Personalized Medicine.

Hope or Hype?

Diagnosinginheritedformsofbreastcancer:
Upcloseandpersonal

Denise- patient

Up to 10% of breast cancer

can be shown to be
inherited and most of these
cancers are traceable to
mutations in the BRCA1 or
BRCA2 genes.
http://www.dnai.org/d/index.html

Dr. Barbara Weberclinician and scientist

Genes and Medicine, Applications, gene testing, Denise,

Decision to have her breasts removed.
Barbara Weber,Seeing who has the marker.

Thesciencebehindthemedicine
http://www.dnai.org/d/index.html.
Applications, Genes and Medicine, gene hunting,
Markers animation.

Applications, Genes and Medicine, gene testing,

making a pedigree animation.

Applications, Genes and Medicine, gene testing,

Testing for BRCA1 and BRCA2 animation

Theendofthestory
http://www.dnai.org/d/index.html.
Genes and Medicine, Applications, gene testing, Denise,
Was she at increased risk and Finding out.

What would you have done if you were

Denise or a member of her family?
Remember that this gene was passed
down from a male ancestor and males
have higher cancer rates if they carry
these genes.

New Frontiers: Personalized Medicine. Hope or Hype?

Individual genome sequencing

Imagine the day when you and your
doctor sit down to review
a copy of your own personal
genome. This vital information about
your biology will enable your
physician to inform you of your
disease susceptibilities, the best
ways to keep yourself healthy and
how to avoid or lessen the impact of
future illnesses.

http://genomics.xprize.org/

Why whole genome sequencing?

Require full functional
understanding. Government
genome project was a man and a
woman from Buffalo. Celera was
Craig Venters genome. Am I the
same as them?
So sequencing was selective and
missed:
-personal mutations
-regulatory mutations in
noncoding sequence
-repetitive sequences because
they are difficult to sequence

The phase problem? Does the linear arrangement

along the length of a chromosome have an impact in
addition to the genotype?

Is the upper
arrangement
better than the
lower one? Are
there cis
effects in the
arrangement of
the genes on
chromosomes?

PersonalDNA
NeilDeGrasseTyson
NovaScienceNow
youtu.be copy
copy of the 2010 commencement speech

youtube fragment within the whole PBS program

Local copy

The Promises of Personalized Medicine

Provide advanced screening for disease.
Select safer, more effective medications and dosages.
Generate better vaccines.
Develop vaccines made of genetic material.
These would activate immune system w/o causing
infection.
Inexpensive, stable, easy to store.
Engineered to carry several strains of a pathogen
at once.
Develop cell-based vaccines.
Lower healthcare costs.
Proactive lifestyle changes, early detection & treatment.
Decrease adverse drug reactions.
Decrease # medications, length of time on medication.

Are We There Yet? Reality Check.

Field of personalized medicine is in its infancy.
Access to personal genome is a long way off , or maybe not.
$5000 genome by 2009 Complete Genomics
For personalized medicine to be realized will require that we
greatly reduce the cost and increase the speed of human
genome sequencing.
This is the goal of the Archon X PRIZE for Genomics.

Personalized Medicine: Genomics and Stem Cell therapies.

Genomics:
Example: Cancers Tumor genotyping
2009 Science 326, 218-220.
lung cancer
non-small cell lung cancer
most common
EML4-ALK fusion
others: mutations in EGFR, Iressa
Genotype every lung cancer.
Check for array of mutations.
Target drug therapy based on specific genes mutated
15-20% of patient tumors can be matched to specific drug.
Reality: better initially, then cancers develop resistance.
NCI: The Cancer Genome Atlas
20 cancer types, 5 years, $275 million in first 2 years.

Disease Targets for

Intervention.
ALS Amyotrophic Lateral
Sclerosis
Huntingtons Disease
Type I Diabetes
Cancers
High Blood Pressure
Mental Illnesses
Asthma
Many are the same diseases that are targeted for
stem cell therapies.
Cell therapies also referred to as regenerative medicine.

NIH Stem Cell Information:

http://stemcells.nih.gov/info/basics/defaultpage.asp

Avideostemcellprimer
Video
Stem Cells
Neil deGrasse Tyson
Nova Science Now
youtu.be copy

Local copy

What are stem cells and why are they important?

Three important characteristics:
1. Capable of dividing to renew themselves for
long periods.
proliferation through mitosis
long-term self-renewal
2. Unspecialized or undifferentiated.
3. Can be induced to differentiate.
blood, heart muscle, nerve, etc.
BUT, what are the signals that
prevent differentiation during the
self-renewal divisions?
This is a key question!
University of Wisconsin

There are two main types of stem cells.

1. Embryonic stem cells.
derived from embryos
in vitro fertilized eggs
2. Adult stem cells.
population in every tissue
typically generate same type of
differentiated cells.
originally thought NOT to be
pluripotent

University of Wisconsin

Recent experiments have revealed

-hematopoietic stem cells of bone marrow can be induced to
form neurons and heart muscle.
-liver stem cells induced to produce insulin.

How Are Human Embryonic Stem Cells Obtained?

Cleavage-stage embryo produced
by in vitro fertilization.

~5 days to reach blastocyst stage.

Identify specific surface markers
found only on undifferentiated ES
cells. These surface markers
change once cells begin to
differentiate.

In suspension culture, hES cells differentiate.

multicellular aggregate

gelatinized solid medium

differentiate further

2007: Shinya Yamanakas lab & James Thomsons lab

Genes for reprogramming differentiated cells to iPS cells.
Using retroviruses as carriers 4 human genes were
identified that could cause a differentiated cell to be
reprogrammed as an induced pluripotent cell (Oct3/4,
Sox2 with Klf4 and c-Myc) when introduced
simultaneously with the virus.
Oct3/4 & Sox2: Master transcriptional regulators.
Klf4 & c-Myc are required to increase induction
efficiency.
HOWEVER,
Viral vectors increase the risk of tumorigenicity.
c-Myc is an oncogene. ~20% mice develop tumors.
http://en.wikipedia.org/wiki/Induced_pluripotent_stem_cells
S. Yamanaka. 2009. Cell 137, 13-17.

2008: Generation of Induced Pluripotent Stem Cells

without viral vectors.
Shinya Yamanakas lab: single plasmid
Expresses c-Myc plus cDNAs for Oct3/4, Sox3, Klf4
Transfection in mice.
iPS cells without plasmid integration.
Produced teratomas when transplanted into mice.
Produced adult chimeras.
Used embryonic fibroblasts.
2008 Science 322, 949-53

Generation and application of iPS Cells

S. Yamanaka 2009

Movies
Neil Theise
CBS January 23, 2009
http://www.youtube.com/watch?v=E2ymkuUc6FU
local copy

Where America Stands: Stem Cell Research

CBS March 16, 2010
http://www.cbsnews.com/video/watch/?id=6305502n
local copy

Potential Uses of Human Stem Cells

Spinal injuries and neuronal regeneration.

Skin cell replacement
Cardiovascular disease
Insulin producing pancreatic cells

You have had the science, but what are the ethical
issues
for hES or iPS cells?
consent & confidentiality of donors
coded but anonymous
exploitation of young women
animal-human chimeras reaching adults
integration of human genes into nonhuman animal tissues
nonhuman primates of particular concern
no animal with hES cells introduced should be allowed to
breed
religious concerns
other ethical issues

Attendance exercise:

For or against stem cell research and

therapy? Post to Bulletin Board