THE MICROBIOME, GENETICS, BIG DATA AND HEALTH CARE

Nigel Ten Fleming, PhDCEO of ADVENTURA CAPITAL SL

SMASHTECH MOBILE WORLD SEMINAR, OCT 9 2014

Nigel Ten Fleming PhDNIGEL@ADVenturaCapital.com

(34) 696 34 27 84

F: mobile world talk Oct 9 2014 TTT 1

Relevant Personal Biography

• Biochemist, on board of pharma companies

• Founder and Chairman of Athena Diagnostics

• First neurogenetic reference laboratory in the US

• Developed algorithms for disease diagnosis and management, by consensus with neurology KOLs

• Algorithms used by medical students for exams

• Apps would have been more useful for applying new knowledge to clinical practice

• Sold for $740 million in 2011

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ADVentura Capital

• 2013: Co-founded ADVentura with group of international serial entrepreneurs, Chairman Oliver Rothschild

• Monthly BIOBASH events

• 2013: Closed a $6.3 M LOI for an initiative

• 2014: Closed a $20 M VC investment for preclinical therapeutic

• 2014: Closing an $11.5 M VC investment for preclinical therapeutic

• 2015: to raise own fund

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Exciting Healthcare Revolution

• A healthcare revolution is emerging, driven by very powerful forces colliding

• Radically new diagnostics and therapeutics will rule medicine within a decade

• The effects on patient care will be dramatic

• The new knowledge is very complex

• Healthcare workers need tools to apply this new knowledge

• Provides a significant business opportunity

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Enormous Data sets

• Giant data sets overwhelm healthcare providers

• Data expanding rapidly every year

• Needs Big Data algorithm analytics combined with intuitive Apps

• This is a data handling problem not a scientific problem

• Genetic and microbiological KOLs will form consensus data

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Enormous Data Sets

HUMAN GENOME PROJECT

25,000 genes24 chromosomes

39 million variations

5,300 diseases with known molecular basis3,273 genes with phenotype causing mutation

8,450 updates in 2011613 new additions 2011

OMIM: http://www.ncbi.nlm.nih.gov/omim

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Enormous Data Sets

HUMAN MICROBIOME PROJECT

100 trillion microorganisms live in human body

500-1000 species40-50 families

Complex ecosystem

250 infectious diseases

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Mobile Medical Technology Game Changer

• Technology is changing at an exponential rate (Ray Kurtweil Google)

• Many believe we are heading towards a new stage of human evolution, that humans control

• We already Cyborgs with implants and enhanced facilities (pumps, eyes, ears, prostheses, exocortex)

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We are Already Cyborgs

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Exponential Rate of Technology Change

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Mobile Tech Meets Biology

• Mobile medical technology is colliding with medical biology

• Electronics + genetics + microbiome = New Medicine

• Frontiers between different disciplines are ripe for hugely disruptive innovations

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A Prediction

In five years, our Smart Phones will all carry:

•Our personal DNA sequence: all of our genetic information

•Our personal Microbiome: all of our body’s microbes

•Our Medical Records

•Real time biometric monitoring

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The Human Genome Project

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Healthcare worker

The Human Genome Project

• 2000: A major disruptive event: medicine will never be the same again

• World’s largest international biological project

• Sequenced human DNA and mapped all human genes

• Mapped 20,500 genes key for health and disease

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The Human Genome Project

• Spawned new genetics industry

• US government invested $5.4BN

• Current Value $1 trillion

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The 1,000 Genome Project

• 2014 Consortium developing baselines for normal human genetic variation:

• 39 million single nucleotide polymorphisms• 1.4 million short insertions and deletions• 14,000 large deletions• new variants being found daily

• Need to consider geographic and ancestral genetic background

• Which variant is a health risks versus being harmless

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DNA Sequencing is Super-Fast

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DNA Sequencing is Super-Cheap

DNA Sequencing costs dropping rapidly:

•$3 BN 13 years (2000)

•$1,000 24 hours (2014)

•$100 <24 hours (~2015)

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What Does your DNA Sequence Look Like?

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Genes, Genes, & More Genes

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The Knowledge Gap

Medical students generally have little genetic training

In 2007, 112 US and Canadian medicals schools were assessed for genetic education:

• Only 50% had a stand-alone genetics course

• 80% have under 40 contact hours in genetics

• Most did not teach how to apply genetic information clinically

Acad Med 2007; 82:441-445

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The Knowledge Gap

In 2014, study of 137 Cleveland Clinic physicians found:

• 84% thought genetics is changing clinical practice

• 97% thought better understanding of genetics benefits patients

• Only 39% felt informed about genetic tests

• But, 36% felt that they could answer patients’ questions

doi:10.1097/GIM.0b013e318228821f

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Genetic Information Needs Tools

• DNA Sequence data reveals disease genes

• Alterations to those genes indicates disease susceptibility and needs medical evaluation

• Genetic information is complex

• Vast amount of data correlation is needed

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Genetic Information Needs Tools

For patients and clinicians, genetic data must be translated into personalized:

• Risk profile

• Algorithm for lifestyle changes

• Treatment options

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Genetic Disease Example

Duchenne Muscular Dystrophy (DMD)

•Athena Diagnostics first to offer DMD testing

•Fatal, debilitating neuromuscular disease

•Mutation at Xp21 caused DMD

•Genetic testing confirms clinical diagnosis

•No cure today, but highly sought after for clinical care

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Disease Example

Duchenne Muscular Dystrophy

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Disease Algorithms Simplify Decisions

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The Epigenome: More Complexity

• Epigenetics is a new branch of the Human Genome Project

• The Epigenome refers to chemical modifications of DNA and histones due to environmental, stress, lifestyle factors that turn on and off genes

• Human Epigenome Pilot Project underway to understand it further

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The Epigenome Alters Genes

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DNA + Epigenome Project

• In time, epigenomic and DNA sequences will be considered together

• Great for more sophisticated diagnosis and treatment

• Much more complex for health professionals

• Opportunity for Big Data Analytics

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The Human Microbiome Project

The microbiome is the community of bacteria, fungi, algae that live in the human body

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The Microbiome Project

• Scientific landmark 2007-2014

• In 2014, first dataset of microbes inhabiting the nasal passages, oral cavity, skin gastrointestinal tract, and urogenital tract

• Scientists shocked by diversity and numbers of microbes living in the human body

• Radical paradigm shift:

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What is a Microbiome?

• Bacteria are the most populous creatures on our planet

• 500-1000 species in 40-50 families of ancient microbes

• Most cannot be cultured so only known by nucleic acid fingerprint

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What is a Microbiome?

• Microbiome weighs 200 – 1,400 grams

• Bacteria outnumber human cells in body 10:1 (100 trillion bacterial cells)

• Bacterial genes outnumber human genes in body 320:1 (8,000,000 vs 25,000)

• Complex ecological balance of players

• When balance upset, disease pathogens enter

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How Does the Microbiome Get There?

• Starts with vaginal culture when baby born • Reinforced by bacteria in mother’s milk

• Built up by exposure to mother’s microbiome on skin and body

• Continually interfaces with the environment

• Microbiomes are highly individual and cultural

• Affected by diet, stress, toxins and antibiotics

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Changing Gut Microbiome in Newborn

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Different Microbiome Composition

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What Does the Microbiome Do?

• Considered new human organs• The second brain• Produces 80% of serotonin for human brain• The second immune system (75%) • Produces vitamins for the host • Protects against allergies• Ferments unused foods• Regulates the development of the gut• Produces hormones to store host’s fat• Provides a second genome

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The Microbiome Protects Against Disease

When ecological balance upset, pathogens enter causing:

• Diabetes• Rheumatoid arthritis• Allergies• Muscular Dystrophy• Multiple sclerosis• Fibromyalgia• Certain cancers• Obesity• Irritable bowel syndrome (IBS)• Depression• Anxiety• Autism• Dental diseases• (etc)

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Medical Paradigm Shift

---------------------------------------------------------------------------------------------

ChlorineIn water

PenicillinSmall molecule

drugs

Monoclonaldrugs

Stem celldrugs

MicrobialDrugs

Salkvaccine

1910 1940 1950 1960 1986 2010 2014

War on pathogens Working with nature

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Medical Paradigm Shift

• Since Pasteur, we have been at war with microbes, considering them the enemy, and adopting a scorched earth policy

• Antibiotics and chlorine have had unintended negative consequences

• We now know that most bacteria are good, and we depend on them for health

• LIVE DRUGS: Probiotics and microbial drugs

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Moving on from Antibiotics

• When Alexander Fleming discovered antibiotics, the pharmaceutical industry took off

• Antibiotics, chlorine and pesticides decimate the natural human microbiome, disrupting the ecological balance, and allowing pathogens to dominate

• Single molecules are doomed to fail against an evolving target

• The antibiotic pipeline is dry

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Overuse of Antibiotics

• Antibiotic Superbugs are emerging due to over-use

• Antibiotic resistance is a global crisis

• We over-use antibiotics in meat production (as a fattener) and in human health.

• US infants before two years of age have had two doses of antibiotics & all US cesarian sections use antibiotics

• Antibiotics in infancy and C-Sections lead to later health problems

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Rise of Bacteriophages

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What Are Phages?

• Phages are very specific viral parasites of bacteria

• Phages never infect human cells

• Phages are ubiquitous, in everything we touch and eat

• Unlike static antibiotic molecules that bacteria learn to avoid, phages co-evolve with bacterial hosts

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Rise of Phages

• Phages were abandoned by pharma when single molecule antibiotics were discovered

• Russia was denied access to antibiotics and continued with phage therapy, now the world leader

• France, Russia, Poland have 75 years of safe effective experience with phage therapy for numerous diseases

• Phage therapy for infectious bacterial diseases is being re-examined as an alternative to antibiotics

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Rise of Phage Drugs

• Phages widely marketed in Russia in pharmacies and on line by Microgen Pharma

• 1970-90’s: FDA trials for Downs Syndrome, HIV and other immunodeficiencies

• 2008: Phase I US phage trials for human leg ulcer therapy proved safe, using cocktail of 8 phages

• Phages are approved by FDA for food microbe decontamination and for parasite crop control

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Microbial Medicines

• Microbes + Genetics = NEW MEDICINE

• Probiotics shown effective for numerous conditions (dental, irritable bowel, liver disease, cholesterol, etc)

• Clearer understanding of microbiome in health and disease has opened new perspectives

• All of genetics and all of the microbiome is specific for the individual

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Fecal Biotherapy

“It’s like the beginning of the space program.”

(Dr. Orenstein, Mayo Clinic)

•Fecal microbota transplantation (FMT) is a microbiome innoculation from a healthy person to an unhealthy person

•Useful for Clostridium difficile infections (over 100,000 deaths/yr) and an epidemic in seniors

•Promoted as first-line therapy, effective in days, with 90-100% success rate in antibiotic resistant cases

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Fecal Biotherapy

• Fecal biotherapy is in its infancy, and is expected to expand quickly

• Fecal biotherapy is ideally paired with diagnostics to monitor the changed gut microbiome

• Currently used for colitis, constipation, irritable bowel syndrome and some neurological diseases

• Obesity, diabetes, Parkinson’s disease, and rheumatoid arthritis are now under investigation

• Concentrated bacterial pills are being developed

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Confluence of Big Events

Failure of antibiotics

The microbiome

Genome analysisPersonalized, predictive

medicine

Stem cells

Monoclonal antibodies

Phage therapy

Fecal microbiota transplants

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The Personalized Healthcare Revolution

• PM is gaining traction in traditional settings, especially in customized cancer therapies matching the genetics of the tumour

• All microbiome, probiotic, fecal transplant, and phage related treatments demand customization to the patient’s specific condition and genetic or microbial ecosystem

• This involves complex data analysis and diagnostics

• There is a need for sophisticated tools

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The Emergence of Patient Empowerment

• PM is patient-centric not provider-centric

• The patient becomes more engaged in the therapeutic process as medical information is democratized through apps and web resources

• Patients are more comfortable using web-based Apps and algorithms for diagnostics and treatment options

• Doc-in-a-Box options are emerging

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Implications of the Personalized Healthcare

• PM is predictive not reactive: massive change to healthcare system

• PM must crunch a lot of data to derive meaningful personal medical solutions

• Unless efficient tools are developed which are cost-saving, they will not be implemented

• The delivery format must be very clear and simple and easy to use for healthcare workers and patients alike

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The Need for Big Data Analytics

• Successful healthcare technology solves important real world problems and saves money

• Complexity of human genetics and the human microbiome presents significant opportunities for Big Data analytics and Smart Apps

• Healthcare workers and patients alike urgently need assistance with applying New Medicine

• Scientific knowledge is not required due to reliance on expert consensus algorithms

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Summary

• Disruptive innovation in healthcare by using microorganisms and genetics

• Enormous amounts of data need coordinating and mapping

• The rate of innovation is outpacing clinical use

• Healthcare workers and patients are overwhelmed

• Sophisticated but user-friendly tools that save the healthcare system money and provide better patient outcomes will be big winners

THANK YOU56