Harnessing Genomics for Global Health: Evolving Infectious ......Sep 16, 2015  · Malaria Eradication: An Audacious Goal “Any goal short of eradicating malaria is accepting malaria;

Harnessing Genomics for Global Health: Evolving Infectious Diseases

The Science of Malaria Eradication

Red Queen Dynamics: The evolutionary Arms race

“Well, in your country," said Alice panting a little, "you'd generally get to somewhere else - if you ran very fast for a long time, as we have been doing."

"A slow sort of country!" said the Red Queen. " Now, here, you see, it takes all the running you can do, to keep in the same place. If you want to get somewhere else, you must run at least twice as fast as that!"

Lewis Carroll, Through the Looking Glass

Howard Markel and Stephen Doyle, New York Times (Op-Ed, April 30, 2003)

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Differential Diagnosis for Febrile Illness

Acute arthritis Persistent arthralgia

Pulmonary symptoms* Gastroenteritis‡

Polyuria, dysuria, sepsis** Cyclic fever†

Conjunctival/mucosal rash Jaundice◊

Purpura**

[Ab. Pain/Diarrhea] Headache Arthralgia Myalgia

Rash Fever

Hemorrhagic fever

Encephalitis

Dengue Chikungunya

Other pathogens Influenza*, measles*, Rubella*, EBV, Meningeococcal infection**, rotavirus‡, cholera, malaria†, leptospirosis◊, RFV, disseminated Gonococceal disease**, typhus.

Phenotype

Genome Scans

Loci Selection

GWAS

Assay Development

Application

Sample Collection

Sequence Validation

Genotyping

Pipeline—From Samples to Application

Malaria Eradication: An Audacious Goal

“Any goal short of eradicating malaria is accepting malaria; it’s making peace with malaria; it’s rich countries saying: ‘We don’t need to eradicate malaria around the world as long as we’ve eliminated malaria in our own countries. That's just unacceptable.” • Melinda Gates, 2007 • February 6, 2013_v7 © 2012 Bill & Melinda Gates Foundation | 4

Move to rapidly scale up diagnostics and sequencing

Equipment and Supplies Infrastructure Training

The impact of genomic surveillance

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Challenge in 2003 • Drugs for neglected diseases

• Old – discovered in the first half of 20th century • Limited therapeutic window • Unknown mechanism

• Missed the revolution in drug discovery • Science discovery and drug discovery uncoupled • Technology lagged • Fragmented efforts

DNA: the genetic

material 1944

DNA structure

1953 Genetic code 1966

Recombinant DNA 1972

DNA sequencing

1977

Genbank established

1982 PCR 1985

Human Genome Project 1990

Atavoquone 1951

Suramin 1921

Melarsapol 1949

Leap-frogging into 21st Century

• Genomic revolution • Genetic engineering of parasites • Whole genome sequencing

• New Chemical Entities identified • Success in developing assays • Success in High Throughput Screening (HTS) • Exploration of “chemical space”

• Combining genomics and chemistry • New target identification • RNAi identification of essential pathways

• Concerted scientific effort on problem of drug and vaccine discovery

DNA: the genetic

material 1944

DNA structure

1953 Genetic code 1966

Recombinant DNA 1972

DNA sequencing

1977

Genbank established

1982 PCR 1985

Human Genome Project 1990

Atavoquone 1951

Suramin 1921

Melarsapol 1949

HTS 1999

RNAi 2000

Genetically engineered

parasites 1990s

First genome 2002

Education and Leadership Training

Education and Leadership Training

• Study diseases in natural setting led by endemic scientists • Training and mutual learning with new goals • Technology is creating the opportunity for innovation

Defeating Malaria: From the Genes to the Globe

Stamp Out Malaria!

MANAGING A RESEARCH LABORATORY

Who and What constitutes a laboratory

Personnel

Equipment

Reagents

Infrastructure

Personnel

Laboratory Office

Designs and executes research

projects

Training required to comply with regulations

Provides administrative

support

Aware of regulation, maintains records

Equipment

Ordering/ Inventory

SOP

Training

Maintenance/ Disposal

Reagents..

Ordering/ Inventory

SOPS (CHP, EP)

Storage/disposal

Infrastructure

Basic (Air, Heat, Water)

Specialized (Vivarium, BSL2, BSL3, Insectary)

The Regulatory Landscape

Internal checks External checks

COMS

IACUC

IRB

EHS

RMAS

NIH

CDC

State/City

Accreditation bodies

AAALAC

USDA

Resources

ORARC

EHS

Operations

NIH OBA

AALAS

Guidance document

CDC, USDA

Internal External

Leadership Roles Responsibility

Expectations

Response Hierarchy

Principal Investigator

Laboratory Manager

Investigator/Buddy

Facility personnel Security Occupational Health EHS

PI Operation Director

Dean

Agents.. Plasmodium species::Malaria

HIV::AIDS

Mycobacterium species::Tuberculosis

Trypanosoma species:: Chagas Disease

Neisseria species:: Gonorrhea

Streptococcus species:: Pneumonia

Gut Bacteria:: IBD, Cancer

Vector Biology:: Mosquitoes

Laboratories…

BL3

BL2

BL1

Containment

PPE

Practice

The Risk Pyramid

ABL2 ACL2

ABL3