HudsonAlpha Alabama Policymakers 2021

Alabama Policymaker’s Edition
2021-2022

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EXECUTIVE SUMMARY

It’s been thirty years since the start of the Human Genome Project (HGP), an bold initiative to sequence
and catalog the three billion letters that compose humanity’s genetic instruction book. The findings from
that work have transformed fields like pediatrics, oncology, infectious disease, and drug development.
The technological advances spurred by the HGP today shape agriculture, energy, forensics and archeology.
Pocket-sized DNA sequencing machines bring DNA analysis to the field, pandemic hot spot or even the
space station. In addition to the technological leaps resulting from the HGP, there have been thousands of
jobs created and billions in economic impact for the nation and the world.

The HudsonAlpha Institute for Biotechnology focuses on translating the power of genomic information into
real world results. A global leader in biotechnology and genomic research, we’ve made important discover-
ies in childhood genetic disorders, cancer, and neurodegenerative disorders like Alzheimer and Parkinson’s
disease. Our agricultural team specializes in understanding how genomics shapes the way plants function
in response to their environment. Over forty bioscience companies have made HudsonAlpha home, working
in fields from drug discovery to disease detection and informatics to gene editing.

This Biotechnology Discoveries and Application Guidebook highlights the recent findings and breakthroughs
as well as the potential uses of genomics and biotechnology. The articles showcase a small sampling of the
thousands of scientific advances around the globe during the past three years. The content is divided into
two sections: new findings and foundational concepts.

New research discoveries are categorized into:
• Genetics and genomics in the clinic
• Genetics and society
• Cancer
• Bacteria, viruses and other pathogens
• Agriculture

The foundational technologies, along with twenty applications of genomics are described in detail beginning
on page 36.

Building on the foundation of the HGP, genomics today influences conversations in agriculture, health,
informatics and ethics, impacting funding, regulation, legislation and business. This guidebook was created
to provide content and context around these discussions. We are excited to share it with you.

Richard M. Myers, PhD Neil E. Lamb, PhD J. Carter Wells
President and Science Director Vice President for Educational Outreach Vice President for Economic Development
HudsonAlpha Institute for Biotechnology HudsonAlpha Institute for Biotechnology HudsonAlpha Institute for Biotechnology
M.A Loya Chair in Genomics [email protected] [email protected]
[email protected]

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Biotechnology Discoveries
and Applications

An overview of recent research findings and their potential impacts

© Copyright HudsonAlpha 2021
Image Credits
Unless otherwise stated, images in this publication were purchased or provided by:
Adobe® Stock, FreePix, Pixabay®, Pexels®, Shutterstock®, Unsplash.com, University of California Davis, Envato
RightsLink, Biorender.com, Sellers.com, TACF, NASA library and HudsonAlpha Institute for Biotechnology library

GUIDEBOOK CONTENTS

About HudsonAlpha Institute for Biotechnology ...................................................5

Recent Findings..........................................................................................................11
Types of Genetic Testing...................................................................................12
Genetics and Genomics in the Clinic................................................................14
Genetics and Genomics in Society...................................................................18
Cancer...............................................................................................................20
Bacteria, Viruses and Other Pathogens...........................................................24
Agriculture........................................................................................................28

Foundational Concepts...................................................................................................35
Key Technologies
DNA Sequencing.....................................................................................36
RNA and Protein Analyses......................................................................36
Bioinformatics.................................................................................................37
Applications
Agriculture........................................................................................................38
Cancer...............................................................................................................39
Comparative Genomics.....................................................................................40
Copy Number Variation.....................................................................................41
Criminal Justice and Forensics........................................................................42
Epigenetics........................................................................................................43
Genetic Information Nondiscrimination Act (GINA).........................................44
Genetics of Eye Color........................................................................................45
Genome Editing.................................................................................................46
Gene Therapy....................................................................................................47
Identifying Genetic Influence on Disease.........................................................48
Infectious Disease.............................................................................................49
Noninvasive Prenatal Testing...........................................................................50
Personal Genome Analysis...............................................................................51
Pharmacogenomics..........................................................................................52
Precision Medicine and Precision Health........................................................53
Public Health Genomics...................................................................................54
Recombinant DNA and Genetic Engineering...................................................55
Stem Cells.........................................................................................................56
Synthetic Biology...............................................................................................57

HudsonAlpha Educational Resources ...................................................................58



HUDSONALPHA
INSTITUTE FOR BIOTECHNOLOGY

To learn more about HudsonAlpha,
visit hudsonalpha.org

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science for life®

About HudsonAlpha

The HudsonAlpha Institute for Biotechnology is a national and international leader in
genetics and genomics research and biotech education located in Huntsville, Alabama.
This nonprofit Institute is dedicated to developing and applying scientific advances to health,
agriculture, learning and commercialization. HudsonAlpha’s vision leverages the synergy
between research discoveries, education, economic development and health diagnostics
and treatments in genomic sciences to improve the human condition around the globe.
The state-of-the-art facilities also co-locates nonprofit scientific researchers with
entrepreneurs, educators and health professionals.

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

Current research focus areas are:

Basic Research Pediatrics Neurological Cancer
Foundational research Undiagnosed and Psychiatric Disorders Multiple forms of
aimed at improving childhood genetic cancer, including
scientific theories disorders including Alzheimer disease, breast, ovarian,
and understanding Parkinson disease, ALS, prostate, kidney, brain,
Huntington disease, bipolar colon and pancreatic
disorder, schizophrenia,
autism and epilepsy

Genomic Health Agriscience Immunogenomics Computational Biology
Leveraging the power Applying genomic Application of genomic and Bioinformatics
of the human genome knowledge to crop technology to Deep computational analysis
to diagnose, predict and improvement and understand the and interpretation of vast
prevent disease bioenergy to immune system’s amounts of data, critical
create a more role in health to the interpretation of the
sustainable world and disease science of genomics

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Agriculture Research

HudsonAlpha uses the power of genomics to improve Faculty at the HudsonAlpha Genome Sequencing Center
sustainable crops for use as food, energy and fiber. have generated reference genomes for more than 150 plants,
By combining their expertise in evolutionary biology, approximately half of plants sequenced as high-quality
genome editing and plant genomics, faculty at the references worldwide. Reference genomes serve as a point
of comparison for future studies and lay the foundation for
HudsonAlpha Center for Plant Science and Sustainable downstream functional studies for the improvement and
Agriculture created a pipeline to accelerate plant breeding production of domesticated crops.
programs to develop the next generation of crops.
This pipeline relies heavily on the strong foundation of the Advances in computational biology and plant biotechnology
high-quality genome sequencing generated at the Institute. allow HudsonAlpha faculty to identify key genes related to
important crop traits such as increased yields, drought
tolerance, or pest resistance. The beneficial traits can be
introduced into existing crop lines using accelerated breed-
ing programs or precision genome editing. Current research
focuses include peanuts, cotton, the common bean, barley,
poplar trees, pecans, duckweed and bioenergy crops like
switchgrass, miscanthus and sugarcane.

Computational Biology and Bioinformatics

The HudsonAlpha Strategic Software Group develops and uses computer applications
to analyze genomic and clinical datasets to support the interpretation of genomic data.
The software engineering team develops innovative solutions to advance the research
missions of HudsonAlpha. For example, they create and deliver exceptional technology
solutions to physicians to help bring genomic health to patients by producing actionable
recommendations and real-world results. Driven by the mission of advancing the technology
of genomics, the HudsonAlpha Strategic Software Group is working on discoveries that will
positively impact the world around us. The ability to acquire DNA sequences has grown at
an unprecedented rate. HudsonAlpha is developing the tools to apply this massive amount
of data to healthcare at a scale and scope not previously appreciated. By testing the limits
of sequencing technology, the team has developed unparalleled expertise in the acquisition,
analysis and application of genomic information.

Research Partnerships and Support

HudsonAlpha partners with other research institutes and life sciences companies around the globe and at the International
Space Station —­ to make genomic discoveries.

Government support comes from:

NIH- National Institute of NIH- Human Genome National Science National Aeronautics U.S. Department
Diabetes and Digestive Research Institute Foundation and Space U.S. Department of Energy
and Kidney Diseases of Agriculture
NIH- National Institute Administration
NIH- National Institute of of Arthritis and 7
Neurological Disorders Musculoskeletal and
and Stroke Skin Diseases

NIH- National Cancer NIH- Heart, Lung, and
Institute Blood Institute

NIH- National Institute NIH- National Institute of
on Aging Mental Health

Educational Outreach

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 educa-
tors at HudsonAlpha reach students, educators, medical practitioners and the community through
hands-on classroom modules, in-depth school and workshop experiences along with digital learn-
ing opportunities. HudsonAlpha also provides educational opportunities for healthcare providers
and learning tools for patients who are making medical decisions using their personal genomic in-
formation. Additionally, the team builds genomics awareness through community outreach classes
and events. During the 2019–2020 academic year, 1,953,528 individuals were impacted through
HudsonAlpha Educational Outreach. Over the past decade, HudsonAlpha has reached nearly
7.5 million people with these programs and resources.

EDUCATION HIGHLIGHTS
 Educator Professional Learning from single day workshops
to on going classroom support
 Student Experiences from field trips, classroom visits,
camps, internships opportunities and mentoring opportunities
 Classroom Kits and Digital Resources (see p. 60)
 Clinical Applications where genetic counselors provide
patient and provider education and support

Genomic Health

HudsonAlpha is empowering people to be informed genomic The Smith Family Clinic for Genomic Medicine, LLC on the
healthcare consumers and members of society. The genomic campus of HudsonAlpha, provides patients with undiagnosed
health team conducts cutting-edge research into hereditary and misdiagnosed diseases with genome sequencing and
disease risks and early disease detection. The genomic health interpretation. The clinic provides valuable tools not only for
program is also designed to educate health professionals and diagnosis but also for prediction and prevention of disease.
clinical researchers in the technologies, applications, ethics
and social impacts of the practice of genomics as it is The HudsonAlpha Clinical Services Lab, LLC is trusted by
increasingly being integrated into clinical care. scientists and medical providers around the world to sequence
genomes for their patients. The CAP/CLIA testing results
The HudsonAlpha Health Alliance, LLC delivers are used by researchers, healthcare systems and other
individual genomic data and health solutions laboratories to provide whole genome sequencing, population
to such groups as physician networks, pop- health screening arrays and tumor sequencing.
ulation groups and employers. The Health
Alliance develops customized genomic health
screening programs and/or pharmacog-
enomic testing for their groups to decrease
healthcare costs and improve health outcomes.

Results also identify medications that work well
for an individual's genetic makeup to prevent fewer
medical reactions. Healthcare groups, colleges and Native
American tribes have discovered the benefits of genomic
health through the Health Alliance.

The Health Alliance is ensuring that healthcare providers
and patients understand all aspects of genomic test options,
results and actionable next steps by offering clinical decision
support and consulting services of HudsonAlpha’s experienced
clinical lab and diagnostic professionals, genetic counselors
and knowledgeable genomic educators.

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Entrepreneurship and Economic Development

HudsonAlpha strengthens and diversifies the economy by CAMPUS HIGHLIGHTS
fostering success in life sciences companies of all stages and n 152 acre campus in Cummings Research Park —
sizes. HudsonAlpha offers turnkey and build-to-suit labora- 2nd largest research park in the United States
tory and office space for lease in an energizing environment n Superior physical space, high-end labs and equipment
with superior shared amenities. Bioscience enterprises on Nearly 500,000 SF in 4 buildings on campus with
campus benefit from access to HudsonAlpha researchers as sites available for construction and ground lease
well as strategic support through investor forums, workforce n 5th building, approximately 115,000 SF, opening in 2023
and business assistance, marketing resources and bioscience n NIH biosafety standards
networking events. n Alabama is top 5 in workforce recruitment and training
n Bioscience incentives and custom tax packages from state
n Longest double-helix walking pathway in the world

With a talented, readily available workforce, world-class Fostering entrepreneurs, supporting biotech companies and
space, strategic location, business friendly environment and
a “can-do” attitude, HudsonAlpha should be on the short list building a life science hub
for any biotech venture. HudsonAlpha supports entrepre-
neurs, biotech companies large and small, angel, venture The resident associate companies that call HudsonAlpha
capital and private equity investors, site selectors and invest- home are working in multiple fields within the biosciences
ment banks specializing in mergers and acquisitions — including drug discovery and development, data sciences,
all benefiting those on the HudsonAlpha campus. infectious disease detection and treatments, biospecimen
analysis and procurement, genetic and genomic testing,
The more than 45 companies on campus consist of: bioinformatics, production of reagents and materials for
n Diagnostics and therapeutics research and genomic sequencing services. HudsonAlpha
n Medical devices offers sites for developing bioscience headquarters, R&D
n Drug discovery and development facilities, lab, office and manufacturing. As part of the
n Research instruments and tools HudsonAlpha campus, all resident associate companies
n AgBio receive access to shared spaces and services.

Culture of collaboration with a proven record of success Some of the associate companies started as spin outs from
HudsonAlpha offers associate companies opportunities HudsonAlpha research laboratories while some relocated
to advance business growth. Subject matter experts are from other areas of the country because of the benefits of
available to the first-time entrepreneur and the seasoned this unique ecosystem. Companies have the flexibility to
business executive for advice and counsel on accessing capi- grow and expand on the HudsonAlpha biotech campus.
tal, assessing intellectual property and commercial viability
of a product, navigating regulatory environments, securing
partnerships and developing and executing exit strategies.

9



RECENT FINDINGS

A sampling of research advances from the
United States and abroad during the past three years

11

TYPES OF GENETIC TESTING

Genetic tests use various laboratory methods to examine your
DNA. They range from studying a single letter of the DNA
sequence to analyzing the entire genome.

Prenatal:

There are two types of prenatal tests
related to genetic conditions: screening
and diagnostic. Prenatal screening tests
generally measure the concentration of specific
proteins or hormones in the mother’s bloodstream
to identify the risk of having a child with certain
genetic disorders, such as Down syndrome. Recent
noninvasive techniques are even able to collect and
test pieces of fetal DNA that circulate in the mother’s
blood. These approaches do not diagnose a disorder,
but signal that further testing should be considered.
Diagnostic tests directly analyze fetal DNA, often
obtained through invasive procedures such as
amniocentesis or chorionic villus sampling (CVS).
Prenatal diagnostic tests may study the number
and structure of the chromosomes in fetal Lifestyle:
cells, or identify the sequence of a specific
gene or region of the genome.
Genetic testing to identify lifestyle and
wellness-related traits is an emerging field.
These tests provide information on topics
ranging from earwax type and personality style
to nicotine dependence and muscle
performance. Since many of these traits
are influenced by multiple genetic and
Pediatric: environmental factors, the accuracy and

utility of these tests is unclear.

Between two and three percent of all children
have a physical birth defect or clinical disorder.
These may be seen at birth, or become evident
during childhood. All infants born in the United States
undergo newborn screening to identify disorders that
can affect a child’s long-term health. Using a few
drops of blood from a baby’s heel, clinical laboratories
test for at least 29 diseases, most of which are genetic in
nature. Children who have symptoms of a genetic disorder
or do not meet developmental milestones may undergo
diagnostic genetic testing to identify or rule out a
specific condition. This may be a targeted test for a
specific mutation, a test of a single gene or a handful
of genes known to be associated with the child’s Adult:

symptoms, or a genome-wide analysis to more Genetic testing in adults generally falls
broadly search for answers. into one of three categories:

Diagnostic testing seeks to identify disease-causing
mutations to explain a patient’s existing set of symptoms.

Predictive/Presymptomatic testing
detects mutations for disorders that often appear later in life.

These tests are usually ordered for individuals who have a
family history of a disease but have no signs of that
disease at the time of testing.

Carrier testing identifies people who carry a single copy of a
mutation that - when present in two copies – causes disease.

The individual is healthy but could pass along the mutation
to a child. Couples may decide to have carrier testing to
determine their risk of having a child with certain
genetic conditions.

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Pharmacogenomic: How does a human genome get sequenced?

Some genes are responsible for how the body processes Your genome is your unique sequence of DNA, 3 billion letters long.
medications. Pharmacogenomic testing looks for changes
in those genes and seeks to correlate that information to It’s found in almost every cell in your body.
a person’s response to medications. It seeks to predict the
most effective drug at the right dose, as well as identify those DNA Adenine
drugs that may cause harmful side effects. For example,
warfarin is a drug that helps prevent blood clots, strokes Bases Thymine
Sugar Cytosine
and heart attacks. Individuals who have specific genetic phosphate Guanine
variants require lower doses for therapy. Similar variants backbone

are associated with medications for depression and The letters A,T, C and G represent the chemical
chemotherapy. While these types of tests are currently elements, or bases, of DNA.

used for only a few health issues, they will become
increasingly important in the years ahead. At the moment,

no single pharmacogenomics test can predict an
individual’s response to all medications. In addition,

no such tests are available for most over
the counter medications.

Ancestry: DNA is extracted from a sample and loaded on to
a sequencing machine.
Because certain patterns of DNA variation are
more commonly found among individuals of specific 1 The machine determines
backgrounds, DNA analysis can shed light on where an the sequence of segments
individual’s ancestors likely came from. The more of these of DNA.These are
patterns that two people share, the more closely related 2 called reads.
they are. Genetic ancestry testing usually examines DNA 3 The ‘reads’ from the sequencing machine are matched
variation on the Y chromosome (to study the male line), to a reference sequence. This is called mapping .
the mitochondria (for details about the female line) or

single letter changes throughout the genome (to
estimate the overall ethnic background). This type

of testing does not reveal any medical or
health-related information and while it may

provide geographic origins for distant
ancestors, it cannot provide the
names of those ancestors.

Cancer:

Genetic testing may be useful as a predictive test for 4 Analysis
individuals with a family history of certain types of
Within the 3 billion letters in your genome are 20,000 genes.
cancers (such as breast, ovarian and colorectal). A positive These make up about 2% of the sequence. The position of most
test result indicates the person has inherited a genetic of our genes is known, and is marked on the reference sequence.
Every person has millions of differences (called variants)
mutation that significantly increases his or her lifetime risk of from the reference sequence.
developing cancer. These individuals may have more frequent Most of these difference are harmless – they are the
cancer screenings or chose to undergo surgery to reduce the reason we are different from each other. Some
differences could be causing a disease.
cancer risk. In some cases, this type of genetic testing for
inherited mutations may also be appropriate when cancer Bioinformatics specialists use a variety of tools and
has already been detected. In addition, genetic testing of the techniques to filter these differences down from
millions to just a handful that could be harmful.
tumor cells may be requested to determine which
cancer-causing mutations have been acquired by the If it is not clear which difference is causing disea,se
researchers anaylze the genome further.
tumor. This knowledge may aid in diagnosis and
shape a physician’s choice of therapy
to treat the cancer.

DNA Profiling:

DNA profiling identifies an individual’s unique
pattern of DNA variation and is often used in
parentage testing and criminal investigations.
A parent shares 50% of his or her genetic variation
with a child. A paternity or maternity test compares the
DNA patterns between the child and alleged parents
to look for evidence of genetic sharing. Forensic DNA
testing can link a perpetrator or victim to a crime
scene as well as exonerate individuals convicted of
crimes they did not commit. There are limitations

to this type of testing, including the
inability to distinguish between identical

twins and the challenge of assessing
samples with degraded or low
amounts of DNA.

13

RECENT FINDINGS — GENETICS AND GENOMICS IN THE CLINIC

Polygenic risk Polygenic risk scores show a lot of promise, because they can
scores reveal help people responsibly monitor the aspects of their health where
disease risk, pose they are most genetically vulnerable. Sometimes small lifestyle
risks of their own changes can prevent large health complications down the road,
leading to better outcomes and lower costs. However, it is also
Most diseases and health outcomes possible those test results cause someone to live in fear of some-
cannot be narrowed down to changes thing that never comes to pass, potentially taking drastic steps to
in a single gene. Instead, they are stop what might not have been a real threat for them. Conversely,
the result of dozens or even hundreds of others might ignore signs of a problem because they feel they are
genes working together in concert with environmental factors. On their not at risk, given their test results showed a low likelihood for a
own, each genetic variant has only a tiny influence on disease risk, but particular outcome. Many researchers feel a larger population of
the collective impact may be quite large. Polygenic risk scores (PRS) individuals should be tested and followed before PRS are ready
use machine learning and large databases to aggregate the effect of for disease prediction and prevention. These polygenic risk scores
multiple genes for a specific disease. Over the past year, PRS have been show immense potential for creating a more genomically literate
created for a variety of health outcomes, from obesity to heart disease, society, specifically in regard to the way a person’s genome
diabetes to depression. They are hypothesized to provide physicians and impacts their health. It’s important that the score comes with the
patients a more accurate estimate of disease risk. Some organizations appropriate guidance though, or else it could wind up doing more
are even looking to develop web-based platforms that will allow con- harm than good.
sumers to upload their existing direct-to-consumer genetic information REFERENCE: Sugrue L.P. and Desikan R.S. What Are Polygenic Scores and
to obtain personal risk scores.
Why Are They Important? Journal of the American Medical Association (2019)
321:1820-21 doi: 10.1001/jama.2019.3893.

Building a genetic map of Set of projects show
psychiatric disorders value, limits for
genetic sequencing
The burden of psychiatric disorders continues to grow worldwide with of newborns
more than a fourth of the population being affected with one or more
disorder in any given year. Psychiatric disorders refer to a wide range The National Institutes of Health
of mental health conditions that affect a person’s mood, thinking and funded a series of four projects in 2013
behavior. Results from research in twins and large-scale genomics with the shared goal of studying the use
studies suggest that genetic variation has a major influence on of genetic sequencing for newborns. The
psychiatric disorders. program, called NSIGHT, summarized find-
The Cross-Disorder Group of the Psychiatric Genomics Consortium is an ings in June 2019. While sequencing shows great promise as a tool
international group of researchers who seek to map out the genetic land- for quick diagnosis of acutely ill newborns, the practice likely isn’t
scape of psychiatric disorders in an effort to improve and customize the ready to replace the standard newborn screening tests.
diagnosis, prognosis and therapy of the disorders. In a recent publication
in Cell, the team reported results from the largest study on the genetics For one dataset, initial sequencing was used on 35 infants
of psychiatric disorders to date. admitted to the neonatal intensive care unit (NICU). Of those
Researchers performed genetic analysis on over 230,000 patients with 35 babies that received whole-genome sequencing, 20 also
anorexia nervosa, autism, ADHD, schizophrenia, bipolar disorder, depres- received a diagnosis, 11 got a change in care management, four
sion, obsessive-compulsive disorder or Tourette Syndrome and nearly had improved outcomes, and one life was saved, according to
500,000 control individuals without the disorders. The researchers dis- the clinicians running the program.
covered 109 genetic variants that were associated with at least two of the
eight disorders and 26 that were associated with four or more. Using this Sequencing was expanded to a larger group in order to survey
knowledge, clinicians could estimate a person’s genetic risk to develop parents and clinicians on how useful they found the test. Both
other disorders based upon the disorder with which they are diagnosed. parents and medical professionals agreed the sequencing was
The study also shows that the genes in which the variants are found are useful, with those caring for the sickest children the most likely to
usually active during the second trimester of pregnancy. Because this find the tests to be valuable. Parents even felt that negative reports
is a crucial stage in the development of the nervous system, the gene were helpful. Analysis of results continues, specifically in regard to
variants may play a role in brain development and confer a broad risk of cost effectiveness.
psychiatric disease.
The Consortium plans to continue mapping the genetic landscape of Researchers did note that sequencing is most helpful in unique
genetic disorders through the analysis of other genetic variations and cases. For the vast majority of infants, current newborn screening
also epigenetic changes that could give insights to interactions between protocols are highly effective and cost efficient. Newborn sequenc-
genes and the environment. ing has a lot to offer, but it isn’t ready to be elevated to the first line
of defense.
REFERENCE: Cross-Disorder Group of the Psychiatric Genomics Consortium.
Genomic relationships, novel loci and pleiotropic mechanisms across eight psychiatric REFERENCE: The NSIGHT program held a public webinar June 24, 2019 to dis-
disorders. Cell (2019) 179:1469-1482 doi:10.1016/j.cell.2019.11.020. cuss findings from the four funded projects. Videos of each session can be found at
https://www.genome.gov/event-calendar/NSIGHT-Final-Public-Session.
14

Pharmacogenomic testing: how Science snapshots
variations in DNA can affect the
body’s response to medications n The All of Us research initiative seeks to build a diverse human
database with more than 1 million Americans. More than 350,000 have
The right medication can cure diseases and save lives. However, a enrolled since the program began in mid 2018 — completing surveys,
drug that works for one person may not work for another person with sharing data from their electronic medical records and donating
the same disease or condition. A growing collection of scientific samples for genetic testing. Half of the participants are from racial or
evidence suggests that variations in DNA can affect the body’s ethnic minority groups. The initial set of data are available for study
response to medications. through the All of Us Researcher Workbench, currently in beta testing.

Some people have genetic variants that affect the rate their body The laboratory of HudsonAlpha faculty researcher
breaks down a certain drug. If a drug is broken down too quickly, it Shawn Levy, PhD is testing technologies associated with
is eliminated from the patient’s body before it can work at effective long-read sequencing for the All of Us initiative.
levels. Alternatively, if a drug is broken down too slowly, the drug
builds up in the patient’s system and causes severe side effects. Other REFERENCE: National Institutes of Health. All of Us Research Program
people can have genetic variants that cause them to have severe side Begins Beta Testing of Data Platform. N.p., 27 May 2020. Web 18 August 2020.
effects to the drug that are unrelated to the rate of drug metabolism. https://allofus.nih.gov/news-events-and-media/announcements/all-us-research-
program-begins-beta-testing-data-platform.
Using genomic sequencing to detect these variants in a person’s
genome, called pharmacogenomic testing, can help doctors predict n The Encyclopedia of DNA Elements is a world-
whether certain medications or doses will be effective for the patient, wide effort to understand the human genome.
or if they are likely to have an adverse reaction to that drug. Respons- For nearly two decades, researchers have been
es to more than one hundred medications are currently known to be developing a map of the millions of DNA switch-
influenced by the genome. es that regulate when and where genes are
turned on and off. Results from the most recent
In 2018, the FDA issued a safety communication about their phase of ENCODE were simultaneously published
concern with firms offering genetic tests and suggesting how to use in over a dozen papers. Six thousand additional
the genetic test results to make decisions about medication treat- datasets were generated from 500 cell and tissue sam-
ments that are not supported by recommendations in the FDA-ap- ples. Nearly 1 million new regulatory regions were identified in the
proved drug labeling or other scientific evidence. Medical decisions human genome, along with nearly 340,000 similar regions in mice.
based on inaccurate information can result in harm to the patient if
they do not receive the most appropriate medication or dose, or if they The laboratory of HudsonAlpha faculty researcher
receive a medication that causes harmful side effects. Richard M. Myers, PhD contributed to this research.

Because some pharmacogenomic test manufacturers are still mar- REFERENCE: The ENCODE Project Consortium. Expanded encyclopedias of DNA
keting their tests with claims not grounded in sound science, the FDA elements in the human and mouse genomes. Nature (2020) 583:699-710. DOI: 10.1038/
has taken additional steps to help inform physicians and the general s41586-020-2493-4.
public. They are actively maintaining a web-based resource that lists
some of the gene-drug interactions that it has evaluated and believes n Historically, researchers have used a single “reference genome”
have sufficient scientific evidence to suggest that patients with certain developed for an individual species. While beneficial, these references
genetic variants are likely to have altered drug metabolism. are limited in their ability to capture the variety of DNA sequenc-
es present within a population. Scientists have begun developing a
REFERENCE: U.S. Food and Drug Administration/Center for Drug Evaluation and multi-genome human reference that is as universal and complete as
Research. FDA Announces Collaborative Review of Scientific Evidence to Support possible, representing 350 human genomes and known as a “pan-ge-
Associations Between Genetic Information and Specific Medications. 20 February 2020. nome.” They estimate that a full human pan-genome may include as
https://www.fda.gov/news-events/press-announcements/fda-announces-collabor many as 40 million bases of DNA missing from the current reference.
ative-review-scientific-evidence-support-associations-between-genetic
REFERENCE: National Human Genome Research Institute. NHGRI funds centers for
advancing the reference sequence of the human genome. N.p., 24 September 2019. Web
15 August 2020. https://www.genome.gov/news/news-release/NIH-funds-centers-for-
advancing-sequence-of-human-genome-reference#.

n Researchers have pinpointed a previously unknown cause of epi-
lepsy in infants, hidden in a gene called SCN1A. The mutation incorpo-
rates a damaging piece of genetic code, called a poison exon, into the
final instructions for the SCN1A protein. The poison exon prematurely
cancels the protein’s production and leads to the seizure disorder by
disrupting neural function. Other studies have identified the presence
of hundreds of similar poison exons across the genome, suggesting
this mechanism may be a component of other human diseases.

The laboratories of HudsonAlpha faculty researchers Greg Barsh MD, PhD,
Richard M.Myers, PhD and Greg Cooper, PhD contributed to this research.

REFERENCE: Carvill G.L. et al. Aberrant Inclusion of a Poison Exon Causes Dravet
Syndrome and Related SCN1A-Associated Genetic Epilepsies. American Journal of
Human Genetics (2018) 103:1022-29 doi: 10.1016/j.ajhg.2018.10.023.

15

RECENT FINDINGS — GENETICS AND GENOMICS IN THE CLINIC

Gene editing: deletions and rearrangements, some as large as a whole chro-
promises and pitfalls mosome. While it is well known that gene editing can cause "off
target" mutations, these studies suggest a much larger landscape
CRISPR is a gene editing technology that creates targeted of CRISPR-influenced errors.
and specific changes to DNA. It is widely used in a labora- Because of the unknown nature of CRISPR-based gene editing,
tory setting to cheaply and efficiently study the function many countries limit its use to human somatic cells, banning
of specific genes. However, CRISPR-based gene therapy editing in germline, or reproductive, cells. The CRISPR-baby
to treat genetic disease in humans is gaining popularity. scandal rocked the scientific community and sparked controversy
Recent studies suggest that while gene therapy shows across the globe when a Chinese scientist secretly created the
promise, direct gene editing of human embryos should be world’s first genetically edited babies. He was recently sentenced
approached with caution. to prison for illegally practicing medicine, supporting the notion
that the practice of human gene editing should be approached in a
CRISPR Promising Results methodical and cautious manner, backed by supportive research
in accepted experimental models.
Treating Rare Inherited Diseases
Beta thalassemia and sickle cell disease are inherited blood dis- REFERENCES: CRISPR Therapeutics. CRISPR Therapeutics and Vertex
orders caused by mutations that affect the production or structure Announce New Clinical Data for Investigational Gene-Editing Therapy CTX001™ in
of hemoglobin, the protein that carries oxygen in red blood cells. Severe Hemoglobinopathies at the 25th Annual European Hematology Association
Promising preliminary results presented at a scientific meeting (EHA) Congress. 12 June 2020. Web. 31 August 2020. https://crisprtx.gcs-web.com/
this year report that due to CRISPR-based therapy three people news-releases/news-release-details/crispr-therapeutics-and-vertex-
with these disorders no longer require the blood transfusions they announce-new-clinical-data.
previously relied on to treat their symptoms. For the gene therapy, NPR. In A 1st, Scientists Use Revolutionary Gene-Editing Tool To Edit Inside
bone marrow stem cells were removed from the affected individ- A Patient. 4 March 2020. Web. 31 August 2020. https://www.npr.org/sections/health-
uals and the gene that turns off fetal hemoglobin production was shots/2020/03/04/811461486/in-a-1st-scientists-use-revolutionary-gene-editing-
disabled with CRISPR. The edited cells were transfused back to tool-to-edit-inside-a-patient.
the patient and the now active fetal hemoglobin, which is normally Alanis-Lobato, G. et al. Frequent loss-of-heterozygosity in CRISPR-Cas9-
turned off after birth, can carry oxygen throughout the body. edited early human embryos. Preprint posted to Biorxiv 5 June 2020. doi:
In Vivo Gene Editing 10.1101/2020.06.05.135913.
In another promising advance for gene editing, scientists used Zuccaro, M.V. et al. Reading frame restoration at the EYS locus and allele-specific
CRISPR to try to edit a gene while the DNA was still inside the chromosome removal after Cas9 cleavage in human embryos. Preprint posted to
person’s body. Scientists engineered a harmless virus to Biorxiv 18 June 2020. doi: 10.1101/2020.06.17.149237.
deliver the instructions to manufacture the CRISPR gene-editing Liang, D. et al. Frequent gene conversion in human embryos induced
machinery within the body. The virus was injected into the eye of by double strand breaks. Preprint posted to Biorxiv 20 June 2020. doi:
patients with blindness due to a rare genetic disorder. Once inside 10.1101/2020.06.19.162214.
the eye, the CRISPR machinery repaired the genetic defect that AP News. China convicts 3 researchers involved in gene-edited babies.
caused the blindness in hopes that the person’s vision is 30 December 2019. Web. 31 August 2020. https://apnews.com/
ultimately restored. 7bf5ad48696d24628e49254df504e3ee.

CRISPR Cautionary Tales

Not all of the buzz surrounding the advancement of CRISPR gene
editing to treat human disease is positive. Three recent studies
that were published on the preprint server bioRxiv reveal how
gene editing can go awry. Each of the studies set out to edit one
gene in human embryos but showed large-scale, unintended DNA

Student-designed performed the experiment to investigate DNA
experiment marks repair efficiency in microgravity. After the
first use of CRISPR CRISPR damage, cells were monitored using
in space PCR and sequencing-based tests to measure
how effectively DNA repair mechanisms dealt
Four high school students from with the injury. This experiment marks the first
Minnesota won the 2018 Genes in use of CRISPR in space. The entire investigation;
Space competition with their idea for growing yeast cells, inducing DNA lesions, PCR and
simulating the DNA damaging effects of cosmic radiation using DNA sequencing took place on the space station. The success of the
CRISPR. The students designed a CRISPR Cas9 system that made experiment provides further evidence that terrestrial genomic tools
targeted changes in the DNA of yeast cells. Following further devel- are viable in space.
opment help from Boeing, MiniPCR and NASA, the student’s experi- REFERENCE: ISS National Laboratory. History in the Making: Student Experiment
ment launched in early 2019. International Space Station astronauts
Edits DNA with CRISPR Technology in Space. N.p., 24 May 2019. Web. 20 July 2019.
16 https://www.issnationallab.org/blog/history-in-the-making-student-experiment-
edits-dna-with-crispr-technology-in-space/

Early testing, markers, and risk Gene and cell therapies
factors for Alzheimer disease offer pricey miracles

Diagnosis of Alzheimer disease is currently made with clinical A recent report identified nearly 300 new gene and cell therapies
assessments of memory and cognitive impairment along with diag- currently in development. For those who receive the treatments, they
nostic tests, such as MRI and PET scans, which are expensive and can often seem miraculous, especially for diseases where clinicians
unavailable for some patients. have had few or no prior options.
Blood test for Alzheimer disease diagnosis Gene therapy was successfully used in one clinical trial to cure
An international team of researchers have developed a blood-based X-linked severe combined immunodeficiency (SCID-X1), sometimes
test for the diagnosis of Alzheimer disease that is more accurate than called “bubble boy disease.” The genetically inherited condition inhibits
MRI brain scans and as accurate as PET scans and spinal taps. The normal immune function. By taking out bone marrow, introducing
test measures a form of tau protein in blood, which is a protein re- synthetic, functional DNA to blood stem cells in that bone marrow,
sponsible for the devastating tangles that promote damage within the then reintroducing the marrow into the body, scientists were able
brain. The test can not only differentiate between Alzheimer demen- to restore immune function. The Food and Drug Administration
tia and other forms of dementia, but can also predict how quickly a recently approved another gene therapy a little further along the trial
person’s cognitive ability will decline by measuring the amount of the process — Zolgensma® treats infants with spinal muscular atrophy,
protein in their blood. The test needs to undergo further clinical trials which affects motor neuron function. The treatment works by intro-
but could be available within the next two to three years. ducing healthy copies of the affected gene through a virus and it has
Disruption of blood-brain barrier early marker led to significant improvement in patients.
In a recent study published in Nature, researchers suggest that the Huntington disease also saw an important trial for a type of gene
APOE4 gene, long known to increase a person’s risk for Alzheimer dis- silencing treatment called antisense oligonucleotide. The treatment
ease, causes damage to the blood-brain barrier (BBB) which normally works by introducing specifically designed DNA molecules that bind
helps to keep toxins out of the brain. They found that people who were mRNA made by the disease-causing gene, leading to the mRNA’s
cognitively healthy and carried at least one copy of APOE4 had a leaky destruction. The trial showed the treatment wasn’t harmful to
BBB in two brain regions important for memory and cognition. Surpris- patients and reduced levels of the mutant huntingtin protein were
ingly, these effects preceded any signs of tissue loss, suggesting that observed in patient’s cerebrospinal fluid.
BBB disruption is an early event in the onset of neurodegeneration. Other promising cell therapies use induced pluripotent stem cells
Genetic risk factor for multiple neurodegenerative diseases (iPSCs) to replace non-functioning or poorly functioning cells.
Pluripotent cells can develop into other kinds of cells and iPSCs can
A group of researchers recently uncovered gene variants that double be generated from other adult cells, making them relatively easy to
a person’s risk of multiple neurodegenerative diseases including obtain. In Japan, researchers used iPSCs to halt age-related macular
Alzheimer disease, amyotrophic lateral sclerosis, and frontotem- degeneration, successfully reprogramming skin cells to become eye
poral dementia. The gene, TET2, codes for a protein involved in DNA cells. In this first clinical trial, the treatment prevented further vision
demethylation, or removing chemical groups from DNA that changes loss. Scientists have also used iPSCs reprogrammed from donor skin
how it is read. Other studies suggest that DNA becomes more methyl- to generate brain cells that were implanted into a patient with Parkin-
ated as we age, meaning the TET2 genetic variants with impaired de- son disease. That trial is in a very early stage and researchers plan to
methylation processes discovered in this study might mimic the aging treat an additional six patients by the end of 2020. These treatments
process, putting people at higher risk of neurodegenerative disorders. can generate incredible results, but they are also expensive to develop
While these tests and biomarkers still require further testing, they and administer. For example, the single shot required for the spinal
provide promise for affordable, early detection of Alzheimer disease muscular atrophy treatment costs $2.1 million, leading some to call
and other neurodegenerative diseases. it the most expensive shot in the world. The conversations about
widespread use of these treatments will have to factor cost in with
The laboratories of HudsonAlpha faculty researchers Richard M. accomplishment.
Myers, PhD and Greg Cooper, PhD contributed to the TET2 research.
REFERENCES: Palmqvist, S. et al. Discriminative accuracy of plasma phos- REFERENCES: Mamcarz E. et al. Lentiviral Gene Therapy Combined with Low-Dose
pho-tau217 for Alzheimer Disease versus other neurodegenerative disorders. JAMA Busulfan in Infants with SCID-X1. New England Journal of Medicine (2019) 380:1525-34
(2020) 324:772-781. doi: 10.1001/jama.2020.12134. doi: 10.1056/NEJMoa1815408.
Montagne, A. et al. APOE4 leads to blood-brain barrier dysfunction predicting cognitive U.S. Food and Drug Administration. FDA approves innovative gene therapy to treat
decline. Nature. (2020) 581:71-76. doi: 10.1038/s41586-020-2247-3. pediatric patients with spinal muscular atrophy, a rare disease and leading genetic
Cochran, N. et al. Non-coding and loss-of-function coding variants in TET2 are cause of infant mortality. N.p., 24 May 2019. Web. 18 July 2019. https://www.fda.gov/
associated with multiple neurodegenerative diseases. The American Journal of Human news-events/press-announcements/fda-approves-innovative-gene-therapy-treat-ped
Genetics (2020) 106:632-645. doi: 10.1016/j.ajhg.2020.03.010. iatric-patients-spinal-muscular-atrophy-rare-disease
Tabrizi S.J. et al. Targeting Huntingtin Expression in Patients with Huntington’s Disease.
New England Journal of Medicine (2019) 380:2307-16 doi: 10.1056/NEJMoa1900907.
Cyranoski D. ‘Reprogrammed’ stem cells implanted into patient with Parkinson’s
disease. Nature (2018) doi: 10.1038/d41586-018-07407-9.

17

RECENT FINDINGS — GENETICS AND SOCIETY

Genetics heat up Lack of diversity leaves gaps
cold cases but in genetics research
privacy is a
growing concern Genetics research has been largely based on populations of
European ancestry. This significantly limits its potential
When DNA is found at a crime usefulness for everyone.
scene, it is typically analyzed and Across the 3 billion base pairs that make up the human genome,
that analysis is run through a people share 99.9 percent of their nucleotides. The small regions
database of existing criminals’ of difference allow researchers to conduct genome wide associ-
DNA to search for a match. Up ation studies (GWAS), hoping to link DNA change to health risks.
until recently, a major limitation When studying complex health issues like heart disease, hun-
of the technology has been this: dreds of genetic markers analyze the constellation of genes that
a suspect must already be in a determine a person’s risk. However, when looking across ances-
criminal database in order to tries, the necessary data points might occur in different places,
make a match. First-time or altering the shape of the constellation. The most recent GWAS
“un-caught” criminals would not aggregations show that nearly 78 percent of participants come
be identified through DNA forensics. from white European ancestry. Their findings do not necessarily
equally apply to populations outside the original study group.
Forensic genetic genealogy is a popular new tool to uncover clues
in criminal cold cases and recent crimes that lack a suspect using Even fundamental tools, like a reference genome, don’t translate
traditional methods. The approach scans public databases to identify universally across ancestry. Research published in November
families with a potential connection to DNA samples recovered from 2018 found that people of African descent had nearly 300 million
crime scenes. The branches of those family trees are then searched base pairs of information not represented in the standard
in hopes of finding a suspect. human reference genome.
Without diverse sources of genomic information, tomorrow’s
This new approach was thrust into the media spotlight in April data-driven, personalized treatments will continue to focus on
2018 when authorities arrested and later convicted, one of people of European ancestry, potentially excluding underrepre-
America’s most notorious serial killers after DNA analysis of mate- sented populations from these benefits. This imbalance of infor-
rials from a crime scene were partially matched with a suspected mation hurts other forms of medical discovery as well because
relative through an ancestry DNA database. That case led to a slew diversity often reveals new mechanisms of genetic resilience.
of similar arrests, where DNA was used to identify a suspect through Multiple factors lie behind this information inequality.
familial ties. To date, the expense of genetic testing has restricted its access to
While most probably agree it is beneficial to catch and prosecute the wealthy or well-insured — a population that is disproportion-
killers, bioethicists believe the approach used in these cases raises ately white. Individuals may be less likely to volunteer for research
several ethical issues for consideration. For example, investiga- studies due to fears that their data will be shared with law en-
tors typically submit the DNA in these cases without the suspect's forcement or other government agencies. Historical examples of
unethical research practices that focused on minority populations
consent, potentially giving law enforcement an immense is another barrier to participation.
amount of personal and medical information about The shortcomings of our current trove of genetic data cannot be
them before they are ever accused of a crime. overlooked, nor can we underestimate the value of expanding that
Not to mention, just because someone wants to dataset to include greater diversity. Efforts to overcome these
know more about their ancestry from a con- challenges begin by directly involving underrepresented commu-
sumer genetics service does not necessarily nities in the design and implementation of genomic analyses.
mean they consent to their genetic data being REFERENCE: Sirugo G., Williams S.M. and Tishkoff S. The Missing Diversity in
used to track their relatives.
As a result of the increased use of forensic Human Genetic Studies. Cell (2019) 177:26-31 doi: 10.1016/j. cell.2019.02.048.
genetic genealogy, most major consumer
genealogical database companies have created
barriers against law enforcement access and
give subscribers the option to opt out of having their

genetic profile shared with law enforcement. In addition,
the U.S. Department of Justice has developed an interim policy for
genetic genealogy, limiting its use to violent crimes or unidentified
human remains where no match is found in the existing FBI genetic
database. The policy went into effect in November 2019 with final
guidance to follow.

REFERENCES: Yeager A. (2018, April 27) Genealogy Website Helped Crack Golden
State Killer Case. Retrieved July 5 2018, from https://www.the-scientist.com/the-
nutshell/genealogy-website-helped-crack-golden-state-killer-case-36328.
U.S. Department of Justice. Department of Justice Announces Interim Policy on Emerg-
ing Method to Generate Leads for Unsolved Violent Crimes. N.p., 24 September 2019.
Web. 5 September 2020. https://www.justice.gov/opa/pr/department-justice-
announces-interim-policy-emerging-method-generate-leads-unsolved-violent.

18

Poverty leaves a lasting Science snapshots
genetic impact
n Scientists recently expanded the library of DNA nucleotides from
Adding more complications to the balance of nature versus nurture, A, T, C and G to include B, S, P and Z. The four new nucleotides were
scientists published research in April 2019 demonstrating that pover- crafted in a laboratory but integrate into the double helix without
ty creates a lasting genetic impact in individuals. The study suggest- disrupting its structure. Researchers call their expanded genetic al-
ed that socioeconomic status can become embedded across wide phabet hachimoji — which means “eight letter” in Japanese. The syn-
swathes of the genome by impacting levels of DNA methylation. thetic nucleotides can pair: B with S, P with Z and can be transcribed
DNA methylation is part of the epigenetic process that determines into RNA. Scientists have long dreamed of ways to create customized
the degree to which certain genes are expressed. Genes are often proteins that execute a specialized task. Having twice as many genetic
described as being on or off, but they are less like flip switches and building blocks at their disposal could significantly improve the design
more like dimmer switches. The level of activation or silencing can options for tailor-made biological based drugs and therapies.
matter a great deal in ensuring that a gene does its job correctly. DNA Hachimoji could also find use as a storage tool for safely encoding
methylation is one of the factors that adjusts that dimmer switch. information long-term.
This study found poverty-linked changes in methylation at 2,500 sites REFERENCE: Hoshika S. et al. Hachimoji DNA and RNA: A genetic system with eight
across 1,500 genes. It’s important to note that the biological impact of
poverty-linked methylation is unknown. Further research is required building blocks. Science (2019) 363:884-7 doi: 10.1126/science.aat0971.
to determine the functional consequence of methylation changes at
these sites. n The consumer genetics market
Health studies have frequently linked socioeconomic status to long- continues to boom, in part because of
term health outcomes, even when that socioeconomic status is not affordable sequencing costs and pub-
a factor at the time of the health issue. It is not understood what lic interest, but also because the data
mechanisms translate the experiences of poverty into long-term generated helps to fuel both public
medical issues, but altering DNA methylation may be a critical and private research. Some groups
pathway. Understanding how changing methylation across these are looking to give people more con-
2,500 genetic loci impacts health outcomes could reveal key factors trol over how their genomic data gets
in how socioeconomic status influences human health, even long used while cutting them in on the profits from research.
after that status changes. Both academic and pharmaceutical research rely on diverse sets of
de-identified genomic data. Direct-to-consumer genetics companies
REFERENCE: McDade T.W. et al. Genome-wide analysis of DNA methylation in rela- can offer that kind of data to these research organizations. Many
tion tosocioeconomic status during development and early adulthood. American Journal companies offer people information about their genome and afford-
of Physical Anthropology (2019) 169:3-11 doi: 10.1002/ajpa.23800. able testing in exchange for the ability to use the information, but
now some companies are converting customers into a kind of partner.
Lab-based sugar substitute For example, LunaDNA lets users store genetic records on the
LunaDNA platform. When researchers buy those records, that
Sugary confections are a central feature of many holiday celebrations, individual is given shares in LunaDNA. The model ultimately
family gatherings and restaurant menus around the world. And while results in profit-sharing. Encrypgen takes a different approach,
jellybeans, candy corn, pastries and pies might invoke a sweet sense letting researchers use their platform to purchase de-identified
of comfort and joy, excessive sugar consumption can lead to obesity, genomic profiles directly from users with a cryptocurrency called
type 2 diabetes and heart disease. In order to feed their sweet tooth DNA Tokens. Both approaches give the consumer greater agency
but also stay health conscious, many people use sugar substitutes over the availability of his or her data as well as a more direct
in place of sugar. interest in money made from their genetic information.
Stevia is a popular natural sweetener obtained from plants grown REFERENCE: https://www.lunadna.com/how-it-works
in South America that is 250 times sweeter than sugar. Scientists
analyzed stevia to determine at a molecular level how it achieves this n In an attempt to stay ahead of the science, the World Anti-Doping
level of sweetness. They found that two molecules, Reb M and Reb D, Agency has banned gene editing technologies that could enhance
gave stevia its sweetness without the bitter aftertaste associated with athletic performance. The agency has previously banned genetically
the most common molecule, Reb A. However, Reb M and Reb D are modified cells and other types of enhancement-based gene therapy,
present in less than one percent of the stevia leaf, so extracting them but the current guidelines didn’t address CRISPR-type editing. These
from the plant is not feasible. approaches are still in their infancy — and focused on treating disease
Two companies discovered a process to create the calorie-free sweet- — but some researchers have acknowledged being approached by
eners through fermentation. They developed a yeast strain that pro- non-Olympic athletes looking for a performance boost. Since gene
duces the same enzymes used by the stevia plant. In a fermentation editing leaves no telltale DNA signature, detection will be challenging.
tank, the yeast converts simple sugars, like sucrose or dextrose, into Perhaps the only way to detect its existence will be comparing an ath-
Reb M and Reb D. The sweetener is being tested in over 300 products lete’s current genome sequence to one obtained in childhood.
with some expected to hit shelves this year. REFERENCE: Le Page M. Anti-doping agency to ban all gene editing in sport from

REFERENCE: Winnipeg Free Press. Cargill starts making next-generation 2018. New Scientist 9 Oct. 2017. Web. 23 July 2018 https://www.newscientist.com/
sweetener for 2020 debut. 16 November 2019. Web. 4 September 2020. article/2149768-anti-doping-agency-to-ban-all-gene-editing-in-sport-from-2018/.
https://www.winnipegfreepress.com/business/cargill-starts-making-next-
generation-sweetener-for-2020-debut-565030932.html. 19

 

RECENT FINDINGS — CANCER Glioblastoma

Genomics- 2021 U.S. estimates: 24,530 new cases of

oncologydriven brain and other nervous system cancer

Nearly all cancers are caused by genetic changes that alter important biological pathways and 18,600 deaths
controlling cell growth and survival. Specific genetic changes influence the rate of cell
growth, determine how aggressively the cancer will spread and control Genetic studies have identified three key
whether one drug will be more effective than another at killing the cancer cells. pathways often mutated in glioblastoma
Over the past decade, advances in genomic technologies, tumor analysis and drug tumors. Additional work has uncovered
development have changed the landscape of cancer diagnosis and treatment. abnormal patterns of gene activity and the
In the laboratory, genomic information obtained from cancer cells has reshaped master switches controlling those genes.
understanding of how cancer forms. In the clinic, this same information is beginning to These patterns vary widely, even
guide therapeutic decisions, improving outcomes for patients with cancer. across a single tumor. This variation
may explain the historically poor
Lung adenocarcinoma response to therapy. Classifying
glioblastomas by their overarching
2021 U.S. estimates: 235,760 new cases and 131,880 deaths activity patterns may point towards
Lung cancer is composed of several subtypes. The two most common are more effective combination
non-small-cell lung cancer and small-cell lung cancer, which respectively treatments.
comprise 76 percent and 13 percent of all US lung cancers. Overall mortality
from lung cancer is declining in the United States. Recent analyses suggest
a significant part of this decline is due to improvement in survival for non-
small-cell lung cancer. These improvements are driven by newly approved
drugs and immunotherapies that are targeted to particular genetic muta-
tions present within the tumors.

Melanoma Endometrial

2021 U.S. estimates: 106,100 new cases and 7,180 deaths 2021 U.S. estimates: 66,570 new cases

As with most forms of cancer, the majority of melanomas are and 12,940 deaths
sporadic. They are not caused by genetic mutations inherited
from a parent, but from mutations that randomly occur in the Genomic studies subdivide endometrial
pigment-producing cells called melanocytes. Many genetic cancer into four main categories. This
mutations associated with melanoma are well documented. classification system is more effective at
Intriguingly, melanomas that form on parts of the body that predicting progression and outcome than
get little or only periodic sun exposure have different patterns prior approaches. Within each category,
of DNA mutation compared to melanomas from chronically characteristic genetic changes have opened
sun-damaged sites. Knowledge of commonly-mutated genetic the door to targeted treatment options.
pathways has led to several targeted therapies approved for Many are in early stage clinical trials.
both early stage and metastatic melanomas. These treatments
often result in long-term cancer control and survival.

Cancer results from the stepwise accumulation of genetic mutations
which increase cell growth and/or create a favorable environment for
tumor expansion.
third mutation

first mutation second mutation

  

normal cell increasing numbers of genetic change Cancer

20

Breast  Precision oncology

2021 U.S. estimates: 284,200 new cases Because each person’s cancer is genetically unique, the one-size-fits-all treatment
and 44,130 deaths approach that has been historically followed leads to treatment failure for many
patients. Taking a more personalized approach to cancer treatment helps clinicians
Genetic testing categorizes breast cancer decide which treatment a patient's tumor is most likely to respond to, sparing the
subtypes based on the presence or patient from receiving treatments that are unlikely to help. This practice, called
absence of specific DNA mutations. precision oncology, involves unraveling a patient’s genetic code and developing a
A recent international study of 110,000 tailored treatment plan based upon the genetic makeup of their cancer.
breast cancer patients was able to identify
more than 350 genetic changes across Common treatment options used in precision medicine include targeted therapies,
nearly 200 cancer-related genes. These gene therapy, and immunotherapy. Advances in science and medicine have led to
findings point to even more precise cancer the development of many drugs and therapies that target specific parts of cancer
classification strategies as well as new cells, like proteins or genes. Some genetic mutations cause cancer cells to produce
treatment pathways. too much, too little, or mutant versions of proteins that are involved in cancer cell
growth, spread, and survival. Targeted therapies, which are usually small molecule
Ovarian drugs or antibodies, target these proteins to kill cancer cells. Targeted therapies
are currently FDA approved for more than fifteen different types of cancer.
2021 U.S. estimates: 21,410 new cases
and 13,770 deaths Driver mutations, the main mutation giving cancer a growth and survival
advantage, have been identified for many types of cancer. The number of targeted
For most ovarian cancer patients, within 3 years therapies specific to these types of mutations are growing. Over the past five years,
of their initial treatment the cancer has returned. the FDA has approved at least three oncology drugs that target key genetic drivers
Drugs known as PARP inhibitors have been found of cancer, rather than specific types of tumors. These ‘tissue agnostic’ therapies
to significantly delay the length of time before are effective against tumors with a specific genetic alteration, regardless of the
cancer comes back. The medications are most cancer’s location. They present an example of the amazing advances that are
effective for ovarian tumors with specific genetic being made in precision medicine.
mutations that reduce the cell’s ability to repair
its DNA. Recent clinical trials suggest PARP The field of precision oncology is rapidly growing as evidenced by the FDA's
inhibitors may be beneficial as a first-line initial approval of ten new precision oncology drugs in 2020. Precision medicines as a
treatment in addition to their role as follow-up whole now account for more than one out of every four drugs the agency has
maintenance therapy. approved in the past six years. The FDA also approved the use of 17 existing
precision medicines for new uses to add to the arsenal of available precision drugs.

REFERENCES: https://www.fda.gov/news-events/press-announcements/fda-approves-third-oncolo-
gy-drug-targets-key-genetic-driver-cancer-rather-specific-type-tumor
http://www.personalizedmedicinecoalition.org/Userfiles/PMC-Corporate/file/PM_at_FDA_The_Scope_
and_Significance_of_Progress_in_2019.pdf

Colorectal PRECISION ONCOLOGY

2021 U.S. estimates: 149,500 new

cases and 52,980 deaths

Like many cancers, colorectal cancers are
associated with both genetic and epigenetic
mutations. Genetic mutations directly alter
the DNA instructions (genes). In contrast,
epigenetic mutations change how the cell
processes the DNA instructions. They often
modify a gene’s activity to make more or
less of that gene’s protein. These changes
cause cells to undergo rapid growth,
evade destruction or develop resistance
to treatment. Knowledge of these
epigenetic pathways has led to a new
class of therapeutic drugs called
epigenetic modifiers.

REFERENCES: Siegel R.L. et al. Cancer Statistics, 2021, CA:

A Cancer Journal for Clinicians. 71:7-33 (2021).

Precision Medicine in Cancer Treatment: National Cancer Institute graphic

21

RECENT FINDINGS — CANCER

Researchers However, the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes
assemble (PCAWG) Project team recently completed the largest whole-genome
database of tumor sequencing project to date. The team performed whole-
cancer genomes genome sequencing and analysis on more than 2,500 samples from
38 different primary cancers and matching normal tissue samples,
Cancer is a genetic disease that is char- including brain, skin, esophagus and liver.
acterized by the uncontrollable growth An interesting finding was that about 95 percent of the tumors had at
of abnormal cells that often travel to least one identifiable DNA mutation in their genome that appeared to
and invade other parts of the body. It is drive the cancer. These mutations, known as driver mutations, are
commonly caused by the accumulation responsible for cancer development and progression. About 13 per-
of many different types of DNA muta- cent of the driver mutations occurred in those non-coding portions of
tions. Cancer is an extremely diverse DNA that are not regularly analyzed. Many cancer drugs are designed
disease, meaning that one person’s cancer genome can look entirely to target specific proteins affected by driver mutations. Unearthing
different from another person’s cancer genome. As we move closer to driver mutations in non-coding regions of a patient’s tumor genome
an era of precision medicine and personalized cancer treatment, it is could open the door to new avenues of treatment that would other-
critical to understand the thousands of different types and combina- wise be missed.
tions of mutations that can cause cancer. These studies represent a big step toward uncovering and under-
standing all of the major cancer-causing mutations. In an effort to
To date, cancer research has mainly focused on well-known can- continue the momentum of this collaborative endeavor, the Project
cer-associated genes, specifically mutations in the protein-coding team has made all of its data and analytic tools freely available to the
components of those genes. However, this only represents a mere research community.
1 percent of the entire genome. Therefore, a majority of the genome
has been largely unstudied and unsequenced as it relates to muta- REFERENCE: The ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium.
tions associated with cancer. Pan-cancer analysis of whole genomes. Nature. 578:82-93 (2020) doi: 10.1038/s41586-
020-1969-6.

Mutations in normal Genomic analysis of
cells could help with childhood cancer patients
early cancer detection identifies potential targets
for treatment
Early cancer detection remains a critical
goal for medicine, as earlier recognition The availability of targeted therapeutics for pediatric cancers pales
of cancer generates better results for in comparison to those available for adults. However, a recent study
patients. Advancements in sequencing suggests that some FDA-approved drugs could be repurposed to
technology and major cancer research treat pediatric cancer.
projects have allowed us to study fully-developed tumors more
completely, giving a better developed picture of the mutations in those Solid tumors account for about 50 percent of pediatric cancers.
tumors. However, in order to use that information for early detection, They are generally assumed to be heavily influenced by germline
we must also know which mutations occur in normal cells. DNA variants, mutations inherited from the parent’s germ cells and
A study published in July 2019 examined somatic mutations, those present in all of the child’s cells, in addition to somatic mutations that
that occur in body cells and often in response to environmental only occur in the cancer cells. However, germline genomic analysis is
factors. Researchers discovered these mutations lurking in otherwise not regularly used when determining the course of therapy for such
normal tissue across 95 percent of the 500 person cohort. Sun-ex- patients. Scientists at the Cleveland Clinic have shown that such an
posed skin, the lining of the esophagus and the lungs all showed analysis could be valuable when selecting a treatment strategy for
higher rates of somatic mutation, which points to contributing these young cancer patients.
environmental factors like ultraviolet light, air pollution, smoking and
eating habits. A correlation was also found between the individual’s During the study, scientists analyzed germline DNA from over 1,500
age and the overall number of mutations. patients under the age of 29. They found that many of them carried
Many of those mutations will not lead to cancer, though it’s likely germline mutations in known cancer-causing genes. Some of the
some will. The study calls for even more extensive sequencing of mutations are known to be treatable with drugs already approved by
normal tissues and precancerous lesions in order to compare the FDA for adult patients. In fact, thirty-four percent of the patients
the various factors surrounding somatic mutations - exposure to had at least one mutation that was potentially druggable.
environmental mutagens, natural cellular architecture and rate of
cell division. Differentiating between somatic mutations that lead to This study highlights the importance of sequence analysis of both
cancerous cells and those that do not may lead to tests that predict germline and cancer genomes in pediatric and adolescent patients.
the development of cancer much earlier. By detecting more druggable targets, more approved drugs could be
available, giving these young patients a wider range of therapeutic
REFERENCE: Yizhak, K. et al. RNA sequence analysis revealsmacroscopic somatic options in their battle against cancer.
clonal expansion across normal tissues. Science (2019) 364:eaaw0726 doi: 10.1126/
science.aaw0726. REFERENCE: Akhavanfard S, et al. Comprehensive germline genomic profiles of
children, adolescents and young adults with solid tumors. Nature Communications
22 (2020) 11:2206 doi: 10.1038/s41467-020-16067-1.

Rallying the body AI to more accurately
to beat cancer detect tumors

A drug to cure cancer remains a holy grail Once an idea that existed only in science fiction,
for scientists and doctors, but some of the artificial intelligence (AI) is now a part of our daily lives.
most promising advancements in cancer Personal digital assistants answer our questions and make our
treatment recently come from rallying the grocery lists, our smart homes adjust the temperature before we
body’s own natural defenses. Scientists have return home and driverless cars are on the horizon. In addition to
made major strides using genetics to summon simplifying tasks in our daily lives, the potential applications of AI
a more aggressive response fro the human immune system. The ap- in biomedical research and health care, especially cancer research,
proach, called immunotherapy works by teaching the immune system are quickly growing.
how to recognize cancerous cells and how to attack them. AI has the ability to recognize patterns in large volumes of data,
extract relationships between complex features in the data and identify
CAR T-cell Therapies characteristics in data that cannot be perceived by the human brain.
Scientists and physicians are leveraging these capabilities of AI to
The FDA has approved immunotherapy treat- improve cancer screening, cancer diagnosis and treatment planning.
ments for acute lymphoblastic leukemia and For example, a group of scientists developed an AI-based system
lymphoma. The treatments, called Kymriah that searches digital images of tissue samples from confirmed
and Yescarta respectively, are chimeric anti- cancer cases for those most similar to a new digital image of an un-
gen receptor (CAR) T-cell therapies. T-cells diagnosed case. Based on the known, verified findings of the majority
help guide the body's immune system in its of similar images, the system recommends a diagnosis for the new
assault on dangerous cells. Doctors remove case. This is just one example of the many ways in which research-
T-cells from the patient’s body and genetically ers and clinicians are combining AI technology with their own clinical
engineer them to seek out a specific protein expertise to help improve the accuracy and speed of diagnosis, aid
on the surface of the tumor cells. This repro- clinical decision-making and lead to better health outcomes.
grams the T-cells to attack either the leuke-
mia or lymphoma specifically. These “living REFERENCE: Kalra, S. et al.Pan-cancer diagnostic consensus through
drugs” are then infused back into the patient’s searching archival histopathology images using artificial intelligence. npj
bloodstream. Clinical trials have shown Digital Medicine. 3:31 (2020).
these immunotherapies can offer a cure to
patients who had few or no other treatment Liquid biopsies
options. However, because the drugs must be meet next-generation
manufactured for each individual, they cost sequencing
between $375,000 and $475,000 per person.
In order to take advantage of the growing number of targeted cancer
Tumor Infiltrating therapies, clinicians must be able to genetically characterize a
Lymphocytes patient’s tumor. Traditionally, clinicians rely on tissue biopsies, or
small pieces of tumor tissue taken from the patient’s body, to analyze
A separate immunotherapy utilizes tumor infil- tumor DNA. However, tissue biopsies can be invasive, risky, costly and
trating lymphocytes (TILs) which are a specific painful, making it difficult to perform repeated biopsies on a patient to
type of T-cell often found in tumors. Scientists first track tumors as they respond to treatment and change over time.
analyze the DNA of the tumor to identify mutations Liquid biopsy tests are a promising, minimally-invasive alternative to
present in the cancer. They then extract TILs from the traditional tissue biopsy. Usually performed on blood samples,
the tumor, specifically searching for those that will liquid biopsies look for specific genetic changes in DNA isolated
react to the patient’s specific mutations. These from whole circulating tumor cells or fragments of DNA shed from
are grown in the lab until billions of immune cells the tumor. The genetic information helps guide treatment decisions,
are present, which are then infused back into including the selection of targeted therapies.
the patient along with additional antibody treatments. This therapy Until late 2020, the only FDA-approved liquid biopsy tests on the
successfully eliminated tumors from a woman with metastatic breast market targeted single genes. However, two newly approved tests,
cancer, marking the first time immunotherapy has beaten late-stage Guardant360Dx and FoundationOne Liquid CDx, marry next-genera-
breast cancer. If perfected, doctors hope it can be used to destroy tion sequencing with liquid biopsy testing. The tests use next-gener-
metastasized tumors in other parts of the body too. ation sequencing to analyze multiple cancer-related genetic changes
Cancer treatment advances on many fronts, but genomic-driven in cell free-DNA in blood. Both tests are approved as companion
immunotherapy appears poised to offer researchers and physicians diagnostics, meaning they provide key information about the safe and
a road map, not just for introducing effective treatment into the body, effective use of a corresponding cancer drug.
but also for teaching the body how to fight for itself more successfully.
REFERENCES: https://www.fda.gov/news-events/press-announcements/fda-
REFERENCES: U.S. Food and Drug Administration. FDA approval brings first gene approves-first-liquid-biopsy-next-generation-sequencing-companion-diagnostic-test
therapy to the United States. 30 August 2017. Web. 30 July 2018. https://www.fda.gov/ https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-liquid-
newsevents/newsroom/pressannouncements/ucm574058.htm. biopsy-next-generation-sequencing-companion-diagnostic-test
U.S. Food and Drug Administration. FDA approves CAR-T cell therapy to treat adults
with certain types of large B-cell lymphoma. 18 October 2017. Web. 30 July 2018. 23
https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm581216.htm.
Zacharakis N. et al. Immune recognition of somatic mutations leading to complete
durable regression in metastatic breast cancer. Nature Medicine (2018) 24:724-730.
doi:10.1038/s41591-018-0040-8.

RECENT FINDINGS — BACTERIA, VIRUSES AND OTHER PATHOGENS

What’s the difference?

l Endemic l Outbreak l Epidemic l Pandemic

The constant presence of a The incidence increases above The outbreak has spread to The epidemic has
disease at the usual incidence endemic levels (often suddenly) larger geographic areas spread globally

What are infectious diseases? What are zoonotic diseases?

Infectious diseases are illnesses caused by microorganisms like Zoonotic diseases are illnesses that spread between
animals (both wild and domesticated) and people.
bacteria viruses fungi parasites As many as 60 percent of known human infectious
diseases are zoonotic. Often the animals don’t expe-
While most microorganisms are harmless, or even beneficial, a small rience symptoms but are reservoirs ­— live “holding
percent can cause serious disease. These are sometimes described as tanks” for the microbe. Spillover events occur when
“pathogens” and are often informally called germs. the pathogen jumps from its traditional host to a
new species, like humans.
How do infectious diseases spread?
Common Zoonotic Diseases and Animal Reservoirs:
Infections are transmitted in different ways, depending on the type of infection
Cats..........................toxoplasmosis
l direct contact with bodily fluids that contain infectious particles
l touching a contaminated surface and then touching eyes, nose or mouth ........................................ pasteurella
l direct or indirect contact with animals or insects ...........................................ringworm
l contaminated food or water
Bats ...................................Ebola virus
Why are pandemics becoming more likely?
....................................................... SARS
The number of infectious disease outbreaks around the world has ...................................................... MERS
risen over the last 40 years. The risk that an outbreak expands into an ...................................................... rabies
epidemic or pandemic has also increased due to:
Dogs ..................................... rabies
l Increasing human population and urbanization
l Unclean water and poor sanitation ........................................noroviruses
l Global trade and travel ........................................... ringworm
l Increased contact between humans and animals ..........................................hookworm
l Changing climate
l Weak healthcare infrastructure in outbreak-prone areas Ticks ............................. Lyme disease
l Increasing drug resistance for disease-causing bacteria
.............. Rocky Mountain spotted fever
24
Mosquitoes ....................... malaria

................................................dengue
...................................West Nile virus
............................................Zika virus

Birds................bird flu (H1N1, H5N1)

.........................................salmonellosis

Cows ............................ brucellosis

.................................Escherichia coli
........................................... ringworm
.................................... salmonellosis

Rodents ............................hantavirus

..................................................... plague
.......................................... rat-bite fever

Genomic studies and COVID-19 Resources about the
COVID-19 pandemic
Genetic tools have been critical to help scientists understand and respond to the
COVID-19 pandemic. Genomic sequencing first determined the SARS-CoV-2 virus HudsonAlpha Institute for Biotechnology
was responsible for the unidentified cluster of respiratory infections in the Wuhan has created a series of brief videos explaining
province of China. Scientists sequenced genetic material from patient samples key concepts associated with COVID-19
and analyzed the non-human genetic fragments. They determined a new member and the SARS-CoV-2 virus.
of the coronavirus family was causing the infection. Early studies also found the New videos are uploaded regularly.
genetic recipe of the novel virus was very similar to bat coronaviruses, suggesting The entire collection can be found at
the virus likely originated in bats. hudsonalpha.org/beyond-the-blog.

Once laboratories knew the genetic sequence, they could develop tests to diagnose General COVID-19 Overview
infections. These tests use a technology called polymerase chain reaction (PCR) What is the Coronavirus?
to detect small amounts of genetic material from the virus. PCR-based tests are Symptoms and Testing
the gold standard for diagnosing COVID-19. To reduce costs and maximize impact, Early Warning Defenses, Facemasks
some labs combine small amounts of individual patient samples into a single Strains and Mutations
pool. If the pool tests negative, all samples are virus free. If the pool tests positive, Changing recipe—UK variant
researchers test each of the initial samples to determine which contains the virus. Metabolism
A modified version of PCR testing can detect the virus in wastewater samples. Reinfections
This gives college campuses, hospitals and neighborhoods an important early COVID-19 Transmission
detection tool. COVID-19 Spread and Prevention
A small fraction of virus samples from patients undergo a genomic "deep dive" to Herd Immunity
track how the virus changes over time. A worldwide network of labs scans these COVID-19 Risk Assessment
viral genomes for changes in the genetic recipe (also called variants or mutations). Asymptomatic Spread
All viruses undergo these modifications over time. Most are unimportant, but some Children and COVID-19
alter how the virus infects people or how ill it can make patients. Viral sequenc- COVID-19 Testing
ing lets public health experts track the spread of different strains. The UK, South How is COVID-19 Testing Done?
African and Brazilian variants are examples of these changes. Researchers then Testing and Transmission
determine if the strains respond to current treatments/vaccines or if they need to Molecular vs. Antigen Testing
develop new ones. Wastewater Testing
COVID-19 Treatment
Pandemic Preparedness and Responses Treatments Overview
Anti-Viral Drugs
l Surveillance to monitor potential infectious threats Antibodies and Treatment
l Prevent and extinguish outbreaks before they escalate to pandemic scale Antibodies
l Communicate protective and preventative actions to minimize transmission Convalescent Plasma
l Detect, report and track cases rapidly and accurately Pooled Testing
l Reduce interactions between infected and uninfected populations — COVID-19 Vaccines
travel restrictions, quarantine, physical distancing, school and business closures Vaccines
l Decrease infectivity of patients and severity of illness through treatments with Manufacturers Vaccine Approvals
antivirals, antibodies etc. Distribution
l Reduce susceptibility of uninfected people through vaccines Immune Response


25

RECENT FINDINGS — BACTERIA, VIRUSES AND OTHER PATHOGENS

The measles Universal flu vaccine shows
vaccine promise in first clinical trial
protects
against more Flu vaccines are typically tailored to the most likely
than measles subtypes of influenza a person will face in the
coming flu season. The vaccines cause the body to
Measles is one of the generate antibodies against a specific part of an
most contagious diseases influenza protein called hemagglutinin (HA).
known to mankind, killing Made up of a head and a stalk, this viral
an average of 2.6 million protein helps the influenza virus enter
people each year before human cells. Because existing vaccines
the development of a target the head - which varies from strain to strain — they must be
vaccine. Widespread vaccination in the early 2000’s led to a sharp updated annually to match the varieties predicted to be most prevalent.
decline in the number of deaths attributable to measles. However, Universal flu vaccines seek to target the stalk regions of the HA
lack of access to vaccinations and the refusal to vaccinate has led protein that are shared among influenza strains. By teaching the body
to an increased rate of cases, with almost three times as many to recognize and target this part of the virus, the vaccine equips the
cases reported worldwide in 2019 compared to the previous year. immune system to fight a broader range of influenza, providing longer
This decline in vaccination rate is especially concerning to many in lasting protection.
the medical field because there is strong evidence that by prevent- Although the stalk region is difficult to target, a group of researchers
ing measles, the vaccine also preserves the body’s immunity to presented data from a Phase I trial suggesting they have overcome
other infectious diseases. the challenge. The group developed a flu vaccine that causes the
It has long been observed that survivors of the measles often have body to make antibodies against the conserved stalk region. Although
a diminished immunity that leaves them vulnerable to infection by the trial only tested safety and measured immune responses to the
other pathogens, although the reason behind this phenomenon is vaccine, studies in mice suggest it is protective against the flu.
poorly understood. Two research groups set out to determine why
measles survivors lose immunity to pathogens they had previously REFERENCES: Nachbagauer, R. et al. A chimeric hemagglutinin-based universal
acquired through illness or through vaccination. influenza virus vaccine approach induces broad and long-lasting immunity in a random-
Scientists at Harvard University examined blood samples from 77 ized, placebo-controlled phase I trial. Nature Medicine. (2020) https://doi.org/10.1038/
unvaccinated children before and after natural measles infections. s41591-020-1118-7 and https://www.sciencemag.org/news/2020/12/innovative-
The scientists were looking at the children’s antibody repertoire, or universal-flu-vaccine-shows-promises-it-first-clinical-test
the presence of antibodies against more than 400 viral and bacteri-
al pathogens. They found that after measles infection, antibody HIV successfully edited
diversity drastically decreased. In some cases, infected children out of live mice in trial
lost between 11 percent and 73 percent of the antibodies they had
prior to infection. Scientists have eliminated HIV from some
live mice using CRISPR-based gene editing,
A second, independent study published marking a potential major step forward
in Science Immunology also supports the for treating the disease.
importance of the measles vaccine to a HIV works by hijacking the replication
child’s overall immunity. Using measles-like process of the body’s cells. Acute HIV
virus in ferrets, the researchers showed that infections feature rapid replication of the virus.
resistance to the flu was lost in ferrets as a When HIV transitions into AIDS, that rapid replication is also
result of the measles-like infection. accompanied by severe damage to the immune system and
Both studies point to the importance of the significant susceptibility to opportunistic infections. In these cases,
measles vaccine not only to avoid a poten- antiretroviral therapies can be used to control replication and
tially deadly infection with measles virus, but manage symptoms. However, there is no current treatment for latent
also to prevent the loss of immunity to other HIV, where the virus integrates into the cellular genome across a
pathogens that a child has built up through- number of organs. Latent HIV does not replicate as quickly, but it also
out their lifetime. does not leave the body.
Scientists have turned to gene editing to remove the latent HIV from
REFERENCES: Mina, M.J. et al. Measles virus infection diminishes preexisting the genome. Using CRISPR Cas9 as a kind of genetic scissors, the
antibodies that offer protection from other pathogens. Science. (2019) 366:599-606 researchers were able to snip the HIV from the genome of live mice.
doi: 10.1126/science.aay6485. The treatment worked on only a fraction of the mice in the study,
Petrova, V.N. et al. Incomplete genetic reconstitution of B cell pools contributes so understanding what limited the success of the technique is also
to prolonged immunosuppression after measles. (2019) Science Immunology. crucial to using it more broadly. This is only among the first stages
4:eaay6125 doi: 10.1126/sciimmunol.aay6125. along a long road before the treatment can be used on people, but it
is a promising step forward.
26
REFERENCE: Yin C. et al. In Vivo Excision of HIV-1 Provirus by saCas9 and Multiplex
Single-Guide RNAs in Animal Models. Molecular Therapy (2019) 5:1168-86 doi: 10.1016/
j. ymthe.2017.03.012.

Transplanting gut microbes Science snapshots
to treat non-gut diseases
n The human digestive system is one of the most microbially
The human gut microbiome, made up of trillions of microorganisms complex ecosystems on Earth, with several hundred microbial
such as bacteria, viruses and fungi, is known to affect how the human species inhabiting the human gut. Changes in the gut microbi-
body functions, both in health and disease. Imbalance of the normal ome have been linked to many diseases, so the ability to mea-
gut microbiota, which often happens after antibiotic treatment or sure a person’s gut microbes is important in both research and
infection with bacteria like Clostridium difficile (C. diff), has been linked the clinic. The National Institute of Standards and Technology
with gastrointestinal conditions such as inflammatory bowel disease (NIST), along with many microbiome researchers, are working
and irritable bowel syndrome and extraintestinal disease such as to create a reference standard of gut microbes that is as close
obesity, type 2 diabetes and neurological conditions. as possible to those in the actual human gut. The reference
A promising procedure dating back to the fourth century has standard (ideally a stool-like material) could be run alongside
re-emerged as a potential treatment for diseases and disorders experimental samples (for example, stool from a person with a
caused by an imbalanced gut microbiome. The procedure, called fecal gut disorder) to help researchers and clinicians identify chang-
transplant, involves transplanting the bacteria contained within a fecal es in the microbiome.
sample from a healthy donor into the large intestine of an affected REFERENCE: Katsnelson, Alla. Standards Seekers Put the Human
patient. The treatment is not formally approved by the FDA but has
received a special exception for use in recurrent C. diff infection. It has Microbiome in Their Sights. ACS Cent. Sci. 2019, 5, 6, 929–932.
been widely used in the past decade to treat such patients, curing
80–90 percent of patients with recurrent C. diff infection. Researchers n Scientists have created a comprehensive catalog of all
believe that fecal transplant helps to reestablish the beneficial strains the known genomes of bacteria living inside our digestive
of bacteria in the gut. system. The freely accessible Unified Human Gastrointestinal
Due to the success and strong safety record of fecal transplant in Genome Collection includes over 200,000 genomes from more
C. diff infection, researchers are now branching out to test whether than 4,600 bacterial species. The research team developed
fecal transplant could prove successful in other diseases linked to a companion catalog of over 170 million proteins
changes in the gut microbiome. Fecal transplant studies have been produced by these bacteria. The specific activity of
performed for conditions ranging from metabolic syndromes like more than 70 percent of the gut bacteria in this
obesity to autism spectrum disorder to multiple sclerosis to diseases collection remains unknown.
of the liver and pancreas. REFERENCE: Almeida et al. A unified catalog of 204,938
One such study suggests that fecal transplant could be useful for
treating symptoms of autism in children. During the study, eighteen reference genomes from the human gut microbiome. Na-
children with autism received daily fecal transplants for seven to eight ture Biotechnology (2020). DOI: 10.1038/s41587-020-0603-3.
weeks. The treatment increased the children’s gut microbial diversity
and parents reported slow but consistent improvement in their child’s n Red blood cells donated by healthy volunteers
autism spectrum disorder symptoms. The microbial diversity and are used in life-saving transfusions worldwide.
behavioral gains were long-lasting, both being observed at the two- However, blood has to be compatible between the
year post-treatment mark. donor and the recipient to prevent serious immune
responses triggered by the sugar molecules, or blood antigens,
Similar to the autism study, many of the preliminary fecal transplant on the surface of red blood cells. The blood types A, B, and AB
studies are not randomized, controlled trials and are too small to be have these antigens on their surface, while Type O blood lacks
conclusive. Larger clinical trials are required before this type of fecal these antigens making it compatible in people having the other
transplant can be widely considered as a therapy. These findings sig- blood types.
nificantly add to a growing body of evidence that the gut microbiome Type O blood is incredibly valuable in the medical world, both
controls wellness and disease throughout the body, not just in the gut. because it helps protect against blood shortages and because
REFERENCES: Kang D-W. et al. Long-term benefit of microbiota transfer therapy it can be deployed quickly in an emergency situation where you
don’t have time to determine a patient’s blood type. Research-
on autism symptoms and gut microbiota. Scientific Reports (2019) 9:5821 doi: 10.1038/ ers have successfully used genes from human gut bacteria to
s41598-019-42183-0. convert type A blood into universal type O.
www.the-scientist.com/news-opinion/curious-cure--human-waste-66261 To convert the type A blood, researchers discovered two en-
zymes, both from the gut bacterium Flavonifractor plautii, that
work in tandem to eliminate the troublesome blood antigens
from type A blood cells. If the process proves widely viable, it
could more than double the currently available supply of
universal donor blood.
REFERENCE: Rahfeld P. et al. An enzymatic pathway in the human gut

microbiome that converts A to universal O type blood. Nature Microbiology (2019)
4:1475-85 doi: https://doi.org/10.1038/s41564-019-0469-7.

27

RECENT ADVANCES — AGRICULTURE Entrepreneurial and small business
opportunities arise for the food industry
Creating a pipeline to diversify including farmers, restaurateurs, food
and increase crop yields service providers and exporters among
across the world others involved in the agriculture process.

New employment possibili- Next generation crops deliver
ties are created. These may promising new revenue streams for
include processing, storage farms, restaurants, school systems,
and distribution jobs. food banks and many others
in the food industry.
These efforts positively
impact both urban
and rural economies
throughout
the nation.

Farmers continue to grow the new
crops over the seasons and report back
on findings to share information with
the agricultural community.

Farmers plant next generation crops and
share and receive feedback with partners
28 like food and drink producers.

Field and genetics work are fueling the next
generation of breeding and improving production
of crops — leading to sustainable agriculture.
The following infographic shows this new cycle:

Diverse seeds from a seed library are planted to test new and/
or potential crops for different states across the country.

Beans

Higher Fast to
Yields grow

Tasty!Barley

Drought
Tolerant

Once crops can be tested,
agriculture teams consult
with agronomists, farmers,
food manufacturers,
consumers and other
agriculture agencies on
what plants work best for
each region of the land.

The plant’s DNA is
sequenced and analyzed to get
reference points in the plant’s
genome where the plant is
producing. Soils are also tested to
see what is most productive.

The team selects plants based on field 29
outcomes and genetics findings to fuel
next generation of breeding crops and
improve production of the tested crops.

RECENT FINDINGS — AGRICULTURE

Bioengineered food labels That labeling comes
in 4 potential forms:
In early 2020, the USDA put requirements into place for labeling
bioengineered food. The term ‘bioengineered’ refers to food common- n Symbols: There are accepted symbols
ly called GMO's — genetically modified organisms. More specifically, that say either "Bioengineered"
bioengineered foods have undergone transgenesis — a specific type or "Derived from Bioengineering."
of genetic modification where DNA sequences from another organism
are added to the genome to change some important characteristic or n Text Label: Producers can put text on product
trait. These modifications could increase yield, improve pest resis- packaging that says "Bioengineered" or "Contains a
tance, create herbicide tolerance or even prevent browning. Bioengineered Food Ingredient."
In 2016, Congress tasked the USDA with developing labeling stan-
dards for bioengineered food. The USDA determined that only foods n Digital: Producers can make their package scannable, either
that either resulted from transgenesis or included an ingredient re- through QR codes or by developing new technology. In this case,
sulting from transgenesis would require special labeling, found next they can simply say "Scan for more food information" on the label.
to the nutritional information panel or on the front of the package. If they use a scannable label, they are also required to include a
The USDA keeps a list of foods that come in bioengineered varieties. phone number, which must be able to provide that same informa-
This list includes certain types of alfalfa, apples, canola, corn, cotton, tion to consumers 24/7.
eggplant, papaya, pineapple, potato, salmon, soybean, squash and
sugarbeets. The current USDA list, along with additional details about n Text Message: Producers have the option to list a phone num-
each crop, is at https://www.ams.usda.gov/rules-regulations/be/ ber for shoppers to text for more food information. That number
bioengineered-foods-list. would immediately respond in a text message with the same infor-
There are a handful of exceptions to the labeling requirements. mation you would get by scanning the product with a digital label.
For example, non-food products made from bioengineered foods
won’t be labeled. Neither will products from animals given bioen-
gineered feed, as the bioengineered DNA is broken down by the
animal’s digestive system. Because their genetic material is re-
moved during preparation, highly-processed foods like corn syrup
or soybean oil aren’t required to carry the label, even if derived from
bioengineered plants. The labeling rules also won’t apply to foods
developed through the newer “gene-editing” techniques like CRISPR,
because they don’t contain DNA from other organisms and mimic the
spontaneous genetic variation that occurs through natural selective
breeding. Some manufacturers have announced their intention to
voluntarily disclose the presence of these exceptions alongside those
required by law.

First gene-edited food cess, inactivating gene function. Pre-dating CRISPR, TALEN genome
editing can be used to silence genes or make small directed changes
The first genome-edited food product hit the to the nucleotide sequence. The TALEN-edited soybeans silence two
commercial market in early 2019. Calyxt®, an genes that play a role in fatty acid synthesis. Products of genome
agriculturally focused biotech company, pro- editing must meet the same standards as any food item, but under
duced gene-edited soybean oil, which it sold current USDA guidelines the soybeans are not regulated like other
to restaurants for frying, salad dressings and products of bioengineering and do not carry the “GMO”label. There is
sauces under the name Calyno Oil. The com- an estimated $150 million price tag for the development of a
pany compares it to sunflower and olive oil more traditional transgenic crop, with more than a quarter of that
but with three-times the fry life and longer expense required for regulatory testing and approval. In contrast, the
shelf life. Calyno Oil contains roughly 80 per- cost to develop a genome-edited crop could be as much as 90 percent
cent greater levels of oleic acid, reduced amounts of lower and could make it to market five years faster.
unsaturated fat and contains no trans fats per serving. Companies like Calyxt claim that using genome editing technology
allows the production of new foods quicker and more cost-effectively,
The company says they are responding to consumer pressure for without introducing foreign DNA or changing the taste of familiar
"healthier food options", as well as the 2015 FDA mandate to re- products. Less than a year after the introduction, Calyno Oil is being
duce the use of trans fats. In March 2019, the FDA authorized the purchased by more than two dozen companies, including Sysco®, the
use of qualified health claims and 'heart healthy' labels for Calyno world’s largest food-service distributor.
Oil. The soybeans were edited using transcription activator-like
effector nucleases (TALEN) — enzymes that make targeted dou- REFERENCE: Calyxt. First Commercial Sale of Calyxt High Oleic Soybean Oil on the
ble-stranded breaks in DNA. The cell's DNA repair mechanisms U.S. Market. N.p., 26 Feb 2019. Web. 24 July 2019. https://calyxt.com/first-
respond to fix the break, but a few nucleotides are lost in the pro- commercial-sale-of-calyxt-high-oleic-soybean-oil-on-the-u-s-market/.

30

Science snapshots

n First identified in 1903, chestnut blight resulted chestnuts
in the destruction of an estimated 4 billion ma-
Cosmo the bull ture American chestnut trees over the following
half century. The genome of Cryphonectria par-
In the beef industry, male cattle are more desirable than females asitica, the fungus that causes chestnut blight,
because they are about 15 percent more efficient at converting feed was recently sequenced. Researchers hope to
into weight gain. More weight gain means more beef yield per cow, al- identify key clues within the genome to uncover
lowing ranchers to keep fewer cattle on their farms. Producing more the mechanisms that allow this pathogen to
male cattle is not only economically desirable but also environmen- destroy chestnut trees.
tally favorable because fewer cattle also means a lower production of
greenhouse gas emissions. The laboratories of HudsonAlpha faculty researchers Jane
Like most sexually reproducing animals, cows have a 50 percent Grimwood, PhD and Jeremy Schmutz contributed to this work.
chance of giving birth male offspring. However, scientists at the
University of California, Davis, seek to increase cows’ likelihoods of REFERENCE: Crouch J.A. et al. Genome Sequence of the Chestnut Blight
producing male offspring using genome-editing technology. Fungus Cryphonectria parasitica EP155: A Fundamental Resource for an
Archetypical Invasive Plant Pathogen. Phytopathology (2020) 110:1180-1188. DOI:
10.1094/PHYTO-12-19-0478-A.

Cosmo n Thanks to their antlers, deer qualify as the only mammal that
can regrow lost body parts. Unlike horns (which are made of ker-
Cosmo, a 110-pound bull calf born in April 2020 at UC Davis, was atin and remain attached to an animal), antlers are made of bone
genome-edited as an embryo so that he will produce more male and shed and regrow annually. Antler development is influenced
offspring. Scientists used CRISPR-based genome editing to make by nutrition, habitat and genetics. Scientists have identified two
targeted cuts in a chromosome and insert the SRY gene, in a process genes, Uhrf1 and s100a10, that work in tandem to control antler
called gene knock-in. SRY, typically found on the Y chromosome, development in red deer. Uhrf1 promotes cell division and growth
encodes for sex determining region Y (SRY) protein that is responsible and s100a10 regulates the rapid hardening (calcification) of the
for the initiation of male sex characteristics, like the formation of antlers. Because these same genes are also present in humans,
testes. Cosmo’s offspring should be 75 percent males, with 50 understanding bone growth in deer may shed light on treatments
percent XY males and 25 percent XX animals that co-inherit the for bone diseases and fractures.
SRY gene and develop male traits. REFERENCE: Ker D.F.E. et al. Identifying deer antler uhrf1 proliferation and
The SRY gene was integrated in a region of bovine chromosome
17 known as a genomic safe harbor site, meaning the genetic inser- s100a10 mineralization genes using comparative RNA-seq. Stem
tion doesn’t interfere with nearby genes. Scientists will not know if Cell Research and Therapy (2018) 9:292 doi: 10.1186/s13287-018-1027-6.
inheriting the SRY gene is enough to trigger the male developmental
pathway in XX embryos until Cosmo reaches sexual maturity in a year n A farmer’s entire crop harvest can be lost if insects, the
and can produce offspring. weather, or soil conditions do not cooperate during the growing
REFERENCE: Owen, J.R. et al. Production of a gene knock-in bull calf by season. Crops containing genetically modified traits, like herbi-
cide tolerance, drought resistance and insect resistance, allow
embryo-mediated genome editing. Poster presented at: American Society of farmers to grow and successfully harvest more food using fewer
Animal Science meeting (2020). resources like water and pesticides. These biotech crops have
been widely grown for more than 20 years. In 2018, the global area
planted with biotech crops was more than 450 million acres. The
economic impacts are also impressive, with US farmers realizing
96 billion dollars in additional income from biotech crops between
1996 – 2018. Globally, for every extra dollar invested in biotech
seed crops compared to the cost of conventional seed, farmers
gained an average $3.75 in extra income.
REFERENCE: Brookes, G. & Barfoot, P. GM crop technology use 1996-2018:

farm income and production impacts, GM Crops & Food, 11:4, 242-261 (2020).

31

RECENT FINDINGS — AGRICULTURE

Using genomics for Unraveling the diversity of
cotton improvement domesticated barley

Cotton is an important fiber crop that has been grown for thousands Knowing the genetic changes, or DNA variants, that plants need
of years and globally provides income for more than 100 million to produce useful traits like drought tolerance or pest resistance
families across more than 150 countries. However, cotton supply can accelerate plant breeding programs to develop next gener-
is increasingly threatened due to drought-like conditions, high- ation crops. However, due to the high costs of genotyping, plant
salinity soils and pest emergence. Producing new varieties of breeding has historically been based on the presence or absence
cotton to withstand these conditions but also have improved crop of traits that breeders can visually measure. This means plants
production, fiber quality and sustainability is a major goal in the with the most economically valuable traits are selected to breed
agricultural community. for the next generation, completely blind to genetic variation.
One strategy to produce new varieties of cotton is to rediscover Because of this phenotype-based breeding, the genomes, or DNA,
agriculturally beneficial traits like disease or drought resistance that of individual varieties of a crop can differ considerably. These
were lost from the wild cotton genome during domestication and differences present barriers for manipulating important plant
genetically reintroduce them into domesticated cotton. In a paper characteristics in breeding. In order to improve crop breeding,
published in Nature Genetics in May 2020, a group of researchers did researchers have begun sequencing domesticated crop plants
just that by comparing the genomes of wild and domesticated cotton in order to unravel their genomes and identify genes that confer
species to try to understand more about cotton fiber development. beneficial agricultural traits.
The researchers sequenced and assembled reference-grade ge- For example, an international research team is well on their way
nomes for the five major types of domesticated cotton and compared to fully characterizing the barley genome. Results from their
them with two wild cotton genomes. major sequencing project were published in the journal Nature in
To their surprise, the wild and domesticated genomes turned out to late 2020. The group sequenced approximately 22,000 barley seed
be very similar, meaning domesticated cotton genomes retained a samples in an effort to fully characterize the barley pan-genome,
lot of gene content and genomic diversity relative to the wild plants. which represents the genomic diversity of the different varieties of
Although there was a lack of diversity between wild and domesticated the entire barley species.
cotton, further analysis did identify unique genes related to fiber and
seed traits in two domesticated species. The results from the study The group observed that two barley varieties can differ in the
suggest that researchers will not be able to reach back as easily into number of genes and in the arrangement and orientation of large
the wild cotton gene pool to introduce lost traits like disease resis- parts of individual chromosomes, called structural variants.
tance back into domesticated cotton plants. The researchers found two structural variants that particularly
Just because researchers cannot reach back into cotton’s own gene interested them. In the first, a link was established to ‘mutation
pool to introduce beneficial traits does not mean that they cannot breeding’ in the 1960s and has since spread unnoticed through
introduce them using other means. A group of researchers in Texas breeding to present-day varieties. In the second, the observed
turned to a model plant called Arabidopsis to pinpoint genes that may variation occurred and was selected during environmental
provide survival and growth advantages to cotton. By overexpressing adaptation as barley production spread from its origins in the
two genes that are known to increase stress tolerance in Arabidopsis, Middle East.
AVP1 and OsSIZ1, in cotton, the researchers doubled cotton fiber yield. The results from this study confirm that major structural variants
During a particularly dry year, the fiber yield from the modified cotton can play a role in both crop evolution and breeding. They also
was up 133 percent from that of wild-type cotton. The two genes point to the importance of studying pangenomes since the only
that were overexpressed are in most other crop plants, meaning the way the structural variants could have been discovered is through
results can be applied to other crops like wheat, rice and corn. the complete genome sequencing of diverse varieties of barley.
Despite current progress, researchers still face major challenges.
REFERENCES: Esmaeili, N., et al. Towards doubling fibre yield for cotton in the The entire diversity of barley has not yet been recorded. In a next
semiarid agricultural area by increasing tolerance to drought, heat and salinity step, the researchers want to take a closer look at wild barley, the
simultaneously. Plant Biotechnol. J. (2020) https://doi.org/10.1111/pbi.13476 direct ancestor of today's cultivated crop.
Chen, Z.J., et al. Genomic diversifications of five Gossypium allopolyploid species REFERENCE: Jayakodi, Padmarasu et al. The barley pan-genome reveals the
and their impact on cotton improvement. Nat Genet 52, 525–533 (2020).
hidden legacy of mutation breeding. Nature. (2020) doi:10.1038/s41586-020-2947-8.
32

Genomes published for pigweed and Palmer
major types of weeds amaranth. A reference
genome is a repre-
Weeds are a major threat to agricultural crops, competing for import- sentative example of
ant resources like food, space and sunlight. As weeds grow, they take a set of genes from
soil space away from crop plants, cause sunlight blocking shadows a specific organism.
to sit over the crop plants and soak up nutrients from the soil that They are important
are necessary to sustain and nourish the crop plants. All of this can to help researchers identify disease- or resistance-causing genetic
lead to stunted crop growth, discolored leaves and fruits, increased variation. Although draft genomes had been previously published for
susceptibility to disease and insect infestation and ultimately, losses waterhemp and Palmer amaranth, the techniques used in this study
in profit for farmers. provided a much clearer and richer picture of the species' gene se-
Herbicides are chemicals that farmers use to destroy unwanted quences. These high-quality reference genomes will make it possible
weeds, or damage them enough that they no longer compete with the to pinpoint herbicide resistance genes.
crops. While herbicides were initially successful at controlling agri- For example, researchers believe that some instances of herbicide re-
cultural weeds, weed resistance to herbicides has become a major sistance are due to changes in the speed at which the weeds detoxify,
concern in crop production worldwide. The plant genus Amaranthus or metabolize, herbicides. Faster herbicide metabolism would allow
contains some of the most troublesome agricultural weeds, many weeds to remove the herbicides from their systems before they cause
of which have become resistant to herbicides over time. It is widely damage. With the reference genome, researchers will be able to
unknown how these plants acquire resistance to herbicides. A study compare resistant weed genomes with the reference genome to find
published in 2020 in the journal Genome Biology and Evolution brings genetic variation in metabolic genes with the hope of either knocking
researchers one step closer to identifying the genetic cause of the out or modifying the responsible molecule to avoid early metabolism
herbicide resistance. of the herbicide.

In the study, a research group published high-quality reference REFERENCE: Montgomery, J.S. et al. Draft Genomes of Amaranthus tuberculatus,
genomes for three Amaranthus species—waterhemp, smooth Amaranthus hybridus and Amaranthus palmeri. Genome Biology and Evolution, 12(11):
1988-1993 (2020).

USDA, EPA update Similarly, the EPA’s updated rules state that plants engineered to
biotechnology crop regulations produce pesticides are exempt from regulatory approval if they have
a low-risk plant and pests could have been created using traditional
In America, crops developed with genetic technology are regulated by breeding approaches.
three federal agencies. The United States Department of Agriculture Proponents note the new rules are based on decades of scientific
(USDA) oversees whether any genetically engineered (GE) plant poses research on agricultural biotechnology. They argue that streamlining
a risk to become a plant pest in the environment. The United States the regulatory process reduces regulatory burdens for low-risk plants
Environmental Protection Agency (EPA) regulates those GE plants increasing the likelihood of innovation in new product development.
that produce biochemicals used as pesticides. The Food and Drug However, some environmental and public health advocacy groups say
Administration (FDA) ensures the safety and labeling of all GE the rules now leave most genetically engineered plants unregulated
plant-derived food and feed. by the USDA and the EPA, leaving consumers unaware of new
The USDA and the EPA modified their regulatory requirements in biotech products.
2020, allowing certain categories of GE plants to bypass the The new rules don’t affect the food safety oversight role of the FDA.
regulatory process if they met specific conditions.
Previously, developers of GE crops had to undergo a lengthy approval REFERENCES: https://www.aphis.usda.gov/aphis/ourfocus/biotechnology/
process to show their products weren’t plant pests. Under the modi- biotech-rule-revision/secure-rule/secure-about
fied USDA regulations, plants created with biotechnology are exempt https://www.epa.gov/sites/production/files/2020-09/documents/10014-10-prepub-
from regulatory approval if: fr-doc-admin_esignature2020-08-31.pdf
• the modified plants don’t pose a plant pest risk
• conventional breeding techniques could have developed the
same type of plant
• the trait combinations are identical to previously-approved plants
The regulations also affirm that as long as there is no plant pest risk,
crops developed using gene editing techniques will not require regu-
latory approval. The USDA has published a list of exempt plant-trait
combinations, which developers can use to determine whether a new
GE plant requires regulatory approval. Developers can also submit an
“Am I Regulated?” request to the USDA for regulatory determination.

33



FOUNDATIONAL CONCEPTS

KEY TECHNOLOGIES AND APPLICATIONS

ONLINE BIOTECH BASICS

HudsonAlpha offers
easy-to-understand explanations
of the following foundational concepts at
hudsonalpha.org/biotech-basics.
Twenty-three key technologies and applications
are described in detail. Language and
concepts are intentionally geared to a
high school or public audience.

35

KEY TECHNOLOGIES RNA and Protein Analyses
DNA Sequencing

In 1977, Fred Sanger and Alan Coulson published a As sequencing techniques identify
method to rapidly determine the specific order of the the genetic recipes of an organ-
adenine, thymine, cytosine and guanine nucleotides in any ism, understanding the func-
DNA sequence. This technology ultimately transformed tion of those genes becomes
biology by providing a tool for deciphering complete genes increasingly important. This
and later entire genomes. Improvements in process paral- includes determining the
lelization, automation and analysis led to the establishment presence, absence or relative
of factory-like sequencing centers in the 1990s and early amounts of RNA produced by
2000s. These spearheaded the effort to sequence the a gene under different condi-
genomes of many organisms, including humans. tions. Initially, these approaches
examined one or only a handful of
The need for even greater sequencing capability at a more RNA sequences at a time. During the
economical price led to the development of new technologies last decade, researchers developed techniques to study tens
based on different chemistries and refined for accuracy and of thousands of RNA fragments simultaneously arrayed on
speed. Second generation approaches reduced the volume a glass slide. Called microarrays, these could identify which
of reagents and increased the number of simultaneous genes are active or silent in a given cell type, classifying the
sequencing reactions in a single experiment, allowing them genes that distinguish a liver cell from a neuron or the set of
to analyze short stretches of DNA ~50-500 nucleotides in genes activated or silenced across different types of cancer.
length. These short read technologies produce 150 times
more sequence than the first generation systems, at Second and third generation sequencing technologies (see
1/150th the cost. column at left) have been modified to also identify RNA
expression across cells. This approach, known as RNA-seq,
Third generation long-read technologies sequence DNA frag- yields more precise results than microarray analysis and
ments tens of thousands of nucleotides long. This approach has become the standard tool for measuring genome-wide
solves a key problem of short-read systems - which tend to gene expression.
miss regions that are repetitive. It also dramatically reduces
the complexity of fragment assembly - much like the dif- Large-scale technologies have also been developed to identi-
ference between assembling a puzzle with 1,000 tiny pieces fy protein activity and interactions. This represents part of the
versus 200 much larger pieces. Long-read sequencing
is increasingly used to generate the initial refer- field of proteomics, which seeks to understand the entire
ence sequence of an organism, analyze RNA protein complement (amounts, locations, inter-
transcripts and characterize epigenetic actions and even activities) of an organism’s
modification that influence gene ex- cells. For example, tissue microarrays,
pression. While long-read sequenc- tiny slices of tissue from a single or
ing has a higher error rate than multiple samples, can be tested with
short-read technologies, there are antibodies to identify the locations
approaches to increase accuracy. of proteins within the cell and their
Often, short- and long-read relative amounts. Building on these
sequencing are used in combina- methods, efforts are continuing
tion, building on the strengths of towards a Human Proteome Project
both approaches. (HPP) to systematically catalog
all the proteins manufactured in
HudsonAlpha Clinical Services Lab, LLC the body. The scale and complexity
is a leader in short- and long-read sequencing of this project is much greater than
and analysis. www.clinicallab.org the Human Genome Project as a single
gene can direct the production of multiple
different versions of a protein and each protein

can in turn be modified in a number of different ways.
In October 2020, a draft HPP was reported, covering >90
percent of the human proteome.

36

Bioinformatics KEY TECHNOLOGIES

Acquiring DNA sequence has now become routine and new Digital information is
technologies can sequence a bacterial genome in a single measured as bytes.
day. Similarly, microarray experiments shed light on the RNA
levels produced by tens of thousands of genes. Current anal- One thousand bytes is approximately the amount
ysis platforms are capable of generating terabytes of data in of space required to store this paragraph of text.
a single run. For reference, one terabyte is equal to A million bytes is a megabyte. An average MP3
1,000 gigabytes (see column at right for measurements). song is about 3.5 megabyte of digital data.
Streaming a movie utilizes 1 billion bytes
Understanding the meaning of all that information is a (a gigabyte) per hour.
daunting challenge. Deciphering the data requires a biologi- The Microsoft Xbox® One game console ships with
cal knowledge of what to look for, algorithms (computer 1 trillion bytes (a terabyte) of storage, which could
programs) capable of detecting interesting features and hold 1,000 copies of the Encyclopedia Britannica.
computers powerful enough to perform complex analyses A quadrillion (1015) bytes of digital information
efficiently and rapidly. Fortunately, advances in all three areas (a petabyte) would fill approximately 20 million
have kept pace and the resulting field of bioinformatics seeks four-drawer filing cabinets with text, like watching
to characterize functional sequences in genes and genomes super 4K video for 27,115 years straight.
through computational models. In addition, the data must be An exabyte is approximately 1,000 petabytes —
managed – stored in a form that is useful to the researcher it’s been suggested that five exabytes would equal
and readily accessible. This has led to the development of all the words ever spoken by mankind.
many databases that store and provide data and analytical
tools for researchers. The primary mission of all these data-
bases is to provide unlimited, free access to anyone interest-
ed in studying genomic sequences. It is no exaggeration to
say that these databases and the immediate access to them
through the internet have changed the way that nearly all
biological research is done.

Many bioinformatics experts, particularly in the early days
of the genome sequencing efforts, were computer
scientists who formed partnerships with biologists. With
the growth of the field of genomics, it is not unusual today
for a student to be trained in a truly interdisciplinary way
by developing deep expertise in both biology and
computational science.

37

APPLICATIONS
Agriculture

The demand for crop production is rising due to increased
human population, greater worldwide meat and dairy con-
sumption and the expanding role of biofuels. Studies suggest
that agricultural production must double between 2005 and
2050 to meet this growing need. Increasing crop yields, rather
than clearing additional farmland, is believed to be the more
sustainable path. However, crop yields are not increasing fast
enough to keep up with projected demands. The additional
challenges of drought, temperature change and poor soil
quality further strain the productivity of agricultural systems.

Developing new high-yield seeds adapted for our environmen- Genetically Modified (GM) Crops
tal conditions is a cornerstone of increased food production.
This begins with the ability to locate and characterize agricul- GM crops contain genetic sequences from other organisms.
turally important versions of specific genes. These discoveries Although the subject of some controversy, more than 17
can then be shared with the farmers and commercial plant million farmers across 26 countries currently plant biotech
breeders who are developing new varieties of crops. Such a crops (also known as genetically modified organisms or
collaborative approach blends the field of genomics with the GMOs). To date, over 2 billion acres of biotech crops
ancient practice of agriculture, increasing yields and ensuring have been harvested globally. At least 57 different plants
global food security. have been the focus of biotech research over the last two
decades. Of this number, ten are in commercial produc-
Sequencing Plant Genomes for tion and 29 have received regulatory approval in the Unit-
ed States. Herbicide tolerance has consistently been the
Food and Bioenergy Needs primary trait introduced into the crops, followed by insect
resistance and the combination of both traits. Biotechnology
Over the last decade, genome sequencing projects have crops reduce the need for plowing to control weeds, leading
been completed for a number of plants, including rice, corn,
soybean, canola and wheat. These efforts provide a better un- to better conservation of soil and water and a decrease
derstanding of the genes that contribute to growth rate, seed in soil erosion and soil compaction. A reduction
and fruit characteristics and susceptibility to climate change in plowing also allows farmers to signifi-
or infectious agents. To capture the full landscape of cantly reduce the consumption of fuel
diversity within a species, multiple varieties of and decrease greenhouse gas emis-
a single crop are sequenced and compared. sions. Researchers are also develop-
Knowing which genes control desirable ing biofortified food plants to boost
traits allows researchers to select for the levels of nutrients, vitamins
specific type high-yield strain as well and minerals in foods. GM crops
as develop plants that are more have faced several roadblocks due
resistant to drought or disease. to concerns about environmental
A number of plants are also being risks, evolution of resistance in
analyzed for their potential contri- weeds and potential health risks.
bution to bioenergy. These include This has prompted the development
corn, soybean and switchgrass. of alternative techniques such as gene
For example, soybean not only editing (described more on page 46).
accounts for 70 percent of the world’s
edible protein, but soybean oil is the
principle source of biodiesel.

HudsonAlpha Genome Sequencing Center is using genomic
sequencing to improve crop yields and advance agriculture
and sustainability. www.hudsonalpha.org/gsc

38

APPLICATIONS

Cancer

The second most-frequent cause of death worldwide, cancer Over the past decade, advances in genomic technologies,
is a collection of diseases that are characterized by un- tumor analysis and drug development have transformed the
controlled growth of cells and their spread to surrounding landscape of cancer diagnosis and treatment and given rise
tissues. All cancers are genetic diseases because changes to the field of precision oncology. Large-scale studies such
in the genes that control cell growth and division are in- as The Cancer Genome Atlas and the Pan Cancer Analysis
volved. However, only about 5 percent of cancers are strongly of Whole Genomes have sequenced the genomes of nearly
hereditary – primarily caused by mutations that are inher- 40 tumor types, identifying genes commonly mutated across
ited from parent to child. Therefore, most cancers do not cancer types. RNA expression studies provide additional
result from inherited mutations, but instead develop from insight into which genes are activated or silenced in cancer
an accumulation of DNA damage acquired during a lifetime. cells. Many of these research findings have been adapted for
These cancers begin with a single normal cell that becomes patient care, resulting in testing panels that analyze dozens
genetically damaged. The transformation from that initial or even hundreds of cancer-related genes within a patient’s
cell into a tumor is a stepwise progression. The number of tumor. These data are being used to classify patients into
genetic mutations that are required to convert a genetically
normal cell into an invasive tumor is not known but most groups that correlate with cancer subtypes and respons-
likely varies among cancer types. These genetic changes may es to a specific drug or clinical outcome. This in-
involve single letter or base substitutions, large deletions formation helps physicians identify the most
or duplications, or chromosomal rearrangements impact- optimal treatment or course of action.
ing vast sections of the genome. Most cancer cells have a
number of both large-scale chromosome abnormalities and
single letter mutations.

Historically, the diagnosis and staging of cancers has been
based on the appearance of the cancer cells under a mi-
croscope and the spread to surrounding or distant tissues.
Treatment decisions and options are often based upon this
information. However, in many cases, individuals with simi-
lar-appearing tumors will show markedly different responses
to treatment. We now know that differences at the mo-
lecular level, not visible under a microscope, are
responsible for the varying outcomes.

HudsonAlpha research teams are work-
ing to reveal hidden information within
cancer genomes and tumors leading
to better diagnostic treatments.
www.hudsonalpha.org/cancer

39

APPLICATIONS
Comparative Genomics

Although the human genome is perhaps the most famous
sequencing project, scientists have assembled a genomic
library of more than 200 different organisms. Knowing the
genome of each species provides insight into the function of
its DNA; however, there is additional information gained by
comparing genomes across organisms. This field of compar-
ative genomics helps discover previously undetected genes,
identify the regulatory regions that control gene activity and
determine gene function as it relates to health and disease.

While humans may seem to have little in common with Comparative genomics provides a powerful tool for studying
organisms such as fruit flies, roundworms or mice, they are evolutionary changes among organisms, identifying genes
all composed of cells that must take in nutrients and remove that are conserved among species as well as gene
waste, interact with neighboring cells and the outside envi- and genetic changes that give each organism its
ronment and grow and divide in response to specific signals. unique characteristics.
To varying degrees, each of these organisms contains a
digestive, circulatory, nervous and reproductive system and is Genomic comparison also extends to genes involved in
impacted by disorders that impair these systems. During the disease. If we examine the current list of human disease
evolutionary process, as organisms diverged and gave rise to genes, approximately 20 percent have a homolog in yeast and
new species, many key proteins such as enzymes underwent nearly two-thirds have one in flies and worms. Initial studies
little change. In general, the nucleotide and amino acid suggest these counterparts may function in nearly identical
sequences of these key proteins have similarly been con- ways, meaning these organisms can serve as models for
served across the species. understanding human disease and potential treatment.
For example, studying genes involved in DNA repair in yeast
Scientists directly compare the DNA sequence of these or-
ganisms using sophisticated computer programs that line up or bacteria has offered valuable insight into this process
multiple genome sequences and look for regions of similari- in humans and the role that mutations of these
ty. These similar segments, or conserved sequences, suggest genes play in the development of
the DNA sequence has an important functional role – for some cancers.
example, a gene or a regulatory element that
controls the activity of a gene. Less critical
DNA segments would accept sequence
changes without clinical consequence:
subsequently, these segments would
vary among species. Genes that
have relatively high sequence
similarity are referred to as
homologous genes or homologues.

40

APPLICATIONS

Copy Number Variation

For years, single nucleotide polymorphisms (SNPs) were
thought to be responsible for the majority of human variation.
Until recently, deletions, duplications and insertions
involving multiple nucleotides were thought to be relatively
rare. However, scientists have discovered these changes,
known as copy number variants (CNVs), occur much more
frequently than was suspected. These structural changes,
50 nucleotides or greater in size, alter the number of copies
of a specific DNA segment.

It came as a surprise to many scientists just how much DNA CNVs can be detected using microarrays, as well as short-
variation is due to copy number changes. Previous studies read and long-read sequencing technologies. There are sev-
based primarily on SNPs suggested that any two randomly eral publicly available CNV catalogs. Determining whether a
selected human genomes would differ by 0.1 percent. CNVs CNV is associated with disease is challenging and the inter-
revise that estimate: the two genomes differ by at least 1.0 pretation of CNVs is still evolving. They have been implicated
percent. While this may not seem like a major increase, in the development of multiple disorders, including neurode-
remember that the human genome is composed of approx- velopmental disorders like intellectual disability, epilepsy and
imately 3 billion nucleotides, so the estimated number of autism spectrum disorders, as well as in Crohn’s disease,
nucleotides that vary between two random individuals has
increased from 3 million to 30 million. Humans are still congenital heart and kidney malformations, Parkinson
nearly 99 percent identical at the DNA sequence level, but disease and schizophrenia. In some cases the
the CNV research has broadened our understanding of how associated CNV is rare, but in other dis-
and where we differ. eases, the identified risk variant is quite
common. It is also likely that CNVs may
It has been suggested that CNV regions influence gene influence individual drug response
activity by directly increasing or decreasing the number of and susceptibility to infection
copies of that gene, leading to a concurrent change in the or cancer.
amount of protein. Alternatively, CNVs may alter the
performance of nearby regulatory signals that activate
or silence genes without directly impacting the
copy number of the gene itself.

41

APPLICATIONS
Criminal Justice and Forensics

DNA profiling, popularly known as DNA fingerprinting, has
transformed personal identification, whether in forensic
cases, missing persons, mass disasters or paternity
disputes. It has become ubiquitous in law enforcement.
It is used to exclude individuals suspected of crimes, help
convince a jury of an individual’s guilt and in some cases,
set free individuals wrongly convicted of crimes.

DNA analysis is also used to suggest ancestral origins; there scenes have been used to predict the skin tone, eye color,
are several companies offering Y-chromosome and mito- hair color and facial shape of suspects. This data is fed into
chondrial DNA studies to determine, for example, to which a software program to generate a sketch of what the suspect
of the ancient tribes of Britain a man belongs or whether a potentially looks like and is released to the public. In several
man or woman has African, Native American or Celtic DNA cases, these sketches have led to arrests and confessions.
markers. It is possible to use forensic DNA profiling in the
same way to determine the ethnic or geographical origin of Legislatively, forensic phenotyping is allowed on a limited
the individual from whom the DNA sample came, provid- basis in some countries (such as the UK) and forbidden in
ing additional information that could be used to narrow the others (Germany). However, for most of the world, including
number of potential suspects. For example, in 2007, a DNA the United States, legislation that addresses DNA forensic
test based on genetic biomarkers indicated that one of the methods is silent about the ability to infer ethnicity or
suspects associated with a bombing in Madrid was of North physical traits.
African origin. Using other evidence, police confirmed the
suspect was an Algerian, confirming the test result.

Recently, this testing has been extended to identify external
and behavioral features. Scientists have identified many of
the genetic variants related to hair, skin and eye color and
are exploring other genes that influence traits, such as facial
height and width as well as nose and lip shape. Using this
“forensic molecular photo fitting”, genetic data from crime

42

APPLICATIONS

Epigenetics

While identical twins (twins who share the same genetic
information) generally look alike when young, obvious dif-
ferences often emerge as they age. The differences may be
due to the varied environment of each twin — for example,
one may lift weights and become very muscular while the
other never exercises and gains weight. Recent advances in
the relatively new field of epigenetics suggest an additional
role for the environment in health and disease by altering
the activity of particular genes. Activating genes to begin the
protein-making process is a key area of study. By identifying
the signals that turn genes on and off, investigators hope to
understand not only gene function under normal conditions
but also how improper on/off signaling may lead to disorders
such as cancer, diabetes, heart disease and obesity.

Epigenetics encompasses modification to DNA, including the For many mammals (humans included), differences in diet
addition of small chemical tags called methyl groups. Other and level of stress during fetal development and shortly after
changes modify histones, which are the protein complexes birth alter the pattern of on/off gene activity, leading to higher
DNA wraps around as part of its coiling and packaging pro- risk of obesity, Type 2 diabetes and cardiovascular problems.
cess. These modifications alter the patterns of gene activity,
but do not change the actual DNA sequence. They can be Other epigenetic changes increase the risk of cancer by
remembered across thousands of cell divisions and at times silencing or overactivating genes associated with cell growth,
from parent to child. Many epigenetic changes can be added evading the immune system or leading to metastasis.
or removed in response to differences in the environment During tumor development, there are widespread epigenetic
or behavior. modifications. Some of these can be used to guide treatment
or develop new classes of epigenetic-based drugs.
This field includes some of the most fascinating biological
phenomena, including X-chromosome inactivation, imprint-
ing (when the DNA copy inherited from a particular
parent is silenced, while the other copy remains
active) and cellular differentiation as
we develop.

Studies of identical twins suggest
that at birth, twins share similar
patterns of epigenetic modification.
As they age and are exposed to dif-
ferent diets and environments, the
twins' patterns become markedly
different, leading to altered activa-
tion and silencing patterns. Current
research suggests environment al-
terations to these epigenetic patterns
can change an individual’s risk
for disease.

43

APPLICATIONS

Genetic Information
Nondiscrimination Act (GINA)

While most Americans are optimistic about the use of
genetic information to improve health, many have concerns
that genetic information may be used by insurers to deny,
limit or cancel health insurance and by employers to dis-
criminate in the workplace. Consequently, for many years,
lawmakers, scientists and health advocacy groups have
argued for federal legislation to prevent genetic discrimina-
tion and protect genetic privacy.

Several privacy protections are in place depending on As required by the passage of GINA, in 2013 the Health
whether an individual’s genomic information is being used Insurance Portability and Accountability Act (HIPAA)
in research, clinical applications, or other uses. Published in Privacy Rule was modified to establish that genetic infor-
1991, The Federal Policy for the Protection of Human Sub- mation is Protected Health Information (PHI). This means
jects-also known as the "Common Rule"- establishes the that covered entities must implement safeguards under the
baseline standard of ethics for government-funded research HIPAA Privacy Rule to prevent unauthorized use or disclosure
in the United States. Among other things, the Common Rule of HIPAA protected genetic information.
requires informed consents for genomic research and should
clarify the uses of research results, including with whom While the Common Rule, GINA and HIPAA protect people
the information will be shared. However, the Common Rule against discrimination by their health insurance companies
only protected the genetic information of people involved in and employers, few laws prohibit police from accessing
government-funded research. genetic data stored in public or private databases. Several
private genetic testing companies have created barriers
In 2009, the Genetic Information Nondiscrimination Act
(GINA) took effect across America, paving the way for people against law enforcement access and give subscribers
to take full advantage of the promise of personalized medi- the option to opt out of having their genetic pro-
cine without fear of discrimination. GINA protects Americans file shared with law enforcement. The U.S.
against discrimination based on their genetic information Department of Justice has also developed
when it comes to health insurance and employ- an interim policy for the use of genetic
ment. The law, together with existing nondis- genealogy in police cases, however
crimination provisions from other laws, more legislation is likely on the
prohibits health insurers or health plan horizon given the increased use
administrators from requesting or of genetic genealogy.
requiring genetic information of an
individual or the individual’s family
members or using it for decisions
regarding coverage, rates or pre-
existing conditions. The law also
prohibits most employers from
using genetic information for hiring,
firing or promotion decisions.

44

APPLICATIONS

Genetics of Eye Color

In 1907, Charles and Gertrude Davenport developed a model
for the genetics of eye color. They suggested that brown
eye color is dominant over blue eye color. This would mean
that two blue-eyed parents would always produce blue-eyed
children but never ones with brown eyes. For most of the past
100 years, this version of eye color genetics has been taught
in classrooms around the world. It is one of the few genetic
concepts that adults often recall from their high school or
college biology classes. Unfortunately, this model is overly
simplistic and incorrect – eye color is actually controlled by
several genes.

In humans, eye color depends on the level of a pigment
called melanin present in the iris. Melanin is produced
and stored inside specialized cells known as melanocytes.
Blue eyes contain minimal amounts of melanin. Irises from
green–hazel eyes show moderate pigment levels, while
brown eyes are the result of high melanin concentrations.

To date, eight genes that impact eye color have been iden- A recent study that compared eye color to OCA2 status
tified. The OCA2 gene, located on chromosome 15, appears showed that only 62 percent of individuals with two copies of
to play the major role in controlling the brown/blue color the blue eyed OCA2 allele actually had blue eyes. Blue eye
spectrum. OCA2 produces a protein called P-protein that is color was also found among 7.5 percent of the individuals
involved in the formation and processing of melanin. OCA2 with the brown-eyed OCA2 alleles. A number of other genes
alleles (versions of the gene) related to eye color alter P- (such as TYRP1, ASIP and SLC45A2) also function in the mel-
protein levels by controlling the amount of OCA2 RNA that anin pathway and shift the total amount of melanin present
is generated. The allele that results in high levels of in the iris. The combined efforts of these genes may boost
P-protein is linked to brown eyes. Another allele, associated melanin levels to produce hazel or brown eyes or reduce total
with blue eye color, dramatically reduces the
P-protein concentration. melanin resulting in blue eyes. This explains how two
parents with blue eyes can have green or brown
While studies suggest that about three- eyed children (an impossible situation under
fourths of the eye color variation can the Davenport single gene model). The
be explained by genetic changes in combination of color alleles received by
and around OCA2, it is not the only the child resulted in a greater amount
genetic influence on color. of melanin than either parent indi-
vidually possessed.

45

APPLICATIONS Programmable nucleases are not without their challenges.
They can be difficult to correctly deliver to the appropriate
Genome Editing cells, the frequency of DNA modification can be very low and
they occasionally cut DNA at “off target” sites. Techniques
Tools that directly modify genetic sequences allow scientists that increase specificity and efficiency have been developed
to explore the functional impact of DNA mutations as well to address these challenges, but additional tweaking is still
as engineer changes that create drug-producing bacteria, needed. A number of regulatory and safety hurdles must still
disease-resistant crops or life-saving genetic therapies. be cleared and there are many ethical, social policy implica-
These approaches are analogous to the “find and replace” tions waiting to be addressed. However, genome editing has
feature in word processing software – they scan the genome shown immense promise — the first wave of modified crops
for a specific sequence and then make a targeted, controlled and human therapies are moving from the laboratory to the
change within that sequence. field and clinic.

All genome editing tools rely on some sort of programmable There are four key components of a CRISPR-Cas9 system:
nuclease – an enzyme guided to a DNA sequence of interest
in order to cut across the DNA strand. This cut triggers a 1. Target DNA: This is the region of the genome to be modified.
DNA repair process that can knockout (disrupt) the genetic
instructions or replace them with a different set of informa- 2. Cas9: This bacterial enzyme unzips and cuts the target DNA.
tion. There are three programmable nucleases — zinc finger To date, most approaches use the Cas9 protein found in the
nucleases (ZFNs), transcription activator-like effector nucle- bacteria Streptococcus pyogenes.
ases (TALENs) and the clustered regularly interspaced short
palindromic repeat (CRISPR) system. CRISPR has proven 3. PAM sequence: PAM stands for Protospacer Adjacent Motif. It
especially powerful and has quickly become a mainstay of is part of the target sequence DNA and is one of the factors that is
genome editing protocols in microbes, plants and animals. required to define the cutting site.

Genome editing tools have provided researchers with an un- 4. Guide RNA: A short fragment of RNA binds to Cas9 and con-
precedented ability to modify cells. This leads to applications tains a recognition sequence that matches the target. With different
in basic research, human disease therapy and agriculture. guide RNA sequences, the Cas9 enzyme can be directed to recog-
For example, CRISPR is being used to systematically study nize almost any DNA sequence. The guide RNA leads Cas9 to the
the effect of silencing every gene in zebrafish and mice, as desired location in the genome, binds the target sequence and trig-
well as human cells grown in the lab. These projects identify gers Cas9 to cut both strands of target DNA. This double stranded
genes essential for development and normal function. break provides the opportunity to edit the genome.

Gene editing can replace a genetic mutation with the correct How CRISPR works 3. Guide
DNA sequence, helping scientists understand how diseases
occur. For example, studies are underway using gene editing 1. Target 4. PAM RNA
tools to explore metabolic diseases like diabetes and high
cholesterol as well as neurodegenerative disorders and DNA Matching Genome 2. Cas9
chronic infections. These same approaches may Sequence
provide power tools for treatment: CRISPR-based
clinical trials are underway for cancer, blood disorders
and inherited eye diseases.

In agriculture, gene editing serves as a modern method of DNA is cut
selective breeding — identifying and promoting traits that
make crops and animals more hardy, nutritious and sus- Repair
tainable. The appropriate gene can be edited directly within CRISPR-Cas9 Targeted Genome Editing
an existing elite plant or animal, eliminating the issue of
time-consuming back crosses or the concern of introducing Human Cells Animal Cells Bacteria and
additional unintended genetic sequences. This approach is Parasites
expected to reduce the time to develop a new product and the
associated cost ten-fold. Gene Knockout *
Gene Editing

CRISPR-Cas-9 DNA repair mechanisms

46

APPLICATIONS

Gene Therapy

Doctors have now successfully made the leap from iden-
tifying disease-causing genes to fixing them. Nearly fifty
years after the concept was first proposed, researchers and
clinicians have gained approval for multiple forms of gene
therapy, introducing healthy genes to correct or improve
genetic disorders. While these treatments have a long way to
go before they become a go-to for clinicians, the successes
of gene therapy do point to a promising future.

Ideally, gene therapy inserts a normal (functioning) copy of a Example of a gene therapy, CAR-T cell therapy
gene into a cell to replace a non-functioning version. Genes
do not enter cells on their own, so a process is needed to
carry the corrected gene into the body’s cells. The most com-
mon mechanism is an altered form of a virus. Viruses have
the capability of infecting and inserting their genetic informa-
tion into cells. Researchers are able to exploit this capability
of viruses while removing the viral genes responsible for
causing illness.

Although the concept of gene therapy is simple in theory, improved light sensitivity and functional vision for 93 percent
there are several technical roadblocks that have to be over- of the more than two dozen children and adults that went
come. The inserted gene must remain active in the body’s through clinical trials. However, the treatment costs $425,000
cells long-term. Successful gene therapy in actively dividing per eye, raising questions about how quickly it and similar
cells is hard, because it is difficult to retain the added gene treatments could become mainstream options.
through multiple rounds of cell division. It’s also challenging
to ensure the therapeutic gene reaches the organs and body In 2019, the FDA approved Zolgensma™, a gene therapy
tissues where symptoms occur. to treat very young children with spinal muscular atrophy
caused by mutations in the SMN1 gene. A modified
The path to success has been littered with repeated cycles
of enthusiasm and disappointment. Initial thera- adeno-associated virus delivers a fully functional copy of
pies provided no clinical benefit or led to un- the gene to motor neuron cells through a one-
expected adverse outcomes like cancer or time IV infusion. The treatment leads to
patient deaths. Researchers returned to significant improvement in patients,
the drawing board in the early 2000s but costs $2.1 million.
and developed a new generation of
techniques, safety modifications Gene therapy clinical trials are in
and improvements. This reboot process for hemophilia, sickle cell,
has led to several recent clinical various muscular dystrophies and
advances, delivering treatment to immune disorders. Each presents
a wider circle of patients. a challenge in cellular engineer-
ing, balancing risks and benefits.
In 2018, the first gene therapy was Pricing, reimbursement and market
approved in the U.S. to correct a size remain significant hurdles to
specific disease-linked gene in a rare wide-scale adoption. Additionally, the
form of childhood blindness. The vision emergence of gene editing tools like
problems come from mutations of the RPE65 CRISPR (page 46) offers the ability to edit
gene, which scientists targeted by injecting billions the existing gene rather than add an extra
of virus particles directly into the eye. The virus delivers a copy. It remains to be seen whether gene editing and
healthy copy of the gene. The treatment, called Luxturna™, gene therapy will co-exist or if one will give way to
the other.

47

APPLICATIONS

Identifying Genetic Influence on Disease

Much progress has been made in identifying the genetic Twenty years ago, researchers knew of almost no genetic
causes of single gene diseases such as cystic fibrosis, phe- variants involved in complex disease. However, GWA stud-
nylketonuria and Huntington disease. This has led to more ies have transformed this landscape: As of January 2021,
accurate risk analysis, better testing approaches and, in the GWAS Catalog (https://www.ebi.ac.uk/gwas/) lists more
some instances, more effective methods of treatment. Even than a quarter of a million SNP-trait associations identified
though there are thousands of single gene disorders, they through various research studies. Intriguingly, some genetic
are rare, affecting less than 3 percent of the population. regions have been associated with multiple disorders, sug-
gesting common biological pathways influence a number of
In contrast, other diseases, including cleft lip, cardiovascular cellular processes.
disease, psychiatric disorders and cancer, affect much of
the world’s population. While these diseases have a strong Even with these successes, the majority of the genetic risk
genetic component, they arise from a combination of genetic for common disease remains undiscovered and the contribu-
risk factors that are also influenced by the environment. tion by a single genetic variant to the overall clinical picture
Few of the contributing genes are believed to make more is often small. As a result, scientists believe that many of the
than a modest contribution to overall risk, perhaps increas- genetic risks for disease are caused by a number of so-called
ing it by 5 or 10 percent. It is the specific combination of rare variants, genetic changes that are each present in less
multiple predisposing alleles (DNA changes) and environ- than 1 percent of the population. This view represents a shift
ments that leads to physical symptoms. For this reason, they from previous beliefs that complex diseases were caused by
are often called complex or multifactorial disorders. Iden- variants that were much more common. Projects aimed at
tifying the factors that influence disease is a major goal for sequencing the genomes of a larger number of individuals
biomedical research. will hopefully identify many of these rare variants, allowing
this hypothesis to be tested. In addition, as emerging tech-
Traditional methods of determining the genes responsible for nologies in DNA sequencing continue to drive down costs,
single-gene disorders do not work well for complex diseas- many believe GWA studies will shift from examining specific
es. Fortunately, thanks to the advent of second-generation sites of known genetic variation towards full sequencing of
technology to cheaply analyze DNA changes, scientists have the entire genome. At that point, identifying even the rarest
used a process known as genome-wide association (GWA) to of variation becomes feasible.
identify the genetic factors involved in complex disease.

The premise behind GWA studies: if a specific
genetic variation increases the risk of devel-
oping a disease, that variation will occur
more frequently – and hold up under
rigid tests for statistical significance
– in individuals who have the disease
compared to those not affected.
Basically, there is an association
between the specific allele and the
incidence of disease.

48