Over the past 15 years, our research faculty have secured more than $300 million in federal grants. They’ve authored more than 1,000 peer-reviewed publications, leading to several being named to the most highly cited researcher list. The HudsonAlpha Genome Sequencing Center has helped sequence more than half of all high-quality plant genomes in the public record. Our human health researchers provided genetic diagnoses to over 500 children with rare diseases and discovered dozens of disease-risk genes in cancer, neurodegenerative, neurodevelopmental, and autoimmune diseases. HudsonAlpha continues moving genetics and genomics into the future to help improve the human condition. Sharing scientific discoveries is an integral part of being a research scientist. We hope you enjoy this brief look into the amazing science achieved at HudsonAlpha over the last few years.
RESEARCH REPORT 2021 –2022
SCIENCE FOR LIFE
RESEARCH REPORT 2021 –2022
contentS
From the desk of Rick Myers .............................................................5 DISCOVERIES IN GENOMICS Greg Barsh Science Highlight.............................................................8–9 Thomas May Science Highlight........................................................10–11 Diversity in Genomics......................................................................12–13 New Scientific Tools........................................................................14–17 Rick Myers Science Highlight..........................................................18–21 Nick Cochran Science Highlight......................................................22–25 Unraveling the high incidence of dementia in Latin America........26–27 Sara Cooper Science Highlight.......................................................28–31 Greg Cooper Science Highlight........................................................32–35 Long read sequencing......................................................................36–37 Jane Grimwood, Jeremy Schmutz & THE HGSC Science Highlight......38–41 Alex Harkess Science Highlight......................................................42–43 Kankshita Swaminathan Science Highlight....................................44–45 Josh Clevenger Science Highlight...................................................46–47 Expanding Opportunities for Agricultural Research....................48–51 Expanding Barley’s Reach...............................................................52–55 HudsonAlpha Wiregrass..................................................................56–57
trainee highlights
biotrain...........................................................................................60–61 HBCU GOMA Co-op program...............................................................62–63 GRAD STUDENTS.................................................................................64–65 Faculty highlights . ..........................................................................68–73 adjunct Faculty & scientific Advisory board .................74–75 references & funding . ....................................................................78–79
INNOVATION
Neil Lamb, PhD and Rick Myers, PhD
4
FROM THE DESK OF
CHIEF SCIENTIFIC OFFICER RICK MYERS O n April 25, 2008, the HudsonAlpha Institute for Biotechnology officially opened its doors. 2022 saw significant campus growth, with the opening of a state-of-the-art greenhouse that will allow our agricultural and plant genomics team to more efficiently care for and manipulate growing conditions for the plants they study. Construction is also underway for the global headquarters of HudsonAlpha associate company, Discovery Life Sciences. HudsonAlpha has added more than $3.2 billion to the Alabama economy and is home to more companies than ever. Over the past 15 years, our research faculty have secured more than $300 million in federal grants. They’ve authored more than 1,000 peer-reviewed publications, leading to several being named to the most highly cited researcher list. The HudsonAlpha Genome Sequencing Center has helped sequence more than half of all high-quality plant genomes in the public record. Our human health researchers provided genetic diagnoses to over 500 children with rare diseases and discovered dozens of disease-risk genes in cancer, neurodegenerative, neurodevelopmental, and autoimmune diseases. Our founders envisioned a place where scientists, researchers, educators, entrepreneurs, and the public would brainstorm, collaborate, and work together to improve the human condition worldwide. Their dream is still alive today. We are making significant impacts in the state of Alabama and beyond, even though our Institute looks slightly different now. Since 2008, we have expanded our campus in both physical footprint and the breadth of ongoing research. This past year saw a leadership expansion on campus as well. I stepped back from my role as President of HudsonAlpha and transitioned into Chief Scientific Officer. Together with our new President, Dr. Neil Lamb, I aim to ensure that HudsonAlpha continues moving genetics and genomics into the future to help improve the human condition. Sharing scientific discoveries is an integral part of being a research scientist. We hope you enjoy this brief look into the amazing science achieved at HudsonAlpha over the last few years.
Richard M. Myers, PhD Chief Scientific Officer President Emeritus M. A. Loya Chair in Genomics Faculty Investigator
5
SCIENCE HIGHLIGHTS
AND RESEARCHER SPOTLIGHTS
HUDSONALPHA INSTITUTE FOR BIOTECHNOLOGY
6
DISCOVERIES IN
RESEARCH REPORT
7
WhY aren’t all BLACK bears
?
I n mammals, pigment, or melanin, is produced by melanocyte skin cells. There are two types of mela- nin: eumelanin is black or brown, and pheomelanin is red or yellow. Different levels of eumelanin and pheomelanin can produce a wide array of colors in animals. In addition, mutations in melanin biosynthe- sis underlie several conditions associated with im- paired fitness or disease or unusual color morphs of large animals that are specifically targeted for trophy hunting. HudsonAlpha faculty investigator Greg Barsh, MD, PhD , is an expert in morphological variation. He and his lab use color and color variation as an experimental platform to study cellular and molecular pathways that are involved in different processes throughout the body. Barsh and collaborators from the University of Memphis and the University of Pennsylvania recently set out to study the genetics behind an interesting group of black bears 1 . In Yellowstone National Park, black bears outnumber their brownish-colored grizzly bear
GENE VARIANT RESPONSIBLE FOR CINNAMON MORPH BLACK BEAR
Barsh and his colleagues set out to determine when, where, and how the U. americanus cinnamon morph arose. With help from partners in state, provincial, and federal wildlife agencies, and university partners in North Ameri- ca, the team collected hundreds of DNA and hair samples from North American bears. It is widely accepted that genetic variation in melanin biosynthesis gives rise to differences in hair, eye, and skin color. By studying photos of bears and chemically ana- lyzing their corresponding hair samples, the team deter- mined that in both bear species, light-colored hair is due to reduced amounts of eumelanin. Genome sequence analysis of nearly 200 bears uncovered different missense mutations in the gene Tyrosinase-related protein 1 (TYRP1) : cinnamon-col- ored black bears have a mutation called
TYRP1 R153C , while most (but not all) grizzly bears have a mutation called TYRP1 R114C . The TYRP1 gene produces an enzyme within melanocytes that helps produce eumelanin, so it makes sense that the cinnamon and grizzly bears have less eumelanin. Furthermore, functional studies determined that the TYRP1 R153C and TYRP1 R114C mutations interfere with melanin synthesis and distribution. When the team looked at other species,
cousins, and in coastal areas of the Pacific Northwest, if someone says “brown bear,” they mean grizzly bear. But not all brown bears are grizzly bears. American black bears ( Ursus americanus ), which one would logically assume are black, actually come in a wide range of colors, including brown (also known as cinnamon), blond, or bluish-grey. Others have coats that are a mixture of several colors. So, how do you tell a cinnamon-colored Ursus
cinnamon-colored black bear
they were surprised to find the TYRP1 R153C variant responsible for cinnamon U. americanus is identical to one previously described as a cause of oculocutaneous albi- nism (OCA3) in humans. OCA3 is often observed in people of African or Puerto Rican ancestry and is characterized by reddish skin and hair and frequent visual abnormalities. According to Emily Puckett, PhD, the lead author of the manuscript, bears with TYRP1 mutations have normal skin and can see just fine.
americanus from its brown (grizzly) Ursus arctos cousin? Differences in body shape and size can be subtle. One hypothesis for the cinnamon color of Ursus americanus is that it mimics the appearance of a grizzly bear, helping with camouflage or defense. Barsh, along with other researchers at HudsonAlpha, the University of Memphis, and the University of Pennsyl- vania, have discovered what causes the cinnamon color, shedding some light on this color confusion.
HUDSONALPHA INSTITUTE FOR BIOTECHNOLOGY
8
GREG BARSH
The result of the Barsh lab studies on bears illustrate how genetic variation in melanin biosynthesis can underlie iconic phenotypes and inform a better understanding of color variation and recent evolution in large carnivores.
American Black Bear cub
within their environments. Here, the researchers suggest crypsis as a broader adaptive mechanism for large-bodied species. These results illustrate how genetic variation in melanin biosynthesis can underlie iconic phenotypes and
WHEN AND WHERE DID THE CINNAMON MORPH ARISE?
The TYRP1 R153C variant was primarily found in the south- west United States, at lower frequencies moving north- ward to Southeast Alaska and the Yukon Territory. TYRP1 R153C was associated with the cinnamon color in black bears and the chocolate and light brown colors, meaning it accounts for almost all of the color diversity among U. americanus . The researchers used their data to learn more about the TYRP1 R153C mutation. One idea is that it may have started in grizzly bears and was transferred to black bears, but demographic analysis indicated that was not the case. Instead, the TYRP1 R153C mutation arose spontaneously about 9,360 years ago in black bears living in the western United States, then spread as the bears moved across their current geographic range. The R153C variant that arose in black bears over 9,000 years ago must have provided an adaptive advantage to the bears based on its wide range today. The team used genet- ic modeling and simulations to predict the selective forces acting on the cinnamon morph. Their predictions ruled out two popular ideas: mimicry and thermoregulation. As to why the coat color variant arose in the first place, the team presents a new hypothesis: crypsis. Crypsis refers to the ability of an animal to conceal itself and blend into the environment. Generally, crypsis is found in prey species and ambush predators who color match
inform a better understanding of color variation and recent evolu- tion in large carnivores. ■
Greg Barsh, MD, PhD, is a faculty investiga- tor and Smith Family Chair in Genomics at the HudsonAlpha Institute for Biotechnology
RESEARCH REPORT
9
FAMILY HISTORY
AND GENETIC
SCREENING
I t has long been recognized that common diseases like heart disease, cancer, and diabetes, as well as rare diseases like hemophilia, cystic fibrosis, and sickle cell anemia, can run in families. A complete family health history is an important and powerful tool for the diagnosis and prevention of such diseas- es. An accurate family health history can establish the disease transmission pattern and predict which family members are most likely to be affected, allowing individ- uals with increased risk to talk with their doctors about screening options or preventative care. Advances in genetic sequencing technology enable scientists to continue to unlock the secrets of the human genome, connecting the diseases long observed to be heritable with tangible genetic causes. Genetic testing is useful for diagnosing Mendelian diseases caused by a single, specific genetic variant. The rise of consumer genetic testing companies and the falling price point
of genetic testing make it more desirable for individu- als seeking insight into their genetic health. However, experts in the field of bioethics, including HudsonAlpha Faculty Investigator Thomas May, PhD , heed caution for universal genetic testing for seemingly healthy individu- als until the scientific field can gather more information on its costs and benefits. May is also the Floyd and Judy Rogers Endowed Professor in the Elson S. Floyd College of Medicine at Washington State University. Dr. May and his colleagues at HudsonAlpha and the University of Alabama at Birmingham (UAB) are part of a large-scale genetic testing initiative that provides valuable insight into the utility of genetic testing as a companion to family health history. The Alabama Genomic Health Initiative (AGHI) was launched in 2017 and provides genomic testing, interpretation, and genetic counseling free of charge to Alabama residents 1 . It provides both rare disease diagnostic testing and
HUDSONALPHA INSTITUTE FOR BIOTECHNOLOGY
10
THOMAS MAY
population-level testing of medically actionable gene- disease associations. As of fall 2022, more than 6,000 individuals partici- pated in the population cohort. Participants completed an in-depth family health history questionnaire and received genetic testing that looked at 59 genes deemed actionable by the American College of Medical Genetics (ACMG). HudsonAlpha genetic counselors reviewed the personal and family health history questionnaires and triaged the individuals into disease risk categories. After comparing individuals with a high-risk family history report and those with a positive genetic testing re- sult, researchers noticed a discordance between reported risk and genetically identified risk. There was a percentage of individuals with high-risk family history reports that did not have positive genetic testing results. This did not surprise researchers because genetic testing is limited by the number of gene-disease associations validated by the field, whereas family health history reflects a wide range of heritable conditions. There is obviously great power in having a robust family health history, but what about individuals who do not have access to such information? Adoptees, individuals who are estranged from their families, children of gamete donation, and children from families where the paternity is
unknown are all groups of individuals who might not have the benefit of a robust family health history. Could genetic testing help these individuals learn more about their personal health? May is a member of the Genomic Family History Project consortium that aims to create guidance concern- ing the use of genetic testing to fill gaps in family health history for adopted persons and to recommend best practices in these areas. The consortium comprises experts in genetics, bioethics, adoption psychology, law, pediatrics, and other stakeholders in the adoption com- munity working together to develop best practices related to genomics and adoption. They are working to develop guidelines surrounding the types of genetic tests and the most appropriate age for such testing to occur for adop- tees. Their goal is to provide a set of best practices that will allow adoptees to fill in the gaps in their family health history without the unnecessary stress of potential false positive genetic testing results. The group primarily focuses on genetic conditions that generally manifest at ages when routine screening does not occur, like Lynch syndrome, for example. Individuals with the Lynch syndrome genetic variant are generally diagnosed with colon cancer before the age of 50. So testing individuals who lack knowledge of their family health history for Lynch syndrome before this critical age would allow them to obtain earlier colonoscopies should they carry the genetic variant. The consortium held a symposium in
2021 to discuss several issues related to genetic testing for adoptees. One work- ing group determined that what, when, and how genetic testing is facilitated and results are returned is a person- al decision for each adoptee. A second group concluded that the primary focus of guidelines on gene panels for adopted persons should be genetic information for which adopted persons experience health inequity compared to non-adoptees. Above all else, they stressed the importance that adoptees and adoptive parents understand the power and limitations of genetic test- ing and the information gleaned from it. ■
(l to r) Chris Powell, Tom May, PhD and Sarah Sharman, PhD, sit down to discuss the importance of genetic screening on the Tiny Expeditions podcast.
To learn more, listen to
RESEARCH REPORT
11
Joycelyn Williams, senior biology major, Oakwood University (l), Jherni Fisher, junior Chemistry major, Alabama A&M University (r).
= T he ability to sequence and analyze the hu- man genome changed the course of medi- cal diagnosis and disease treatment. DNA from a simple blood draw can diagnose hundreds of genetic diseases. But, only some populations are reaping the benefits of life-changing genomic discoveries. As of June 2021, 86 percent of genomic studies were conducted on white individuals of European ancestry 1 . Those indi- viduals only comprise 16 percent of the global population, leaving many populations underrepresented and even absent from genomic research. Diverse representation in genomic research facili- tates more discoveries in biology, a better understanding of health disparities, a more accurate prescription of safe and effective treatment to diverse patients, and an improved interpretation of genetic tests. Failure to include sufficient diversity among research participants denies
DIVERSIFYING STEM and testing programs. These include deep-seated mistrust in medical research, concern about how genomic data will be used, data privacy concerns, and lack of access to genomic technology and research trials. Each of Hudson- Alpha’s mission areas is committed to increasing diver- sity across the STEM fields, from patient participation to access to educational and career opportunities.
INCREASING ACCESS TO GENETIC TESTING AND DIVERSITY IN CLINICAL TRIALS
To increase diversity among genomic research partici- pants while increasing minority access to genetic testing, education, and clinical trials, scientists and clinicians must acknowledge and help individuals overcome the barriers to participation in genetic research. This means engaging with and educating underrepresented communities about the benefits of genetic research to their future health. Many research initiatives are trying to increase the diversi- ty in genetic research programs and data sets. Several HudsonAlpha research labs and the genetic counseling team are involved in research initiatives to in- crease access to genetic testing for individuals in rural and underserved communities. Enrolling participants in these studies also contributes meaningful genomic data from
some populations full participation in the benefits of research findings and inhibits a richer understanding of gene-disease relationships among all populations. Critical health-related discoveries and breakthroughs could be ineffective or unsafe for people of non-European descent. The genetics community needs to overcome several barriers to recruit diverse participation in genetic research
HUDSONALPHA INSTITUTE FOR BIOTECHNOLOGY
12
=
underrepresented populations that helps create a more complete picture of human genomics.
INCREASING DIVERSITY IN STEM EDUCATION AND THE STEM WORKFORCE Increasing diversity among genomic research participants while increasing minority access to genetic education and the STEM workforce is vital to changing the genomics landscape. Several HudsonAlpha education and institute programs aim to increase access and diversity in STEM education and the workforce. Enrolling students from local historically Black colleges and universities (HBCU), and high schools ensures they gain experience and knowledge in the field of genetics and genomics. HBCU GOMA CO-OP PROGRAM HudsonAlpha offers HBCU internships in collaboration with the Alabama Governor’s Office of Minority Affairs (GOMA) and Alabama’s 14 historically Black colleges and universities. The HBCU GOMA Co-op program builds a talent pipeline from HBCUs in Alabama to the state’s workforce. The year-long internships allow students the opportunity to gain experience working in a lab while learning about biotechnology and related fields. *( To meet a current GOMA student, read the story on pgs. 62-63). NATIONAL SCIENCE FOUNDATION SORGHUM STUDY Two HudsonAlpha faculty members were awarded a supplemental National Science Foundation (NSF) grant to continue researching nitrogen efficiency in the grain and biomass crop sorghum. A new collaborator joined the team for the two-year supplement– Alabama A&M Uni- versity (AAMU), a public HBCU. Through the educational portion of the project, the team hopes to engage and retain more minorities who are underrepresented in STEM fields, especially in agricultural sciences, by mentoring and cross-training young researchers at AAMU. *( To learn more about this project, see pgs. 44–45).
ALABAMA GENOMIC HEALTH INITIATIVE (AGHI) HudsonAlpha has been part of the Alabama Genomic Health Initiative (AGHI) since its launch in 2017. AGHI is a state-funded research initiative that aims to prevent and treat disease by providing genomic testing, interpretation, and genetic counseling free of charge to residents. As of late 2021, AGHI has enrolled more than 7,000 individuals representing all 67 Alabama counties 2 . (Read more on p.10) SOUTHSEQ SouthSeq is a program focused on enrolling a diverse population of sick infants representing racial and ethnic minorities, as well as those from medically underserved communities. The study uses genome sequencing to diagnose critically ill NICU babies. (Read more about SouthSeq on p.32) ALL OF US Researchers at HudsonAlpha are also part of a large, nationwide program called All of Us . The program aims to gather health data from more than one million Americans, reflecting its rich diversity. They hope to include individu- als of many races and ethnicities, age groups, geographic regions, gender identities, and health statuses. As of June 2022, the All of Us research database includes data from more than 372,000 participants, with nearly 80% identify- ing with groups historically underrepresented in medical research 3 . The first set of All of Us long-read sequencing data was made possible by HudsonAlpha in collaboration with Discovery Life Sciences (DLS) , a company located on the HudsonAlpha campus. HudsonAlpha is on track to complete a long-read genome for more than 2,000 All of Us participants. INFORMATION IS POWER INITIATIVE HudsonAlpha’s Information is Power Initiative offers free or reduced-cost genetic tests that look at several dozen genes associated with increased risk for breast, ovarian, colon, and endometrial cancers. Initially focusing on north Alabama, the initiative expanded its reach to individuals throughout the state, forging collaborations with #NowIn- cluded, Montgomery-area physicians, and HBCUs in the state of Alabama to reach more medically underserved areas. To date, more than 6,000 people across Alabama have taken the test and now have more power over their own health decisions. * (To learn more, visit information-is-power.org).
BRIDGES The COVID-19 pandemic drastically changed the
educational landscape for several years. Students began learning online, missing out on valuable hands-on learning experiences. With the support of an NSF EPSCOR grant, HudsonAlpha is providing minority students affected by the pandemic the opportunity to participate in real-world research. The year-long internship, called Boosting Retention, Interest, and Diversity through Guided Experiences in STEM (BRIDGES) , allows recent college graduates the opportunity to learn critical thinking and experimental design, get experience in molecular biology, plant biology, and genomic technologies for measuring gene expression, and learn about career opportunities available to them in the STEM field. ■
To learn more, listen to
RESEARCH REPORT
13
NEW T
LS
DRIVE INNOVATION AND COLLABORATION
T he human mind is a brilliant thing, capable of storing decades of memo- ries, inventing entire fictional worlds, and solving some of our world’s most pressing issues. Throughout history, humans invented tools and technolo- gies that help them more easily achieve their goals and ambitions. HudsonAlpha is home to many such state-of-the-art tools to bring hypotheses to life and garner answers to complicated scientific questions. Over the past two years, HudsonAlpha added several new laboratory tools to its arsenal, thanks to private and public funding: a new cell culture suite, a confocal microscope, and a chromium controller. CELL CULTURE SUITE Cell culture is a mainstay in research labs worldwide. It allows researchers to remove cells from an animal or plant and grow them in a controlled laboratory to be used for experiments. Established cell lines are easy to study and manipulate yet share many molecular and biological processes with humans, allowing researchers to safely query the inner workings of cells without starting with a living animal or human. Information gleaned from cell lines can be translated into more complex organisms, like humans and plants.
Specialized equipment is necessary for successful cell culture. The equipment needs to maintain the appro- priate environment for the cell lines while keeping the cell culture working environment clean to avoid contamination by other biological organisms, like bacteria and fungi. At HudsonAlpha, cell culture plays an important role in much of its human health research. In March 2022, the Institute unveiled a new cell culture suite to help support these growing research programs. The new suite includes much of the specialized equipment necessary for growing
Research Associate Katie Trausch-Lowther, culturing iPSCs in the cell culture room.
HUDSONALPHA INSTITUTE FOR BIOTECHNOLOGY
14
Senior Scientist Lindsay Rizzardi, PhD, is using the chromium controller in single-cell analysis to study neurodegenerative diseases.
cells in culture, including cell culture hoods, incubators, centrifuges, and microscopes. This facility is important to the Institute’s research projects and serves as an ad- vanced training space for graduate students and others seeking to learn hands-on skills for STEM-based careers. One research area that will rely heavily on the new space is the Memory and Mobility (M&M) Program led by Drs. Nick Cochran and Rick Myers . Their labs study several neurodegenerative diseases, including Alzheimer’s, Huntington’s, Parkinson’s, ALS, and rare conditions such as frontotemporal dementia (FTD) and corticobasal syndrome (CBS). The research teams use cell culture to study the genetic causes of neurodegenerative diseases, develop sophisticated blood-based biomarkers for early detection and disease monitoring, and discover new therapeutic approaches for these devastating diseases. CHROMIUM CONTROLLER The neurodegenerative disease research programs at HudsonAlpha also use a new technology called single-cell analysis to unravel the genetic underpinnings of neurode- generation on a cell-by-cell basis. The pathology of
neurodegenerative diseases involves the progressive loss of specific populations of neurons, microglia, or other brain cells. Being able to query cells on a cell-type-specific basis is paramount to uncovering more precise information on the genetic differences in diseased brains. In March 2022, with the help of private funding, the program purchased a piece of equipment that drastically reduces the time it takes to run single-cell experiments. The tool, called a high-throughput chromium controller, uses advanced microfluidics to separate single cells and barcode them for downstream analysis in a matter of minutes. By partitioning hundreds to tens of thousands of cells in just minutes, the chromium controller saves researchers countless hours per experiment. Using single-cell analysis, HudsonAlpha research- ers can ask endless questions about the cause and progression of neurodegenerative diseases. For example, combining single-cell analysis with CRISPR/ Cas9 gene editing allows researchers to target specific regions of the genome one at a time to determine if they control gene expression changes involved in neurodegenerative diseases. cont. on p. 16
RESEARCH REPORT
15
Matthew Knuesel, PhD, at the fast pressure liquid chromatography machine to help speed up protein purifications
HUDSONALPHA INSTITUTE FOR BIOTECHNOLOGY
16
Graduate student Brianne Rogers from the Myers Lab using the confocal microscope to look at differentiated neurons generated from iPSC cultures.
CONFOCAL MICROSCOPE The ability to look closely at cells, peering into their internal organelles, visualizing their interactions with other cells, and pinpointing the location of various nucleic acids and proteins within the cell, revolutionized the field of biology and beyond. Early microscopes offered low-resolution glances into the cellular world. However, as technology advanced, so did the detail in which research- ers could observe cells. Microscopes evolved from simple magnifying glasses to compound microscopes to the super-powerful electron microscopes of today. One microscope that is extremely powerful in biolog- ical research is the confocal microscope, which provides high-resolution imaging of live cells at multiple depths, creating an almost three-dimensional picture. Looking closely at cell biology in 3D rather than 2D allows scien- tists to zero in on key processes more accurately and with
less cost than animal models, opening doors to faster, less costly cures. Thanks to contributions from DOE research funding and private donors, HudsonAlpha recently acquired a confocal microscope. This high-tech instrument will sup- port fundamental human health research, including the development of diagnostic tools, the identification of bio- markers that monitor disease progression and aid in drug development, and the discovery of targets for possible new therapies. Researchers in Dr. Kankshita Swaminathan ’s lab are using the microscope in their efforts to create bioproducts from the sugars in the stem. The confocal scope allows researchers to visualize targeted changes in specific plant structures and have more confidence in their constructs for transformation, saving both time and money. ■
RESEARCH REPORT
17
TO ADVANCE FUNCTIONAL NEUROLOGICAL STUDIES N eurodegenerative diseases slowly cause neurons and other brain cells to die, robbing those affected by the disease of their memory, mobility, and other important functions. This devastating class of diseases, which consists of hundreds of different types, affects tens of millions of people globally. Unfortunately, there are few effective treatments and no cures for neurodegenerative diseases to date. fundamental knowledge about the role the human genome plays in neurodegenerative diseases. A major challenge that the research team is currently addressing is the lack of brain-specific model systems. The team took various approaches to address this challenge, including creating new laboratory techniques that could benefit others in the field. By collaborating with some of the world’s leading
brain anatomists, Myers’ lab analyzes postmortem brain samples from individuals with or without various neuro- psychiatric and neurodegenerative diseases to identify biological differences between the two. They are also pushing the forefront of laboratory techniques to grow specific types of human neurons in a dish in the lab, a feat that has historically been extremely difficult. Having human neurons in the lab allows the research team to perform cutting-edge genetic tests on human cells more easily, without needing brain samples. Through studying brain tissue from individuals with neurodegenerative diseases, Myers’ lab hopes to identify gene candidates and risk factors for diseases such as Huntington’s disease, Parkinson’s disease, Alzheimer’s disease, frontotemporal dementia (FTD), ALS, bipolar disorder, and schizophrenia. Such studies have helped identify genes involved in several of these disorders.
Researchers must have an intimate knowledge of the molecular underpinnings of these insidious diseases to understand how to treat and cure them. Over the past de- cade, researchers found many neurodegenerative diseas- es are caused by genetic factors, although the exact genes involved have not been elucidated for many of them. In addition, researchers predict that many of these diseases likely have more than one genetic cause or a combination of genetic and environmental causes. HudsonAlpha faculty investigator Rick Myers, PhD , and his lab focus their efforts on foundational human genomics, diving into the human genome to understand how changes contribute to neurodegenerative diseases, as well as basic biological processes. Like most foundational genomic labs, Myers and his team rely on experimental models, like cells or simple model organisms, to gain
Myers’ lab hopes to identify gene candidates and risk factors for diseases such as Huntington’s disease, Parkinson’s disease, Alzheimer’s disease, frontotemporal dementia (FTD), ALS, bipolar disorder, and schizophrenia.
18
RICK MYERS
Because collecting human brain tissue from living, developing brains is not feasible, the lab has worked extensively to develop efficient cellular models of human brain cells, including from individuals with and without disease. Induced pluripotent stem cells (iPSC) are blood or skin cells that are reprogrammed to a pluripotent, stem-cell-like state. Once reprogrammed, iPS cells can be turned into any type of cell using a cocktail of sup- plements, growth factors, and proteins that mimic what naturally happens in the body. By transitioning iPSCs into neurons or other brain cells, researchers in the Myers lab can perform experiments on them, including testing drugs or other treatments. These cells help Myers’ lab transfer data gleaned from experimental models closer to human beings.
Another cutting-edge technology the Myers’ lab uses is single-cell analysis. This allows the team to study brain diseases on a cell-by-cell basis. Historically, brain sam- ples include all the cell types of the brain mixed together. If only one subtype of cell is involved in the disease pathol- ogy, its signal could be covered up by more abundant cell types. Looking at individual cells provides scientists with new, more precise information on the genetic and genomic differences between the brain of someone with a disease compared to the brain of someone without the disease. Single-cell genomics proved to be successful in the lab’s quest to identify genetic contributors to Alzheimer’s disease. The researchers used single-cell technologies to measure gene expression and DNA accessibility in
cont. on p. 20
Senior Scientist Jacob Loupe, PhD, uses the lab’s flow cytometer to isolate specific cell types from brain dissections to study how various cells regulate gene expression.
19
Brianne Rogers and Lindsay Rizzardi, PhD from the Myers lab examine iPSCs differentiating into neurons for use in single cell functional genomics studies of Alzheimer’s and other neurodegenerative diseases.
NEURO
HUDSONALPHA INSTITUTE FOR BIOTECHNOLOGY
20
brain tissue from unaffected donors and those with Alzhei- mer’s disease. Using the single-cell technology, the team identified ZEB1 and MAFB as candidate transcription fac- tors playing important roles in Alzheimer’s disease-spe- cific gene regulation in neurons and microglia 1 . These findings lay the groundwork for further research into the two candidate genes, including the potential for therapeu- tic targets for manipulating gene regulation in Alzheimer’s disease. One application of the data gleaned from the different tools and technologies developed and applied in the Myers Lab is the development of blood-based predictive diagnos- tic biomarkers for neurodegenerative disorders. Myers’ lab is no stranger to the biomarker field, having previously discovered cell-free nucleic acid biomarkers of colorectal adenoma, early lesions in the colon that could eventually develop into cancer 2 .
Using this same technology, the team, led by senior scientists Ben Henderson, PhD, and Brian Roberts, aims to uncover biomarkers that can diagnose early-stage disease, track disease progression, and monitor ther- apeutic effectiveness in neurodevelopmental diseases like Alzheimer’s disease, Parkinson’s disease, ALS, and Huntington’s disease. By comparing blood plasma from control samples to samples from patients diagnosed with a neurodegenerative disease, the team identifies small RNA molecules that are unique to patients with the dis- ease. If such biomarker signatures can be validated, they could become integrated into clinical care as a screen for people with a family history of neurodegenerative disease or people having undiagnosed neurological symptoms. ■
To learn more, listen to
Richard M. Myers, PhD, Chief Scientific Officer, President emeritus and
M.A. Loya Chair in Genomics, research and his lab focus on genomic and genetic analysis of human traits and disease.
RESEARCH REPORT
21
GENE regulation in
DISEASE
M icroscopic analysis of postmortem brain tissue from individuals with Alzheimer’s disease reveals many changes thought to contribute to cellular damage to the brain. The current belief in the field is that Alzheimer’s disease-related brain changes result from a complex interplay between ab- normal tau and beta-amyloid proteins, along with other yet-to-be-discovered factors. Beta-amyloid proteins clump together and form plaques that collect between neurons, while neurofibrillary tangles are abnormal accumulations of tau protein that build up inside neurons. Both abnor- malities disrupt cell function, causing cell damage and cell death. The progressive build-up of beta-amyloid and tau protein begins long before individuals show their first symptoms of the disease. While increased levels of beta-amyloid and tau pro- teins are implicated in the pathology and devastation of Alzheimer’s disease, less is known about how and why the proteins accumulate and function incorrectly in the first place. In rare cases, a single gene mutation directly caus- es Alzheimer’s disease through the beta-amyloid pathway. These include single-gene variants in amyloid precursor protein ( APP ), Presenilin 1 and 2 ( PSEN1/2 ). However, for most common cases of Alzheimer’s, genetic contributors come in the form of non-determinant risk, such as through a form of apolipoprotein E ( APOE ∑ 4 ), which is less directly linked to the key pathologies of the disease. Changes in the genetic code are not the only way a gene’s function can be altered. Gene expression is
controlled by transcription factors and other transcription- al elements that cause genes to be expressed more or less than needed. Certain non-coding regions of DNA can also regulate gene expression. Promoters, located close to the transcription start site, provide binding sites for transcrip- tion factors. Enhancers are located further from the start site and provide binding sites for other proteins that help activate transcription. Changes in the function of promot- ers and enhancers can affect gene expression. A prominent theory in the neurodegenerative disease field is that toxic levels of accumulation of beta-amyloid and tau proteins in neurons can lead to disease. Hudson- Alpha faculty investigator Nick Cochran, PhD , and his lab investigate gene regulation processes involved in Alzhei- mer’s disease development and function as one possible cont. on p. 24
The burden of aLZHEIMER’S DISEASE IS PREDICTED TO DOUBLE EVERY 20 YEARS, REACHING 139 MILLION PEOPLE BY YEAR 2050
HUDSONALPHA INSTITUTE FOR BIOTECHNOLOGY
22
NICK COCHRAN
Research Associate, Sam Bartley, in the new Cochran lab.
RESEARCH REPORT
23
contributor to this process. They currently focus on identi- fying genetic factors that alter known Alzheimer’s disease risk factor genes, as well as discovering new risk factors for the disease. One of the genes that the lab has focused on in a recent study is MAPT , which encodes for tau protein. To determine changes in MAPT regulation that may con- tribute to Alzheimer’s disease pathology, researchers need to understand MAPT and tau protein at baseline in individ- uals without Alzheimer’s disease. Many datasets useful for understanding gene regulation for other genes are not helpful for MAPT , because its function is in brain cells that often lack the necessary gene regulation datasets. Cochran’s lab is facing the challenge and develop- ing its own datasets to study tau. They are taking many cutting-edge computational and experimental approaches to understand which regulatory elements are necessary and sufficient for tau expression. One approach the lab is widely using is cell culture of neural precursor cells, differentiated neurons, and inhibitory and excitatory neuron cultures.
NEW HUDSONALPHA INSTITUTE FOR BIOTECHNOLOGY FACULTY INVESTIGATOR, NICK COCHRAN, PHD
In September 2021, HudsonAlpha added another neurogenomics lab to its roster, led by Faculty Investigator Nick Cochran, PhD. Cochran is a familiar face at HudsonAlpha, having begun his journey as a postdoctoral fellow in Rick Myers’s lab in 2015. The Cochran lab investigates gene regulation processes involved in Alzhei- mer’s disease development and progres- sion. One of the genes that the lab focuses largely on currently is MAPT, the gene that encodes for tau protein which is involved in Alzheimer’s disease pathogenesis. He also helps foster collaborations with international groups like the Research Dementia Latin America (ReDLat) consor- tium that aims to identify the unique genet- ic and socioeconomic/social determinants of health that drive Alzheimer’s disease and other dementias in Latin America. Cochran earned a PhD in neurobiology from the University of Alabama at Birmingham in 2015 and a bachelor of chemical engineering from Auburn University in 2010.
24
Faculty Investigator Nick Cochran, PhD, and team members Rebecca Hauser, PhD, Sam Bartley, and Brianne Rogers helping to identify regulatory elements of MAPT results.
expression of MAPT in neurons compared to precursor cells and other cell types. Understanding how MAPT is regulated may point to new strategies to achieve tau reduction, which could be therapeutically beneficial. Developing drugs to stop the regulatory element’s ability to turn on genes that drive Alzheimer’s disease pathology could prevent the onset or slow the progression of the disease. While the lab is currently focused on fully investigating their MAPT dataset, they do plan to look at the regulation of other neurodegen- erative disease genes in the future, including SNCA , which codes for alpha-synuclein (important in Parkinson’s dis- ease) and APP , which is the precursor gene for the other key neuropathology in Alzheimer’s, beta-amyloid. ■
Using genomic approaches and the neural cell culture models, the team identified several regulatory elements of MAPT , some of which are proximal to its promoter and some that are over 500,000 bases away 1 . Chromatin capture and single-nucleus RNA- and ATAC-seq were used to identify regions within the MAPT locus and nominate regions correlated with MAPT expression. A luciferase reporter assay and CRISPR inhibition of the regulatory regions helped confirm their function. Previous groups identified an H2 inversion on chromo- some 17 that influences Parkinson’s disease, progressive supranuclear palsy (PSP), and Alzheimer’s disease. Using their ever-growing dataset, researchers in the Cochran lab found that in neurons, there is a regulatory region outside of the inversion that strongly influences MAPT expression. Based on their data, the lab believes that the regulatory elements could be neuron-specific and explain the high
To learn more, listen to
RESEARCH REPORT
25
UNRAVELING THE HIGH INCIDENCE OF
G lobally, Alzheimer’s disease and other dementias affect about 55 million people, with nearly 10 million new cases diagnosed yearly. This number is predicted to double every 20 years, reaching 139 million by 2050, making the need for preventative measures and better diagnostic tools critical. Studies show that significant damage to the brain has already occurred by the time individuals show signs of dementia. As such, available treatments show little benefit for individuals already impaired with dementia. Preventative dementia research is complicated by the difficulty of finding the appropriate participant base. Participants should be people guaranteed, or highly likely, to develop dementia — a population that is hard to identify because the cause of most common types of Alzheimer’s disease is largely unknown. A rare subtype of Alzheimer’s disease, called autosomal dominant Alzheimer’s disease (ADAD), presents a unique opportunity for researchers because several genetic causes are identified for the dis- ease, and mutation carriers always develop the disease at roughly the same age range. One family in Antioquia, Colombia, with a long history of ADAD, became a key cohort for Alzheimer’s disease research, serving as the subject of dozens of studies and one clinical trial. The dementia field is learning a lot about the cause and progression of this devastating disease from this family. In return, they received an answer to their decades-long question about why so many family members were suffering from, and ultimately dying from, this devastating disease. HudsonAlpha faculty investiga- tors Rick Myers, PhD, and Nick Cochran, PhD , are part
of the ongoing efforts to understand the dynamics of dementia by studying families in Latin America overburdened by the disease.
HOW A COLOMBIAN FAMILY FOUND ANSWERS WHILE GIVING BACK TO ALZHEIMER’S DISEASE RESEARCH Several decades ago, a neurologist named Francisco Lopera began studying the family in Antioquia because of their high incidence of very early onset Alzheimer’s disease. On average, the disease strikes individuals in this family in their mid-40s and results in death within 10 to 12 years. To date, more than 6,000 individuals from 26 extended families are enrolled in the study. By analyzing the individuals’ genomes, researchers discovered that many carry a rare genetic mutation for early-onset Alzheimer’s disease in a gene called Presenilin-1 (PSEN1) 1 . The mutation is referred to as PSEN1 E280A after the mutation’s location on the gene. Other Colombian families, unrelated to the Antioquia family, were also found to have high incidences of ear- ly-onset Alzheimer’s disease. Many of these families were from small, isolated towns like Antioquia. Small towns and villages in rural Colombia are often genetically isolated, meaning there is little genetic diversity because of a lack of immigration into the area. This creates the perfect environment for amplifying rare mutations, like the PSEN1 mutation. A recent publication confirmed the role of ances- try and genetic isolation in the mutational landscape of dementia in Colombia 2 . A group of researchers, including Drs. Cochran and Myers, analyzed the genomes of 900
HUDSONALPHA INSTITUTE FOR BIOTECHNOLOGY
26
IN LATIN AMERICA
Colombian individuals with or without various dementias for deleterious variants in disease-causing and risk-con- ferring genes and examined participants’ global and local ancestry proportions. Through these analyses, researchers identified 21 pathogenic variants in Alzheimer’s disease- and fronto- temporal lobar degeneration-motor neuron disease-re- lated genes. PSEN1 harbored the most variants. Unique variants from three continental ancestries — African, European, and Native American — were identified. The results show the significant role that demographic history plays in shaping a population’s genetic risk for disease and emphasize the importance of inclusiveness in genetic studies. THE AGE OF ONSET OF DEMENTIA IS LIKELY LINKED TO GENETIC FACTORS Ongoing studies focusing on the Antioquia family are trying to unravel the mysteries behind the age of onset of dementia. Most individuals in the large Colombian family carrying the PSEN1 E280A mutation develop mild cognitive impairment (MCI) at a median age of 44 and dementia at age 49, although some individuals have been reported to develop MCI nearly three decades after their family’s median age. The predictable age of onset and existence of rare outliers make this family a valuable source of potential genetic variants that delay the onset of Alzheimer’s disease. Dr. Cochran and his lab, along with collaborators at the University of California, Santa Barbara, Universidad de Antioquia, Icahn School of Medicine at Mt. Sinai, and Washington University in St. Louis, were part of a re-
cent study that analyzed the genomes of 344 individuals from the Antioquia family to gain insight into the genetic landscape of age of disease onset 3 . The research team identified several gene candidates that are likely involved in Alzheimer’s disease age of onset, although further studies with more individuals are necessary for confirma- tion. One promising hit was a new variant in the gene CLU , previously implicated as a genetic risk factor for late-onset Alzheimer’s disease. While the Antioquia family is the largest known dominant Alzheimer’s disease family, they still represent a small group for statistical purposes. Recruitment of more patients with early-onset dementias from South American countries will help overcome this limitation in future studies. One such effort to increase Latin American representation in genetic research is Multi-Partner Consortium to Expand Dementia Research in Latin America (ReDLat) 4 . The multinational effort, which in- cludes Dr. Cochran and his lab, seeks to expand dementia research in Latin America, focusing especially on under- served and diverse populations. The consortium aims to identify the unique genet- ic and socioeconomic determinants of health that drive Alzheimer’s disease and other dementias in Latin Amer- ica. The five-year project aims to collect neuroimaging, genetic and behavioral data on over 4,000 individuals from Argentina, Brazil, Chile, Columbia, Mexico, Peru, and the U.S. to offer a unique understanding of the genetic and environmental underpinnings of dementia. ■
Above, Dr. Cochran explains the population health study results from Antioquia, Columbia.
RESEARCH REPORT
27
Page 1 Page 2 Page 3 Page 4 Page 5 Page 6 Page 7 Page 8 Page 9 Page 10 Page 11 Page 12 Page 13 Page 14 Page 15 Page 16 Page 17 Page 18 Page 19 Page 20 Page 21 Page 22 Page 23 Page 24 Page 25 Page 26 Page 27 Page 28 Page 29 Page 30 Page 31 Page 32 Page 33 Page 34 Page 35 Page 36 Page 37 Page 38 Page 39 Page 40 Page 41 Page 42 Page 43 Page 44 Page 45 Page 46 Page 47 Page 48 Page 49 Page 50 Page 51 Page 52 Page 53 Page 54 Page 55 Page 56 Page 57 Page 58 Page 59 Page 60 Page 61 Page 62 Page 63 Page 64 Page 65 Page 66 Page 67 Page 68 Page 69 Page 70 Page 71 Page 72 Page 73 Page 74 Page 75 Page 76 Page 77 Page 78 Page 79 Page 80Made with FlippingBook - Online magazine maker