molecular based medicine

8/9/2019 Molecular Based Medicine

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Molecular based (Molecular based (i.e, personalizedi.e, personalized))

MedicineMedicine

By I&C President Ryan WittBy I&C President Ryan Witt

[email protected]@gmail.com


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ScheduleSchedule

Bio 101Bio 101

Molecular MedicineMolecular Medicine


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RememberRemember

AskAskQQss

AlwaysAlwaysask Why/how, What, and Whenask Why/how, What, and When

Try toTry to understand EVERYTHING!nderstand EVERYTHING!


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Our BodiesOur Bodies Made up of 10 to 100 trillionMade up of 10 to 100 trillion cellscells

CellsCells makemake upupTissuesTissues

Tissues makeTissues make OrgansOrgans

(i.e., Skin, lungs, brain)


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MoleculesMolecules SoSo whatwhat andand wherewhere are molecules?are molecules?

What:What: A group ofA group oftwo or more atomstwo or more atoms bonded to onebonded to one

anotheranother.. ((Pauling, Linus (1970).Pauling, Linus (1970). General ChemistryGeneral Chemistry. New York: Dover Publications, Inc... New York: Dover Publications, Inc.. ISBNISBN 00--486486--6562265622--55 ))

WhereWhere: Everywhere: Everywhere IncludingIncluding insideinside ANDAND outsideoutside of cellsof cellsH20Water


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Now, lets look atNow, lets look at

functionfunction


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The DriverThe Driver

Molecules are the drivers of your cells.Molecules are the drivers of your cells.

Forming the structure ofForming the structure ofDNADNA, RNA, proteins,, RNA, proteins,enzymes, and EVERYTHING pushing our body toenzymes, and EVERYTHING pushing our body todo what it does!do what it does!


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Proteins

Newly discovered / other components:Methylases (methylate DNA), mRNA, alternative splicing, micro-RNA, tRNA


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DNADNA

Been called the Master Plan and yourBeen called the Master Plan and yourdestiny.destiny. Is there merit?Is there merit?

Codes for ALL playersCodes for ALL players proteins, enzymes, microRNA, RNA, etc.proteins, enzymes, microRNA, RNA, etc.

But, DNA is the code not an actor / player itselfBut, DNA is the code not an actor / player itself


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Reality 101Reality 101

DNADNAisntisnteverything!everything! DNA mutations change our DNADNA mutations change our DNAthroughout our lifetimethroughout our lifetime++ Expression and function is partially independent of DNA (i.e., epigeneticsExpression and function is partially independent of DNA (i.e., epigenetics

(methylation); post(methylation); post--translational modifications)translational modifications) Expression and endExpression and end--conformation of molecules is what matters mostconformation of molecules is what matters most ---- that is,that is, whatwhat

playersplayers (i.e., RNA, glycoproteins, proteins)(i.e., RNA, glycoproteins, proteins) will bewill be active, and how are they functioningactive, and how are they functioning..


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3 fun examples of environment/our actions +3 fun examples of environment/our actions +

DNA, and their results!DNA, and their results!


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Example: Stubbing your ToeExample: Stubbing your Toe

(DNAchange)(DNAchange)

+

Rubbing

You can either rub or not! Depending on which affects the

molecular characteristics describing you in a diff t way!


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Ex: form of DietingEx: form of Dieting

(methylation change)(methylation change) Excessive alcohol consumption has beenExcessive alcohol consumption has been

shown to alter DNA methylation in the colon ofshown to alter DNA methylation in the colon of

humans.humans.


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Lights Effect:Lights Effect:VisionVision

(nothing to DNA; only protein changes)(nothing to DNA; only protein changes)


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Lights Effect:Lights Effect:VisionVision

(nothing to DNA; only protein changes)(nothing to DNA; only protein changes)


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In our BRAINS too!In our BRAINS too!

Technology is not only changing our lives, its changingTechnology is not only changing our lives, its changingour BRAINS.our BRAINS.

-- Dr Gary Small, Director of the UCLA Center on Aging & Professor ofDr Gary Small, Director of the UCLA Center on Aging & Professor ofPsychiatry and Behavioral Sciences at UCLAPsychiatry and Behavioral Sciences at UCLA


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Coming back to the QComing back to the Q

Is our DNA everything?Is our DNA everything?

Our actions change our molecules, whichOur actions change our molecules, whichchange our cells, organs, and bodies!change our cells, organs, and bodies!


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RealityReality

Reality isReality is

We are a product ofWe are a product ofenvironmentenvironment // actionsactions plus ourplus ourblueprintblueprint..

The blueprint is the start; everything from there isThe blueprint is the start; everything from there isup to you!up to you!


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L

astlyL

astlyBeware!Beware!

ALWAYSALWAYSask, What, Why, When and Howask, What, Why, When and Howhttp://www.youtube.com/watch?v=R34Sguwxe2ohttp://www.youtube.com/watch?v=R34Sguwxe2o


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44--

slideR

ecapslideR

ecap


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MoleculesMolecules

Two or more atoms bound together!Two or more atoms bound together!

Molecules make up the components of cells,Molecules make up the components of cells,

tissue, organs, and us as a wholetissue, organs, and us as a whole


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How your body worksHow your body works


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Our actions affect our bodiesOur actions affect our bodies ----

at the molecular levelat the molecular level

Rubbing


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Take Home PointsTake Home Points

1.1. Our actionsOur actions the molecular attributes describing thosethe molecular attributes describing thoseactions.actions.

2.2. Blueprint / cards dealt (DNA) + choices and environmentBlueprint / cards dealt (DNA) + choices and environment

3.3. Expression levels, the sequences of molecules, among otherExpression levels, the sequences of molecules, among other

factorsfactorswhich constantly are changingwhich constantly are changingare the keys toare the keys tounderstandingunderstanding the underlying molecular mechanismsthe underlying molecular mechanismsdescribing our actionsdescribing our actions, at any given moment., at any given moment.

(DNA is code, not the actor!)(DNA is code, not the actor!)

1 & 3 are VERY important for next lecture know them well!


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COOL!COOL!

WoooooooooooooooofWoooooooooooooooof -- done! (next isdone! (next is

Medicine!)Medicine!)

Any questions?Any questions?


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BreakBreak

Ask your doc about molecular testing if you have aAsk your doc about molecular testing if you have adisease, infection, or simply want to learn more aboutdisease, infection, or simply want to learn more aboutyourself.yourself.

What to testWhat to test ----

DNADNA

Expression levels, sequence, and functionality ofExpression levels, sequence, and functionality of

molecules (DNA

, micromolecules (DNA

, micro--RNA

, RNA

, proteins, etc)RNA

, RNA

, proteins, etc)


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Break:Break: Myths about Genetic TestingMyths about Genetic Testing

and Molecular Medand Molecular Med1.1. Insurers can drop you based on results.Insurers can drop you based on results.

GINA prohibitsGINA prohibits ----

1.1. Denying coverageDenying coverage to a healthy individualto a healthy individual or chargingor chargingthat personthat person higherhigherpremiumspremiums based solely on abased solely on a genetic predispositiongenetic predisposition to developing a diseaseto developing a diseasein the future.in the future.

2.2. EmployersEmployers fromfrom usingusingindividuals'individuals' genetic information whengenetic information whenmakingmakinghiring,hiring, firing, job placement, orfiring, job placement, or promotionpromotion decisionsdecisions..

3.3. prohibits health insurers from using genetic information toprohibits health insurers from using genetic information todetermine eligibility or premiums, prohibits insurers and employersdetermine eligibility or premiums, prohibits insurers and employersfrom requesting or requiring that a person undergo a genetic test,from requesting or requiring that a person undergo a genetic test,and prohibits employers from using genetic information to makeand prohibits employers from using genetic information to make

employment decisions.employment decisions. AMA siteAMA site

2.2. If someoneIf someone diddidhappen to get a hold of my DNA, they could clone anhappen to get a hold of my DNA, they could clone anidentical copy of meidentical copy of me!!


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MedicineMedicine

(the standard, then(the standard, then

innovation)innovation)


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Key pointKey point

There areThere are

Our actions and

characteristics

the Molecules describing them&

Rubbing

Rubbing


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Things can get very hazyThings can get very hazy

Cancer


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MedicineMedicine

When it comes to medicine, challenge isWhen it comes to medicine, challenge is

Clinical SymptomsClinical Symptoms Where & What isWhere & What ismolecularmolecular--CauseCause

Stuffy nose

Fever

Headache

Slurred speech

Twitchy eye


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Medical Diagnostics:Medical Diagnostics:

standard / currentlystandard / currently Differential diagnosisDifferential diagnosis

1.1. What is the most likely causeWhat is the most likely cause

2.2. Physical ExaminationPhysical Examination checking your signs andchecking your signs andsymptomssymptoms

3.3. Imaging Tools (MRIs, CT scans, fMRI, etc)Imaging Tools (MRIs, CT scans, fMRI, etc)

4.4. HistopathologyHistopathology looking under a microscope tolooking under a microscope todistinguish cell / tissue characteristicsdistinguish cell / tissue characteristics


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TreatmentTreatment

Treatment by Treatment by trialtrial--andand--errorerror and and oneone--sizesize--fitsfits

allall

AMA and medical terminologyAMA and medical terminology


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RightRightnownow

Many of the same diseases byMany of the same diseases bymodern classificationmodern classificationhavehave differentdifferent

molecular characteristics/driversmolecular characteristics/drivers..

Meaning:Meaning:NSCLC of squamousNSCLC of squamous typetype >>MDM2 mutationMDM2 mutation? p53? p53

mutation? And/or EGFR mt? Met? Etc.mutation? And/or EGFR mt? Met? Etc.

Picture Source:http://www.iftheshoefitz.com/


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InnovationInnovation(Currently, not the standard)(Currently, not the standard)


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BUTBUT

Wait a minute!Wait a minute!

What about the molecular drivers?What about the molecular drivers?


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Molecular ProfilingMolecular Profiling

Now we have the capability toNow we have the capability to

take a sample of diseased or infected cells (or a persons normaltake a sample of diseased or infected cells (or a persons normalcells), andcells), and examine it at the molecular levelexamine it at the molecular level ---- looking at RNA,looking at RNA,protein structure, expression levels, and genetic makeup (DNA).protein structure, expression levels, and genetic makeup (DNA).

The methods are there (immunohistochemistry, DNA arrays,The methods are there (immunohistochemistry, DNA arrays,RNA microarrays, realRNA microarrays, real--time quantitative PCR)time quantitative PCR) Which is bestWhich is best unsureunsure!!


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Cool! Whats the value?Cool! Whats the value?

Predictive to suggest treatment? Nonot byPredictive to suggest treatment? Nonot by

itself (if no clinical experiments are performed)itself (if no clinical experiments are performed)I.e., MammaPrint, EGFR test, Tissue of OriginI.e., MammaPrint, EGFR test, Tissue of Origin

But itBut it couldbecouldbe(predictive), if inferences are made(predictive), if inferences are made

by some personby some person(as you will see)(as you will see)


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Profiling provides insights into the molecularProfiling provides insights into the molecular

mechanisms governing/describing yourmechanisms governing/describing yoursymptomssymptoms ---- AKAAKA

Knowledge!!!!!Knowledge!!!!!


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What can be done with knowledge:What can be done with knowledge:Applying Molecular Profiling to TreatmentApplying Molecular Profiling to Treatment

CANCERCANCER

XelodaXeloda Thymidine Phosphorylase overexpressionThymidine Phosphorylase overexpression

EGFREGFR&& METMET overexpressionoverexpression

FUS1FUS1,, MDM2MDM2, &, & P53P53 therapytherapy


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FUS1FUS1,, MDM2MDM2, &, & P53P53 therapytherapy


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Application is to ALL diseasesApplication is to ALL diseases

With every ailment, there are respective proteins, genes, and molecules driving itsWith every ailment, there are respective proteins, genes, and molecules driving itsprogression.progression.

Bacterial InfectionsBacterial Infections

AzithromycinAzithromycin antibiotic; works on various strains of bacteria (antibiotic; works on various strains of bacteria (inhibits 50Sinhibits 50Sribosomal subunit from actingribosomal subunit from acting))

ALSALS

SOD1 geneSOD1 gene targettarget ---- ArimoclomolArimoclomol

AlzheimersAlzheimers,, MSMS,, ParkinsonsParkinsons, Crohns, Lupus, Crohns, Lupus


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ValueValue

By seeing aBy seeing a comprehensive picturecomprehensive picture of ones expression levels,of ones expression levels,

sequences, and so forth, one hassequences, and so forth, one has a more clear viewa more clear viewof theof the

underlying molecules and structure of molecules, henceunderlying molecules and structure of molecules, hence a morea more

clear perspective on the likely outcomes of a therapeuticclear perspective on the likely outcomes of a therapeutic

intervention.intervention.


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KnowledgeKnowledge

NearlyNearlyevery drug approved on the market by a regulatoryagency has a known molecularmode of action.

If you distinguish the molecular characteristics of a diseasefrom normal cell characteristics, then you can match drugs

perfectly with those disease characteristics and knownmolecular signaling pathways within a disease!

Hence, less of a trialHence, less of a trial--andand--error / oneerror / one--sizesize--fitsfits--all approach.all approach.

Idea that fuels (i) Molecular Medicine, (ii) Personalized Med,(iii) Combination Therapies and (iii) Drug Repositioning


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Without molecular knowledge,Without molecular knowledge,

and continued trialand continued trial--

byby--

error Rx

error Rx

W/o mDx, you haveW/o mDx, you have ----

a)a) DifferentDifferent responses to the same treatments, in regards toresponses to the same treatments, in regards to

the safety and effectiveness of that therapy.the safety and effectiveness of that therapy.

http:

//learn.genetics.utah.edu/content/health/pharma/intro/http:

//learn.genetics.utah.edu/content/health/pharma/intro/

Life?Death?


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W/o molecular testing and treatmentW/o molecular testing and treatment

b)b) Resistance Development & your Window ofResistance Development & your Window of

Opportunity isOpportunity is lost!lost!

1.1. Personal levelPersonal level

2.2. Society at largeSociety at large


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Translation, PleaseTranslation, Please

W/o molecular profiling and continued trialW/o molecular profiling and continued trial--byby--errorerrortreatmenttreatment ----

1.1. Therapies available are no longer effective;Therapies available are no longer effective; must findmust find

something elsesomething else.. AntibioticsAntibiotics

2.2. Not everything is available nowNot everything is available now avg new canceravg new cancertherapy takes 14 yrs of testing before final approval.therapy takes 14 yrs of testing before final approval.

3

.3

. In the instance of antibiotic resistance and infectiousIn the instance of antibiotic resistance and infectiousdiseases, this means spreading these adverse effects todiseases, this means spreading these adverse effects tosociety!society!


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QuestionsQuestions

Any questions?Any questions?

(ask: HOW, WHY, WHAT, WHEN!)(ask: HOW, WHY, WHAT, WHEN!)


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Benefits of mBenefits of m--based Medicinebased Medicine

a)a) More specific detection and classification of existingMore specific detection and classification of existingdiseases, leading to more accurate prognoses and earlierdiseases, leading to more accurate prognoses and earlierdetection.detection.

b)b) Predictive/predisposition tests and actionable things you canPredictive/predisposition tests and actionable things you can

do with such infodo with such infoc)c) Better idea of whatBetter idea of whatmolecularlymolecularlyto target and how toto target and how to

most effectively and efficiently treat a patient with amost effectively and efficiently treat a patient with aparticular illness or infection.particular illness or infection.

http://learn.genetics.utah.edu/content/health/pharma/intro/http://learn.genetics.utah.edu/content/health/pharma/intro/

Less adverse side effects from metabolism variants (PGx) via dosageLess adverse side effects from metabolism variants (PGx) via dosagevariations for difft patients, combination drug adverse reactions, and sidevariations for difft patients, combination drug adverse reactions, and sideeffects in generaleffects in general

Better idea of what will work, and gives u additional ideas of what to use asBetter idea of what will work, and gives u additional ideas of what to use asan Rxan Rx


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Increasing Trends inIncreasing Trends in

MolecularT

estingMolecularT

esting Learning aboutLearning about #lungcancer#lungcancer mgmt trends. EGFRmgmt trends. EGFR

mut'n testing is up from 2mut'n testing is up from 2--3% to ~103% to ~10--12% from early12% from earlyto late 2009; should rise more in next yr.to late 2009; should rise more in next yr.

-- Tweet from Oncologist in Seattle, WA

.Tweet from Oncologist in Seattle, WA

. The biology of lung cancer differs from one patient toThe biology of lung cancer differs from one patient to

the next, depending on age and sex, according tothe next, depending on age and sex, according toscientists at Duke University Medical Center. Thescientists at Duke University Medical Center. Thefindings may help explain why certain groups offindings may help explain why certain groups of

patients do better than others, even though they appearpatients do better than others, even though they appearto have the same disease.to have the same disease.

-- http://www.brightsurf.com/t/52409/http://www.brightsurf.com/t/52409/


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Myths about Genetic TestingMyths about Genetic Testing

and Molecular Medand Molecular Med1.1. Insurers can drop you based on results.Insurers can drop you based on results. GINA prohibitsGINA prohibits ----

1.1. Denying coverageDenying coverage to a healthy individualto a healthy individual or chargingor chargingthat personthat person higherhigherpremiumspremiums based solely on abased solely on a genetic predispositiongenetic predisposition to developing a diseaseto developing a diseasein the future.in the future.

2.2. EmployersEmployers fromfrom usingusingindividuals'individuals' genetic information whengenetic information whenmakingmakinghiring,hiring, firing, job placement, orfiring, job placement, or promotionpromotion decisionsdecisions..

3.3. prohibits health insurers from using genetic information toprohibits health insurers from using genetic information todetermine eligibility or premiums, prohibits insurers and employersdetermine eligibility or premiums, prohibits insurers and employersfrom requesting or requiring that a person undergo a genetic test,from requesting or requiring that a person undergo a genetic test,and prohibits employers from using genetic information to makeand prohibits employers from using genetic information to make

employment decisions.employment decisions. A

MA

siteA

MA

site

2.2. If someoneIf someone diddidhappen to get a hold of my DNA, they could clone anhappen to get a hold of my DNA, they could clone anidentical copy of meidentical copy of me!!


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Where to go from hereWhere to go from here

Talk with your doc about molecular testing if you have a disease,Talk with your doc about molecular testing if you have a disease,infection, or simply want to learn more about yourself and theinfection, or simply want to learn more about yourself and theunderlying molecular mechanisms of your disease, infection orunderlying molecular mechanisms of your disease, infection orbiological actions.biological actions.

Molecular profiling, molecular testing, genetic testingMolecular profiling, molecular testing, genetic testing

What to testWhat to test ----

DNA

DNA

genetic testinggenetic testing Expression levels, sequence, and functionality of moleculesExpression levels, sequence, and functionality of molecules

(DNA, micro(DNA, micro--RNA, RNA, proteins, etc)RNA, RNA, proteins, etc) ---- molecular profilingmolecular profiling


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What Are We (I&C) Doing?What Are We (I&C) Doing?

Bringing innovation to you at theBringing innovation to you at the fastest ratefastest rate

possiblepossible is our goal.is our goal.1.1. CommunityCommunity--based education and resource sharingbased education and resource sharing

2.2. Building an interface to empower you to make a differenceBuilding an interface to empower you to make a difference

3.3. Working to integrate these innovations and patient optionsWorking to integrate these innovations and patient options

into physicians workflow.into physicians workflow.


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Why do we say this?Why do we say this?

(pharmacogenomics slide)(pharmacogenomics slide) WellWell ----have you ever wondered why you respondedhave you ever wondered why you responded

differently than your best friend to the SAMEdifferently than your best friend to the SAMEtreatment?treatment?thetheAnswer:Answer:

Diff genetic makeup and molecular expression expressionsDiff genetic makeup and molecular expression expressionsthan your friendthan your friend

Meaning, the things that break down the treatment in yourMeaning, the things that break down the treatment in yourbody are different as are those things that clear them frombody are different as are those things that clear them fromyour body, as are your molecular profiles in the cells you wishyour body, as are your molecular profiles in the cells you wishto target.to target.

HenceHence, we have effectiveness, we have effectiveness andandsafety differences!safety differences!

molecular based medicine

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