The future of research and innovation at HudsonAlpha
Looking toward the next 15 years
On April 25, 2008, HudsonAlpha Institute for Biotechnology opened the doors to its flagship building on its Huntsville, Alabama campus. For 15 years, the non-profit genetics and genomics research institute maintained a steadfast commitment to pushing the limits of genomic science and translating new insights into real-world solutions. HudsonAlpha exemplifies what can be achieved when innovative minds and state-of-the-art technology push the frontiers of our knowledge about the world.
HudsonAlpha’s researchers do not plan to slow down anytime soon, pledging to advance technology, collaboration, and big science over the next 15 years and beyond. The HudsonAlpha mission remains to use the power of genomics to improve life–whether that be the diagnosis, treatment, and prevention of human disease or improvements to plants that provide us with nutritious food, sustainable fuel, and fiber sources, and a healthy environment.
“Progress in science depends on new techniques, new discoveries, and new ideas, probably in that order.”
At the forefront of Genome sequencing
The field of genomics hinges on the ability to look at the very basis of life itself: DNA. Advances in DNA sequencing technology have enabled a surge in genomic discoveries over the past few decades. Each new generation of sequencers offers faster, cheaper, and more accurate data acquisition.
Scientists at HudsonAlpha are some of the best in the world at sequencing, analyzing, and interpreting organismal genomes, having sequenced more than 200 novel plant reference genomes and tens of thousands of human genomes. They’ve remained at the forefront of innovation, developing and applying technologies to create the most accurate, high-quality genomes. Focusing on the next fifteen years and beyond, HudsonAlpha will continue accelerating its progress, finding faster, cheaper, more accurate, and more sensitive ways to interrogate the genomes of our living world.
HudsonAlpha’s research labs are committed to staying at the forefront of sequencing technology. In early 2023, the HudsonAlpha Genome Sequencing Center (GSC) was one of the first research institutes to acquire a new PacBio Revio sequencing machine. The Revio is a long-read sequencer, using a technology called “HiFi,” that produces about 15 times more data and uses fewer consumables and packaging than its predecessor, the PacBio Sequel IIe. It is the fastest, cheapest, and most accurate long-read sequencing platform to date.
Scientists across the Institute and the world are lining up to take advantage of this new technology to answer some of our world's most pressing questions. For the HudsonAlpha GSC, long-read sequencing technology helps produce genomic data across economically valuable crops and environmentally relevant species to improve crop breeding and investigate the plants’ roles in natural ecosystems.
One project benefitting from long-read sequencing is a collaboration between the GSC and scientists at North Dakota State University (NDSU) and the University of Minnesota. The project aims to improve three essential food crops, beans, barley, and peas. The GSC team uses the Revio to expand the number of common bean, barley, and pea genomes to support breeding and crop improvement efforts at NDSU. Because of technological advances and their computational prowess, the GSC can now routinely produce “pan-genomes,” which are multiple genomes of the same species. Pan-genomes are important for crop breeding programs because they offer a more comprehensive understanding of genetic diversity within plant species, allowing scientists and breeders a more robust picture of potentially beneficial genomic variation.
Although the GSC has already sequenced multiple bean genomes, including the first published bean genome, the Revio provides a lower-cost way to quickly produce reference genomes for more varieties of beans. For barley, which has a large genome at 5.1 billion base pairs, the GSC demonstrated the efficiency of HiFi sequencing that is now used for all their plant genomes. The higher throughput of the Revio will allow them to sequence six barley genomes in a week, greatly expanding their ability to produce barley pan-genomes. The pea genome is complex and repetitive, sized at 4.3 billion base pairs. Long-read sequencing will help create a pea pan-genome that covers major diversity across domesticated pea strains and provide a solid genome resource backbone for these crop improvement programs. The GSC is engaged in similar efforts for pecans and strawberries.
Another investigator relying on long-read sequencing technology is Greg Cooper, PhD, and his lab, who develop and apply cutting-edge genetic and genomic technologies to improve the diagnosis of rare diseases, especially neurodevelopmental disorders in children. Neurodevelopmental disorders, most of which are genetic in nature, affect 2-3% of children and cause a range of physical and cognitive disabilities, including intellectual disability, autism, seizures, and growth delays. Identifying the changes in DNA that lead to these diseases can provide a precise diagnosis, guide treatment approaches, and give families the answer to their years-long medical mystery.
Cooper and his lab have sequenced the genomes of more than 1,800 individuals with a neurodevelopmental disorder, affording 30 percent of them a diagnosis using traditional genome sequencing technology. Now, the team is using long-read genome sequencing, which provides a clearer, more comprehensive view of genetic variation. Ongoing work in the lab shows that long-read genome sequencing can diagnose at least 40 percent of children with neurodevelopmental disorders, including about 10 percent who would be undiagnosed even after current, state-of-the-art genome sequencing.
Over the next several years, Cooper and his lab aim to use long-read genome sequencing to test more than 10,000 children with undiagnosed neurodevelopmental disorders. They also want to work with clinicians to implement long-read sequencing in clinical settings. Rapidly scaling up the use of long-read genome sequencing will dramatically advance the ability to find diagnostic answers for families struggling with highly challenging childhood medical conditions.
“Very few places can do long-read genomes at scale, certainly not with the capacity we can. That represents a huge leap forward for the genomics community. We are already building the data to prove that. We're making lots of Mendelian disease discoveries that wouldn't be possible without long-read sequencing technology.”
Advances in genome analysis to drive discovery
Sequencing complex genomes would be meaningless if scientists did not know how to analyze the data and draw significant conclusions from it. Beyond sequencing thousands of different organisms across the tree of life, HudsonAlpha scientists also develop innovative pipelines and computational tools to help deal with large sets of genomic data and analyze complex genomes faster and more accurately. They are experts at identifying genes and gene variants contributing to various traits and diseases in plants and animals.
Identifying genes controlling important traits in plants
Identifying genes that control important plant traits is crucial for developing new crop varieties with improved yield, quality, and resilience to environmental stress. Scientists can use genomic information to help crop breeders and farmers grow crop varieties suited to specific growing conditions, resistant to pests and diseases, or having improved qualities, like taste or nutrient content, that are more appealing to consumers. This helps farmers increase crop yields and produce more food and fiber to feed and clothe a growing global population using more environmentally friendly farming practices.
Perennial grasses for bioproducts
Members of the HudsonAlpha Center for Plant Science and Sustainable Agriculture aim to be stewards of sustainability, using genomics to create more efficient crop plants to help bring sustainable practices and products to market. Faculty Investigators Jane Grimwood, PhD, Jeremy Schmutz, and Kankshita Swaminathan, PhD, develop genomic tools to study and improve perennial grasses, like switchgrass and Miscanthus, which are promising candidates for bioenergy and bioproducts. By identifying genetic factors contributing to biomass size, nitrogen uptake, and other traits, scientists can introduce the desirable features into agronomically important lines to create productive, sustainable grasses.
They are also part of a collaborative team developing a pipeline in the Southeast to create products from locally engineered and grown perennial grasses. The Greening the Southeast project is supported by an NSF Engines Development Award. It will use underutilized marginal land, improve atmospheric carbon sequestration, reduce imports, create new jobs, and decarbonize industries.
Disease resistance in commodity crops
In many crop plants, a single fungal or bacterial infection could wipe out an entire field in mere days. This is especially detrimental to small farmers who rely on each harvest to sustain their quality of life. Faculty Investigator Josh Clevenger, PhD, and his lab use genomics alongside new computational tools and breeding methods to identify genetic contributors to pest and fungal resistance in commodity crops like peanut, cacao, and beans. Once gene variants conferring resistance are identified, they can be bred into existing elite lines and distributed to farmers. Clevenger’s team identified a gene variant that confers resistance to a disease devastating to peanut farmers. Breeding peanuts with the resistance variant will offer peace of mind to farmers worldwide.
Dr. Clevenger is also part of HudsonAlpha Wiregrass, a partnership between HudsonAlpha and the city of Dothan, Alabama. A major goal of the HudsonAlpha Wiregrass research mission is to use the power of genomics to develop more drought- and disease-resistant varieties of peanuts and other agriculturally important crops to thrive in the Wiregrass region.
Understanding genes that control flowers
Flowering plant reproduction is a fundamental process responsible for most of our plant-based diet. By understanding the genes that control flowers, scientists can increase the yields of major crop species that produce food and products like fiber and oil. At HudsonAlpha, Faculty Investigator Alex Harkess, PhD, and his lab study plant reproduction through the lens of plant diversity exploring the variation across nearly 400,000 species of flowering plants on our planet to identify mutations that control how flowers develop and function.
Industrial hemp is a promising crop as a sustainable fiber, oil, and protein source. Female plants are the most economically valuable due to their higher biomass production and exclusive ability to yield seeds rich in beneficial lipids and proteins.
Through a USDA-NIFA-funded grant, Harkess and his lab will build several high-quality hemp genomes and use them to identify and analyze the hemp sex chromosome pairs. The team aims to identify the master sex determination genes in hemp, which can be modified to increase the proportion of female plants, making it a sustainable and valuable crop for farmers and consumers.
“Throughout my career, we were limited to asking questions in one species or model system at a time. Advancements in genetic sequencing technology removed these limitations, allowing my lab to ask questions across all species. We can now use genomics to explore reproduction genes that control how flowers function to increase food production."
Identifying genes and gene regulatory networks involved in human disease
Just as genes control commercially valuable traits in plants, genetic factors also play a foundational role in human health and disease. Genes regulate all our bodies’ functions. However, changes in genes or gene expression, when and in which cells genes are activated, can lead to disease. Many diseases, such as diabetes, cancer, and Alzheimer's disease, have a complex genetic basis involving many genes and environmental factors. Identifying the genes and gene networks involved in human diseases is critical for understanding the underlying biological mechanisms of these diseases, developing new treatments, and ultimately improving patient outcomes.
Gene expression in neurodegenerative diseases
Neurodegenerative diseases often involve dysregulation in the expression of specific genes critical to brain function. By understanding how genes are turned on or off, a process called gene regulation, scientists can shed light on the underlying processes contributing to disease progression. HudsonAlpha Faculty Investigator Nick Cochran, PhD, and his lab are currently focusing on understanding how the gene that encodes tau, a protein involved in the pathology of Alzheimer’s disease and other dementias, is regulated. Tau protein accumulation in neurons in the brain occurs along with abnormal function and is a key hallmark of Alzheimer’s and related dementias. By understanding how tau expression is regulated, our scientists may be able to uncover potential therapies for tau-related diseases.
Integrated stress response in brain diseases
The integrated stress response (ISR) is an essential biological function that helps cells respond to stress, which may come from infections or toxins. When something is very wrong, it can trigger cell death. For neurons, which can’t be regenerated or replaced, an overactive stress response can mean irreversible damage or loss of neurons in the brain. HudsonAlpha Faculty Investigator Rick Myers, PhD, and his lab, in collaboration with colleagues at Altos Labs, are looking at the ISR in brain and neurological diseases. Using their expertise in identifying genetic on and off switches, the Myers lab is investigating how the ISR is regulated at the genomic level. This understanding will potentially lead to the discovery of new drugs that could mitigate levels of active ISR in the brain and which, in turn, might have broad applicability to neurological diseases, especially dementias and related late-onset diseases.
Additionally, the lab is helping develop blood-based biomarkers to measure ISR because it is believed that lowering the ISR could result in decreased cell death and healthier neuronal function. Such a biomarker would be a game-changer for developing new treatments for diseases such as Alzheimer’s, Parkinson’s, and ALS because scientists and clinicians could measure the effectiveness of new therapies based on ISR activity.
Whole genome sequencing to identify new cancer predisposition genes
Cancer occurs when one or more genes are mutated, leading to uncontrolled cell division. Scientists have already identified dozens of inherited cancer risk genes, but many more are likely to be found. HudsonAlpha Faculty Investigator Sara Cooper, PhD, and her lab are dedicated to identifying new genes or variants predisposing individuals to cancer. The lab is collaborating with cancer clinics to perform whole genome sequencing on individuals with a strong family history of cancer at a young age. Collecting data from many varied individuals increases the pool of potential genetic mutations the team might identify.
During a pilot project with Clearview Cancer Institute, the team collected DNA samples from 13 individuals. This pilot serves as a proof of concept that the team could collect, sequence, and analyze a patient’s genome. The data they generated also helps optimize and improve the team’s genome analysis and informs the design of future more extensive studies.
Cancer drug resistance mechanisms
Among the numerous challenges faced in battling complex diseases like cancer, developing resistance to chemotherapy remains a formidable foe. Sara Cooper, PhD, and her lab are focused on identifying genes and mechanisms critical to developing chemoresistance and establishing reliable methods for detecting them in clinical samples. The team uses genome-wide CRISPR screening methods to identify genes associated with chemotherapy resistance in pancreatic and ovarian cancer. The data generated from the CRISPR screen can lead to tools that predict a patient’s likelihood of developing resistance to standard treatments and help make informed treatment decisions. Some of the targets identified by the screen could also be used to identify and produce new therapeutics for cancer treatment.
Developing technology to advance genomic research
Technology revolutionizes the field of genetic and genomic research, enabling scientists to answer the most prominent scientific questions with unprecedented speed and accuracy. At HudsonAlpha, the work does not end when interesting genetic variants or genetic factors are discovered. HudsonAlpha scientists are experts at developing technology and experimental methods to further understand the biological consequences of genetic variation, whether they can be targeted for treatment or better crops, and much more.
Plant transformation
Developing new varieties of plants with desirable characteristics, such as drought tolerance or increased crop yield, was historically accomplished using plant breeding based on phenotypic traits that breeders can see or measure. This process is time-consuming, often requiring many generations to develop a plant with the desired characteristics. Plant transformation is a genetic engineering tool for introducing genes into plant genomes at a quicker rate than traditional breeding. It provides a vital tool for much research, including studying gene functions, interactions, and applications for crop improvement. Efficient genetic transformation is performed routinely for many plant species, but several economically important species are still not easily or successfully transformed.
HudsonAlpha Faculty Investigator Kankshita Swaminathan, PhD, and her lab are experts at plant transformation, having established transformation methods for historically difficult species. The team used CRISPR/Cas9 to mutate an endogenous gene in several types of perennial grass called Miscanthus. It was the first reported successful genome editing in Miscanthus. The proof of concept study opens the door for genetic improvement of both Miscanthus and switchgrass for bioenergy feedstock and material for renewable bioproducts. Dr. Swaminathan and her lab aim to increase the speed and throughput of plant modifications for complex species to enable the engineering of desirable traits.
Engineering hybrid sex chromosomes
From a commercial standpoint, the sex of individual dioecious plants holds significant importance in food production. Only female flowers bear fruits in certain crops, such as melon, squash, strawberries, and grapes. Additionally, within specific species, one sex may possess greater commercial value due to desirable traits like enhanced taste or faster growth. The ability to determine the sex of dioecious plants early in their lifecycle or to engineer a specific sex within an individual plant would give plant breeders and growers an advantage, saving them time, money, and other resources.
Alex Harkess, PhD, and his lab aim to leverage a pipeline they developed to characterize sex chromosomes and sex-determining genes across all orders of flowering plants. The project represents the most extensive genomic sampling of dioecious plant species. The vast amount of data the research group generates will serve as an invaluable resource for plant breeding. Building upon this information, Harkess's team plans to engineer artificial sex chromosomes to genetically modify hermaphroditic crops.
Accelerating plant and animal breeding using genomics
When focusing on complex plant genomes, it is hard for software to map short DNA reads to a reference genome and accurately identify molecular markers like single-nucleotide polymorphisms (SNPs) that correlate with an observed trait. HudsonAlpha Faculty Investigator Josh Clevenger, PhD, and his lab focus heavily on innovating solutions for crop communities that still struggle with cost-effectively utilizing genomics. Their computational platform, Khufu, allows researchers to perform highly accurate, low-coverage whole genome sequencing of complex genomes for a fraction of the traditional cost.
Khufu uses DNA sequence analysis to map traits to genes accurately–it is 99.9 percent accurate at calling single-nucleotide polymorphisms correlated to a given trait. It helps quickly and accurately identify selection markers and quantitative trait loci to rapidly introduce beneficial characteristics such as disease, drought, or pest resistance into cultivated agricultural crops. The Khufu team works with several international groups to support small commodity crop breeding programs, like coffee, cacao, and beans, many of which are focused on crop improvement and sustainability.
Single-cell spatial genomic technology
When looking for genetic factors impacting specific traits or diseases, looking at each individual cell within a tissue sample is often helpful. Historically, samples included all the cells in a tissue sample in one large batch, sometimes called “bulk.” For example, a blood sample comprises many different types of cells, such as red and white blood cells, which have different bodily functions. However, in a “bulk” analysis, all these cells are mixed, and if only one type of cell is involved in the trait or disease, the other cells might cover up its signal.
Single-cell technology allows for studying one cell type at a time to determine contributors to beneficial traits in crops or diseases in humans. Scientists in the Myers lab at HudsonAlpha used single-cell technology to identify potential genetic factors that were not previously linked to Alzheimer’s disease. Further studies could lead to more efficient treatments.
Using genomic technology to answer basic biological questions
HudsonAlpha Faculty Investigator Greg Barsh, MD, PhD, is a medical geneticist who studies the genes and mechanisms that underlie color patterns in domestic and wild mammals. Different signaling pathways act across different tissues during development to create the specific patterns we’re all familiar with, like zebra and tiger stripes or cheetah and Bengal spots. Barsh and his lab discovered and further investigated the first gene (Transmembrane aminopeptidase Q (Taqpep)) responsible for creating the distinctive patterns of a cat’s coat. Results from experimental animal models point to an important role for Taqpep in human biology and disease.
By combining forward genetics for gene discovery in non-model mammals like cats with experimental genetics in mice and cultured cell lines, Barsh and his team aim to further explore Taqpep mutations and their role in mammalian patterning. They are also characterizing Taqpep’s relationship with another biological pathway called Wnt/Dkk. A deeper understanding of these pathways will provide new insights into how cells and tissues develop into organized structures in all mammals and provide the foundation for tissue engineering and regenerative medicine.
With a steadfast commitment to innovation, collaboration, and pushing the boundaries of scientific knowledge, HudsonAlpha's scientists are poised to continue their relentless pursuit of improving lives through the power of genomics. As we look ahead to the next 15 years and beyond, we can only imagine the profound impact that HudsonAlpha will have on human health, agriculture, and the world we inhabit. Relying on the synergy between research, education, and economic development, HudsonAlpha is primed to shape the future of genetics research and pave the way for a brighter, healthier tomorrow.
Image credit: Adobe Stock, Unsplash, HudsonAlpha Archives, Jill Amey, Cathleen Shaw
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