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"Biotech 101" Course presented as part of the Texas Life Science Conference, November 2010
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Biotech 101Biotech 101Biotech 101Biotech 101
Texas Life Science ConferenceBioHouston
Jason E. Moore, M.S., M.B.A.Vice President PLx Pharma IncVice President, PLx Pharma Inc.
November 12, 2010
Course OverviewCourse Overview
• Overview of the science behind biopharma• Difference between “pharma” and “biotech”Difference between pharma and biotech• Understanding the “foundational
biotechnologies” and bioinformaticsbiotechnologies and bioinformatics• Trends in biotechnology commercialization –
what technologies are being advancedg g• Overview of the drug development process and
related economics• Houston/Texas Biotech (over lunch)
Biotechnology DefinedBiotechnology Defined
The integration and application of science and engineering to life processes to solve
problems or manufacture products
• Includes applications in…– Healthcare and PharmaceuticalsHealthcare and Pharmaceuticals– Agricultural production (crops and livestock)– Biodefense
Environmental remediation forensics paternity archaeology– Environmental remediation, forensics, paternity, archaeology – Much more
A Little Molecular BiologyA Little Molecular Biology
• Cells are the basic building blocks of all li i hi
• All cells…– Have same basic design
M d f thliving things• Many different cell types,
each of which performs a
– Made of the same construction materials
– Operate using essentially the same processeseach of which performs a
very specific task• Despite diversity, many
same processes– DNA is the genetic material of
almost all living things– DNA directs cell construction
unifying properties • This unity provides the
foundation for modern
DNA directs cell construction and operation, while proteins do all the work
– All cells speak the same foundation for modern biotechnology
genetic language
Schematics of Cell and NucleusSchematics of Cell and Nucleus
Human ChromosomesHuman Chromosomes
From Chromosome to DNA Base PairsFrom Chromosome to DNA Base Pairs
• Chromosomes in cells are tightly packed DNAg y p
• Various structures are evident as DNA is unwoundas DNA is unwound
• The DNA double helix becomes apparentbecomes apparent
• DNA base pairs carry the i f ti f DNAinformation of DNA
What is the DNA Double Helix? What is the DNA Double Helix?
Chromosomes and Chromosomes and Genes Genes –– Units of HeredityUnits of Heredityyy
Gene: a sequence of nucleotides in DNA or RNA that is the functional unit of inheritance controlling
46 chromosomes in each human (diploid) cell
that is the functional unit of inheritance controlling expression of traits, by specifying the structure of a particular protein or controlling the function of other genetic material
Chromosomes, Genes and Chromosomes, Genes and BasepairsBasepairs
The “Central Dogma”…The “Central Dogma”…
Cell Nucleus
Chromosome
ProteinGraphics courtesy of the National Human Genome Research Institute
Gene (DNA)Gene (mRNA), single strand
Translation and the Genetic CodeTranslation and the Genetic Code
The particular sequence of codons corresponds to an amino acid, which are
what proteins are made of
Proteins Do the WorkProteins Do the Work Triose phosphateisomerase
• Proteins: (100,000 produced in humans)– Have structural roles– Receptors and transporters– Messengers/signals– Catalyze chemical reactions– Generate force– Regulate genes– The key actors in normal development and disease– The key actors in normal development and disease
– MAKE EXCELLENT TARGETS FOR NEW TREATMENTSNEW TREATMENTS
Summary: Cells, DNA & ProteinsSummary: Cells, DNA & Proteins
• 15-100 trillion cells in the human body• 3.1 billion base pairs in each cell• 2.4 million base pairs in the largest human gene• 20,000-25,000 genes in the human genome• 46 chromosomes in each cell• About 100,000 proteins produced by the human body
Proteins perform many functions are very specific and• Proteins perform many functions, are very specific, and make excellent targets for new treatments
Biotechnology Defined…AgainBiotechnology Defined…Again
The integration and application of science and engineering to life processes to solve g g p
problems or manufacture products
Biotechnology Tools and Biotechnology Tools and ProductsProducts
• Because biological systems and molecules are extraordinarily specific in their interactions…
• Biotechnology’s tools and techniques are also specific• As a result, biotechnology products, are expected to
bebe…– Very precise– Have greater potential to solve specific problems – Generate gentler or fewer side effect and have fewer unintended
consequences
• Biotech medicines use the human body’s machinery—y ycells, genes, proteins, enzymes and antibodies—to fight disease.
Human Genome ProjectHuman Genome Project• Definition: Genome• Completed in 2003, the HGP was a 13-
year project toyear project to – determine the sequences of the 3 billion
base pairs that make up human DNA– identify all the 20 000-25 000 genes in– identify all the 20,000-25,000 genes in
human DNA– store this information in databases– improve tools for data analysisimprove tools for data analysis– transfer related technologies to the
private sector, and – address the ethical, legal, and social , g ,
issues that may arise from the project• Though the HGP is finished, analyses
of the data will continue for many years
Origins and Progression of DiseaseOrigins and Progression of Disease
• Genetic makeup• Diet• Exercise• Pollutants• Virus• Injury• Development• Development• Personality/attitude
Baylor’s HGSCBaylor’s HGSC
• One of 3 large-scale sequencing centers funded by NIHfunded by NIH
• 78 automated sequencers• 220 staff• 24/7 operation24/7 operation• Sequencing other
important genomes– Bovine
Chi– Chimpanzee– Drosophila– Honey Bee– Microbial
Mouse– Mouse– Orangutan– Rat– Rhesus monkey
Sea Urchin– Sea Urchin
How the Human Genome Stacks UpHow the Human Genome Stacks Up
Organism Genome Size (Bases) Estimated Genesg ( )Human (Homo sapiens) 3 billion 25,000
Laboratory mouse (M. musculus) 2.6 billion 25,000
Mustard weed (A thaliana) 100 million 25 000Mustard weed (A. thaliana) 100 million 25,000
Roundworm (C. elegans) 97 million 19,000
Fruit fly (D. melanogaster) 137 million 13,000
Yeast (S. cerevisiae) 12.1 million 6,000
Bacterium (E. coli) 4.6 million 3,200Human immunodeficiency virus 9700 9y(HIV) 9700 9
Source: US Department of Energy Human Genome Project
Humans, chimps almost a matchAugust 31, 2005
By Steve Sternberg, USA TODAY
August 31, 2005Humans and chimpanzees share an almostidentical genetic inheritance, scientists reportThursday in a landmark comparison that they callan "elegant confirmation" of Charles Darwin's
"Evolutionary analysis is a handmaiden tohuman medicine," says Eric Lander of theBroad Institute of the Massachusetts Instituteof Technology and Harvard.
For example, in a discovery that could offerinsights into Alzheimer's researchers found
Clint the chimpanzee, whose genome sequence appears in 'Nature,' helped an elegant confirmation of Charles Darwin s
theory of evolution.
Although scientists have long believed thathumans and chimps are related, thiscomprehensive analysis of their separate genomesoffers the best proof of their shared genetic past.
insights into Alzheimer s, researchers foundmutations that turn off the human caspase-12 gene, which causes damaged cells toself-destruct. Those mutations weren't foundin chimps, which aren't as susceptible toAlzheimer's. Knocking out caspase-12 inmice makes their brain cells more likely to
pshow there's little difference between man and ape. Yerkes National Primate Research Center, AFP/Getty Images“ Th 3 billi ti l tt i th t
p g pThe 3 billion genetic letters in the two geneticblueprints are 96% identical with just 40 milliondifferences, the researchers report in the journalNature.
By delving more deeply into those differences,h h t l i h h
"We can peek into evolution's lab notebook andsee what went on there," says Francis Collins,director of the National Human Genome ResearchI tit t
ysurvive with Alzheimer's-like damage.
Researchers also identified mutations inhumans that were important for survival,including a gene associated with speech anda gene that ramps up response to sugar, and t i l ti b t t ti l ti k t
AFP/Getty Images
“…The analysis offers clues to the cause of diseases such as Alzheimer's and to why
“…The 3 billion genetic letters in the two genetic blueprints are 96% identical with just 40 million differences, the researchers report in the journal Nature.…”
researchers hope to explain why humans aresusceptible to certain diseases; why ourevolutionary paths diverged from ancestral chimps6 million years ago; and, on an even more basiclevel, what makes us human.
Institute.
The analysis offers clues to the cause of diseasessuch as Alzheimer's and to why chimps andhumans are susceptible to different diseases.
advantage in lean times but a potential ticketto diabetes today.
"Reading these two genomes side by side,it's amazing to see …”
diseases such as Alzheimer's and to why chimps and humans are susceptible to different diseases..…”
99% of Human Genes 99% of Human Genes Have a Mouse CounterpartHave a Mouse Counterpartpp
…which makes laboratory mice excellent models ofdisease and well suited for testing of new medicines.
“Small Molecule” vs “Large Molecule” “Small Molecule” vs “Large Molecule” ggDrugs”Drugs”
Biological Products are Biological Products are DifferentDifferent
• Generally (much) largerGenerally (much) larger
• Made in living systems (e.g. yeast or mammalian cells)
– More complicated– Elaborate folding– Sugars may be attached
(“glycosylation”)– Several forms of theSeveral forms of the
active molecule may be present
(Zantac)
“Ph ” “Bi t h”“Ph ” “Bi t h”“Pharma” vs. “Biotech”“Pharma” vs. “Biotech”
“Biotech” and “Pharma” “Biotech” and “Pharma” ---- Terms of ArtTerms of Art
• Technical definition– Pharmaceutical: Chemically synthesized, small-molecule drug
(b t t t l)(but, note taxol)– Biotech drug: Biologically derived, large molecule drug (but, note
synthesized oligonucleotides and polypeptides)
“Biotech” and “Pharma” “Biotech” and “Pharma” ---- Terms of ArtTerms of Art
• Investor-speak– Pharma (or “Big Pharma”): Any of the larger, revenue-producing
i th t ll t bli h d d h k t dcompanies, that are well established and have marketed products; less risky
– Biotech: • Smaller life science companies, less well established, may or may
not have marketed products; riskier (can include small medical device companies)
• But may include large well established life science companies that• But may include large, well established life science companies that focus on biological therapeutics (eg, Amgen, Genentech)
Core Biotechnologies and Their Use in Core Biotechnologies and Their Use in ggDetecting and Treating Human IllnessDetecting and Treating Human Illness
(Very Brief) Introduction to Core (Very Brief) Introduction to Core BiotechnologiesBiotechnologiesgg
• Monoclonal • Biosensors• Monoclonal antibodies
• Cell culture
• Biosensors• Nanobiotechnology• MicroarraysCell culture
• Cloning• Recombinant DNA
• Microarrays• ‘Omics
Epigenetics• Recombinant DNA• Tissue engineering• Protein engineering
• Epigenetics• Bioinformatics
• Protein engineering
Spectrum of Biological TherapiesSpectrum of Biological Therapies
• Blood collection and transfusion
• Vaccines– Traditional preventative
• Protein therapeutics– Hormonal therapies– Monoclonal antibodies
– Therapeutic vaccines
• Nucleotides– siRNAMonoclonal antibodies
• Regenerative medicine– Tissue grafts/organs
siRNA– Other oligonucleotides and
thioaptamers
N t h th i• Therapeutic Cloning• Autologous tissues
– Cell-based therapies
• Nanotech therapies• Epigenetics approaches• Gene therapyGene therapy
Monoclonal AntibodiesMonoclonal AntibodiesImmune system cells are used to make proteins• Immune-system cells are used to make proteins called antibodies
• “Lock and key” relationship• Lock and key relationship• Incredibly specific population of proteins; used to:
– Identify environmental pollutants & biowarfare agents– Detect harmful microorganisms in foodDetect harmful microorganisms in food– Distinguish cancer cells from normal cells– Diagnose infectious diseases in humans, animals, and plants– Are the basis for a highly specific class of therapeutic compounds
“Lock and Key”“Lock and Key”
• FDA approved for the treatment of certain (HER2+) early-stage breast cancers
• Herceptin is a monoclonal antibody that interferes with the HER2 receptor
• HER proteins regulate cell growth survival• HER proteins regulate cell growth, survival, adhesion, migration, and differentiation—functions that are amplified or weakened in cancer cells
• When it binds to defective HER2 proteins, the HER2 protein no longer causes cells in the breast to reproduce uncontrollablyuncontrollably.
• This increases the survival of people with cancer
HerceptinHerceptin & HER2 Signaling& HER2 Signaling
Targeted Therapies in Targeted Therapies in CancerCancer
Therapeutic Antibodies Have Therapeutic Antibodies Have Come of Age!Come of Age!
• 18 moAbs approved by FDA to date, including Tanox’s (Genentech’s) Xolair®
• ~350 in clinical trials• $10 B in revenues in 2004; $30B market by 2010
Si Ab l b l $500M• Six moAbs → global revenues > $500M• Market expected to grow by 20% per year over next 5
yearsyears• Better toxicity profiles/faster approval??
Monoclonals Also Used In Monoclonals Also Used In
• Biosensors– Molecular diagnostics
• measuring protein and drug levels in serum • typing tissue and blood • identifying infectious agents • identifying clusters of differentiation for the classification and follow-
up therapy of leukemias and lymphomas • identifying tumor antigens and auto-antibodies
id tif i th ifi ll i l d i th i• identifying the specific cells involved in the immune response • identifying and quantifying hormones
– Biowarfare agent detectors– Hazmat sensors– Home pregnancy tests
BiosensorsBiosensors
• Biology + microelectronics• Detecting devices composed of
– Biological component, for example… • cell• enzymeenzyme• antibody
– Tiny transducer
• Rely on great specificity to identify and measure substances at extremely low concentrations
CancerCancer--Detecting Detecting NanosensorNanosensor
Cell CultureCell Culture
• Growing cells outside of living organisms (in vitro)• Research tool• Use to create therapeutic
productsP i t• Primary types– Mammalian cell culture– Plant cell culture– Insect cell culture
Industrial BioreactorsIndustrial Bioreactors
Industrial BioreactorsIndustrial Bioreactors
• Mammalian Cells• Microbial Biopharma• Peptide Synthesis• Fermentation• Chemical Synthesis• Adenoviral, AAV and lentiviral vectors Chemical Synthesis• Highly Potent APIs• Cell Therapy
Adenoviral, AAV and lentiviral vectors• Replication competent adenovirus• Plasmid DNA• Other viral products
Recombinant DNA TechnologyRecombinant DNA Technology
• Recombinant DNA is made by combining genetic material from different sources– Plant and animal breeding– Molecular recombination
Genetic Recombination & Cellular Genetic Recombination & Cellular Clones Clones –– The Human Insulin GeneThe Human Insulin Gene
Genetic Recombination Genetic Recombination ---- Cohen & Cohen & Boyer and the Birth of BiotechBoyer and the Birth of BiotechBoyer and the Birth of BiotechBoyer and the Birth of Biotech
1973, 1980
• Invented gene splicing/genetic recombination
• Cohen: no commercial value and t t bl
• Nonexclusively licensed with low fees
• 467 companies licensed; $300
unpatentable
• Berg: Refusal to patent
• Established seminal patents; technology • 467 companies licensed; $300
MM in revenues• Genentech & Boyer
is basis of BT industry
• Among the earliest examples of technology transfer
EPOGEN®EPOGEN®
• Recombinant erythropoetin alfa
• Human erythropoetin transfected into Chinese Hamster ovary cellsHamster ovary cells
CloningCloning
• “Clone”: A genetically identical gene, cell, or organism• Allows generation of a population of genetically identical
molecules, cells, plants or animals• Types
Molecular or gene cloning– Molecular, or gene, cloning– Cellular cloning– Plant and animal cloning (aka, reproductive cloning)
• Reproductive versus therapeutic cloning• Extremely broad possible
applicationsapplications…
Fertilization Fertilization vsvs. Cloning . Cloning (somatic cell nuclear transfer)(somatic cell nuclear transfer)
Fertilization Fertilization vsvs. Cloning . Cloning (somatic cell nuclear transfer)(somatic cell nuclear transfer)
Reproductive Cloning of PetsReproductive Cloning of Pets
2004: Genetic Savings & Clone delivers Little Nicky, the first commercially- produced pet
"In FDA's analysis of the available data on animal clones, no differences were detected in overall behavior and health ofy p p
clone, to client from Texas. detected in overall behavior and health of juvenile and adult animal clones and conventional animals, even at the level of blood chemistry."—FDA press release 10/31/03—FDA press release 10/31/03
Regenerative MedicineRegenerative Medicine
• Regenerative Medicine: The development and application of innovative medical therapies to fully or partially restore damaged parts of the human organism and to support the regeneration ofto support the regeneration of damaged organs
• Tissue engineering: materials science + molecular biologyscience + molecular biology
• Natural regenerative proteins
• Stem cells
• Other cell-based therapies
Regeneration in NatureRegeneration in Nature
• Outstanding Examples– Planarian– Crayfish
• Inverse Relationship– Increase complexityIncrease complexity– Decrease regenerative
ability
Regeneration in HumansRegeneration in Humans
High Moderate Low
Clinical NeedsClinical Needs
• Cardiovascular– Myocardial infarction– Stroke
• Bone– Non-union fracturesNon union fractures– Tumor resections
• Nervous– Spinal Cord Injury– Degenerative diseases
Stem CellsStem Cells
• Stem cells are…– undifferentiated (unspecialized) cells – with the capacity for unlimited or prolonged self-renewal and – the ability to give rise to differentiated (specialized) cells.
• Two typesTwo types– Adult stem cells– Embryonic stems cells
Adult Stem CellsAdult Stem Cells• WHERE are they found?
– Found among adult tissue or organs such as the bone marrow liver skeletal musclemarrow, liver, skeletal muscle, brain, and skin
• Limited developmental potential; multipotent not p ; ptotipotent
• Better behaved, easier to manageL th i bilit t• Lose their ability to proliferate/differentiate after a time in culture
• Less moral ambiguityLess moral ambiguity • Less legal controversy
“Stem cells found in adults show surprising versatility, but it’s not yet clear whether they can match the power of cells from embryos. -- G. Vogel, Science 287:1418,2000
Hematopoietic Stem Cells Hematopoietic Stem Cells (HSCs)(HSCs)( SCs)( SCs)
Multipotent stem cells that give rise to all the blood cell types…
Embryonic Stem CellsEmbryonic Stem Cells
• WHERE are they found?D i d 5 6 d ft– Derived 5-6 days after fertilization from inner portion of blastocyst (mass of approximately 64 cells )of approximately 64 cells.)
• WHAT can they do?– Differentiate into all
specialized cells in the bodyspecialized cells in the body– Totipotent
A Little Developmental A Little Developmental Biology…Biology…gygy
Stages of EmbryogenesisStages of Embryogenesis
Day 22 cell embryoDay 22 cell embryo D 3 4D 3 4Day 1
Fertilized eggDay 1Fertilized egg
2-cell embryo2-cell embryo Day 3-4Multi-cell embryoDay 3-4Multi-cell embryo
Day 5-6BlastocystDay 5-6BlastocystDay 11-14
Tissue DifferentiationDay 11-14Tissue DifferentiationTissue DifferentiationTissue Differentiation
Derivation and Use of Derivation and Use of Embryonic Stem Cell LinesEmbryonic Stem Cell Linesyy
Isolate inner cell mass(destroys embryo)Isolate inner cell mass(destroys embryo)Outer cells
(forms placenta)Outer cells(forms placenta)
Inner cells(forms fetus)Inner cells(forms fetus) Culture cellsCulture cells
“S i l ”Day 5-6BlastocystDay 5-6Blastocyst
Li
“Special sauce”(largely unknown)
BlastocystBlastocyst
Heart muscleKidney
LiverHeartrepaired
Heart muscleKidney
Diseases Stem Cell Therapy Diseases Stem Cell Therapy Might TreatMight Treatgg
Alzheimer’s Disease Parkinson’s Disease Various Leukemias
Hodgkin’s Lymphoma Non-Hodgkin’s Lymphomas Immune Deficiency Disease
Liver Failure Heart Disease Diabetes
Stroke Multiple Sclerosis Huntington’s DiseaseStroke Multiple Sclerosis Huntington s Disease
Osteoarthritis Rheumatoid Arthritis Coeliac Disease
Crohn’s Disease Lupus Erythematosus Periodontal Disease
Sickle Cell Anaemia Thalassemia Psoriasis
Deafness Blindness Osteoporosis
Spinal Injuries Burns Blackfan Diamond Anaemia
Fanconi Anaemia
Stem Cell CompanyStem Cell Company
• Geron is developing biopharmaceuticals for the treatment of cancer and chronictreatment of cancer and chronic degenerative diseases, including spinal cord injury, heart failure and diabetes.
• GRNCM1—Cardiomyocytes for Heart Disease
• GRNIC1—Islet Clusters for Diabetes
• GRNVAC2—Dendritic CellsGRNVAC2 Dendritic Cells for Cellular Vaccines
Tissue EngineeringTissue Engineering
• Repair/replace damaged tissues– Enhance natural regeneration
Cell SourceEmbryonic stem cells
Adult stem cellsProgenitor cellsProgenitor cells
SignalsGrowth factors
ECMMetalsGrowth factors
DrugsMechanical forces
MetalsCeramics
Synthetic polymersNatural polymers
Rice BioengineeringRice Bioengineering
• Biomaterials and Drug Delivery• Biomedical Imaging and
Diagnostics
• Jennifer West Lab– Tissue Engineered Vascular
Grafts Diagnostics • Cellular and Biomolecular
EngineeringC t ti l d Th ti l
– NO-Releasing Polymers– Mechanisms of Restenosis– Medical Applications of Metal
N h ll• Computational and Theoretical Bioengineering
• Supramolecular Biophysics d Bi i i
Nanoshells
and Bioengineering• Systems and Synthetic
Biology
• AuroLase® Therapy – Uses "optically tunable"
nanoparticles that can convert • Tissue Engineering and
Biomechanicslight into heat to thermally destroy a solid tumor
Other Cell Based TherapeuticsOther Cell Based Therapeutics• Cell therapy describes the process of introducing new
cells into a tissue in order to treat a disease. • There are many other non-stem cell potential forms of
cell therapy– The transplantation of mature functional cells that areThe transplantation of mature, functional cells that are
autologous (from the patient) or allogeneic (from another donor).– The application of modified human cells that are used to produce
a needed substancea needed substance.– The xenotransplantation of non-human cells that are used to
produce a needed substance. The transplantation of transdifferentiated cells derived from the– The transplantation of transdifferentiated cells derived from the patient's own differentiated cells.
Cancer VaccinesCancer Vaccines• Cancer vaccines induce an • PROVENGE is designed to induceCancer vaccines induce an
immune response against cancer cells
• PROVENGE® is the first
PROVENGE is designed to induce an immune response against prostate cancer.
• Has FDA approval for the autologous cellular immunotherapy -- made using cells from a patient's own immune system
treatment of asymptomatic or minimally symptomatic metastatic hormone resistant prostate cancersystem. cancer.
OpexaOpexa TherapeuticsTherapeutics
• Tovaxin, a personalized T-cell vaccine for the treatment of multiple sclerosis (MS) that is specificallytreatment of multiple sclerosis (MS) that is specifically tailored to each patient's disease profile.
• Tovaxin is designed to reduce the number of specific g pcertain autoreactive T-cells known to attack myelin.
N t h lN t h lNanotechnologyNanotechnology
What is Nanotechnology?What is Nanotechnology?
NanotechnologyNanotechnology
• Nanotechnology: the study, manipulation and manufacture of ultra-small structures and machines
d f f l lmade of as few as one molecule• Nanometer = 10-9 meter = one-billionth of a meter
Most “nano-constructs”
Modern Molecular Cell Biology Modern Molecular Cell Biology isis NanobiotechnologyNanobiotechnologyis is NanobiotechnologyNanobiotechnology
“Human health has always been determined on the nanometer l thi i h th t t d ti f th hiscale; this is where the structure and properties of the machines
of life work in every one of the cells in every living thing. The practical impact of nanoscience on human health will be huge.”
--- Richard E. Smalley, 1996 Nobel Laureate
• “The strongest fiber that will ever be made.”• “The size and perfection of DNA.”• “Molecular pincushions”Molecular pincushions
Rice University Rice University –– “Birthplace of “Birthplace of Nanotechnology”Nanotechnology”gygy
• Nobel Laureates – 1996 Prize in Chemistry, “for their discovery of fullerenes” “Many scientists
believe the discovery– Dr. Richard Smalley– Dr. Robert Curl– (With Sir Harold Kroto)
believe the discovery of fullerenes will prove more important than that of the semiconductor, atomic ( )
• Rice– Home to…
C t f N l S i d T h l
fission, or DNA, because it will impact so many fields.” -- S. Ward Casscells, MD
• Center for Nanoscale Science and Technology • Center for Biological and Environmental Nanotechnology
– Small Times ranks Rice• #1 University in US in nanotechnology commercialization• #1 University in US in overall strength of nanotechnology patent
portfolio
Alliance for Alliance for NanoHealthNanoHealthf• Alliance for NanoHealth is comprised
of eight world-renowned universities and institutions within the Texas Medical Center and the GreaterMedical Center and the Greater Houston Region
• The first multi-disciplinary, multi-institutional collaborative researchinstitutional collaborative research endeavor aimed solely at using nanotechnology to bridge the gaps between medicine biology materialsbetween medicine, biology, materials science, computer technology and public policy
• Bridge disciplines to provide newPresident: Mauro Ferrari Ph DBridge disciplines to provide new
clinical approaches to saving lives through better diagnosis, treatment, and prevention
Mauro Ferrari, Ph.D.
p
Brown Foundation Institute of Molecular Brown Foundation Institute of Molecular Medicine for the Prevention of Human Medicine for the Prevention of Human
DiseasesDiseases• Investigate the causes of human diseases at "Our genes and proteins are the
game officials of our lives Theythe cellular and molecular levels, using DNA and protein technologies
• Current Centers:
game officials of our lives. They already know if you have a cancer
in your future.
Or dementia. Or some other devastating disease.
– Cardiovascular Genetic Research – Cell Signaling – Diabetes and Obesity Research
Hans J Müller Eberhard and Irma Gigli Center for
g
We must identify these genes and proteins in our bodies and discover ways in which they might be altered
to prevent those diseases from i i th fi t l– Hans J. Müller-Eberhard and Irma Gigli Center for
Immunology and Autoimmune Diseases– Human Genetics– Molecular Imaging
occurring in the first place . . .
That research is the role of the IMM"
James T. Willerson, M.D.Founder
– Neurodegenerative Diseases – Proteomics and Systems Biology – Stem Cell Research
S t Ll d d B A B t C t f St k
FounderIMM
– Senator Lloyd and B.A. Bentsen Center for Stroke Research
Contrast
“Nanoclinics”“Nanoclinics”
Drug Delivery
Contrast Agent
Indicator
Cancer Cell Death Indicator
Cancer CellCancer Cell Targeting Therapeutic
DNA as StructureDNA as Structure
• March 16, 2006 Nature• New method yields DNA
hnanostructures that are larger and more complex than previously possible
• The method uses a few hundred short DNA strands to 'staple' a very long strand p y ginto two-dimensional structures
• Can adopt any desired• Can adopt any desired shape, like the 'nanoface' on the cover
MicroarraysMicroarrays
• Research tools• Allows analysis of tens
of thousands of samples simultaneouslysimultaneously– DNA microarrays– Protein microarrays
S ll l l– Small-moleculemicroarrays
– Tissue microarrays– Whole-cell microarrays
• These are biosensors
The Genomics HospitalThe Genomics Hospital
• BCM developing the “Baylor Chip” – Tests 141 genes on a
PERSONALIZEDMEDICINE
Tests 141 genes on a miniature chip
– Tests for 161 important diseases
Eventually will carry out• Eventually will carry out 100,000 to 1 million gene tests
• Vision: Test every
2.5 mm
ypatient at the Baylor Clinic– Prevention– Diagnosis
GeneChip® TrueTag ™ 10K Array(400 chips/wafer format)
Diagnosis– Treatment– Follow-up
Gene TherapyGene Therapy
• Gene therapy: a technique for correcting defective genes responsible for disease development
• Researchers use several approaches for correcting faulty genes:– A normal gene may be inserted into a nonspecific location withinA normal gene may be inserted into a nonspecific location within
the genome to replace a nonfunctional gene– An abnormal gene could be swapped for a normal gene
The abnormal gene could be repaired through “selective reverse– The abnormal gene could be repaired through selective reverse mutation,” a process that returns the gene to its normal function
– The regulation (the degree to which a gene is turned on or off) of a particular gene could be altereda particular gene could be altered
• Use “vectors” – carriers allowing a gene to enter a cell
Vector containing intact gene
Vector binds with cell surface Some improvement in clinically relevant outcome• Survival
Vector enters the cell in a vesicle
• Survival• Reduction in pain• Improved immune function• …
Vector is released from vesicle
Cell machinery producesCell machinery producestherapeutic protein
Vector binds to nucleus, depositsDNA payload inside
Cell machinery integrates DNA
Biotech's Bright HopeScientists are newly optimistic that gene therapy willScientists are newly optimistic that gene therapy will help fight the most serious diseases
By Linda Marsa Special to The TimesGene therapy is making a comeback after a
By Linda Marsa, Special to The Times
August 28, 2006
TO the shrill whine of a high-speed drill, neurosurgeon Dr. Paul Larson makes two nickel-sized holes in Shirley Cooper's skull. Guided by a
series of serious setbacks that threatened to permanently derail human tests. In recent years, European scientists have cured more than two dozen patients suffering from three rare, and in some cases lethal, immune disorders.Gene therapy
involves the y p ycomputerized MRI map, he plunges a long, thin needle through one hole and deep into the brain —and empties the syringe.
A very special payload trickles into her brain: genes that, if all goes well, will help her control the
t f h l
Parkinson's destroys cells in the brain that make dopamine, and the loss of this key brain transmitter
Spurred by this success, plus the development of new techniques aimed at making the therapy safer and more effective, more than 300 gene therapy trials, including the one for Parkinson's at UC San Francisco, are underway in the U.S. and
manipulation of DNA to replace or repair genes
movement of her muscles.It is a day in late May and Cooper, 60, an artist who lives near Seattle, has come to the UC San Francisco Medical Center to find some relief from the Parkinson's disease that is stealing her identity. Without medication, she has trouble walking and talking, and can't hold a paint brush. And the drugs
triggers the disease's crippling symptoms: tremors in the arms, legs and face, stiff or frozen limbs, and impaired balance and coordination. In the trial she's involved in — the earliest of clinical tests, designed to assess safety — scientists have engineered a harmless, stripped-down virus to carry a gene that will boost brain dopamine
abroad.
The approaches include what people traditionally think of as gene therapy: inserting functional genes to replace single, faulty ones to treat relatively rare genetic diseases such as muscular dystrophy cystic
“Gene therapy will evolve into a major
“…Gene therapy is making a comeback ... In recent years, European scientists have cured more than two dozen patients suffering from three rare, and in some cases lethal immune disorders ”talking, and can t hold a paint brush. And the drugs
are wearing off — as they eventually do for all Parkinson's patients. After that, she probably will deteriorate rapidly.
The experimental treatment Cooper is undergoing is intended to reverse that process.
carry a gene that will boost brain dopamine through the enzyme it encodes: amino acid decarboxylase, or AADC.
When the virus is injected into her brain, they hope the gene will be incorporated into healthy brain cells and steadily produce the enzyme.
diseases such as muscular dystrophy, cystic fibrosis, sickle cell anemia, beta thalassemia and hemophilia. But, more and more, gene therapy is being studied as a treatment for lethal ills that are not inherited in any clear, simple way — cancer, hepatitis, AIDS, heart disease — and which also plague millions.
therapeutic method”…lethal, immune disorders…”
y p y p g
Gene Therapy of XGene Therapy of X--Linked Linked AdrenoleukodystrophyAdrenoleukodystrophyy p yy p y
• ALD is always fatal if untreated• Results from a deficiency of an
enzyme (“ALD”) which causes y ( )accumulation of very long chain fatty acids in brain, adrenals, and blood
• Causes demyelination, which d iadvances in zones
• The specific gene that is mutated in X-ALD has been identified (ABCD1 gene)gene)
• Combination gene/stem cell therapy genetically corrects the blood stem cells in the patients' own bone marrow
• Partially restores enzyme function, stopped disease progression
Therapeutic NucleotidesTherapeutic Nucleotides
• Nucleotides: Building blocks of DNA, RNA –and related compoundscompounds
• Consist of…– a heterocyclic base,
a sugar and– a sugar, and – one or more phosphate
groups
• We can synthesize these• We can synthesize these and use them as therapies– Oligonucleotides
A ti th• Antisense therapy• siRNA• Micro-RNA (miRNA)
RNAiRNAi, , siRNAssiRNAs
• RNAi = RNA interference• siRNA = synthetic interfering RNASirna Therapeutics
i t th f f t f th ff t t tSirna Therapeutics i t th f f t f th ff t t tSirna Therapeutics i t th f f t f th ff t t t
• siRNAs can be used in mammalian cells for gene silencingiRNA k b il i k
is at the forefront of the effort to create RNAi- based therapies and leverage the vast potential of this technology to ultimately treat patients.
is at the forefront of the effort to create RNAi- based therapies and leverage the vast potential of this technology to ultimately treat patients.
is at the forefront of the effort to create RNAi- based therapies and leverage the vast potential of this technology to ultimately treat patients.
• siRNA works by silencing key sequences on messenger RNA, which turns off specific genes by cleaving to them on the RNA strand
Sirna was acquired by Merck & Co., Inc. in December of 2006 and is the Center of Excellence for
• Nanosized particles are being research for delivery of siRNA-based drugsRNAi t di h d t t d th li i l t ti l f
is the Center of Excellence for RNA technology within Merck Research Laboratories.
• RNAi studies have demonstrated the clinical potential of siRNAs in dental diseases, eye diseases, cancer, metabolic diseases, neurodegenerative disorders, and gother illnesses
miRNAsmiRNAs andand ThioaptamersThioaptamersmiRNAsmiRNAs and and ThioaptamersThioaptamers
• Discovery-stage company focused on micro-RNA-di t d l th i
• Thioaptamers are a class of nucleic acid (DNA or RNA)
tdirected oncology therapies• miRNAs are small, non-coding
RNA molecules
aptamers• These short nucleic acid
molecules bind to a specific t t l l• Misregulation is a frequent
event in development of some genetic diseases
target molecule• Binding is often just as specific
and strong as with an antibody• miRNA therapies re-introduce
a synthetic version of a miRNA that is depleted in the diseased tissue
• But synthesized chemicals can be easier to produce
• Therapeutic, diagnostic, and tissue. research applications
The “Central Dogma”…The “Central Dogma”…
Cell Nucleus
Chromosome
ProteinGraphics courtesy of the National Human Genome Research Institute
Gene (DNA)Gene (mRNA), single strand
EpigeneticsEpigeneticsTh t d f i h it d h i h t ( ) iThe study of inherited changes in phenotype (appearance) or gene expression caused by mechanisms other than changes in the underlying DNA sequence --non-genetic factors cause the organism's genes to behave (or "express themselves") differently.themselves ) differently.
Pharmacogenetics & Pharmacogenetics & ggPharmacogenomicsPharmacogenomics
‘‘OmicsOmics• The genome and genomics; structural and functional genomics• The proteome and proteomics
– Proteome: Constellation of proteins in a biological system (eg, cell,Proteome: Constellation of proteins in a biological system (eg, cell, organism) or sample
– Proteomics: the qualitative and quantitative comparison of a proteome or proteomes under different conditions to further unravel biological processesbiological processes
• What the structure, functions, and interactions of proteins are in living systems
• Including in normal and diseased states, under various physiological conditions and in all stages of developmentconditions, and in all stages of development
• Metabolomics: The global analysis of metabolites• Pharmacogenomics: the application of genomic technologies to new
drug discovery (vs pharmacogenetics: individual differences )drug discovery (vs. pharmacogenetics: individual differences…) • “’Omics” Requires ‘Systems’ Emphasis
– Interactions among elements of complex systems– Requires sophisticated information managementq p g
Personalized MedicinePersonalized Medicine
Personalized Medicine: The effort to match the right drug, with the right patient, at thethe right drug, with the right patient, at the right time…
Interpersonal Variability is the MotiveInterpersonal Variability is the Motive
Goals of Personalized MedicineGoals of Personalized Medicine
Personalized MedicinePersonalized Medicine??WhyWhy
“The right drug for the right patient at the right time”INEFFECTIVE
The right drug for the right patient at the right time
INEFFECTIVE
INEFFECTIVE
INEFFECTIVE
INEFFECTIVE
Imagine the day when you and your doctor sit down to review a copy of your own personal genome. This vital py y p ginformation 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 illness.
-- From the X PRIZE for Genomics Web Site
Personalized Medicine Made Personalized Medicine Made Possible By…Possible By…yy
• Converging technologies– Sequencing the human q g
genome– Increased understanding
the 100,000+ proteins made by the 25,000+ human genes
– Identifying biomarkers for ll diall diseases
– Nanotechnology• Increasing ability to create
new drugs to treat diseases at the molecular/genetic level– “Designer drugs”
The “Cheap” GenomeThe “Cheap” Genome
• It took 2,000 scientists more than 10 years and $2.7 billion to read the first , yhuman genome – total of around 3 billion base pairs
• Five years ago, the same job took one lab 3 weeks and less than $10,000• Today, Complete Genomics is doing it for ~$1,700!• Effort ongoing to allow large-scale inexpensive human genome analysis
(“$1000 Genome”)
The “Cheap” GenomeThe “Cheap” Genome
• Within a few years, a standard aspect of your health care could include the decoding of every aspect of your
i kgenetic make-up• A key facilitator of personalized medicine• Sequence all children• Sequence all children
– Determine genetic predisposition to acquired diseases– 6,000+ genetic diseases, some treatable– Early diagnosis of genetic diseases
• Sequence all adults– Diagnosis of acquired diseases– Diagnosis of acquired diseases– Early cancer detection– Cancer treatment recommendation
Technology Improving SurvivalTechnology Improving Survival
BioinformaticsBioinformatics
• Context: Massive amounts of complex data; accumulating, organizing, and analyzing data is necessary for the information to be usefuluseful
• Bioinformatics: The field of science in which biology, computer science, and information technology merge into a single discipline
• There are three important sub disciplines within bioinformatics:• There are three important sub-disciplines within bioinformatics: – the development of new algorithms and statistics with which to assess
relationships among members of large data sets; – the analysis and interpretation of various types of data including– the analysis and interpretation of various types of data including
nucleotide and amino acid sequences, protein domains, and protein structures; and
– the development and implementation of tools that enable efficient p paccess and management of different types of information.
Bioinformatics (cont)Bioinformatics (cont)• Makes it possible to…
– Compare genomic sequences of various organisms
– Identify novel genes and suggest functions
– Expedite the identification of genes
– Determine genetic variation in the general populationGenerate 3 D structures of– Generate 3-D structures of gene products
– Analyze changes under normal or disease statesnormal or disease states
Computational Modeling and Computational Modeling and Rational Drug DesignRational Drug Design In silicog gg g
Protein EngineeringProtein Engineering
• Rational design and modification of proteins– Reliance on computational biology and molecular biologyp gy gy– Drug development– Food processing
Industrial manufacturing– Industrial manufacturing
Life Science TechnologyLife Science Technology Commercialization
Some Key PointsSome Key Points
• Most new technologies arise in academic institutions• Majority of early, discovery funding comes from NIH and
other federal agencies– NIH grants more than $31.2 billion annually
• Institutions may obtain patents on inventions and• Institutions may obtain patents on inventions, and license them to companies “technology transfer”
• The real expense of product development and commercialization is paid by companies and their investors
New Drug Development Times & Costs
New Drug DevelopmentNew Drug Development2 4 6 8 10 12 14 160
Development Year
DISCOVERY
PRECLINICAL TESTING
PHASE 1 20-30 Healthy Volunteers
PHASE 2 100-500 Patient Volunteers
PHASE 3 500-10,000 Patient Volunteers
FDA REVIEW &
APPROVAL
PHASE 4
Clinical Development and Approval TimesClinical Development and Approval Times
97.7 (8.1 yrs)
90.3 (7.5 yrs)
Source: DiMasi and Grabowski, Managerial and Dec Econ 2007, in press
Months
Clinical and Approval Times Vary Across Clinical and Approval Times Vary Across Therapeutic ClassesTherapeutic Classespp
12.1
8.5
9.8
7.6
7.5
6.9
8.0
6.3
For years 2002-04Source: Tufts CSDD, 2006Source: Tufts CSDD, 2006
Selected ProductSelected Product--Development ActivitiesDevelopment ActivitiesPRECLINICAL CLINICAL• Pharmacology
– In vitro profiling– In vivo animal models– Safety pharmacology
C bi ti Ph l /T i l
• Protocol design and development• Clinical trial management
– Site & Investigators– Trial monitoring
PRECLINICAL CLINICAL
– Combination Pharmacology/Toxicology Studies
• PK/ADME– In vitro metabolism– In vivo pharmacokinetics
Ti di t ib ti / b l
– Budget & timeline tracking– Regulatory compliance oversight
• Adverse event reporting & pharmacovigilanceCli i l d t t– Tissue distribution/mass balance
• Toxicology– In vitro screening– General Toxicology– Genetic Toxicology
• Clinical data management• Biostatistics• Medical Writing
REGULATORY– Reproductive Toxicology
CHEMISTRY, MANUFACTURING & CONTROLS• Formulation development
REGULATORY • Regulatory strategy development• IND Submission and Amendments• Milestone and ad hoc meetings; other
i tiFormulation development• Process development• GMP manufacturing• Analytical methods development• Product stability
communications• Compliance• NDA preparation and submission• Advisory Committee preparation
• Product stability
Phase I GoalsPhase I Goals
• Establish Time course of Drug levels in blood (PK), Tolerability and Safety in Healthy Volunteers
• Gather evidence that the drug interacts with its molecular target• Gather evidence that the drug interacts with its molecular target (Proof of Target)– Example: Dosing of statin blocks the enzymatic production of circulating
mevalonate (cholesterol precursor) by HMG CoA Reductasemevalonate (cholesterol precursor) by HMG CoA Reductase• Validate methods that might be used to prove pharmacology in Ph II
(surrogate biomarkers of pharmacology and efficacy)• Explore potential issues affecting use in broader populations• Explore potential issues affecting use in broader populations
– Examples: Potential for interactions with other drugs, food effects
Phase II GoalsPhase II Goals
• Gather evidence that the drug has the intended pharmacology (Proof of Pharmacology)
Example: Dosing of statin drug in lowers LDL C in patients with high– Example: Dosing of statin drug in lowers LDL-C in patients with high cholesterol
– Note: Most sponsors are now seeking to establish some aspects of Proof-of-Pharmacology in P1gy
• Explore the pharmacology and safety of the drug in patient populations with different characteristics– Example: Study statins in patients with high cholesterol with and p y p g
without previous history of heart disease• Gather more evidence regarding safety• Establish the dose(s) and patients to be used in large P3 pivotalEstablish the dose(s) and patients to be used in large P3 pivotal
studies
Phase III GoalsPhase III Goals
• Establish the safety and efficacy in populations reflecting the population to be treated
Often requires outcome data (eg morbidity and mortality)– Often requires outcome data (eg, morbidity and mortality)– High cost and time consuming (complex)– Develop more complete picture of risk and benefits
Overall cost of drug developmentOverall cost of drug development
• “On average, it takes $1.2 billion to develop a single new drug…”
• $802 MM also often citeda
•These numbers are “capitalized”; include the cost of failures
•Total out-of-pocket costs for an individual drug…
• $198 million for preclinical period• $361 million for clinical period
• These are best thought of as “big pharma” numbersa DiMasi et al., J Health Economics 2003;22(2):151-185)
The Cost of Drug Development The Cost of Drug Development Continues to IncreaseContinues to Increase
Estimate of Average Capitalized Development Cost per NCE 1976–2001
lions
)lio
ns)
Development Cost per NCE, 1976–2001
$700$700
$900$900
$800$800$802$802
Dol
lars
(Mill
Dol
lars
(Mill
$400$400
$500$500
$600$600
$359$359
$500$500
Nom
inal
N
omin
al
$54$54
$200$200
$300$300
$100$100$125$125
$231$231
Sources: R. Hansen, Ph.D., University of Rochester; S.N. Wiggins, Ph.D., Texas A&M University; J.A. DiMasi, Tufts Center for the Study of Drug Development (2002); Office of Technology Assessment (1993)
$0$019761976 19861986 19871987 19901990 19971997 20012001
PrePre--Approval OutApproval Out--ofof--Pocket Costs per Approved Pocket Costs per Approved New Biopharmaceutical*New Biopharmaceutical*pp
** All R&D costs (basic research and preclinical development) prior to initiation of clinical testing
* Based on a 30.2% clinical approval success rate
Source: DiMasi and Grabowski Managerial and Dec Econ 2007 in pressSource: DiMasi and Grabowski, Managerial and Dec Econ 2007, in press
Annual Growth Rates for OutAnnual Growth Rates for Out--ofof--Pocket R&D Pocket R&D CostsCosts
Source: DiMasi et al., J Health Economics 2003;22(2):151-185
Clinical Development is ExpensiveClinical Development is ExpensiveMean Number of Subjects in NDAs for NMEsa
• Cost drivers– Total enrollment increasing
Mean Number of Subjects in NDAs for NMEs
g– Costs per patient:
• Oncology: $35K• Pain/Inflammation: $15KPain/Inflammation: $15K
– Costs per investigator– Infrastructure costs
Complexity of protocols is Clinical Study “Complexity Index”b
– Complexity of protocols is increasing
– Competition for patients is greatgreat
a Sources: Boston Consulting Group, 1993; Peck, Food and Drug Law J, 1997; PAREXEL, 2002b Source: DataEdge 2002Source: DataEdge, 2002
Drug Development is RiskyDrug Development is Risky
Market Launch FDA Review
Post-Marketing Surveillance115
Phase III Clinical Trials Pivotal Efficacy & Safety
Phase II Clinical Trials POC, Dose Response
2
2 - 510
Preclinical DMPK, Safety
Phase I Clinical Trials Safety/Tolerance PK5 – 10
10 20Preclinical Testing
Basic R h
Screening S h i
DMPK, Safety Chemistry10 - 20
3 000 – 10 000
5
Research Synthesis3,000 10,000
Number of CompoundsSource: PhRMA analysis of Tufts CSDD database
0
Yearsy
Why Do Drugs Fail?Why Do Drugs Fail?
BioCentury, April 12, 2010, PAGE A8 OF 19, “gRED: Small company sensibilities”, by Susan Schaeffer.
New Drug Approvals Are Not Keeping New Drug Approvals Are Not Keeping Pace with Rising R&D SpendingPace with Rising R&D Spendingg p gg p g
R&D Expenditures
New Drug Approvals
R&D expenditures are adjusted for inflationSource: Tufts CSDD Approved NCE Database, PhRMA, 2005
R&D Costs R&D Costs ---- SummarySummary
• R&D costs have grown substantially, even in inflation-adjusted terms
• The growth rate for discovery and preclinical development costs has decreased substantially
• Conversely clinical costs have grown at a much more• Conversely, clinical costs have grown at a much more rapid rate
• New discovery and development technologies (e.g., y g ( ggenomics) may hold the promise of lower costs in the long-run, but likley represent higher costs in the short-runrun
Th k !!Thank you!!
Jason E. Moore, M.S., M.B.A.Jason E. Moore, M.S., M.B.A., ,, ,[email protected]