a high school or public audience.

Educational Outreach

HudsonAlpha’s Educational Programs HudsonAlpha's Educational Outreach team inspires and trains the next generation of life science researchers and workforce while building a more genomically-literate society. The dynamic educators at HudsonAlpha reach students, educators, medical practi- tioners, and the community through hands-on classroommodules, in-depth school and workshop experiences along with digital learning opportunities. HudsonAlpha also provides educational opportunities for healthcare providers and learning tools for patients who are making medical decisions using their personal genomic information. Additionally, the team builds genomics awareness through community outreach classes and events. During the 2019-2020 academic year, 1,953,528 individuals were impacted through HudsonAlpha Educational Outreach. Over the past decade, HudsonAlpha has reached nearly 7.5 million people with these programs and resources.

science for life ®

About HudsonAlpha The HudsonAlpha Institute for Biotechnology is a nonprofit institute dedicated to developing and applying scientific advances to health, agriculture, learning and commercialization. Opened in 2008, HudsonAlpha’s vision is to leverage the synergy between discovery, education, medicine and economic development in genomic sciences to improve the human condition around the globe. The HudsonAlpha biotechnology campus consists of 152 acres nestled within Cummings Research Park, the nation’s second largest research park. The state-of-the-art facilities co-locate nonprofit scientific researchers with entrepreneurs and educators. HudsonAlpha has become a national and international leader in genetics and genomics research and biotech education. It includes more than 40 diverse biotech companies on campus.

Educator Professional Learning HudsonAlpha has several opportunities for teacher professional learning, ranging from single-day workshops to ongoing classroom support. These increase an educator’s comfort in discussing genetic concepts and terminology along with the associated ethical, social and legal issues.

HudsonAlpha scientists are adding to the world’s body of knowledge about the basis of life, health, disease and biodiversity and seeking to enable:

Genomic Research

● Earlier and/or less invasive diagnostics ● Better, more customized treatments for disease ● Improved food, fiber and energy sources

Student Experiences Field trips, classroom visits by industry leaders, summer camp sessions, in-depth internship opportunities and college-level laboratory courses engage students in biotechnology-related fields, increase exposure to career options, provide mentoring opportunities and equip students with a toolbox of content-specific skills.

Significant Research Publications

Current research focus areas are:

Basic Research

Undiagnosed childhood genetic disorders Pediatrics

Neurological and Psychiatric Disorders including Alzheimer disease, Parkinson disease, ALS, Huntington disease, bipolar disorder, schizophrenia, autism and epilepsy

Cancer

Foundational research aimed at improving scientific theories and understanding

Our researchers have been published in more than 700 scientific publications since the beginning of HudsonAlpha in 2008 to help secure a global leadership position in genomic research.

Multiple forms of cancer, including breast, ovarian,

prostate, kidney, brain, colon and pancreatic

Classroom Kits and Digital Resources HudsonAlpha has developed kits and activities to engage elementary and middle school students in hands-on experiences that match state curriculum requirements related to DNA and genetics. Multiple laboratory activities have also been crafted for students in grades 9-12. Activities highlight topics such as trait inheritance patterns, extracting DNA, exploring chromosome behavior in cells, diagnosing genetic disorders, and using bioin- formatics databases. Many of these resources are commercially available to classrooms around the nation through a partnership with Carolina Biological (www.Carolina.com). HudsonAlpha has also launched a suite of free digital resources and activities available at hudsonalpha.org/educatorhub.

Genomic Health

Agriscience

Application of genomic technology to understand the immune system’s role in health and disease Immunogenomics

Computational Biology and Bioinformatics Deep computational analysis and interpretation of vast amounts of data, critical to the science of genomics

Leveraging the power of the human genome to diagnose, predict and prevent disease

Applying genomic knowledge to agriculture and bioenergy to create a more sustainable world

Global Footprint of Research Partnerships

Clinical Applications HudsonAlpha is empowering patients to be informed genomic healthcare consumers and members of society. Our genetic counselors are involved in providing patient education and support for clinical and research activities across the Institute. The genetic counseling team also provides education and training programs for healthcare providers and trainees to support the integration of genomics into routine and specialized medicine.

HudsonAlpha partners with other research institutes and life sciences companies around the globe – and even in space – to make genomic discoveries.

Government support comes from: National Science Foundation Department of Energy Joint Genome Institute US Department of Agriculture National Institutes of Health

Biotech Enterprises

HudsonAlpha strengthens and diversifies Alabama’s economy by fostering success in life sciences companies of all stages and sizes. Its 152-acre biotech campus within Cummings Research Park supports more than 40 tenant companies, from startups to global leaders, with space for more. HudsonAlpha offers turnkey and build-to-suit laboratory and office space for lease in an energizing environment with superior shared amenities. Bioscience enterprises on campus benefit from access to HudsonAlpha researchers as well as strategic support through investor forums, workforce and business assistance, marketing resources and bioscience networking events.

National Human Genome Research Institute National Institute of Arthritis, Musculoskeletal and Skin Diseases National Heart, Lung and Brain Institute National Institute of Mental Health National Institute of Environmental Health Sciences

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Professional Learning for Life Science Educators

Dr. Lamb’s blo

For High School Educators

GTAC Advanced Concepts

Genetic Technologies for All Classrooms (GTAC) is an intensive professional learning experience offered at HudsonAlpha

Institute for Biotechnology that prepares science educators to address high school-level genetics, genomics and biotech content. To learn more about the various GTAC offerings, visit www.hudsonalpha.org/gtac .

GTAC Essential Biology

For Middle School Educators

LifeScience Links is a summer professional learning experience that provides seventh-grade life science teachers updated content knowledge, engaging strategies and authentic lab experienc- es. Educators leave the workshop equipped to link Course of Study Standards to real-world biotech

www.shareable-science.org

: Beyond the Blog

applications and careers. Learn more at www.hudsonalpha.org/lifesciencelinks .

Dr. Neil Lamb presents Beyond the Blog , a companion to Shareable Science, to help make sense of the science related to the coronavirus COVID-19. This ongoing video series offers easy-to-understand explanations of the science behind the disease, how it spreads, and what scientists are doing to help diagnose and treat the disease. Also check page 18 to learn more about COVID.

HudsonAlpha realizes that COVID-19 has shifted the landscape and changed the way teachers interact with their students. HudsonAlpha Beacon is a tool to help educators find life science content from a distance. These virtual opportunities provide teachers with a variety of genetics and biotechnology content, along with technology integration and best practices for virtual delivery. Experiences include unique webinars along with multi-day online sessions that combine synchronous and asynchronous learning.

View now at www.hudsonalpha.org/beyond-the-blog

www.hudsonalpha.org/beacon

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EXECUTIVE SUMMARY

SCIENCE SNAPSHOTS a quick summary of 10 genetics and biotech stories

Now more than ever, there is a critical need to communi- cate the meaning of these scientific findings – using under- standable language that doesn’t stray beyond the boundar- ies of what the data can tell us. Around the world, science educators have stepped into this gap, going beyond the headlines to separate fact from fear. That same goal drove the creation of HudsonAlpha’s Shareable Science Beyond the Blog: a continuously updated library of short videos explaining recent COVID-19 results. These straightforward mini-lessons are at hudsonalpha.org/beyond-the-blog. In spite of the pandemic, scientific research continues to break new ground in agriculture, human health and other bioscience fields. This year’s guidebook brings together 45 of those discoveries, ranging from the production of dairy-identical proteins through fermentation to a gene editing breakthrough that treats thalassemia and sickle cell anemia. An infographic on pandemics rounds out the content. Each story includes a link to the original research article or data source, to give learners first-hand access to the science. For additional background and context, look to our online Biotech Basics series at hudsonalpha.org/biotech-basics . Twenty-four foundational topics provide an introduction to key genomic and bioscience concepts and technologies. For educators, we’ve also included the Alabama Course of Study Alignment Guide , linking the foundational stories to high school life science and career and technical education coursework.

The laboratories of HudsonAlpha faculty researchers Jane Grimwood, PhD, and Jeremy Schmutz contributed to this work. The genome of Cryphonectria parasitica , the fungus that causes chestnut blight, was recently sequenced. Researchers hope to identify key clues within the genome to uncover the mechanisms that allow this pathogen to destroy chestnut trees. 1. First identified in 1903, chestnut blight resulted in the destruction of an estimated four billion mature American chestnut trees over the following half century.

6. The All of Us research initiative seeks to build a diverse human database with more than 1 million Americans.

chestnuts

The laboratory of HudsonAlpha faculty researcher Shawn Levy, PhD, is testing technologies associated with long-read sequencing for the All of Us initiative. from their electronic medical records and donating samples for genetic testing. Half of the participants are from racial or ethnic minority groups. The initial set of data are available for study through the All of Us Researcher Workbench , currently in beta testing. More than 350,000 have enrolled since the program began in mid 2018 — completing surveys, sharing data

2. Scientists have created a comprehensive catalog of all the known genomes of bacteria living inside our digestive system. The freely accessible Unified Human Gastrointestinal Genome Collection includes over 200,000 genomes frommore than 4,600 bacterial species. The research team developed a companion catalog of over 170 million proteins produced by these bacteria. The specific activity of more than 70% of the gut bacteria in this collection remains unknown. 3. CAR T therapy genetically engineers a subset of a patient’s T cells (a specialized immune cell) to recognize a protein on the surface of cancer cells and coordinate their destruc- tion. This form of immunotherapy has experimentally treated a number of different cancers, but has been less effective in treating glioblastoma, an aggressive 4. While there are over 2,000 known mutations in the CFTR gene that are associated with cystic fibrosis, the most common is F508del which deletes the genetic code for the amino acid phenylala- nine at the 508th position in the protein. At least 90% of patients with cystic fibrosis carry one or more F508del mutations. The U.S. Food and Drug Administration recently approved Trikafta ® , a combination of three drugs that target faulty CFTR proteins caused by mutations like F508del. Trikafta helps the damaged protein fold correctly. It also increases the flow of chloride molecules through the protein channel. The protein operates more effectively, improving lung function for patients. The drug is priced at $311,000 per year, but is covered by some insurers. form of brain cancer. A recent tweak to the process incorporates a protein found in scorpion venom. This allows the engineered T-cells to lock on to more glioblastoma cells without attacking the surrounding normal cells. Clinical trials are now underway. 5. Forensic genetic genealogy is a popular new tool to uncover clues in criminal cold cases as well as more recent crimes. The approach scans public databases to identify families with a potential connection to DNA samples recovered from crime scenes. The branches of those family trees are then searched in hopes of finding a suspect. The U.S. Department of Justice has developed an interim policy for genetic genealogy in response to privacy concerns raised among ethicists and legal experts. The approach is limited to violent crimes or unidentified human remains where no match is found in the existing FBI genetic database. The policy went into effect in November 2019 with final guidance to follow.

7. The Encyclopedia of DNA Elements (ENCODE) Project is a worldwide effort to understand how the human genome functions. For nearly two decades, researchers have been developing a map of the millions of DNA switches that regulate when and where genes are turned on and off. Findings from the most recent phase of ENCODE were described in over a dozen papers coordinated for simultane- ous publication. Six thousand additional datasets were generated from 500 cell and tissue samples. Nearly one million new regulatory regions were identified in the human genome, along with nearly 340,000 similar regions in mice.

Neil Lamb, PhD

It’s a supreme understatement to say that 2020 has been eventful. In particular, the COVID-19 pandemic has taken a staggering economic, educational and emotional toll. Activities that traditionally brought people together became potential pathways for infection. Seemingly overnight, physical distancing and learning from home became the standard for millions of households. Around the globe, the pandemic quickly mobilized the scientific and technological workforce in new directions, diving deeper into the fields of biology, immunology and in- fectious disease. Researchers, clinicians and data analysts set aside their usual responsibilities and dedicated them- selves to learning as much as possible about COVID-19 and the SARS-CoV-2 virus. Entrepreneurs, innovators and manufacturers applied those findings to developing tools for improved testing, treatment and prevention. The process of scientific discovery has been on full display. Students are discovering that “The Scientific Method” is nothing like those six easy steps listed in their textbook. The data is messy, contradictory at times, and certainly not resolved by a single experiment.

The laboratory of HudsonAlpha faculty researcher Richard M. Myers, PhD, contributed to this research.

8. Historically, researchers have developed and utilized a single “reference genome” for an individ- ual species, e.g., the Human Genome Project. While beneficial, these references are limited in their ability to capture the variety of DNA sequences present within a population. Scientists have begun developing a multi- genome human reference that is as universal and complete as possible, representing 350 human genomes and known as a “pan-genome.” They estimate that a full human pan-genome may include as many as forty million bases of DNA missing from the current reference. 9. Approximately 10% of the human population is left handed. Prior studies have suggested there is a genetic component to hand- edness, but the specific genes have remained elusive. Analyzing the genomes of approximately 400,000 individuals, including 38,332 “lefties,” identified four DNA regions associated

Neil E. Lamb, PhD Vice President for

Educational Outreach HudsonAlpha Institute for Biotechnology email: nlamb @ hudsonalpha.org twitter: @ neillamb

with left-handedness. The strongest association is located in a gene associated with brain development and patterning. 10. An epigenetics study on aging throws doubt on the saying that one year of a dog’s life is equivalent to seven human years. Patterns of DNA methylation

were compared between 104 Labradors and 320 humans across a range of ages. Changes in DNA

This year’s Guidebook would not have been possible without the dedicated efforts of my colleagues at HudsonAlpha. This includes science writer Sarah Sharman as well as layout and design expert Cathleen Shaw. Special thanks go to April Reis, Jennifer Carden, Jennifer Hutchison, Madelene Loftin and Dasi Price, who served as advisors and reviewers throughout the Guidebook ’s development. I’m humbled and grateful to work with such a talented group of individuals.

methylation occur predictably over time and are one way to measure aging. Dogs and humans showed changes in similar sets of developmental genes. Compared to humans, the process occurs more quickly in young dogs but slows as they get older.

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NEW FINDINGS

Stress really can cause gray hair It turns out that the old wives’ tale that stress can turn your hair gray may be true. Scientists have found that when dark-

DNA double helix can form four-stranded regions

Short, tall and genetic variation Peruvians are some of the shortest people in the world, with average heights of about five feet five inches for men and about five feet for women. A Harvard Medical School-led team of researchers believe they have found the genetic contributor to this short stature in Peruvians. In fact, they report they have identified the single largest genetic contributor to height known to date. The research team conducted a genome-wide association study using height and genotyping data from over 3,000 individu- als from nearly 2,000 households in Lima, Peru. They found five single nucleotide changes, also called single-nucleotide polymorphisms (SNPs), located on areas of the gene FBN1 that are associated with height. FBN1 encodes the protein fibrillin 1, which is involved in tissue development, homeostasis and repair. One of the variants of FBN1 was associated with an almost 2.2-centimeter (0.87") decrease in height that doubled to an almost 4.4-centimeter (1.7") decrease if the individual had two copies of the variant. Height variants discovered prior to this study only influence height by less than 0.5 centimeters, making this the largest variant of height ever reported. Contrary to the effects of the newfound FBN1 variants, previ- ously reported mutations in the FBN1 gene cause Marfan or Marfan-like syndromes, which are characterized by extremely tall stature. This highlights how genetic variants in the same gene can have vastly different effects. REFERENCE: Asgari, S. et al. A positively selected FBN1 missense variant reduces height in Peruvian individuals. Nature (2020) 582: 234-239 doi: 10.1038/ s41586-020-2302-0. southern Pacific Ocean were originally settled by Asian migrants but were colonized by Europeans during the 16th century. Research- ers have long been intrigued by the possibility that Native Americans and Polynesian islanders came in contact before European inter- action. As proof of such a meeting, supporters of the idea point to architectural similarities between Polynesian and Native American ceremonial sites, and agricultural clues such as the presence on the islands of the American sweet potato which exists nowhere else outside of pre-Columbian Americas. To date, however, genetic data has never supported this idea. In a recent study published in Nature , researchers analyzed the genomes of more than 800 people from 15 Native American populations along the Pacific coast of Central and South America and 17 groups currently living on the Polynesian islands. Through a combination of genetic analysis and historical records, the data suggests Native Americans and Polynesians encountered one anoth- er and produced children during a single time period around 1200 CE, nearly 500 years before Europeans arrived. This study highlights the usefulness of genomic analysis to allow researchers to track human migration and contact events that are invisible from an archaeological or historical standpoint. REFERENCE: Ioannidis, A.G. et al. Native American gene flow into Polynesia predating Easter Island settlement. Nature (2020) 583: 572-577 doi: 10.1038/s41586- 020-2487-2. Native American contributions to Polynesian peoples The Polynesian islands in the central and

When someone says “DNA” an image of a double helix shape probably comes to mind. DNA, or deoxyribonucleic acid, usually forms as the classic double helix shape composed of two strands of nucleic acids wound around each other. However, other structures of DNA, such as quadruple helix structures, have been created in test tubes in labs or found in cancer cells. DNA G-quadruplexes (G4s) form within traditional double strand- ed DNA helices when guanine-rich stretches of DNA fold into four-stranded structures through the bonding of guanine bases with each other. G4s are difficult to detect in living cells because the tech- niques required to visualize the DNA kill the cells. To solve this prob- lem, an international research team invented a fluorescent marker to attach to G4s in living cells without disrupting the DNA. Using their new marker, the research team was able to visualize G4s in healthy, living human cells. This study proves G4s exist in cells as stable structures created by normal processes, although their function is still widely unknown. Because G4s form and disappear quickly, the research group thinks they might function to temporarily hold open DNA to facilitate transcription. REFERENCE: Di Antonio, M. et al. Single-molecule visualization of DNA G-quadru- plex formation in live cells. Nature Chemistry . (2020) doi: 10.1038/s41447-020-0506-4.

furred mice are exposed to experimental stress they turn white in mere days. After ruling out both the immune system and stress hormone involvement, the scientists discovered that the mice’s sympathetic nervous systems were to blame for the whitened hair. The sympathetic nervous system is respon- sible for an animal’s fight-or-flight response in the face of stress or fear. The stress trig- gered fight-or-flight response causes the release

of a neurotransmitter called norepinephrine. Norepinephrine causes hair follicle stem cells to prematurely differentiate into melanocytes, the cells that give hair its color. Normally, a population of stem cells exists to replenish melanocytes as they die. However, in the stressed mice the stem cell pool was rapidly depleted, leaving the mice with no new melanocytes to continue producing hair color. By analyzing gene expression in stressed stem cells, the scientists discovered changes in several cell cycle regulatory genes. Activation of such genes triggers the stem cells to leave the G0 resting phase of the cell cycle, enter the cell cycle and terminally differentiate into melanocytes, thereby depleting the stem cell pool. The researchers tested the mechanism on human hair follicle stem cells and found similar results. This study suggests that stress, in addition to aging, could contribute to the graying of hair in humans. REFERENCE: Zhang, B. et al. Hyperactivation of sympathetic nerves drives depletion of melanocyte stem cells. Nature (2020) 577:676-681 doi: 10.1038/s41586-020- 1935-3. Finding free-floating mitochondria Mitochondria are called the powerhouse of the cell because they produce most of the chemical energy needed for cells to function properly. Through cellular respiration, these double- membrane-bound organelles convert oxygen and molecules from food into usable energy called adenosine triphosphate (ATP). While most mitochondria exist within cells, a study published in The FASEB Journal suggests that intact, functional mitochondria can circulate in blood without a cell carrier. The researchers were studying cell-free mitochondrial DNA fragments as a potential cancer biomarker when they noticed that certain fragments were longer and more resistant to degradation than others. Upon further investigation, they identified two popula- tions of cell-free mitochondrial DNA: small, degraded fragments, and long, full-length copies of the mitochondrial genome. Through the use of a wide range of techniques, the scientists concluded that the free-floating, full-length mitochondria were functional, respiratory organelles like their cell bound counterparts. The function of the free-floating mitochondria is currently unknown. The researchers who made the discovery propose that the indepen- dent mitochondria may be released by cells for signaling purposes, although more work is needed to validate this hypothesis. Whatever their function, it is an intriguing finding that mitochondria can func- tion normally while drifting around in the blood of healthy people. REFERENCE: Dache, Z. et al. Blood contains circulating cell-free respiratory compe- tent mitochondria. The FASEB Journal (2020) 34:3616-3630 doi: 10.1096/fj.201901917RR.

Getting by on 20 winks of sleep For most people, a good night’s beauty sleep involves an average of 8 hours of sleep per night. Waking up after a poor night’s sleep can leave you feeling foggy and unwell. In fact, sleeping for less than 6 hours a night several days in a row leads to a decline in cognitive abilities for some people. Chronic sleep deprivation contributes to several disorders including obesity, heart disease, high blood pressure, diabetes and depression. However, we all know someone who functions perfectly fine on less sleep, but how? It turns out that their genes may be the answer. By studying families that require less than the average amount of sleep to feel fully rested, a group of researchers identified several genetic mutations they think dictate the amount of sleep a person requires. Two genes in which they identified mutations, ADRB1 and NPSR1 , both encode proteins that are involved in sleep behavior. After identifying the potential candidate mutations, research- ers bred rats and mice with the same mutations and studied their sleep habits. Rats with the ADRB1 mutation slept about 55 minutes less per day and had altered activity in the dorsal pons area of the brain, known to regulate sleep. Mice with NPSR1 mutations also slept less without the obvious effects on health or memory associated with chronic sleep deprivation. In addition to feeling fully rested with almost half the amount of sleep required by the average person, the families with these genetic variants do not appear to suffer negative health consequences, although longer-term studies are necessary to confirm this. It might be possible to develop drugs to mimic the effects of these mutations, but the researchers caution that they might produce harmful side effects since these genes are also involved in stress and fear regulation. REFERENCES: Shi, G. et al. A rare mutation of ß 1 -Adrenergic receptor affects sleep/wake behaviors. Neuron . (2019) 103:1044-1055 doi: 10.1016/j. neuron.2019.07.026. Xing, L. et al. Mutant neuropeptide S receptor reduces sleep duration with preserved memory consolidation. Science Translational Medicine . (2019) 11:eeas2014 doi: 10.1126/scitranslmed.aax2014.

Genetic signatures of the slave trade

An estimated 12.5 million people were forcibly removed from African countries and transported across the Atlantic Ocean to the Americas during the transatlantic slave trade. Their arrival changed the Amer- icas not only culturally, psychologically, and sociologically over time, but also genetically. For many modern-day African Americans, their ancestral roots are defined by this transatlantic migration. The genetics company 23andMe ® set out to help understand the genetic contributions of these mass movements of people by performing the largest DNA study of African ancestry in the Americas. Over the past decade, researchers studied genetic samples from over 500,000 participants living along the West Coast of Africa and along the eastern coastlines of North, Central, and South Americas where slaves are known to have been traded. With the help of historians, researchers compared the genetic profiles with historical shipping documents from slave voyages. They concluded that the proportion of individuals forced from Africa to the Americas is mirrored in genetic similarities between individuals from those regions. For example, the results confirmed that most Americans of African descent have genetic origins in Angola and the Democratic Republic of Congo, which is consistent with historical records. Variation from the expected genetic patterns can be explained by an increase in secondary slave trading within the Americas after the transatlantic slave trade ended, variable survival rate of slaves in different parts of the Americas and regional differences in the treat- ment of slaves. This study shows how genetic signatures can be used to effectively help trace the movements of populations of people that occurred hundreds of years ago. REFERENCE: Micheletti, S.J. et al. Genetic consequences of the Transatlantic slave trade. The American Journal of Human Genetics (2020) 107: 265-277 doi: 10.1016/j. ajhg.2020.06.012.

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NEW FINDINGS — AGRICULTURE

Vineyard foe A tiny aphid-like insect called phylloxera is capable of single-handedly decimat- ing entire vineyards by feeding on, and ultimately killing, the grapevine roots and leaves. Phylloxera create tumor-like structures, called galls, in the grape vines which afford them a nutrient source as well as protection from other parasites. The galls disrupt the grapevine’s ability to move nutrients and feed itself.

Lab-based sugar substitute Sugary confections are a central feature of many holiday celebrations, family gatherings, and restaurant menus around the world. And while jellybeans, candy corn, pastries and pies might invoke a sweet sense of comfort and joy, excessive sugar consumption can lead to obesity, type 2 diabetes and heart disease. In order to feed their sweet tooth but also stay health conscious, many people use sugar substitutes in place of sugar. Stevia is a popular natural sweetener obtained from plants grown in South America that is 250 times sweeter than sugar. Scientists analyzed stevia to determine at a molecular level how it achieves this level of sweetness. They found that two molecules, Reb M and Reb D, gave stevia its sweetness without the bitter aftertaste associated with the most common molecule, Reb A. However, Reb M and Reb D are present in less than one percent of the stevia leaf, so extracting them from the plant is not feasible. Two companies discovered a process to create the calorie-free sweet- eners through fermentation. They developed a yeast strain that pro- duces the same enzymes used by the stevia plant. In a fermentation tank, the yeast converts simple sugars, like sucrose or dextrose, into Reb M and Reb D. The sweetener is being tested in over 300 products with some expected to hit shelves this year. REFERENCE: Winnipeg Free Press. Cargill starts making next-generation sweetener for 2020 debut. 16 November 2019. Web. 4 September 2020. https://www.winnipegfreepress.com/business/cargill-starts-making-next-genera- tion-sweetener-for-2020-debut-565030932.html. Dairy-identical cheese For those following an exclusively plant-based diet, trying to create a crispy yet gooey grilled cheese sandwich using vegan cheese has historically been a challenge. Dairy-free, plant- based cheeses had a reputation for having a weird, plasticky texture and lacking a true cheese flavor. As veganism and the animal-free food movement continue to gain momentum, there is a growing desire for tastier and more realistic dairy-identical products made without cows. Several food-tech companies, such as Perfect Day ® , New Culture ® and Motif Foodworks ® , have recently set out to produce dairy-identical products in labs using genetically engineered microflora, like yeast, fungi or bacteria. Using cow DNA as a model, scientists synthesize DNA sequences containing instruc- tions for the production of dairy proteins such as casein and whey. The DNA is inserted into the microflora which is then used to produce the dairy proteins through a process called fermentation. During fermentation, carbohydrates like sugars are converted into energy without the use of oxygen. To begin fermentation, the engineered microflora are fed plant sugars, such as glucose and galactose, and other nutrients to support abundant growth. The microflora not only convert the sugars into energy and other fermentation byproducts but also produce the dairy proteins. The proteins are harvested by either collecting them from within the cells or removing them from the fermentation culture liquid, depending on the type of microflora that produced them.

Ginkgo immune system The oldest living Ginkgo biloba tree is thought to be over 1,500 years old, meaning it was cultivated in the early 6th century. Several ginkgo trees even survived the bombing of Hiroshima. As a species, ginkgo has been around for over 270-million-years and has changed very little genetically. However, scientists are still at odds with how the trees have such extraordinary lifespans. A group of researchers set out to determine

Cosmo the bull In the beef industry, male cattle are more desirable than females because they are about 15 percent more efficient at converting feed into weight gain. More weight gain means more beef yield per cow, allowing ranchers to keep fewer cattle on their farms. Producing more male cattle is not only econom- ically desirable but also environmentally favorable because fewer cattle also means a lower production of greenhouse gas emissions. Like most sexually reproducing animals, cows have a 50 percent chance of giving birth male offspring. However, scientists at the University of California, Davis, seek to increase cows’ likelihoods of producing male offspring using genome-editing technology.

the molecular and metabolic mechanisms behind the longevity. By looking at tree cores from young and old Ginkgo biloba trees in China ranging from 15 to 1,353 years old, the team determined that tree growth did not decline from 10- to 600-year old trees. This indicates that the vascular cambium, the layer of stem cells between the bark and the inner wood of the trunk, can maintain continuous growth for several hundred years. The researchers also performed genetic analysis on the vascular cambium stem cells. They found that the genes responsible for the trees’ immune systems do not diminish over time like they do in other organisms as they age. This means the trees have antioxidants, immune cells and hormones that allow them to fight off pathogens and stressors throughout their centuries-long lives. REFERENCE: Wang, L. et al. Multifeature analyses of vascular cambial cells reveal longevity mechanisms in old Ginkgo biloba trees. PNAS (2020) 117:2201-2210. doi: 10.1073/pnas.1916548117. In some cases, production of products further involves forming casein micelle structures, or clusters of casein protein, which more accurately mimics the natural form casein protein takes when suspended in milk water. The food scientists use calcium and various salts to form the micelles, providing additional nutri- tional value to the proteins. After harvesting the proteins, they can be combined with plant fats, water, vitamins, minerals and other components to produce dairy-free versions of products such as cheese, milk and ice cream. Perfect Day recently began selling ice creammade with its animal-free dairy proteins and the reviews so far indicate that it is a dairy-free product that tastes and feels identical to regular ice creammade from cow’s milk. Whether their motivation to eat animal-free dairy products is driv- en by ethical, environmental or health reasons, consumers will soon have a variety of dairy-identical products from which to choose. REFERENCES: Forbes. Got Milk? This $40M Startup Is Creating Cow-Free Dairy Products That Actually Taste Like The Real Thing. 9 January 2019. Web. 30 August 2020. https://www.forbes.com/sites/alexandrawilson1/2019/01/09/got-milk-this- 40m-startup-is-creating-cow-free-dairy-products-that-actually-taste-like-the-re- al-thing/#2e71ce9540dc. Livekindly. Dairy-identical vegan cheese is coming to save the cows. 29 January 2020. Web. 30 August 2020. https://www.livekindly.co/dairy-identical-vegan-cheese- is-coming-to-save-cows. Food Navigator-USA. ‘Real’ cheese… without cows? New Culture makes mozzarella with milk proteins via microbial fermentation. 24 June 2019. Web. 30 August 2020. https://www.foodnavigator-usa.com/Article/2019/06/24/Real-cheese- without-cows-New-Culture-makes-mozzarella-with-milk-proteins-via- microbial-fermentation.

Smartphone DNA testing A device that can fit in your pocket and perform DNA testing in the middle of nowhere in as little as 80 minutes seems like something out of a futuristic, science fiction movie. But thanks to an international team of researchers, this smartphone-based device is a reality. The device uses simple 3D-printed parts to turn a standard smart- phone into a $10, on-the-spot DNA test that achieves 97 percent accuracy. Samples are loaded into the attachable detector, mixed with pre-filled chemicals and heated by the phone itself. The sam- ple lights up or changes color if complementary DNA in the sample binds a probe within the device. This signal is detected through a lens attached to the camera on the phone, and the results are displayed on the phone. Through preliminary testing, the researchers determined the device can detect long and short fragment deletions, single-base substitu- tions and insertions, as well as pathogen-specific DNA sequences from a variety of samples including blood, cheek swabs, urine, milk, river water and plant leaves. They identified genetic conditions like alpha- and beta-thalassemia in blood, E coli bacteria in river water and milk and a bacterium that attacks kiwi fruit plants from samples of the plants leaves. Although this is an early prototype, it shows promise for portable, affordable DNA testing devices that would be invaluable for doctors, farmers, food safety officials and environmental monitoring agencies. Phylloxera was accidentally introduced to Europe in the 1860s and nearly brought French grape cultivation to an end. Because North American grapevines are resistant to phylloxera, many growers graft American roots onto European grapevines to give them tolerance. This is time consuming and expensive. Understanding the manner by which phylloxera invade and destroy the grapevines would make it possible to engineer phylloxera-resistant grapevines. By sequencing the genome of phylloxera and comparing it with its common ancestor aphids, researchers identified a huge new gene family containing nearly 3,000 genes that have evolved in the phyllox- era genome. These genes code for small secreted proteins, called effectors, which scientists think deactivate the basic defenses of the plants, enabling the insects to colonize and feed on the grape vines. Phylloxera originated in North America and researchers believe a co-evolutionary relationship developed with American grape vines, allowing the parasite and host plant to co-exist. However, cultivated European vines lack the ability to ward off the lethal cocktail of effector proteins. REFERENCE: Rispe, C. et al. The genome sequence of the grape phylloxera provides insights into the evolution, adaptation, and invasion routes of an iconic pest. BMC Biology (2020) 18:90. doi: 10.1186/s12915-020-00820-5.

Cosmo and his mother behind him

Cosmo, a 110-pound bull calf born in April 2020 at UC Davis, was genome-edited as an embryo so that he will produce more male offspring. Scientists used CRISPR-based genome editing to make targeted cuts in a chromosome and insert the SRY gene, in a process called gene knock-in. SRY, typically found on the Y chromosome, encodes for sex determining region Y (SRY) protein that is responsible for the initiation of male sex characteristics, like the formation of testes. Cosmo’s offspring should be 75 percent males, with 50 percent XY males and 25 percent XX animals that co-inherit the SRY gene and develop male traits. The SRY gene was integrated in a region of bovine chromosome 17 known as a genomic safe harbor site, meaning the genetic insertion doesn’t interfere with nearby genes. Scientists will not know if inheriting the SRY gene is enough to trigger the male developmental pathway in XX embryos until Cosmo reaches sexual maturity in a year and can produce offspring. REFERENCE: Owen, J.R. et al. Production of a gene knock-in bull calf by embryo-mediated genome editing. Poster presented at: American Society of Animal Science meeting (2020).

REFERENCE: Xu, H. et al. An ultraportable and versatile point-of-care DNA testing platform. Science Advances (2020) 6:eeaz7445 doi: 10.1126/sciadv.aaz7445.

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NEW FINDINGS — EPIGENETICS

Exercise, motivation and genes If you’ve ever lacked motivation to hit the gym, it turns out your genes could be to blame. A recent study suggests that voluntary exercise behavior is influenced by epigenetic changes in early development. These changes, such as DNA methylation, are chemical modifications to DNA that affect gene activity without altering the DNA sequence. In the study, scientists deleted, or knocked out, a DNA methylation gene in a subset of neurons in the hypothalamus of mice thought to be responsible for regulating the amount of food that animals eat. Genome sequencing of hypothalamic neurons showed altered meth- ylation patterns in several genes, some of which could be involved in exercise motivation. Although they weighed more, juvenile knockout mice ate the same amount of food as the normal mice. But, when the mice were offered an exercise wheel, the knockout mice exercised far less than their counterparts. While it still requires translation to humans, the study suggests a possible epigenetic-driven developmental connection between motivation and exercise. REFERENCE: MacKay H. et al. DNA methylation in AgRP neurons regulates vol- untary exercise behavior in mice. Nature Communications (2019) 10:5364 doi: 10.1038/ s41467-019-13339-3.

Researchers assemble database of cancer genomes Cancer is a genetic disease that is characterized by the uncontrollable growth of abnormal cells that often travel to and invade other parts of the

NEW FINDINGS — CANCER

tumor sequencing project to date. The team performed whole- genome sequencing and analysis on more than 2,500 samples from 38 different primary cancers and matching normal tissue samples, including brain, skin, esophagus and liver. An interesting finding was that about 95% of the tumors had at least one identifiable DNA mutation in their genome that appeared to drive the cancer. These mutations, known as driver mutations, are responsible for cancer development and progression. About 13% of the driver mutations occurred in those non-coding portions of DNA that are not regularly analyzed. Many cancer drugs are designed to target specific proteins affected by driver mutations. Unearthing driver mutations in non-coding regions of a patient’s tumor genome could open the door to new avenues of treatment that would other- wise be missed. These studies represent a big step toward uncovering and under- standing all of the major cancer-causing mutations. In an effort to continue the momentum of this collaborative endeavor, the Project team has made all of its data and analytic tools freely available to the research community. REFERENCE: The ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium. Pan-cancer analysis of whole genomes. Nature . 578:82-93 (2020) doi: 10.1038/s41586- 020-1969-6. Genomic analysis of childhood cancer patients identifies potential targets for treatment The availability of targeted therapeutics for pediatric cancers pales in comparison to those available for adults. However, a recent study suggests that some FDA-approved drugs could be repurposed to treat pediatric cancer. Solid tumors account for about 50% of pediatric cancers. They are generally assumed to be heavily influenced by germline DNA variants, mutations inherited from the parent’s germ cells and present in all of the child’s cells, in addition to somatic mu- tations that only occur in the cancer cells. However, germline genomic analysis is not regularly used when determining the course of therapy for such patients. Scientists at the Cleveland Clinic have shown that such an analysis could be valuable when selecting a treatment strategy for these young cancer patients. During the study, scientists analyzed germline DNA from over 1,500 patients under the age of 29. They found that many of them carried germline mutations in known cancer-causing genes. Some of the mutations are known to be treatable with drugs already approved by the FDA for adult patients. In fact, thirty-four percent of the patients had at least one mutation that was potentially druggable. This study highlights the importance of sequence analysis of both germline and cancer genomes in pediatric and adolescent patients. By detecting more druggable targets, more approved drugs could be available, giving these young patients a wider range of therapeutic options in their battle against cancer. REFERENCE: Akhavanfard S, et al. Comprehensive germline genomic profiles of children, adolescents and young adults with solid tumors. Nature Communications (2020) 11:2206 doi: 10.1038/s41467-020-16067-1.

body. It is commonly caused by the accumulation of many different types of DNA mutations. Cancer is an extremely diverse disease, meaning that one person’s cancer genome can look entirely different from another person’s cancer genome. As we move closer to an era of precision medicine and personalized cancer treatment, it is critical to understand the thousands of different types and combinations of mutations that can cause cancer. To date, cancer research has mainly focused on well-known can- cer-associated genes, specifically mutations in the protein-coding components of those genes. However, this only represents a mere 1% of the entire genome. Therefore, a majority of the genome has been largely unstudied and unsequenced as it relates to mutations associated with cancer. However, the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Project team recently completed the largest whole-genome

Skewing X inactivation may activate autoimmune disorders Many autoimmune diseases disproportionately affect women more than men. One such disease, systemic lupus erythematosus (SLE), affects women nearly ten times more frequently than men. However, the molecular basis for the sex disparity is poorly understood. A recent study published in Human Molecular Genetics suggests that X chromosome inactivation could be to blame. Because females carry two X chromosomes compared to men who carry one, mammals evolved X chromosome inac- tivation to randomly silence, or turn off, genes on one of the X chromosomes in females. This allows XX females and XY males to have equal expression of X-linked genes, or genes located on the X chromosome. X chromosome inactivation is largely mediated by a molecule called XIST which recruits multiple proteins to the inactivated X chromosome to initiate and maintain gene silencing. By using RNA sequencing technology, scientists compared expression patterns of X-linked alleles in immune cells from female SLE patients and healthy subjects. They found that SLE patients had skewed X chromosome inactivation in T and B cells, meaning that the inactivation of one X chromosome occurs more frequently than the other. Offering a potential mechanism for the skewed X chromo- some inactivation, the scientists also observed that XIST was upregulated in the immune cells of patients with SLE. Because the process of X chromosome inactivation is limited to female cells, these findings may explain the female predisposition to autoimmune diseases like SLE. The skewed silencing of certain X-linked genes in SLE patients could increase the generation of immune cells that attack the patient’s own tissue, or reduce a patient’s ability to eliminate such cells.

Increasing mutation rates generates treatment resistant cancer cells

Genetic patterns of mimicry: the same… only different In South America, there are many Heliconius butterflies that have identical wing coloration and markings, despite belonging to different

Imagine the devastation that patients feels when they are told the cancer treatment that was working wonders for them for a year is now ineffective

because their cancer is no lon- ger responding to the treatment. This phenomenon, known as drug resistance, is a major setback in many patient’s cancer treat- ment plans. The current understanding is that within the tumor’s population of millions or billions of cancer cells, one or more already contain drug resistance mutations prior to treatment. However, a group of scientists challenged this understanding by turning to an unlikely source: bacteria. An increased DNA mutation rate has been observed in bacteria exposed to stress, like antibiotic treatment. This improves their odds of developing a mutation that will cause resistance to the antibiotic and increase their chance of survival. In a recent Science study, the scientists provide evidence that cancer cells may use a similar mechanism that generates resistance to drug treatment. As in the bacteria, colon cancer cells that survived drug treatment had a stress-induced increase in DNA mutation rate. Specifically, they had shifted gene expression from efficient repair systems towards error-prone repair pathways. The higher mutation rates increased the chance of acquiring drug resistance. In future studies, the scientists hope to determine the mechanism the cells use to increase their mutation rate and find a drug target to stop or delay drug resistance.

species. The bright black, red and white wing color patterns serve as a warning that the butterflies are poisonous, affording them a survival advantage in the face of hungry predators. Over time, some species have evolved and more closely resemble the poisonous species in a process called mimicry. These lookalike butterflies provide evolution- ary biologists with a unique opportunity to study the evolutionary and genetic basis of mimicry. A recent study published in Current Biology aimed to answer the question: Do distantly related species of butterflies use the same genetic path to evolve identical wing-color patterns? An internation- al group of scientists used CRISPR/Cas9 genome editing to knock out an important wing patterning gene, WntA , from the butterflies’ genomes. WntA is known to be important for the generation of Heliconius butterfly stripes. The scientists thought that if WntA played the same role in each of the butterfly species, inactivating it would lead to identical knockout butterflies. However, the knockout butterflies were not identical, having notice- able differences in their wing patterning and coloration. Although evolution of color patterns in the butterflies was driven by similar forces, such as survival and mating success, the study suggests that there are several different genetic pathways that can lead to identical color patterns in butterflies. REFERENCE: Concha, C. et al. Interplay between Developmental Flexibility and Determinism in the Evolution of Mimetic Heliconius Wing Patterns. Current Biology (2019) 29:3996-4009 doi:10.1016/j.cub.2019.10.010.

The laboratory of HudsonAlpha faculty researcher Devin Absher, PhD, contributed to this research.

REFERENCE: Zhang, Y. et al. Skewed allelic expression on X chromosome associated with aberrant expression of XIST on systemic lupus erythematosus lymphocytes. Human Molecular Genetics (published online ahead of print, 2020 Jul 6) doi: 10.1093/hmg/ddaa131.

REFERENCE: Russo M, et al. Adaptive mutability of colorectal cancers in response to targeted therapies. Science (2019) 366:1473-1480 doi: 10,1126/science.aav4474.

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