How omics and bioinformatics are used in the Precision Medicine Lab

Summary

Dr. Judy Crabtree, an associate professor of genetics at LSU HSC, discusses her journey from sequencing the human genome to leading the precision medicine program. She highlights the impact of genomics on personalized medicine, focusing on its application in oncology and drug development. Crabtree also emphasizes the importance of the 'All of Us' research program in diversifying genomic data to address health disparities. Her presentation showcases the evolution of genomics from basic research to clinical practice, aiming to deliver the right treatment to the right patient at the right time.

Takeaways

• 🎓 Dr. Judy Crabtree's academic background includes a PhD in Biochemistry and Genetics from the University of Oklahoma and postdoctoral work at the National Human Genome Research Institute under Dr. Francis Collins.
• 🧬 Dr. Crabtree contributed to the Human Genome Project, which sequenced regions of human chromosome 22 and provided foundational data for understanding human genetic diversity.
• 🏥 Her career transitioned from academia to the pharmaceutical industry, where she worked at Wyeth Pharmaceuticals, and then to LSU Health Sciences Center as a professor of genetics.
• 📈 Dr. Crabtree played a pivotal role in implementing COVID-19 testing and viral sequencing efforts at LSU to track variants, showcasing her adaptability in public health crises.
• 🧬 The Human Genome Project, which Dr. Crabtree was part of, revealed approximately 10 million single nucleotide variants in the human genome, emphasizing the genetic diversity among individuals.
• 🧪 Precision medicine, as described by Dr. Crabtree, aims to tailor healthcare by considering individual differences in genetics, environment, and lifestyle, moving towards personalized treatment plans.
• 🧬 The 'All of Us' research program, supported by the NIH, aims to enroll one million or more participants to better understand genetic variants and their impact on health, with a focus on diversity.
• 🏥 Dr. Crabtree's work at LSU's precision medicine program involves using next-generation sequencing to identify genetic variants that can inform treatment strategies for cancer patients.
• 💊 The field of oncology is leading the way in precision medicine, with targeted therapies designed to hit specific molecular targets identified by genomic variants, aiming for fewer side effects.
• 🧬 Genomic testing in clinical settings is becoming more accessible and cost-effective, with the potential to revolutionize patient care by providing evidence-based, personalized medicine.

Q & A

What was Dr. Judy Crabtree's role in the Human Genome Project?

Dr. Judy Crabtree received her PhD training in biochemistry and genetics from the University of Oklahoma, where she was part of one of the original labs funded to sequence the human genome.

Where did Dr. Crabtree complete her postdoctoral work?

Dr. Crabtree completed her postdoctoral work at the National Human Genome Research Institute at the National Institute of Health in Bethesda, Maryland, under the direction of Dr. Francis Collins.

What disease did Dr. Crabtree study during her postdoctoral work?

During her postdoctoral work, Dr. Crabtree studied the biology of an endocrine tumor disease called Multiple Endocrine Neoplasia Type One.

How long did Dr. Crabtree work in the pharmaceutical industry before joining LSU Health Sciences Center?

The script does not specify the exact duration of Dr. Crabtree's work in the pharmaceutical industry before joining LSU Health Sciences Center in 2009.

What is Dr. Crabtree's current position at LSU Health Sciences Center?

Dr. Crabtree is currently an Associate Professor of Genetics and the Scientific and Education Director of the Precision Medicine Program at LSU Health Sciences Center.

What significant initiative did Dr. Crabtree implement during the COVID-19 pandemic?

During the COVID-19 pandemic, Dr. Crabtree implemented the COVID testing program for the LSU-HSC campus and launched viral sequencing efforts to track COVID-19 variants of concern in Southern Louisiana.

What was the cost and duration of the Human Genome Project?

The Human Genome Project took 13 years to complete at a cost of about 2.7 billion dollars.

What is the All of Us Research Program and how does it relate to precision medicine?

The All of Us Research Program is a cornerstone of the Precision Medicine Initiative that aims to enroll one million or more participants to understand genetic variants better. It includes collecting surveys, biological specimens for whole genome sequencing, and medical records for population-based studies.

How does the LSU Health Sciences Center contribute to the All of Us Research Program?

LSU Health Sciences Center is a flagship institution in the Southern region of the All of Us program, collaborating with other major institutions across the Gulf South to enroll participants and contribute to the understanding of the human genome.

What is the significance of the genomic data generated from the All of Us Research Program?

The genomic data from the All of Us Research Program is significant because it includes a diverse pool of participants, with more than half of the new genomic information coming from people who self-identify with racial or ethnic minority groups, which helps to address the lack of diversity in previous genomic studies.

What is the TSO 500 panel and how does it relate to precision medicine at LSU Health Sciences Center?

The TSO 500 panel is a next-generation sequencing-based approach that contains 523 oncology-related genes. It is used to support solid tumors and will be expanded into hematological malignancies. It also provides an assessment of microsatellite instability and defects in mismatch repair, which support the use of checkpoint inhibitor therapies and overall tumor mutational burden.

Outlines

00:00

🎓 Introduction to Dr. Judy Crabtree's Academic and Professional Journey

Dr. Judy Crabtree is introduced as a distinguished biochemist and geneticist with a Ph.D. from the University of Oklahoma, where she was part of the team sequencing the human genome. Her postdoctoral research at the National Human Genome Research Institute focused on Multiple Endocrine Neoplasia Type One. She then transitioned into pharmaceutical drug development at Wyeth Pharmaceuticals before joining LSU Health Sciences Center (LSU HSC) as a genetics professor. At LSU HSC, she has advanced to Associate Professor of Genetics and serves as the Scientific and Education Director of the Precision Medicine Program. Dr. Crabtree also played a pivotal role in implementing COVID-19 testing and viral sequencing efforts during the pandemic.

05:03

🧬 The Genesis and Evolution of Precision Medicine

The discussion delves into the history of the Human Genome Project, which began in 1990 and concluded in 2003, costing $2.7 billion. The human genome reference sequence, a compilation from 20 anonymous individuals, was created to prevent any single person's genome from being exclusively represented and to protect donor privacy. This foundational work has led to numerous questions about genetic diversity and its implications for disease, drug metabolism, and individual health variations. The precision medicine initiative by the NIH, announced in 2015, aims to address these questions by understanding how genetic variations impact health. A key component of this initiative is the 'All of Us' research program, which plans to enroll over a million participants from diverse backgrounds to enhance the understanding of genetic variants and their effects on health.

10:04

👨‍👩‍👧‍👦 Precision Medicine in Action: The West Family Study

This segment highlights a pioneering study in pharmacogenetics that utilized whole genome sequencing on the West family to predict health outcomes. The study identified genetic variants associated with blood clotting, which helped in predicting the correct anticoagulant medication and dosage for John West, aligning with his actual treatment. The study also forecasted the potential medication needs for John's daughter, Anne, based on her genetic profile, emphasizing the preventive capabilities of precision medicine. This case exemplifies how genomic information can be used to guide personalized treatment plans and risk assessments.

15:07

💊 Targeted Therapies and the Future of Oncology in Precision Medicine

The focus shifts to oncology, where precision medicine is leading the way with targeted therapies based on genomic variants. Traditional chemotherapy's cytotoxic effects are contrasted with newer, targeted therapies that disrupt cancer cell proliferation with fewer side effects. The identification of driver mutations in non-small cell lung cancer and melanoma exemplifies the complexity and potential for personalized treatments. The presentation also discusses the role of immunotherapies that leverage the patient's immune system to combat cancer. The challenge lies in identifying all disease-impacting variants and developing targeted therapies for each, which initiatives like the 'All of Us' research program aim to support.

20:08

🧪 Genomic Testing and Clinical Decision Making at LSU HSC

Dr. Crabtree outlines the various genomic testing methods used at LSU HSC's clinical precision medicine laboratory, including single gene sequencing, gene panels, and next-generation sequencing approaches like TSO 500, whole exome, and whole genome sequencing. The laboratory's process involves sample review, library generation, sequencing, and data analysis to identify and annotate genetic variants. The data is then integrated into the electronic medical record for clinical decision-making. The presentation concludes with a vision of precision medicine's goal to deliver the right drug to the right patient at the right time, improving treatment outcomes and reducing side effects.

25:10

🌟 Concluding Remarks and Q&A Session

The presentation concludes with a Q&A session where Dr. Crabtree addresses the volume of genomic data generated by LSU HSC's lab, the scope of their sequencing efforts, and her personal inspiration for pursuing genomics. She shares a memorable high school biology lesson that sparked her interest in DNA and genomics, highlighting the transformative impact of early scientific education on her career.

Keywords

💡Genomics

Genomics is the study of all the genes in an organism, including their functions, interactions, and mapping of their DNA sequences. In the video, Dr. Judy Crabtree's career is deeply rooted in genomics, starting with her involvement in the Human Genome Project. Genomics is central to the theme of the video as it discusses how genetic information can be used to understand human health, disease, and individual responses to treatments.

💡Human Genome Project

The Human Genome Project was an international scientific research project aimed at determining the sequence of the human genome and identifying the genes it contains. In the script, Dr. Crabtree mentions her contribution to this project, which was a significant milestone in understanding human genetics. The project is foundational to the field of genomics and precision medicine discussed in the video.

💡Precision Medicine

Precision medicine is an approach to disease prevention and treatment that takes into account individual variations in genes, environment, and lifestyle. The video discusses how precision medicine is transforming healthcare by allowing for more personalized and effective treatments. Dr. Crabtree's work in genomics is directly linked to the development and implementation of precision medicine.

💡Pharmaceutical Drug Development

Pharmaceutical drug development refers to the process of discovering new medications and bringing them to the market. Dr. Crabtree transitioned from academia to the pharmaceutical industry, where she worked on drug development. This experience is relevant to the video's theme as it highlights the translation of genomic research into practical applications for improving human health.

💡Single Nucleotide Variants (SNVs)

Single Nucleotide Variants are changes at a single position in a DNA sequence among individuals. The video mentions that SNVs occur approximately one every 300 nucleotides, contributing to human genetic diversity. Understanding these variants is crucial for precision medicine, as they can influence disease risk and response to drugs.

💡All of Us Research Program

The All of Us Research Program is a large-scale effort to gather genetic and health data from one million or more participants to better understand how individual differences in biology, environment, and lifestyle can affect health. Dr. Crabtree discusses this program as a key part of the precision medicine initiative, aiming to include diverse populations to improve the understanding of genetic variants and their impact on health.

💡Next-Generation Sequencing (NGS)

Next-Generation Sequencing is a technology that allows for rapid and cost-effective sequencing of entire genomes. In the video, NGS is highlighted as a game-changer in genomics, making it possible to sequence whole genomes at a fraction of the time and cost of previous methods. Dr. Crabtree's lab uses NGS for COVID-19 testing and anticipates using it for whole genome and whole exome sequencing.

💡Cancer Genomics

Cancer genomics is the study of the changes in the genome that cause cancer. The video discusses how the identification of genetic variants in cancer cells has led to the development of targeted therapies. Dr. Crabtree's work in cancer genomics is an example of how genomic information can be used to improve patient outcomes in oncology.

💡Electronic Medical Record (EMR)

An Electronic Medical Record is a digital version of patients' paper charts. In the context of the video, the EMR is used to integrate genomic data into a patient's medical record, facilitating clinical decision-making. The video emphasizes the importance of EMRs in precision medicine for accessing and utilizing genomic information in healthcare.

💡Immunotherapy

Immunotherapy is a type of cancer treatment that uses the body's immune system to fight cancer. The video mentions immunotherapies as a new approach in oncology that capitalizes on the patient's immune system to target cancers with specific genetic signatures. This highlights the growing importance of understanding the genetic basis of diseases to develop more effective treatments.

Highlights

Dr. Judy Crabtree's introduction includes her extensive background in biochemistry, genetics, and her involvement in the Human Genome Project.

Dr. Crabtree's postdoctoral work focused on the biology of multiple endocrine neoplasia type one under Dr. Frances Collins.

Her transition from academia to pharmaceutical drug development at Wyeth Pharmaceuticals.

In 2009, Dr. Crabtree joined LSU HSC as an assistant professor of genetics, later becoming an associate professor.

Dr. Crabtree's role in implementing the COVID testing program for LSU-HSC campus during the pandemic.

Initiation of viral sequencing efforts to track COVID-19 variants in Southern Louisiana.

The anniversary of Dr. Crabtree's postdoc start coincides with her presentation, marking 25 years in genomics.

The history of the Human Genome Project and its impact on understanding human health and disease.

The astonishing fact that there is approximately one single nucleotide variant per 300 nucleotides in the human genome.

The launch of the NIH Precision Medicine Initiative in 2015 by President Obama.

The All of Us Research Program aims to enroll one million or more participants for whole genome sequencing.

The importance of diversity in genomic studies, with over 50% of new genomic information from racial or ethnic minority groups.

LSU HSC's role as a flagship institution in the Southern region of the All of Us Program.

A study in 2011 demonstrated the predictive ability of precision medicine through whole genome sequencing of a family.

The identification of genetic variants related to blood clotting in the West family study and its implications for treatment.

The potential of genomics to predict disease risk and personalize treatment plans.

The leading role of oncology in precision medicine and targeted therapies based on genetic variants.

The challenge of identifying all disease-impacting variants and developing targeted therapies.

Clinical methods for identifying DNA variants, including single gene sequencing, gene panels, and next-generation sequencing.

The LSU HSC Clinical Precision Medicine Laboratory's focus on next-generation sequencing for oncology.

The process of integrating genomic sequencing data into clinical decision-making for patient care.

Dr. Crabtree's inspiration to become involved in genomics, stemming from a high school biology class.

Transcripts

let me introduce

dr judy crabtree

okay

so

please welcome dr judy crabtree dr

crabtree received her phd training in

biochemistry and genetics from the

university of oklahoma in one of the

original labs that was funded to

sequence the human genome

she did her postdoctoral work at the

national human genome research institute

at the national institute of health in

bethesda maryland under the direction of

dr frances collins studying the biology

of an endocrine tumor disease called

multiple endocrine neoplasia type one

from there she entered the world of

pharmaceutical drug development at wyeth

pharmaceuticals

in 2009 she left the pharmaceutical

industry and joined lsu hsc as an

assistant professor of genetics

she is currently an associate professor

of genetics and the scientific and

education director of the precision

medicine program at lsu hsc

more recently in the pandemic she

implemented the covid testing program

for the

lsu-hsc campus and has launched the

viral sequencing efforts to track

coveted variants of concern in southern

louisiana

so please join me in welcoming dr judy

crabtree

thank you laura

so i'm going to share my screen now

get me set up

oh come

on okay

so thank you for this opportunity i mean

this has just been a great meeting the

past two days we've seen so many great

talks and posters i'm very excited

and so um what's interesting though is

as i was preparing this talk

i realized that today is 25 years to the

day since i started my postdoc and so i

had just finished my phd work under the

direct direction of dr bruce rowe at the

university of oklahoma where we were

sequencing regions of human chromosome

22 as part of the human genome project

and on april 1

1997 i began my postdoctoral study at

the nih under the direction of dr

francis collins now i can tell you if

you've never started a new job on april

fool's day it is quite the experience

and so as the new green postdoc i was

immediately the april fool and the easy

target of many practical jokes in my new

lab

but what i didn't realize at that point

was that this was the beginning of a

translational career built on genomics

and its application to human health and

so i was fortunate to not only

contribute sequencing data to the human

genome project but to also be in the

epicenter of human genomic research in

the u.s upon completion of the human

genome reference sequence in 2003

so at that time i was infused with

optimism about what we could do to

understand human health and disease how

we can further understand what makes

each of us alike but also what makes

each of us different so how are we

different in our responses to

environmental stimuli to pharmaceutical

pharmaceutical drugs to chemotherapy

and since this day in 1997 i've studied

cancer and performed large scale

transcriptomic analyses

um of several tumor and cancer syndromes

i've worked in the drug development and

pharmaceutical industry and then now

here we are 25 years later i'm

translating what i've learned in each of

these varied research environments to

supporting patient management in our cap

accredited clinical precision medicine

laboratory

now in order to understand the current

state of affairs with respect to

precision medicine we kind of need to

start at the beginning so i hope this

isn't repetitive to some people

but it's always fun to look at history

so in the late 1980s a group of

scientific thought leaders that included

francis collins of the nih erie petrinos

from the u.s department of energy eric

lander from the broad institute at mit

and several others they sat down over a

pint of lager and outlined on the back

of cocktail napkins a plan for mapping

and sequencing the complete human genome

so this project launched in 1990 and

ultimately took 13 years to complete at

a cost of about 2.7 billion dollars and

so here you can see the publications the

cover the public effort in nature and

the competing private effort in science

now the key thing that i want you to

remember is that the human genome

reference sequence is not the genome of

one individual it's a compilation from

the 20 anonymous individuals mostly

anonymous

further the 20 individuals were selected

from a pool of over a thousand donors

whose information was ultimately

de-identified so that even those who

contributed do not know if their dna was

used or not and so this was done

intentionally by the architects of the

human genome project to ensure that no

single person's genome was exclusively

represented and also so that no

individual could be identified by their

contribution to the reference genome

now once the reference genome was

complete this opened up a huge number of

questions about the genetic diversity of

humans and so one of the astonishing

facts from the human genome project was

that single nucleotide variants occur

approximately one every 300 nucleotides

so if you do the math that means there

are roughly 10 million single nucleotide

variants in the human genome and these

variations are one contributing factor

to the genetic diversity in humans

and so this opened up a whole new set of

questions so what is the intersection

between disease and genetic variants

what's the relationship between drug

metabolism and genetic variation is

there a cancer genome and does that

cancer genome change over time in in

between the the primary tumor and a

metastasis or a recurrence um how does

the genome impact mental health

behavioral health

it had already been observed that some

diseases were more prevalent in certain

populations and so then questions about

what's the role of genetic variation and

ethnicity

and so over the years that followed the

completion of the human genome reference

sequence it became more and more clear

that we knew too little

the genomic community as a whole began a

sort of haphazard way

collecting information we needed to

answer some of the questions about

genetic variability but as time went on

the cost of full and

and as time went on the cost of whole

genome sequencing um decreased so now

it's approaching a thousand dollars with

a turnaround time of seven to ten days

and so so now the big picture idea was

that if we can perform genomic testing

at an acceptable cost get private

insurance and medicaid medicare buy-in

to perform genomic testing in the

clinical setting we can use this as

evidence-based medicine to identify the

best therapeutic and preventative

interventions to best benefit our

patients

and so to set this up in a more

organized fashion um

we realized that there was a need for a

more concerted effort to understand

genomic variation so the nih announced

its support of precision medicine in

2015 when then president obama in his

state of the union address described

precision medicine as an emerging

approach to disease prevention and

treatment that takes into account

people's individual variations in genes

environment and lifestyle

so this was accompanied by a publication

in the new england journal of medicine

written by then director of the nih

francis collins and past director of the

national cancer institute harold barmus

this perspective further supported the

convictions of president obama that

science offers great potential for

improving human health and this

officially launched the nih precision

medicine initiative in 2015.

now a key part of the precision medicine

initiative is the all of us research

program

this was launched officially about four

years ago and this is a cornerstone of

the precision medicine initiative that

sinks to enroll one million or more

participants that represent the broad

diversity of the united states so that

we can understand variants much better

than we do

so patients will complete surveys

provide biological specimens for whole

genome sequencing and then grant access

if they choose to their medical records

for de-identified population-based

studies that correlate genetics and

genetic variants with disease and

environmental factors such as where you

live

now the all of us network is composed of

national partners in regional medical

centers across the u.s to enroll

participants from all walks of life in

all states of health within the united

states so just this month the all of us

research program hit a key milestone and

released the first set of nearly a

hundred thousand whole genome sequences

more than half of this new genomic

information comes from people who

self-identify with racial or ethnic

minority groups and that's extremely

important because until now more than 90

of participants in the large genomic

studies were all of european descent and

so this lack of diversity has had huge

impacts it deepens the health

disparities and hinders scientific

discovery from fully benefiting everyone

so i do want to point out that lsu hsc

is a flagship institution in the

southern region of the all of us program

we affectionately call this program the

y'all of us network for those of you who

know about the southern dialect

and this is in collaboration with tulane

university the university of mississippi

medical center university of alabama

birmingham and other major institutions

across the gulf south

so this is the website where you can

learn more information about the all of

us program and there's still time to

join either through the website down

here or the app which looks like this

blue banner up in the upper left corner

once you've registered you can then make

an appointment to donate your sample for

sequencing

at one of our participating clinics

so all of this is going to contribute to

our understanding of the human genome

and how genetic variants can impact our

health

and so what i'd like to do now is share

a study with you that was one of the

first studies to come out in

phosgenetics in 2011 to show you the

predictive ability of precision medicine

and so this study used next generation

sequencing to evaluate human health in a

predictive way and in this study the

authors performed whole genome

sequencing of four members of a family

mom dad daughter and son

and as an aside

the family used in this study is the

west family and if you look at the

author list carefully you can see john

west and and west are both authors on

this study so john west was the ceo of

celexa at the time so this is the

company that developed the current next

generation sequencing technology that

was then sold to illumina and is now the

foundation for their current almost

market cornering technology for next

generation sequencing

and so this is the pedigree for the west

family if you aren't used to reading

pedigrees um the squares are males the

circles are females um horizontal lines

indicate either a marriage or siblings

and diagonal lines across the symbol

indicate that the individual is deceased

now the arrows indicate the four

immediate family members of the west

family so we have john his wife

the daughter anne and her brother and

note the multi-generational history of

cardiovascular

and blood clotting problems within this

family so there are several incidents of

myocardial infarction congestive heart

failure deep vein thrombosis and

hypertension

john was

hospitalized twice with venous

thromboembolism in two separate

incidents um during the period of time

when he and his doctor were working out

the appropriate anticoagulant for him to

be taking for his condition

so the whole genome sequencing of this

family identified among other things

multiple variants and genes related to

blood clotting so this process utilized

two carefully curated databases verimed

which correlates genetic variants

associated with disease and farm gkb

which catalogs genetic variants

associated with drug responses now there

are many such databases available now

these were just the first two that were

established at the time of the study

back in 2011.

now a blinded um in a blinded

bioinformatics analysis of these data um

the investigators were able to correctly

predict the type and the dose of the

anticoagulant that john was already

taking so he and his doctor had settled

on clopidogrel after an extensive period

of trial and error to get the dose and

drug um correct for one that worked for

him

now imagine if john had been screened

for known variants before he even took

any medication

well that's essentially what happened

for his daughter

so the study predicted what medication

she may need in the future based on her

genetic profile and interestingly the

medication is different from that her

dad is taking mostly because remember

everybody inherits two alleles and

inherited one risk allele from her

father and a different risk allele from

her mother

so ann was 17 at the time of the study

and now she's 29 years old and has no

health problems as of yet because she

was able to implement some simple

lifestyle changes

and increase her surveillance to help

mitigate her risk for cardiovascular

complications

so this is just one example of how

genomics can impact human health and

disease risk assessment

a second example is within oncology so

the field of oncology is leading the way

in precision medicine and targeted

therapies

because the identification of variants

as biomarkers or targets of disease has

led to new targeted therapies for

patients with cancer

now past treatments

have all been focused on tissue specific

mechanisms or systemic therapies so for

example the traditional chemotherapy

such as microtubule inhibitors platinum

therapies and cyclophosphamides

these are all cytotoxic drugs that kill

all rapidly dividing cells and so there

are also other cancers such as

hormone-responsive breast cancer or

prostate cancers

that have obvious hormone dependence so

the first line of therapy in these

tumors is a systemic hormone deprivation

and the problem with all of these

systemic based chemotherapies is that

they often have some really miserable

side effects for the patient

and so more recent focus has been on

variance and the targeted therapies

and as time has gone by and we've

learned more and more about the

molecular basis of cancers and so shown

here is non-small cell lung cancer and

melanoma and we know that each of these

com each of these common cancers is

actually a collection of more rare

cancers so for example many cancers or

many variants have been detected in

non-small cell lung cancer including

driver mutations and the genes for uh

things like egfr b raf mec1 akt and p10

um and then within within each of these

um driver mutations

there's individual variants that add

further complexity so for example within

the egfr mutations in non-small cell

lung cancer there are at least seven

known individual variants and in

melanoma it's similar the common driver

mutations are in the b raft gene

and these include six individual

variants

so imagine if we had drugs that were

specific for each of these individual

variants and how cool would that be

right

well and that's where we are albeit in

the very very early stages

right now the majority of the drugs that

are seeking and receiving fda approval

in oncology are targeted therapies that

are designed to hit specific molecular

targets that are divine defined by a

genomic variant

so these new drugs interrupt cancer cell

proliferation but in theory they leave

other non-cancer cells more intact

with the goal of less intense side

effects for the patient

there are also new immunotherapies that

capitalize on the patient's immune

system to fight types of cancer with

specific genetic signatures and so now

the challenge is can we identify all the

variants that impact disease and develop

therapies that work best for each of

those different disease-causing variants

so the all of us research program will

help with that in the u.s and similar

programs are in place in other countries

and we also have to start to convince

big pharma to change their strategy and

begin to develop targeted therapies for

newly identified variants instead of

seeking that next billion dollar

blockbuster drug

now in the clinical setting we identify

dna variants in a variety of ways

we can look we can use a single gene

sequencing analysis to look for germline

mutations in particular genes such as

bracha one or two

we can do screenings for variants in the

genes that are

metabolic enzymes such as the cytochrome

p450 enzymes that are responsible for

drug metabolism in the liver and we can

perform gene panels such as oncotype dx

or mammoprint with that contain smaller

number of genes to identify variants and

predict tumor recurrence um in some

particular tumor types

or we can do what we're doing at the lsu

hsc clinical precision medicine

laboratory which is focus on the next

generation sequencing based approaches

so this includes tso 500 whole exome

sequencing and whole genome sequencing

so our initial approach for tso500 will

will support solid tumors and then we'll

expand into hematological malignancies

and then we'll implement hereditary

cancer screening risk identification and

some non-invasive prenatal testing or

nipt

all of which runs on the same next

generation sequencing platform and so

this testing is one of the pillars of

support for our future bid for nci

cancer center designation in the region

and so this is the instrument we have

from illumina called the next c550dx

this instrument is currently in use for

genomic sequencing of sars cov2 for code

19

but we will be pivoting soon to run tso

500 which is a panel that contains 523

oncology related genes

and you can see some of those listed

here along with the different types of

cancer with which they are affiliated

this panel also provides an assessment

of microsatellite instability and

defects in mismatch repair

these support the use of checkpoint

inhibitor therapies

as well as overall tumor mutational

burden which is an indicator of

immunotherapy treatment success

so the way it works in our laboratory is

we have tests that are ordered by a

physician

our pathology partners uh review the

sample and submit the tumor in normal

samples for sequencing in the lab we

process those samples perform library

generation and put them on the sequencer

and then the large amounts of raw data

that result from the next seek i run

through quality assurance quality

control and base calling algorithms to

convert those raw image data files into

a text file format you guys have already

heard about fastq

um and there are also the associated

fred quality scores that are associated

with each base and then following this

base calling the sequencing reads are

aligned with the reference genome and

resulting in a bam file

map sequences are then used

to identify variants and result in a

variant call format or vcf

so we partner with puri and dx for this

service and their algorithms identify

and prioritize single nucleotide

variants based on multiple criteria

these include variant allele frequency

strand bias sequencing depth in the gene

region quality scores etc as well as it

draws from their extensive database of

patient outcomes from other nci

designated cancer centers nationwide to

recommend treatment strategies so the

identified variants are annotated

as to the gene and location that's the

avcf file and then they're often

manually curated to ensure accuracy

quality and adherence to the current

current nomenclature and naming

conventions

so all of this data is distilled into a

report that's integrated into the emr

the electronic medical record and it's

made available for tumor board review

and for clinical decision making

so those sample reports look like this

so it has patient information at the top

and then it has a listing of the

variants that are identified in the

analyze sample

so there's also information about the

responsiveness of this tumor with or a

tumor with this profile to certain drugs

and you can see that here in the middle

um as well as the opportunities for

clinical trials that are associated with

this type of variant and so we can set

the distance parameters to limit

available clinical trials to within so

many miles of the patient

mostly for convenience sake

and then down here at the bottom you can

see the results for tumor mutational

burden which is really the emerging um

marker associated with greater

sensitivity of a tumor to

immunotherapies and also microsatellite

instability status which when high this

this example is low but when it's high

it predicts sensitivity to immune

checkpoint inhibitors

so all of this leads us to the precision

medicine ideal of delivering the right

drug to the right patient at the right

time and so right now we're sort of in

this top level here where we have

patients receiving a drug um and then

there's a small proportion of those

patients who actually respond

what we'd like to do is get to this

stage at the bottom where we have a

different drug for different um genetic

variants that are available within the

oncology and another space this doesn't

necessarily have to be only oncology

driven um even though oncology is

leading the way

but this is where we want to go where we

get the right drug and the right patient

at the right time

and so with that all i'd like to thank

you for your attention and this

opportunity and i'd be happy to answer

any questions

you so much dr crabtree that was an

amazing presentation thank you okay

we have a few questions for you

uh the first one is how much data is

being generated by your lab at um lsu

hsc so is it just genomic data or is in

smp data or do they also generate other

types of data so right now the only data

being generated in our laboratory is um

viral sequences for sars code v2

we are not currently running uh the

ts0500 we are not currently doing whole

genome or whole exome sequencing that is

our next

the next endeavor um mostly just because

we kind of got derailed to do sequencing

for sars kobe too and we have yet to

pivot

that makes sense okay our next question

is how many people are you planning to

get sequence data from in the state of

louisiana and also just in the south in

general

sequence data for

um

whole genome whole exome

or is this the question of how many

samples are we going to run

how many samples are you going okay so

once tso is up and running so this the

instrument that we have is a moderate

throughput um instrument there's one

bigger

that we do not yet have but we can

always buy if we end up

having more samples to process

our laboratory is not going to only

support lsu it's going to support the

entire region and so at the moment we

have the capacity in our current

instrument to run um eight tumors normal

pairs per week

um

but then you know as as need and

demand increases we can always scale

that up

got it uh and then one final question

what originally inspired you to become

involved in genomics

so this is kind of a cool study so

or a cool story so i uh

i had a science teacher named jim martin

and he would die if he knew i was

telling the story

back when i was in high school we were

in basic biology

and

he gave each of us a laminated piece of

paper that had either a circle on the

end or a triangle on the end

and some of us had the points and some

of us had the correlating v right and so

essentially what he handed out to the

whole class was nucleotides

and he lined us up in the hallway and

some of us were the parental strand and

then others of us came in and formed the

replicating strand

and so that was really my first

introduction to

to dna and

anything having to do with dna

sequencing

and so he taught us dna replication in

the hallway the high school and and so

that was really you know that was many

many years ago but um that was really my

first introduction to to dna and it's

kind of stuck ever since then gene

therapy you know i'm i've got a huge

interest in not only dna sequencing and

genomics but but into you know gene

therapy and that translation of what we

can learn from genomics to patient care

great that is a fun story thank you for

sharing

he would die

definitely okay thank you very much of

course well that was again a great talk

by dr trouble