2024 GUIDEBOOK CONTENTS
About HudsonAlpha Institute for Biotechnology ................................2–3 Executive Summary .................................................................................4 Science Snapshots ...................................................................................5 New Findings ......................................................................................6–15
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.
Understanding Transcription Factors in Genomic Research .........16–17 HudsonAlpha Life Science Educator Resources ................................18–28 Alabama 2023 Course of Study Alignment .............................. 21-25 HudsonAlpha Digital Application Resources ............................ 26-28 Snapshot References and Image Credits ..............................................29
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.
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. HudsonAlpha is supported by grants from the U.S. federal government, the state of Alabama, private foundations, the HudsonAlpha Foundation, and philanthropic contributions.
Genomic Research
HudsonAlpha scientists are adding to the world’s body of knowledge about the basis of life, health, disease and biodiversity and seeking to enable:
● Earlier and/or less invasive diagnostics ● Better, more customized treatments for disease ● Improved food, fiber and energy sources
Significant Research Publications
Current research focus areas are: Foundational Research
Plant Genetics Applying genomic knowledge to improve the quality and sustainability of our food, fiber, and fuel production, and our environment's health.
Human Health Leveraging the power of the human genome to diagnose, predict and prevent disease as well as helping others incorpo- rate genomics into practice
Research that improves the understanding of biological phenomena. Includes studies of natural variation, principles of bioethics, and computational biology and bioinformatics
Our researchers have authored more than 1,100 scientific publications since HudsonAlpha opened in 2008 to help secure a global leadership position in genomic research.
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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, and the community through hands-on classroom mod- ules, 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.
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.
Student Experiences Field trips, classroom visits by industry lead- ers, summer camp sessions, in-depth intern- ship opportunities and college-level laboratory courses engage students in biotechnolo- gy-related fields, increase exposure to career options, provide mentoring opportunities and equip students with a toolbox of content-spe- cific skills.
Classroom Kits and Digital Resources HudsonAlpha developed kits and activities to engage elementary and middle school students in hands-on experiences that match state curriculum requirements related to genetics and biotechnology. Multiple laboratory activities have also been crafted for students in grades 9-12. Activities highlight topics such as trait inheri- tance patterns, extracting DNA, exploring chromosome behavior in cells, diagnosing genetic disorders, and using bioinformatics databases. Many of these resources are commercially available to classrooms around the nation through a partnership with Carolina Biological (www.Carolina.com).
Clinical Applications HudsonAlpha is empowers patients to be informed genomic healthcare consumers and members of society. Our genetic counselors provide 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.
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 45 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. Biosci- ence 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.
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SCIENCE FOR LIFE
EXECUTIVE SUMMARY
Over the past year, all of us at the HudsonAlpha Institute for Biotechnology have spent time reflecting on the past and looking forward to the future. It has been 15 years since HudsonAlpha opened its doors in 2008. Those 15 years have been marked by countless new scien- tific discoveries and the translation of those discoveries into applications that make the world around us a better place. I am thankful to have had a front-row seat to HudsonAlpha’s discovery and innovation story and am incredibly hopeful for what the next 15+ years will hold for HudsonAlpha as well as the fields of genomics and biotechnology. Stories of new discoveries and applications bring science to life. Learners of all ages can be inspired by the stories described in this year’s guidebook and celebrate alongside the brilliant scientists who made these stories possible. Since the last guidebook was published, Alabama adopted a new course of study for science in late 2023. The new standards retain many of the improvements present in the 2015 standards, such as an emphasis on three-dimensional science teaching, including science and engineering practices, and cross-cutting concepts with the core science concepts. The concept of inheritance is now explicitly intro- duced in the third-grade standards, and rather than genetic determin- ism, introduces elementary students to the concept that both genes and environmental factors influence many traits. The 7th-grade life science standards include more robust and scientifically accurate genetics and biotechnology standards. Genetics and biotechnology continue to have a prominent place in the Biology course of study, with direct ties to 8 of the 15 standards. HudsonAlpha’s Educational Outreach team strives to meet the needs of Alabama’s students and educators. The development of new kits, curricular materials, and training opportunities is already underway. The It’s All in the Patterns third-grade genetics module is being piloted in AMSTI classrooms across the state. Several newly developed kits for high school biology classrooms both support the new standards and bring cutting-edge genomics discoveries into class- rooms. New field trip experiences on HudsonAlpha’s campus connect- ing science content with career and technical education in agriscience and health sciences are being developed. New professional learning experiences for educators are available through new rounds of GREAT workshops for high school teachers and GPS workshops for middle school teachers. We invite middle and high school educators to join us for week-long summer workshops on HudsonAlpha’s biotech campus, including a newly developed workshop focused on unity and diversity concepts. The mission of the HudsonAlpha Educational Outreach team is to inspire and train students to become the bioscience workforce of tomorrow as well as to cultivate a genomically literate community. I hope that young (and young at heart) readers find themselves blown away by the knowledge and tools available to scientists in 2024 and dream of how they can be a part of making the discoveries of tomorrow. I’ve enjoyed gathering the stories included in this year’s Guidebook. I hope you enjoy learning about them as much as I have.
Kelly East
I’d like to give a huge shout out to the HudsonAlpha writers, reviewers, and designers who made this year’s edition of the guidebook both readable and visually compelling. Thank you Madelene Loftin, Marquasha Carter, Meagan Cochran, Jennifer Hutchison, Nikki Mertz, Sarah Sharman, and Cathleen Shaw. I am beyond grateful for your time, talent, and support.
Kelly East, MS, CGC Vice President for Educational Outreach HudsonAlpha Institute for Biotechnology email: keast@hudsonalpha.org
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SCIENCE SNAPSHOTS a quick summary of 10 genetics and biotech stories
6. Did gastrointestinal issues, a Hepatitis B infection, or liver
1. Bats have robust immune systems that elude deadly viruses and cancer. Researchers identified specific changes in bat genes compared to humans. Key changes thwart viral infection and control inflammatory responses. This knowledge could pave the path to potential treatments for humans in the future. 2. The FDA approved two groundbreaking cell-based gene therapies for sickle cell disease. Both therapies use patients’ own blood stem cells. Casgevy ® , the first CRISPR-based therapy, edits cells to increase fetal hemoglobin. Lyfgenia ® genetically modifies cells to produce HbAT87Q, which functions like normal adult hemoglobin. Both therapies reduce red blood cell sickling, the main contributor to sickle cell disease symptoms." cheese by disrupting microbiome interac- tions. Deleting a specific gene in the invading mold allows bacteria to grow normally and ensures cheese makers can preserve the distinctive flavors of their products. 4. Acrocentric human chromosomes (13, 14, 15, 21, 22) have their centromere very near one chromosome tip. Long-read sequencing has shown their short p-arms are unusually similar and suggests they’ve periodically exchanged ge- netic material during meiosis. This reinforces the hypothesis behind Robertsonian translocations: improper recombination between the p-arms of different acrocentrics joins their q-arms into a single extended chromosome. 3. Bacteria are crucial for forming the rind of cheeses like Parmesan and cheddar. Unwanted molds can spoil the 5. Purple tomatoes, genetically modified to produce anthocyanin in both the skin and fruit, were cleared for commercial production by the FDA. By inserting two snapdragon genes, researchers turned up the plant's levels of the deep purple pigment. This makes the fruit ripen more slowly for less damage during transport, and the pigment is an antioxidant with known health benefits.
disease from heavy drinking kill Beethoven? No one knows, but researchers have a better idea now that they sequenced his genome using preserved DNA from strands of Beethoven’s hair. They found several risk factors for liver disease, including a variant that tripled his risk for liver issues. 7. In late 2022, President Biden issued an Executive order on Advancing Biotechnology and Biomanufacturing Innovation for a Sustainable, Safe and Secure American Bioeconomy . The order pledges to increase funding for innovation in biotechnology, emphasizing medicine, renewable energy, and food security. The order seeks to untangle the regulatory landscape for 8. Accurately determining the impact of a particular genetic change is critical for research and medical care. A study found that 27% of 1,113 genetic changes predicted to be loss-of-function (pLoF) may not actually cause loss of protein function. An updated framework considers additional loss of function evasion mechanisms and lowers the false positive rate in genetic testing. 9. DNA analysis of modern and ancient head lice shows that the tiny parasite was brought into the New World at least twice, once from Asia and more recently from Europe. Using genetic information, researchers found new lice evolutionary relationships and used them to trace human migration patterns. biotechnology products, addressing gaps and ambiguities in regulations among the multiple federal agencies that monitor biotech applications.
head lice
10. A team of researchers found a portion of a skull in eastern China that may change how scientists think about human evolution. The skull may belong to a new group of hominids that
had modern human features long before modern humans were present in this part of the world.
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SCIENCE FOR LIFE
NEW FINDINGS — GENETICS AND GENOMICS
When the initial human genome sequence was released in 2001, the scientific From genome to pangenome
community celebrated the completion of such a monumental and collaborative body of work. However, it became
apparent to scientists that gaps existed in the reference genome. The individuals who donated samples for the first genome were not representative of the diversity across the globe. Also, most of the reference genome came from one person, further limiting its diversity. The Human Pangenome Reference Consortium (HPRC) set out to address the limitations of the original genome by creating a pangenome of many diverse human genomes. The first draft of the human pange- nome was released in early 2023 and is being hailed as a tremendous advancement to the original sequence. The project included samples from 47 genetically diverse individuals, covering over 99% of the human DNA sequence. The pangenome is more than 99% accurate. The pangenome fills gaps in the reference sequence produced by the Human Genome Project, including adding more than 100 million bases. The pangenome reference also opens a window to identifying large genomic variants called structural DNA variants, which have been nearly impossible to find. The HPRC hopes to increase the number of individuals in the pangenome to 350 in 2024 and ultimately grow that number to 700 by the project's conclusion. The human pangenome reference is the next step in deepening our understanding of the human genome and how variations within it may contribute to health and disease risk. n REFERENCE: Liao, WW., Asri, M., Ebler, J. et al. A draft human pangenome reference. Nature (2023) 617, 312–324 . doi.org/10.1038/s41586-023-05896-x
Cells remember better in 3D Human cells contain our entire genome which holds instructions for thousands of protein and RNA molecules. However, a single cell typically expresses only a fraction of its genes, allowing different types of cells to arise in multicellular organisms. Epigenetics tags, which are tiny chemical markers on DNA, heavily influence a cell’s fate by telling it to become a muscle cell, for example. DNA wraps around histone proteins inside the cell nucleus, forming tightly packed chromatin. Histones under- go various modifications that regulate gene expression, creating an "epigenetic memory" crucial for preserving a cell's identity. Research shows that epigenetic modifications greatly influ- ence the 3D structure of chromosomes. A recent computational model-based study observed marked regions collapsing into dense clusters. The study suggests that a cell's 3D genome folding determines which parts receive chemical modifications. Some marks are lost during cell
division, but 3D folding helps restore them, pre- serving the cell's identity. Chemical marks during cell division aid in rees- tablishing genome folding, allowing memory pres- ervation through multiple divisions. “Reader-writer"
Example of nucleotides of DNA wrapped around the core built from histone proteins.
enzymes, specialized in adding these modifications, read existing marks and write new ones nearby. If the chromatin
has a 3D structure, marks accumulate in regions already modified by the parent cell. Evidence also suggests that the 3D dissemi- nation of marks can link neighboring regions, even if they are not directly next to one another along the DNA strand. Without this 3D structure, enzyme activity changes, hindering the preservation of epigenetic memory and potentially affecting cell differentiation. n REFERENCES: Jeremy A. Owen et al., Design principles of 3D epigenetic memory systems. Science (2023) 382, eadg3053. doi:10.1126/science.adg3053 Top figure courtesy of Leonid Mirny, PhD, Massachusetts Institute of Technology https://news.mit.edu/2023/how-cell-identity-preserved-when-cells-divide-1116
More details can be found in the Everyday DNA blog post: Pangenomes, The More the Merrier.
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Don't judge a protein by its length The Human Genome Project yielded a blueprint for the human genome. Even after the DNA code was cracked, understand- ing what it meant was the next challenge. Scientists first set out to identify protein-coding genes. They started with some basic rules for defining protein-coding genes, which included a specific starting signal, a long sequence of code, and a final stop sign. Researchers verified that the sequence between the two signs encoded a protein. The protein-coding segments between the start and stop signs are called an open reading frame (ORF ), and scientists initially thought only ORFs longer than 100 bases would make proteins. Herein lies the microprotein conundrum. Microproteins are short proteins made from short ORFs. Scientists originally thought only long ORFs encoded proteins, but this missed many microproteins. Scientists needed new molecular tools to figure out which ORF regions were being made into proteins. Several of the molecular techniques developed were instrumental in identifying microproteins that were only first discovered in the 1990s. These advancements led to the finding of nearly 7,000 microproteins in humans alone. As with the Human Genome Project, the work in this field has now shifted to determining the function of this class of proteins. Understanding how these
microproteins work could lead to the development of new drugs or even modifications of the proteins themselves, potentially offering significant benefits for treating diseases. Scientists have already discovered some amazing things these microproteins can do. For example, one microprotein helps bacteria hide from antibiotics, while another is involved with how bacteria communicate with each other. Others might control how cells use energy. n
REFERENCE: Arnaud, C., Exploring the world of microproteins. Chemical and Engineering News (2023) 101 (19) and figure NHGRI. https://cen.acs.org/ biological-chemistry/proteomics/Exploring-world-microproteins/101/i19
Mystery prints Human fingerprints are unique and complex ridges of arches, loops, and whorls that are consistent throughout life and can be used to identify individuals. There have been several theories that fingerprints may develop from skin wrinkles or that the ridges follow the blood vessels. Until now, the mechanism that creates fingerprints was a mystery. The arches, loops, and whorls that form on the fingertips start defining in the womb because of signaling between three molecules. WNT tells cells to form the ridges and produces the second molecule, EDAR, which helps create more cells. The third molecule, BMP, prevents EDAR from making more ridges. This complex set of interacting signals forms a Turing pattern system that propagates outwards. As ridges develop, they form sets of waves that start to spread from three initiation sites: the center of the fingertip, under the nail, and the crease near the knuckle. With slight variations in timing, as they make their way to the middle of the fingertip, these interactions form the unique fingerprint pattern. Researchers used mice to examine how these molecules interact. Mice don’t have fingerprints, but the striped ridges
The Unknome Despite much progress, we still don’t know everything about the human genome. A new database aims to catalog human genes and proteins we know little about. The Unknome – the words unknown and genome – has nearly 2 million proteins
and assigns them a “knownness” score based on how much we understand about the genes. The proteins are grouped into families with over 3,000 groups; 805 contain a human protein with a score of zero. Cell biologists used the database to study the genes shared between fruit flies and humans with very low knownness scores. Of the 260 genes with low scores, when compared to fruit flies, 60 homologs of the unknown genes were essential for life, and others were important for growth, development, movement, and resilience against stress. How they function in humans is a mystery despite their importance in fruit flies. As for cell biologists, the next step is to use the database to partner with others for a large-scale study of these unknown proteins. With the many mysterious genes and proteins out there, this new database can help researchers prioritize and learn more about these unknowns. The hope is that the Unknome database will shrink over time. n REFERENCE: Rocha, J. J., et al. Functional unknomics: Systemative screening of conserved genes of unknown function. PLoS Biol (2023) 21(8): e3002222. doi.org/10.1371/journal.pbio.3002222
on the skin of their toes are comparable to human prints. Increasing EDAR led to thick and spaced-out ridges, and decreasing EDAR led to spots. Mouse prints are too tiny to see the shapes found on human fingerprints, so researchers used computer models to sim- ulate the effects seen in the mouse model and could reproduce and create a human fingerprint. n
REFERENCE: Glover, James D. et al. The developmental basis of fingerprint pattern formation and variation (2023) Cell , Volume 186, Issue 5, 940 - 956.e20. doi.org/10.1016/j.cell.2023.01.015
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SCIENCE FOR LIFE
NEW FINDINGS — AGRICULTURE
Plant Gene Atlas The first plant reference genome, Arabidopsis thaliana , was released in 2000. Since then, thousands of increasingly more complex plant reference genomes have been produced for model plant species and agriculturally important plants. These genomes help scientists unravel the relationship between gene function and environment. By figuring out how different genes react to dif- ferent situations, scientists can help plants grow better. However, locating results from the few published functional studies is often difficult, limiting the collaborative reach of the studies. The Joint Genome Institute compiled all of the known functional studies for plant genes, including large-scale tran- scriptomics projects, and combined that with additional genomic data to create a database of plant gene function. The Plant Gene Atlas, released in 2023, includes expression-derived annotations for more than 60,000 plant genes with previously undescribed functions. Key findings include regulation of important classes of genes across model plants’ developmental stages and gene expression changes based on varying nitrogen sources. This lays the groundwork for new potential targets for genome editing or directed breeding. Producing the Atlas led to the development of bioinformatics tools for standardizing data so that experimental results using different methods can be compared to more accurately predict homologous gene function in other plant species. By developing a baseline of evolutionarily conserved gene regions in plants and pat- terns of tissue-specific gene expression, this new database could dramatically increase the pace of plant gene function discovery. n REFERENCES: Sreedasyam, A., et al. JGI Plant Gene Atlas: an updateable tran- scriptome resource to improve functional gene descriptions across the plant kingdom, Nucleic Acids Research (2023) 51(16) 8383-8401 doi.org/10.1093/nar/gkad616 Sun, Y. et al.Twenty years of plant genome sequencing: achievements and challenges. Trends in Plant Science (2022) 27(4): 391-401 doi.org/10.1016/j.tplants.2021.10.006
Spilling the tea on tea genes Tea is a traditional drink consumed on every continent. Produced from young leaves of the Camellia sinensis plant, tea’s popularity is attributed to its flavor, aroma, and potential health benefits. Developing new cultivars of Camellia using conventional breed- ing is challenging because it is a perennial plant that does not self-fertilize. Tea-related research has increased dramatically since genome reference sequences for tea plants were released in 2018, 2019, and 2020. 2023 saw an explosion of discoveries largely due to major updates to the Tea Plant Information Archive, a database for Camellia genomics. Sequencing of 350 tea plant varieties iden- tified more than 15 million genetic variants, single nucleotide polymorphisms (SNPs), as well as small insertions and deletions. High-quality genome sequencing of many tea plants reveals pop- ulation structures and points to genes that play a role in helping Through a series of experiments, the team determined that the sex of Sphagnum is linked to its growth in peat bogs and how it contends with its acidic environment. Female Sphagnum mosses produce thicker, larger leaves, enabling greater carbon storage. In males, interactions between sex chromosomes and genetic variation on non-sex chromo- somes allowed some males to grow better under stressful pH environments. These newly discovered interactions between sex chromosomes, autosomes, and environmental factors open up new avenues of research in this valuable carbon sequestration tool. n REFERENCE: Healey, A.L., et al. Newly identified sex chromosomes in the Sphagnum (peat moss) genome alter carbon sequestration and ecosystem dynamics. Nat. Plants (2023) 9, 238–254. doi.org/10.1038/s41477-022-01333-5 The HudsonAlpha Genome Sequencing Center and the laboratory of HudsonAlpha faculty researcher Alex Harkess, PhD, contributed to this work. Peat moss sex chromosomes impact carbon sequestration Peat bogs are marshy, wetland areas covering about three percent of the earth’s land mass. They store twice as much carbon as all the trees on the planet, aptly earning them the moniker ‘carbon sink.’ Harvesting peat from bogs releases underground carbon stores into the atmosphere as carbon dioxide and methane. Five percent of our annual greenhouse gas emissions are estimated to come from the millions of acres of harvested peatland. Sphagnum mosses are an important part of the peat bog ecosystem, keeping the bogs moist and at the appropriate pH. Understanding Sphagnum’s response to our warming climate is critical for protecting peat bogs. A group of sci- entists produced high-quality reference genomes for two Sphagnum species. The genomes reveal the first Sphagnum moss sex chromosomes to be identified. These are the smallest sex chromosomes observed in nature.
The HudsonAlpha Genome Sequencing Center, led by faculty researchers Jane Grimwood, PhD and Jeremy Schmutz, contributed to this work.
plants thrive in specific regions. Scientists discovered several genes that control specific traits, including leaf structure, disease resistance, and drought tolerance genes. Extensive efforts have been made to charac- terize and preserve genetic diversity in tea plant
seed stock. Genome-wide association studies also revealed mark- ers associated with tiny molecules that play a role in the unique flavors, colors, and aromas of several tea varieties. Population genomics research is unraveling the evolutionary history of Camellia and shining light on the domestication of the tea plant. n REFERENCES: Li H, et al. Application of Multi-Perspectives in Tea Breeding and the Main Directions. Int J Mol Sci. (2023) 24(16):12643. doi: 10.3390/ijms241612643 Li, JW, et al. Molecular markers in tea plant (Camellia sinensis): Applications to evo- lution, genetic identification, and molecular breeding. Plant Physiol Biochem (2023) 198:107704. doi: 10.1016/j.plaphy.2023.107704
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Shorter stature, stronger future– windproof corn takes root
mutation that reduces the amount of the growth hormone auxin in the stalks. In other studies, researchers focused on gibberellin, anoth- er plant growth hormone. Knocking out the gene in the whole plant results in deformed flowers and ears. Using microRNA to suppress two genes that produce gibberellin, mainly in the
Decades ago, wheat and rice production was dramatically increased by forcing the plants to grow shorter. Short plants spend less energy growing stalks and can be planted more densely. Both mean more grain production per hectare planted. Corn, however, is still a tall crop, growing as tall as 4 meters. For years, breeders selected for stiffer stalks to resist rot and larger leaves, which produce oversized, more starchy ears of corn. Along with those traits came increased height. Tall plants are vulnerable to breaking in high winds. A single 2020 wind storm in the U.S. Corn Belt cost an estimated 12 billion dollars in losses to corn growers. Field trials indicate shorter plants can withstand high winds without sacrificing corn production. Shorter plants have agro- nomic benefits such as less need for anti-fungal treatments, and they thrive with later and fewer fertilizer applications. Two major seed producers, Bayer ® and Corteva ® , are working to produce short-stature corn. Using genetic analysis of seedings, breeders are speeding the rate of traditional cross-breeding. Bred spe- cifically for growers in Mexico, researchers select plants with a
leaves and stalks, produces short plants, but leaf loss reduces crop yields. To avoid this, researchers added a genetic switch from a rice virus to make the inserted genes only active in the stalk. Genetically engineered short corn is currently in field trials in the U.S. and being reviewed by the USDA. Research fo- cusing on gene editing to alter the gibber- ellin pathway is also underway. Since gene editing does not add genes, corn produced this way may face fewer regulatory hur- dles. Long an aspirational goal, short corn seems closer to wide-scale production. n
REFERENCE: Kosola, K.R., et al. Short-stature and tall maize hybrids have a similar yield response to split-rate vs. pre-plant N applications, but differ in biomass and nitrogen partitioning. Field Crops Research (2023) 295: 108880. doi.org/10.1016/j.fcr.2023.108880
Carbon capture with genetically modified trees A biotech company, Living Carbon ® , produced genetically modified poplar trees to cap- ture atmospheric carbon. The modified trees grow faster and produce more biomass in green- house experiments. They have three genes inserted, including
one from pumpkin and one from green algae. Their increased growth is due to increasing the efficiency of photosynthesis and reducing photorespiration. During photosynthesis, plants produce sugars but also a toxic byproduct, phosphoglycerate, that must be broken down, wasting energy from photosynthe- sis. Under increased temperature, more phosphoglycerate forms, reducing unmodified trees' efficiency as carbon capture tools. The genetically engineered poplars include a bypass pathway that blocks the movement of carbon dioxide out of chloroplasts, storing it for future use. Planted on private land, the modified poplars grow 53% larger and capture 23% more carbon dioxide than their unmodified counterparts. The roots absorb metals from soils, meaning they can thrive in contaminated soils and will decay more slowly. The company hopes to plant up to 5 million trees by 2025, which could remove up to 600 megatons of carbon from the atmosphere. That amount is equivalent to removing 133 million gas-powered cars. As promising as these results are, the genetically-
modified trees still face challenges. The company avoided many regulations surrounding vector-based genetic engi- neering by using an older technology so they won't produce pollen. Other genetically modified trees, such as apple or American chestnut, have spent years in regulatory review, while Living Carbon has moved from greenhouse to field trials in less than three years. This speed alarmed some forest conservation groups. To address these con- cerns, the company is planting only female trees. n
REFERENCE: Tao, Y. et al. Enhanced Photosynthetic Efficiency for Increased Carbon Assimilation and Woody Biomass Production in Engineered Hybrid Poplar. Forests (2023) 14, 827. doi.org/10.3390/f14040827
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SCIENCE FOR LIFE
NEW FINDINGS — BACTERIA AND VIRUSES Unraveling maternal microbiota It has long been understood that what pregnant women eat and drink affects their developing child. Now, researchers have discovered another surprising influence: the mother’s
ecule byproducts of metabolism, which are likely influenced by the maternal microbiota. The study identified previously unknown microbi- al compounds in
gut bacteria. The gut microbiome, as it's called, might interact with the developing baby in ways scientists never knew before. In the study, researchers compared two groups of mice: normal moms and moms raised in sterile conditions, having no microbiome. The researchers analyzed gene expression and metabolite concentrations in the brain, intestine, and placenta of fetal mice from each group of moms. The study revealed significant differences in gene activity. Male fetuses seemed more sensitive to maternal microbiota than females. In fetuses from germ-free mice, genes related to the immune system were less active in the intestine. At the same time, the brain exhibited variations in genes linked to nervous system development. The placenta showed altered gene expression related to pregnancy regulation. The researchers concluded that variations in the expression of numerous crucial genes were linked to the concentration of small mol-
fetuses. These compounds' absence or lower concentrations in fetuses from germ-free mouse mothers pointed to their likely role in shaping intestinal, brain, and placental develop- ment. Researchers are now investigating these compounds' in other mammals like piglets and calves. This study may help us understand and prevent diseases like allergies and bowel problems caused by imbalances in gut bacteria in early life. This could lead to new ways to prevent and treat these diseases in the future. n REFERENCE: Husso, A., et al. Impacts of maternal microbiota and microbial metabolites on fetal intestine, brain, and placenta. BMC Biology (2023) 21 (1) pubmed.ncbi.nlm.nih.gov/37794486
Longevity association with gut microbiome For ages, humans have been searching for ways to live longer. Research sug- gests our gut bacteria might play a part. A recent study revealed an association between gut microbiome populations and people over 100, also known as cen- tenarians. The study included a cohort of 1,575 individuals divided into smaller study groups based on age. Researchers
Genome-edited mice get human-like COVID-19 Mice are crucial for studying diseases, but until recently, scientists struggled to create mice that model COVID-19. Previous attempts failed because the mice died immediately upon infection. Researchers
had success by inserting a human gene encoding ACE2 receptor protein into mouse embryonic stem cells. ACE2 receptor acts as a doorway for the SARS-CoV-2 virus to enter cells. The modified mice show similar symptoms and activate the same immune cells as humans. The mouse models open up new potential for COVID-19 treatment and prevention research. Not only will the altered mice speed the rate of COVID-19 drug development, but the humanized ACE2 mice can be crossed with other mice to investigate how COVID-19 infection affects people of advanced age or with diabetes or obesity. Scientists used a new technology called genome writing to add large chunks of DNA, like inserting a whole paragraph instead of a single letter. To insert large sections, in this case, more than 2 million nucleotides, researchers used a new delivery method, mSwAP-IN (mammalian Switching Antibiotic markers Progres- sively for Integration). A marker segment of DNA is inserted near the start of the gene. Then, a second marker with a large section of DNA is inserted near the end of the gene. CRISPR then cut out the old gene and swapped it with the new one, guided by the markers. The method allowed scientists to replace a large portion of the mouse gene with the human version, creating mice that act much more like humans with COVID-19. n REFERENCE: Weimin Zhang, et al. Mouse genome rewriting and tailoring of three important disease loci . Nature (2023) 623, 423–431 doi: 10.1038/s41586-023-06675-4
were particularly interested in the gut microbiome of the 297 centenarians. The microbiome makeup of the four non- centenarian groups was compared with the centenarians, revealing some interesting findings. The gut bacteria of people over 100 looked more like the bacteria of young adults than those of older adults (66-99 years old). While the young adults and centenarians had diverse and healthy bacteria, the older adults had more harmful bacteria and less variety. The centenarian group showed an enhanced presence of beneficial Bacteroides bacteria compared to the older cohort. The study also tracked a subset of 45 centenarians for 1.5 years, documenting microbiome patterns. Individuals with less spe- cies diversity were more likely to experience rapid microbiome changes during aging. This instability is a contributing factor to age-related negative health outcomes. Understanding how microbiomes change over a lifespan is increasingly important as people live longer. n REFERENCE: Pang, S., Chen, X., Lu, Z. et al. Longevity of centenarians is reflected by the gut microbiome with youth-associated signatures. Nat Aging (2023) 3, 436–449. doi.org/10.1038/s43587-023-00389-y
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COVID changes the DNA landscape Healthy cells have an organized system for storing their DNA instructions. DNA is wrapped tightly around his- tone proteins to form chromatin, which is packaged into compartments based on transcriptional activity. The A compartment contains actively transcribed genes, and the B compartment includes silenced genes. Each compart- ment has progressive folding and looping, with many loops in the A compartment held in place by cohesion proteins.
Cohesion proteins lock DNA into loops called topologically active domains (TADs). Within TADs, transcription machinery churns out RNA for heavily expressed genes. (see pages 16-17 about Gene Expression) Researchers found that cul- tured human lung cells infected with SARS-CoV-2 had disrupt- ed DNA organization. Some domains had wholly lost shape,
Vampire virus attaches to the neck of a bacteriophage to highjack its ability to infect cells.
and cohesion proteins were often missing, reducing tran- scription in those regions. More importantly, the impacted areas hold genes activated in immune system responses to viruses, including interferon production. A healthy immune response to viral infection involves producing a flood of interferons. Yet COVID-infected patients only make a dribble. The infection’s reshaping of the chromatin architecture could account for this difference. It seems COVID messes with the chemical tags on DNA, making it harder for the cell to "read" and follow the instructions. The loss of an acetyl group on a key histone connected to activating transcription leads to the DNA wrapping tighter around the histone, making it harder for RNA polymerase to bind there. The virus also disguises itself as part of the system, further confusing the cell's machinery. These changes persist even after the infection clears, potentially contributing to the lingering symptoms some patients experience in Long COVID. n REFERENCE: Wang, R., Lee, JH., Kim, J. et al. SARS-CoV-2 restructures host chromatin architecture. Nat Microbiology (2023), 8: 679–694. doi.org/10.1038/s41564-023-01344-8
Vampire virus Scientists recently discovered an interesting new virus in a soil sample from Maryland. Soil typically contains millions of bacte- riophages per gram. These viruses infect bacterial cells and are a significant component of a healthy soil microbiome. Under- graduate students investigating this soil sample repeatedly got unusual DNA sequencing results. What should have been pure cultures of a particular bacteriophage yielded DNA results with sequences from another viral family. Was this contamination? Electron microscopy revealed the answer. Images show a set of phages with an even smaller virus attached to their necks. This tiny virus, found linked to another
virus, may exhibit charac- teristics associated with parasitic behavior. Research- ers hypothesize that the tiny
vampire viruses have lost the ability to make copies of themselves inside cells, which is how viruses repro- duce. Attaching to the larger phage gives the virus the opportunity for ‘simultaneous entry’ as the host phage infects a cell.
Representative virus images
Since characterizing the tiny virus, researchers found other examples in older samples of bacteriophages with molecular ‘bite marks’ on their necks, indicating previous infection by the mini-virus. Researchers continue to investigate this new system at the molecular and ecological level. These discoveries collec- tively enhance our understanding of microbial diversity and their roles in various environments. n REFERENCE: deCarvalho, T., Mascolo, E., Caruso, S.M. et al. Simultaneous entry as an adaptation to virulence in a novel satellite-helper system infecting Streptomyces species. ISMEJ (2023) 17: 2381–2388. doi.org/10.1038/s41396-023-01548-0
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SCIENCE FOR LIFE
NEW FINDINGS — CANCER
Engineered bacteria as a biosensor Intestinal bacteria frequently exchange fragments of DNA – a process called horizontal gene transfer. Scientists have taken advantage of this naturally occurring activity to develop a bacterial
biosensor for colon cancer. The bacteria identify specific DNA fragments shed into the gut by colon tumors. Scientists engineered the genome of Acinetobacter baylyi bacteria, adding a gene that creates resistance to the antibiotic kanamycin, together with a genetic “switch” that silences the gene. If the bacteria encounter and integrate human DNA fragments containing KRAS gene mutations (common in colon cancer), the resistance gene switches on and the bacteria can grow in the presence of the antibiotic. Scientists administered the engineered bacteria via enema to mouse models with and without KRAS- associated colon tumors. Bacteria was extracted from fecal samples of the mice and exposed to kanamycin. Only A. baylyi recovered from the gut of mice with tumors could grow in the presence of the antibiotic, meaning the biosensor was working. Colorectal cancer is one of the most common forms of cancer, with a lifetime incidence of 1 in 23 men and 1 in 25 women. While exciting, significant additional research and testing is needed before this biosensor technology can be con- sidered for humans. This includes working with bacteria better suited to live in the human gut, delivering the bacteria by mouth and ensuring the system is both effective and safe. n
Overcoming chemoresistance Treating cancer becomes more challenging when cancer cells become resistant to treatment, a phenomenon called chemoresistance. This poses a significant hur- dle, especially if only a few treatments exist for a type of cancer. Pancreatic ductal adenocarcinoma (PDAC) is especially challenging to treat because it lacks early diagnostic markers and is diagnosed at later stages. Chemoresistance is common among PDAC patients, exacerbating the difficulty of treatment. These factors make PDAC one of the most lethal forms of cancer, with an 11% survival rate five years post-diagnosis. New research identified genes associated with PDAC patient survival. High expression of the ANGPTL4 gene leads to poor survival, while low expression of this gene is associated with a better response to standard pancre- atic cancer treatment. Additional studies explored how ANGPTL4 gene ex- pression impacts cancer cell response to treatment and the development of chemoresistance. ANGPTL4 overex- pression allows cancer cells to escape the effects of can- cer drugs and ignore cell death signals. Overexpression of ANGPTL4 also enhances cell migration, increasing the likelihood of metastasis. ANGPTL4 is part of a metabolic pathway regulating the expression of genes downstream. Using CRISPR to suppress downstream factors, researchers reversed chemoresistance and reduced cell migration. These techniques made resistant cancer cells more responsive to standard PDAC drugs and reduced cell migration, limiting metastasis. This research was in vitro , but targeting ANGPTL4 or its downstream partners with a drug could be a promising strategy to counter chemoresistance in PDAC. n REFERENCE: Gordon, E.R., Wright, C.A., James, M. et al. Transcriptomic and functional analysis of ANGPTL4 overexpression in pancreatic cancer nominates targets that reverse chemoresistance. BMC Cancer 2023, 23: 524. doi.org/10.1186/s12885-023-11010-1 More details can be heard at the Tiny Expedition podcast at this link https://www.hudsonalpha.org/when-cells-kill-understanding-cancer/
REFERENCE: Cooper RM et al. Engineered bacteria detect tumor DNA. Science . 2023;381(6658):682-686. https://www.science.org/doi/10.1126/science.adf3974
Differences in colon cancer risk Men diagnosed with colorectal cancer (CRC) have poorer prognosis and increased metastasis compared to women. This is particularly true with sporadic CRC, cancer not caused by rare inherited genetic variants. The underlying molecular and biological mechanisms for this phenomenon are unknown. New research may explain these gender differences in CRC outcomes. Researchers developed a mouse model with genetic modifica- tions mirroring characteristic changes seen in CRC. In one model, mice had gene changes in the KRAS oncogene, which normally functions to prevent cells from turning cancerous. This model shows that mutant KRAS regulates a Y-chromosome gene, KDM5D , which promotes metastasis and tumor immune evasion. When this Y-chromosome gene was eliminated in the mouse model, can- cers were less invasive and did not metastasize. Researchers have generally overlooked the Y chromosome as a potential contributor to cancer hallmarks and clinical outcomes because it houses few protein-coding genes beyond sex determination. A gene on the X-chromosome exhibits structural and func- tional similarity to KDM5D . However, research shows that this X-chromosome gene is regulated differently and doesn’t play a role in the invasiveness or metastasis of CRC. Collectively, these findings establish a foundation for crafting precision medicine strategies for treating men facing metastatic CRC. n REFERENCE: Li J, et al. Histone demethylase KDM5D upregulation drives sex differences in colon cancer. Nature . (2023) 619(7970):632-639. doi: 10.1038/s41586-023-06254-7
The laboratory of HudsonAlpha faculty researcher Sara Cooper, PhD, contributed to this work.
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NEW FINDINGS — NEUROLOGY
Neurodevelopmental gene discovered
Age of onset and Alzheimer’s disease
New hope in the search for Alzheimer's disease treatment Since Alzheimer’s disease was first formally defined in 1901, there have been virtually no effective treatments. Most existing drugs may temporarily improve symptoms, but none target the underlying mechanism of the disease. One hallmark of Alzhei- mer's is the abnormal build-up of protein fragments within and between neurons, which causes irreversible damage. Studies show that lower levels of two proteins, beta-amyloid and tau, may slow disease progression. Newer therapies focus on remov- ing these proteins by various mechanisms, including antibodies. Antibodies are a natural part of our immune systems and bind to harmful proteins to destroy them. In January 2023, researchers and physicians presented findings from an 18-month phase 3 trial of the beta-amyloid REFERENCE: Hiatt, S.M., et al. Deleterious, protein-altering variants in the transcriptional coregulator ZMYM3 in 27 individuals with a neurodevelopmental delay phenotype. The American Journal of Human Genetics (2023) 110:(2), 215 - 227. doi: 10.1038/s41586-023-06254-7 The laboratory of HudsonAlpha faculty researcher Greg Cooper, PhD contributed to this work. More details can be heard at the Tiny Expedition podcast at this link https://www.hudsonalpha.org/an-exploration-of- neurodegenerative-diseases/ Approximately 1-3% of children are affected with neurodevelop- mental disorders (NDDs), including developmental delays and intellectual disability. A majority of these conditions are thought to be genetic in origin. Over the past decade, advances in genetic and genomic testing have led to increased rates of diagnosis for children with NDDs, but over 50% of affected children and their families still do not have an answer. A recent project, hinging on data-sharing between 48 different research groups and clinical institutions, described a new NDD caused by genetic changes in the ZMYM3 gene. This work started with a submission to the online GeneMatcher ® database in 2018. Over the next four years, the team collected information on 27 individuals with NDDs who had potentially disease-causing variations in the ZMYM3 gene. What emerged was a consistent set of symptoms that defined a new X-linked neurodevelopmental disorder. Males with disease-causing variants in ZMYM3 were found to have developmental delays and/or intellectual disabilities, autism or autistic features, and atypical facial features. A small- er number also had genitourinary anomalies, short stature, and small head size. A smaller number of affected females were also described with developmental delays and atypical facial features. All variants identified were rare and predicted by protein modeling to be deleterious. Electronic databases, like GeneMatcher, are accelerating genetic discovery, providing an avenue for collaboration and information sharing between scientists across the globe. n
About one in every ten people over the age of 65 is diag- nosed with Alzheimer’s disease (AD). For one large family in Antioquia, Colombia, in South America, the number is far higher; thousands of individuals are affected with rare autosomal dominant early-onset AD. They carry the same variant in the PSEN1 gene. This genetic change, called E280A, dates to the time of the conquistadors and was likely introduced by a single European individual. Family members who inherit the variant have a nearly 100% chance of developing dementia, with an average age of onset of 49 years old. A new study sought to identify other genetic factors in these individuals that could contribute to differences in the age of onset of AD within this large family. The team used DNA samples from 340 affected people whose age of onset was documented in their medical records. Genetic data from this group was compared to other groups with autosomal dominant AD and groups with more typical AD. Scientists identified 13 genetic variants that appear to contribute to differences in age of onset, even among indi- viduals with the same E280A variant. The identified variants are in or near genes associated with how the brain pro- cesses proteins involved in Alzheimer’s disease symptoms, like tau and amyloid-beta. In Alzheimer’s, abnormal levels of these proteins build up, causing damaging plaques and tangles that are hallmarks of the disease. This study identified new genetic factors associated with differences in age-of-onset of dementia. These factors provide a starting point for additional studies on the genetic mechanisms of AD and potential avenues for treatment. n REFERENCE: J. Nicholas Cochran, et.al., Genetic associations with age at dementia onset in the PSEN1 E280A Colombian kindred. Alzheimer's and Dementia (2023) 19(9): 3835-3847. doi.org/10.1002/alz.13021
The laboratory of HudsonAlpha faculty researcher Nick Cochran, PhD, contributed to this work.
antibody Lecanemab in individuals in the early stages of Alzheimer’s disease. The antibody can bind to beta-amyloid before and after it forms plaques and helps remove it from the body. Data showed that the drug significantly reduced levels of beta-amyloid in the brains of those on treatment compared to placebo. There was a moderate but measurable effect on the decline of cognition and function. However, some of the treated individuals had adverse side effects. In July 2023, the FDA approved Lecanumab based on the results of this trial, making it the first new AD drug to be granted traditional approval in over 20 years. This research and approval pave the way for similar treatments for AD, which may change the course of disease for millions of people. n
REFERENCE: van Dyck, C.H., et al., Lecanemab in early Alzheimer’s disease. N Engl J Med (2023) 388:9-21. doi: 10.1056/NEJMoa2212948
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SCIENCE FOR LIFE
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