Precision Medicine, Custom Cures

Panel Composition and Context

• Margaret Anderson (Executive Director, Faster Cures/Milken Institute) introduced the panel, emphasizing the accelerating public interest in precision medicine despite a gap between scientific promise and clinical deployment.
• Francis Collins (former NIH Director) was present as a guest, underscoring the transition from the Human Genome Project to active clinical application.
• Panelists:
  • Mike Polini: President/CEO, Foundation Medicine (focus on cancer genomics and business models).
  • Jim Greenwood: President/CEO, Biotechnology Industry Organization (BIO); former U.S. Congressman (12 years).
  • George Church: Genetics Professor, Harvard Medical School (lead researcher on the Personal Genome Project).
  • Retta Berry: Patient advocate and mother of twins with undiagnosed neurologic disorders.
  • Dr. Chris Austin: Director, National Center for Advancing Translational Sciences (NCATS).

Scientific Fundamentals and Definitions

• Sequencing Spectrum:
  • Whole Genome Sequencing (WGS): Maps all 3 billion base pairs; historically used for inherited germline disorders (e.g., blood-based testing).
  • Whole Exome Sequencing: Focuses only on coding regions of the genome.
  • Targeted Sequencing: Analyzes specific subsets of genes (e.g., 10–500 genes) relevant to a specific condition, often used in cancer.
• Germline vs. Somatic:
  • Germline: Inherited DNA present at birth (blood-based); used to predict predisposition to metabolic or inborn diseases.
  • Somatic: Mutations acquired over time (e.g., cancer); not present at birth and differ from cell to cell.
• Gene Therapy Advances:
  • Sangamo and others are testing gene therapies for HIV in Phase II clinical trials, marking a shift from environment/surgery changes to direct genetic modification.
  • George Church notes that changing genetics is now possible via precise editing, potentially curing conditions previously deemed fatal.

Patient Narrative: The Berry Family Case Study

• Initial Struggle: Twins Noah and Alexis were misdiagnosed with cerebral palsy after years of invasive testing (MRIs, spinal taps) with no answers; Alexis lost mobility and required feeding tubes by age 5.5.
• Breakthrough: Retta Berry self-researched, identifying a medication (Levodopa/Parkinson's drug) that improved Alexis's condition; later, the family engaged in whole genome sequencing at Baylor College of Medicine/Life Technologies in 2010.
• Outcome: Sequencing revealed low dopamine and serotonin levels, providing a definitive genetic diagnosis.
• Current Status: Both children now run track and function normally on targeted therapy; the family transitioned from "diagnostic odyssey" to effective treatment.
• Key Takeaway: A definitive diagnosis enabled treatment, though the family spent 5+ years and significant financial resources to reach it.

Systemic Challenges and Gaps

• The "Phenotype" Deficit: Chris Austin notes that while sequencing (genotype) is efficient, the medical system struggles with phenotype correlation (linking genetic mutations to clinical symptoms).
• Treatment Gap: Of ~7,000 rare genetic diseases, ~6,500 have no available treatment even when the diagnosis is known.
• Discovery Lag: Since 1990, the molecular basis of ~4,500 diseases has been identified, yet therapeutics often lag decades behind (e.g., Sickle Cell disease discovered in 1949; no targeted drug exists).
• Data Silos: Privacy concerns and lack of infrastructure have historically prevented the sharing of genotype, environmental, and trait data necessary for robust research.

Business Models and Industry Trends

• Companion Diagnostics: The FDA now requires paired diagnostic tests (e.g., Herceptin for HER2+ breast cancer; targeted lung cancer drugs for ALK or KRAS mutations) to ensure drugs are given only to genetically appropriate patients.
• Cost and Efficiency:
  • Traditional sequential testing can cost $5,000–$10,000+ per patient, wasting limited biopsy tissue.
  • Foundation Medicine utilizes comprehensive genomic profiling to analyze the "floodlight" of molecular drivers rather than "laser beam" single tests.
• Market Growth: Foundation Medicine reports >1,000 oncologists ordering tests globally; Mike Polini predicts a shift from death sentences to chronic disease management for many cancers.
• Repurposing Strategy: ~2,500 FDA-approved drugs exist that can be repurposed for rare diseases, bypassing the 10–15 year, billion-dollar drug development cycle.

Participatory Medicine and Data Sharing

• Personal Genome Project: George Church advocates for a global, open dataset sharing genomes, environments, and traits.
• Volunteer Uptake: In the Million Veterans Project, 96% of volunteers chose to receive their personal genomic results.
• Patient Advocacy: Retta Berry argues privacy concerns are secondary to the urgency of finding cures; she prioritized open data to save lives over insurance discrimination fears.
• Legislation: The Genetic Information Non-Discrimination Act (GINA) prohibits health insurance and employment discrimination based on genetic data; California recently expanded protections to housing and public accommodation.

Reimbursement and Economic Barriers

• Payer Hesitancy: While payers (CMS, private insurers) acknowledge the inevitability of genomic testing, they struggle with short-term budgeting (10-year cycles) vs. long-term health savings.
• Structural Misalignment: Private insurers may avoid investing in preventative genomic care for older patients who may switch insurers or enter Medicare, where the long-term savings accrue.
• Proposed Solution: Need for "participatory reimbursement" models where patients have "skin in the game" (e.g., HSAs) and healthcare systems are redesigned to reward long-term wellness over fee-for-service volume.

Future Outlook and Recommendations

• Gene Therapy Revolution: George Church predicts a paradigm shift from small-molecule drugs to gene therapy (precise insertion/deletion) and microbial therapies, potentially reducing costs similar to the 1 million-fold drop in sequencing costs.
• Regulatory Hurdles: Current FDA processes treat every unique genetic mutation (e.g., in Duchenne Muscular Dystrophy) as a distinct "new drug," creating bottlenecks for personalized oligo-therapies.
• Clinical Trajectory: Mike Polini highlights a successful timeline: A gene fusion was discovered 14 months ago, leading to a clinical trial where 100% (3/3) of the first non-small cell lung cancer patients responded to an existing drug.
• Call to Action:
  • Chris Austin: Diagnostics are the "kickoff" but the "playbook" to move from diagnosis to treatment is missing; requires "creative destruction" in the healthcare system.
  • Retta Berry: Patients must become advocates, demand sequencing for undiagnosed conditions, and accept that personalized medicine is a necessity, not a luxury.
  • Jim Greenwood: Society must prepare for "participatory medicine" where individuals manage their own health data and expenditures.