Robert Green, M.D., M.P.H., facilitated by Ronnie S. Stangler, M.D., addressed exciting new findings in genomics which are revolutionizing medical care across multiple disciplines, preventing illness and extending healthy lifespan at Aspen Brain Institute’s Expert Series 2.0.

SESSION SUMMARY

• Robert Green, M.D., M.P.H. is Professor of Medicine, Harvard Medical School, Department of Genetics and Director of The Genomes2People Research Program.

• The Genomes2People Research Program conducts implementation science in genomics: medical (impact upon individuals and public health), behavioral (impact on physicians’ and patients’ emotional well-being and behavior); and economic (financial impact on the healthcare system).

• Brain Health can be better understood through the lens of genomics (i.e. how all of our genes interact with one another). All illnesses have a genetic component.

• Genomics 101:
  DNA can be thought of as a long string of chemicals, abbreviated as letters (A, G, C, T), which read like a code. 99% plus of that code is the same in all humans. Variants are usually harmless, although sometimes provide us information about disease risk.

• Genotyping vs Sequencing:
  Genotyping, the process of determining genetic differences between individuals by using a predetermined, fixed set of chosen markers on particular genes, costs $50-$100 (e.g. direct-to-consumer products like 23andMe). Sequencing is the process of determining the full nucleotide order of DNA and whole genome sequencing refers to the process of examining the DNA of the entire genome (i.e. all of an individual’s genes). Whole genome sequencing costs c. $500-$15,000. Interpretation is not automatic and requires great expertise and real time individual input.

• Clinical Uses of Genetic Testing Since Next Generation Sequencing:
  Molecular diagnosis of rare conditions, preconception screening, presymptomatic testing for known genetic conditions, pharmacogenomics, prenatal screening and targeted therapies for cancer treatment.

• Genomics-Based Healthcare:
  In 2001, Francis Collins predicted that “comprehensive, genomics-based health care will become the norm, with individualized preventive medicine and early detection of illnesses by molecular surveillance”. Why has this vision not yet been realized?

• Four Categories of Preventive Genomic Information and Percent of Supposed “Healthy” Population Affected:

  • monogenic mutation carrier (recessive) - 91%
  • atypical response to medication - 80%
  • monogenic mutation carrier (dominant) - 15%
  • elevated polygenic risk - 50%

• Direct-to-Consumer (DTC) testing DTC and the Evolution of Preventive Genomics:
  DTC has encouraged democratization and demystification of genetics; disintermediation; it has also conflated laboratories with care providers; expanded physician authorization loopholes. Given its limited offerings + exaggerated marketing = distortion of genetic utility.

• Arguments for Population Screening of Healthy Persons:
  Diagnosis of unsuspected genetic disease; risk stratification for surveillance and protection; knowledge and personal utility.

• Arguments Against Population Screening of Healthy Persons:
  Rare conditions with low probability could identify/label at-risk individuals who never manifest the condition; unproven value (clinical utility and cost-effectiveness); inadequate expertise in the medical workforce).

• Preventive Genomics for COVID and Beyond:
  While COVID is on all of our minds right now, it must be understood within the context of other major killers which are ”slow pandemics” (e.g. major causes of mortality such as cardiovascular, cancer, mental health and neurodegenerative disorders) in which the role of genomics is profound.

• Q&A with Dr. Ronnie Stangler:

• Genomics is the most intimate science; it is not a solo sport.

• Ethical issues abound in terms of impact in family systems.

• Genetic markers are not fully deterministic - discussion of penetrance/epigenetics/other mitigating factors.

• Obstacles to greater implementation include fear of discrimination; downplay of benefits/exaggeration of risks.

• Major challenges include lack of diversity in those sequenced to date, limited access for vulnerable populations, and requirement for major public health educational agenda.

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