Molecular based (i.

e, personalized)
Medicine

By I&C President Ryan Witt

witt.rj@gmail.com
 Schedule
 Bio 101
 Molecular Medicine
 Remember

Ask Qs
 Always ask “ Why/how, What, and When”
 Try to understand EVERYTHING!
 Our Bodies
 Made up of 10 to 100 trillion cells
Cells make up
Tissues

Tissues make
Organs
 Molecules
 So… what and where are “molecules?”
 What: A group of two or more atoms bonded to one

another. (Pauling, Linus (1970). General Chemistry. New York: Dover Publications, Inc.. ISBN 
0-486-65622-5 )

Where: Everywhere
Water
H20


 Including inside AND outside of cells

Now, let’s look at
function…
 The Driver
 Molecules are the drivers of your cells.
 Forming the structure of DNA, RNA, proteins,
enzymes, and EVERYTHING pushing our body to
do what it does!
 Environment / e
xtra-cellular sig
el l s wo r k! n als
hi s i s ho wc
T
DNA
RNA Proteins

Newly discovered / other components:

Methylases (methylate DNA), mRNA, alternative splicing, micro-RNA, tRNA
 DNA
 Been called “the Master Plan” and “your
destiny.”
 Is there merit?
 Codes for ALL players – proteins, enzymes, microRNA, RNA, etc.
 But, DNA is the code… not an actor / player itself
 Reality 101
DNA isn’t everything!
 DNA mutations change our DNA throughout our lifetime
+
 Expression and function is partially independent of DNA (i.e., epigenetics
(methylation); post-translational modifications)
 Expression and “end-conformation” of molecules is what matters most -- that is, what
players (i.e., RNA, glycoproteins, proteins) will be active, and how are they functioning .
 3 fun examples of environment/our actions +
DNA, and their results!
 Example: Stubbing your Toe
(DNA change)

+
Rubbing

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

molecular characteristics describing you in a diff’t way!
 Ex: form of Dieting
(methylation change)
 “Excessive alcohol consumption has been
shown to alter DNA methylation in the colon
of humans.”
 Light’s Effect: Vision
(nothing to DNA; only protein changes)
 Light’s Effect: Vision
(nothing to DNA; only protein changes)
 In our BRAINS too!
“Technology is not only changing our lives, it’s
changing our BRAINS.”
- Dr Gary Small, Director of the UCLA Center on Aging & Professor of
Psychiatry and Behavioral Sciences at UCLA
 Coming back to the Q
 Is our DNA everything?

Our actions change our molecules, which

change our cells, organs, and bodies!
 Reality
 Reality is…
 We are a product of environment / actions plus our
“blueprint.”
 The blueprint is the start; everything from there is
up to you!
 Lastly
Beware!

ALWAYS ask, “What, Why, When and How”

http://www.youtube.com/watch?v=R34Sguwxe2o
4-slide Recap
 Molecules
 Two or more atoms bound together!
 Molecules make up the components of cells,
tissue, organs, and us as a whole
How your body works
Our actions affect our bodies --
at the molecular level

Rubbing
 Take Home Points
1. Our actions  the molecular attributes describing those
actions.
2. Blueprint / cards dealt (DNA) + choices and environment
3. Expression levels, the sequences of molecules, among other
factors—which constantly are changing—are the keys to
understanding the underlying molecular mechanisms
describing our actions, at any given moment.
(DNA is code, not the actor!)

1 & 3 are VERY important for next lecture – know them well!
 COOL!
 Woooooooooooooooof - done! (next is
Medicine!)

Any questions?
 Break
 Ask your doc about molecular testing if you have a
disease, infection, or simply want to learn more about
yourself.
What to test --
 DNA
 Expression levels, sequence, and functionality of
molecules (DNA, micro-RNA, RNA, proteins, etc)
 Break: Myths about Genetic Testing
and Molecular Med
1. Insurers can drop you based on results.
 GINA prohibits --
1. “Denying coverage to a healthy individual or charging that person
higher premiums based solely on a genetic predisposition to developing
a disease in the future.”
2. “Employers from using individuals' genetic information when
making hiring, firing, job placement, or promotion decisions.”
3. “prohibits health insurers from using genetic information to
determine eligibility or premiums, prohibits insurers and
employers from requesting or requiring that a person undergo a
genetic test, and prohibits employers from using genetic
information to make employment decisions.” – AMA site

2. If someone did happen to get a hold of my DNA, they could clone an

identical copy of me!
 Medicine
(the standard, then
innovation)
 Key point
There are –
Our actions and & the Molecules describing them
characteristics

Rubbing

Rubbing
Things can get very hazy
Cancer
 Medicine
 When it comes to medicine, challenge is

Clinical Symptoms Where & What is

molecular-Cause
Stuffy nose
Slurred speech
Fever
Twitchy eye
Headache
 Medical Diagnostics:
standard / currently
 “Differential diagnosis”
1. What is the most likely cause
2. Physical Examination – checking your signs and
symptoms
3. Imaging Tools (MRIs, CT scans, fMRI, etc)
4. Histopathology – looking under a microscope to
distinguish cell / tissue characteristics
 Treatment
 Treatment by “trial-and-error” and “one-size-
fits all”

AMA and medical terminology

 Right now
Many of the same diseases by modern classification have
different molecular characteristics/drivers.

Meaning:
“NSCLC of squamous type” –> MDM2 mutation? p53
mutation? And/or EGFR mt? Met? Etc.

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

 Innovation
(Currently, not the standard)
 BUT
 Wait a minute!
…What about the “molecular drivers?”
 Molecular Profiling
 Now we have the capability to
take a sample of diseased or infected cells (or a person’s “normal
cells”), and examine it at the molecular level -- looking at RNA,
protein structure, expression levels, and genetic makeup (DNA).

 The methods are there (immunohistochemistry, DNA arrays,

RNA microarrays, real-time quantitative PCR)
 Which is best – unsure!
 Cool! What’s the value?
 Predictive to suggest treatment? No…not by
itself (if no clinical experiments are
performed)
I.e., MammaPrint, EGFR test, Tissue of Origin
 But it could be (predictive), if inferences are
made by some person…(as you will see)
 Profiling provides insights into the molecular
mechanisms governing/describing your
symptoms -- AKA

Knowledge!!!!!
 What can be done with knowledge:
Applying Molecular Profiling to Treatment
CANCER
 Xeloda – Thymidine Phosphorylase overexpression

 EGFR & MET overexpression

 FUS1, MDM2, & P53 therapy

FUS1, MDM2, & P53 therapy
 Application is to ALL diseases
With every ailment, there are respective proteins, genes, and molecules
driving its progression.

Bacterial Infections
 Azithromycin – antibiotic; works on various strains of bacteria ( inhibits
50S ribosomal subunit from acting)

ALS
 SOD1 gene target -- Arimoclomol

…Alzheimer’s, MS, Parkinson’s, Crohn’s, Lupus

 Value
 By seeing a comprehensive picture of one’s expression levels,
sequences, and so forth, one has a more clear view of the
underlying molecules and structure of molecules, hence a
more clear perspective on the likely outcomes of a therapeutic
intervention.
 Knowledge
 Nearly every drug approved on the market by a regulatory
agency has a known molecular mode of action.
 If you distinguish the molecular characteristics of a disease
from “normal cell” characteristics, then you can match drugs
perfectly with those disease characteristics and known
molecular signaling pathways within a disease!

Hence, less of a trial-and-error / one-size-fits-all approach.

Idea that fuels (i) “Molecular Medicine”, (ii) Personalized Med,

(iii) Combination Therapies and (iii) “Drug Repositioning”
 Without molecular knowledge,
and continued trial-by-error Rx…
W/o mDx, you have --
a) Different responses to the same treatments, in regards to
the safety and effectiveness of that therapy.
 http://learn.genetics.utah.edu/content/health/pharma/intro/

Death?
Life?
W/o molecular testing and treatment
b) Resistance Development & your Window of
Opportunity is lost!
1. Personal level

2. Society at large
 Translation, Please
W/o molecular profiling and continued trial-by-error
treatment --
1. Therapies available are no longer effective; must
find something else.
 Antibiotics
2. Not everything is available now – avg new cancer
therapy takes 14 yrs of testing before final approval.
3. In the instance of antibiotic resistance and
infectious diseases, this means spreading these
adverse effects to society!
 Questions
 Any questions?

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

 Benefits of m-based Medicine
a) More specific detection and classification of existing
diseases, leading to more accurate prognoses and earlier
detection.
b) Predictive/predisposition tests and actionable things you can
do with such info
c) Better idea of what—molecularly—to target and how to most
effectively and efficiently treat a patient with a particular
illness or infection.
 http://learn.genetics.utah.edu/content/health/pharma/intro/
 Less adverse side effects from metabolism variants (PGx) via dosage
variations for diff’t patients, combination drug adverse reactions, and side
effects in general
 Better idea of what will work, and gives u additional ideas of what to use
as an Rx
 Increasing Trends in
Molecular Testing
 “Learning about #lungcancer mgmt trends. EGFR
mut'n testing is up from 2-3% to ~10-12% from early
to late 2009; should rise more in next yr.”
- Tweet from Oncologist in Seattle, WA.
 “The biology of lung cancer differs from one patient
to the next, depending on age and sex, according to
scientists at Duke University Medical Center. The
findings may help explain why certain groups of
patients do better than others, even though they
appear to have the same disease.”
- http://www.brightsurf.com/t/52409/
 Myths about Genetic Testing
and Molecular Med
1. Insurers can drop you based on results.
 GINA prohibits --
1. “Denying coverage to a healthy individual or charging that person
higher premiums based solely on a genetic predisposition to developing
a disease in the future.”
2. “Employers from using individuals' genetic information when
making hiring, firing, job placement, or promotion decisions.”
3. “prohibits health insurers from using genetic information to
determine eligibility or premiums, prohibits insurers and
employers from requesting or requiring that a person undergo a
genetic test, and prohibits employers from using genetic
information to make employment decisions.” – AMA site

2. If someone did happen to get a hold of my DNA, they could clone an

identical copy of me!
 Where to go from here
 Talk with your doc about molecular testing if you have a disease,
infection, or simply want to learn more about yourself and the
underlying molecular mechanisms of your disease, infection or
biological actions.
 “Molecular profiling”, “molecular testing”, “genetic testing”

What to test --
 DNA – “genetic testing”
 Expression levels, sequence, and functionality of molecules
(DNA, micro-RNA, RNA, proteins, etc) -- “molecular profiling”
 What Are We (I&C) Doing?
 Bringing innovation to you at the fastest rate
possible is our goal.
1. Community-based education and resource sharing
2. Building an interface to empower you to make a difference
3. Working to integrate these innovations and patient options
into physicians’ workflow.
 Why do we say this?
(pharmacogenomics slide)
 Well --have you ever wondered why you responded
differently than your best friend to the SAME
treatment?
the Answer:
 Diff genetic makeup and molecular expression expressions
than your friend 
 Meaning, the “things” that break down the treatment in
your body are different as are those “things” that clear
them from your body, as are your molecular profiles in the
cells you wish to target.

Hence, we have effectiveness and safety differences!