Wk 3.2 Ethics, Legislation, and Ownership in Human Genomics Research

Learning Objectives

❏ Describe pertinent rules and regulations that aim to protect patients

and research participants in the United States

❏ Explain why the increase in large-scale genetic biobanks raises ethical

concerns alongside likely benefits for science/medicine

❏ Distinguish between adequate and inadequate informed consent based

on the criteria established via the revised Common Rule.

❏ Use the case studies presented (Henrietta Lacks and HeLa cells, Moore

vs. Regents of the UC, and diabetes research in the Havasupi Tribe) to

highlight the importance of informed consent and other ethical

considerations in research/medicine.

❏ Explain how de-identification and broad consent might address consent issues in large-scale genetics research. Evaluate whether these approaches may or may not be adequate.

❏ Explain the criteria required for receiving a patent, and describe the

arguments and outcome of the Myriad BRCA1/2 patenting Supreme Court case

Administrative Updates and Course Context

Deadlines and Assignments - Paper topic and justification submissions are due tomorrow night. Students who have started but not submitted are encouraged to finalize their work. - An optional "Turnitin Clarity" assignment is available on Bruin Learn to allow students to familiarize themselves with the platform. - Feedback forms for guest lecturers (e.g., Doctor Garrison) are available on Bruin Learn under the relevant modules; these are used by lecturers for merit reviews and teaching documentation. - The midterm exam is approximately $2$ weeks away. Learning objectives, clicker questions, and Perusall questions are recommended study resources.
Course Progression Recap - Week $1$ and $2$ : Covered basic bioethical frameworks and core issues in medical genetics (testing in the clinic). - Week $3$ (Tuesday): Doctor Garrison discussed genetic determinism, the history of eugenics, and community navigation of genetic variants (e.g., Ashkenazi Jewish community) regarding discrimination/stigma. - Today's Focus: Ethical questions in genomics research, emphasizing respect for persons/autonomy, and case studies regarding ownership versus the benefits of scientific research.

Foundations of Human Subjects Research

The Belmont Report ( $1970$ s) - Designed to address human subjects research rather than clinical practice. - Three Key Principles (later expanded to four in biomedical ethics): - Respect for Persons: Upholding autonomy and protecting those with diminished autonomy. - Beneficence: Minimizing harms while maximizing potential benefits. - Justice: Fair distribution of research burdens and benefits.
Foundational Guidelines - Nuremberg Code ( $1940$ s): Established post-WWII ethics for human experimentation. - Declaration of Helsinki ( $1960$ s–Present): Continually updated international guidelines. - Note: These documents serve as foundational guidelines but are not legally enforceable requirements in the same way as federal law.

US Privacy and Non-Discrimination Legislation

HIPAA: Health Insurance Portability and Accountability Act ( $1990$ s) - Primary function: Protecting privacy and security of Patient Health Information (PHI) and ensuring insurance portability (covering preexisting conditions and continuity during job loss). - Limitations: Does not apply to entities not considered "covered," such as direct-to-consumer genetic testing companies (e.g., $23$ andMe). - UCLA Case Study ( $2008$ ): UCLA Health paid ″ $865,000$ ″ in settlements after employees at Ronald Reagan, Santa Monica, and the Neuropsychiatric Hospital were caught "snooping" in celebrity medical records, including those of Britney Spears, Tom Cruise, and Maria Shriver.
GINA: Genetic Information Nondiscrimination Act ( $2009$ ) - Explicitly protects individuals from discrimination by employers and health insurers based on genetic information. - Target: Protects asymptomatic individuals with genetic predispositions from having their DNA usage solely as a metric for coverage or employment decisions. - Exclusions: Does not apply to life insurance, disability insurance, long-term care insurance, US military members, or small businesses with fewer than $15$ employees.

The Common Rule: 45 CFR 46

Overview: The legal codification of the Belmont Report principles within US federal policy.
Subpart A: Specifically covers health and human services policy regarding informed consent and ethical conduct.
Institutional Review Boards (IRBs): These boards are required to review research involving human subjects to ensure procedures meet ethical expectations.
Informed Consent Standards: - Disclosure: Researchers must provide adequate information for a participant to make a decision (purpose, duration, procedures, risks, benefits, alternatives). - Comprehension: Subjects must understand the information and be capable of giving assent. - Voluntariness: Participation must be entirely voluntary with no coercion. - Paternalism: The historical antithesis of autonomy where clinicians/researchers acted "for the good" of patients without their consent (a hallmark of the negative eugenics movement).

Case Study: Moore v. Regents of the University of California ( $1990$ )

Context: John Moore, a leukemia patient treated at UCLA in the $1970$ s, sued after discovering his doctor had used his cells to derive and patent a cell line without his knowledge or consent.
Legal Conflict: Moore sued based on "property rights," claiming he owned the biological material and should be compensated for the commercialized patent.
Court Ruling: The court ruled that Moore did not own the cells once they were removed and altered in the lab. The rationale included: - The cells were significantly altered by research, making them legally distinct from the original biological material. - Concerns about the precedent of people being able to "buy or sell" personal body parts (organ selling vs. gamete donation).
Ethical Outcome: While Moore lost on property grounds, the court acknowledged potential issues with informed consent, though that required a separate legal path.

Case Study: Henrietta Lacks and Hela Cells ( $1950$ s)

Context: Henrietta Lacks, a Black woman treated for aggressive cervical cancer at Johns Hopkins Hospital, had her tissue samples taken by researcher George Gey without her consent.
The Hela Line: These cells became the first "immortal" cell line, capable of reproducing indefinitely in a laboratory setting. They became a cornerstone of modern biomedical research.
Legacy and Injustice: Lacks' family was not notified for decades, even after Hela cells were globalized. This case highlights issues of justice for minoritized communities.
Recent Legal Developments: - In $2023$ , the Lacks estate settled a lawsuit against Thermo Fisher. - In February $2024$ , a settlement was reached with Novartis.
Modern Impact: The genome of Hela cells was published years ago without consulting the family, raising concerns as the genetic info of the cells implicates her living descendants.

Case Study: The Havasupai Tribe lawsuit ( $2010$ )

Context: Members of the Havasupai Tribe provided DNA samples to Arizona State University (ASU) researchers in the early $2000$ s specifically for diabetes research.
Breach of Trust: The samples were used for unauthorized studies on migration (conflicting with tribal origin stories), inbreeding/interrelatedness (a taboo topic), and schizophrenia.
Settlement: In $2010$ , the case was settled for ″ $700,000$ ″, and the physical blood samples were returned to the tribe. ASU researchers were barred from the reservation.

Biobanking and "Big Data" Initiatives

Project Examples: - All of Us (NIH): A precision health initiative aiming to collect genetic, lifestyle, and environmental data from at least $1,000,000$ people.
Biobanks (Genetic Biorepositories): Facilities that store biological samples (blood, tissue) and their corresponding digitized data for long-term research access.
Benefits of Biobanking: - Facilitates the discovery of cures and drug development (Big Pharma). - Efficient reuse of samples for multiple studies without repeated recruitment. - Reaching specialized populations (ancestry research).
Concerns and Ethical Tensions: - Anonymity: Genetic data is never truly anonymous; studies show re-identification is possible using zip codes and genealogy databases. - Return of Results: Debates over whether researchers have an obligation to report clinically significant (pathogenic) findings to participants. - Familial Implications: One's genetic data inherently reveals information about relatives.

Updated Common Rule ( $2017/2018$ Revision)

Future Use Clauses: Informed consent must now include statements on whether samples might be used for future research. Researchers can remove identifiable information to proceed without new consent.
Broad Consent (Open Consent): Allows participants to give a "general description" of potential research areas, permitting researchers to reuse samples for different studies within that scope without recontacting participants.
UCLA's Universal Consent: A process blurring the lines between clinical medicine and research, where patients are asked if their clinical samples can be used for research, with options regarding the return of actionable findings.

Patenting and Genetic Intellectual Property

USPTO Patent Criteria: Items must be new, useful, non-obvious, and NOT products of nature.
Gene Patenting in the $1990$ s: During the Human Genome Project, companies like Myriad Genetics patented genes ( $BRCA1$ and $BRCA2$ ) and all current/future variants.
Impact of Myriad Patents: Myriad heavily enforced their rights, forcing all testing through their labs, maintaining private databases, and restricting independent research on the genes.
Modern Perspective: This exclusivity led to a landmark Supreme Court case ( $2013$ ) questioning the validity of patenting DNA sequences.

Questions & Discussion

Ethical Reflections on Biobanks: - Participant Question: Is the current method of informed consent good enough for genomic info? - Class Debate on Broad Consent: - Some students feel it is an adequate balance to allow scientific progress. - Others (approximately $50\%$ ) expressed concern over "data leaks" and historical misuse of data (e.g., manipulating data to support racist ideologies). - The question remains whether genetic data can ever be considered truly "de-identified."
Reflection on Ownership: - Clicker Results: A plurality of students believed they own "some but not all" of their biological materials. Most believed they own their kidneys, yet current law specifies you do not own samples given for research once they are provided via informed consent.
UCLA Universal Consent Activity: Students will engage in an activity in Friday sections regarding UCLA’s specific consent knowledge.
Actionable Findings: The modern trend (including at UCLA Health) allows participants to opt-in to receiving results if research uncovers something medically significant in their genome.

Learning Goals and Outcomes

Ethical Questions in Genomics: Outline questions related to genetics research, focusing specifically on respect for persons and autonomy.
Tensions in Research: Use case studies to explore the conflict between scientific progress and individual rights, including autonomy, ownership, and commodification.
US Regulations: Describe rules protecting patients and research participants in the United States.
Genetic Biobanks: Explain the ethical concerns (and scientific benefits) raised by large-scale genetic biobanks.
Informed Consent Criteria: Distinguish between adequate and inadequate informed consent based on the revised Common Rule.
Case Study Applications: Apply the importance of informed consent to the following cases: - Henrietta Lacks and HeLa cells. - Moore vs. Regents of the University of California. - Diabetes research in the Havasupai Tribe.
Addressing Consent Issues: Explain how de-identification and broad consent aim to address consent issues in large-scale research and evaluate their adequacy.
Patenting and Myriad Case: Explain patent criteria and describe the arguments and outcome of the Supreme Court case regarding Myriad BRCA1/2 patenting.

Human Subjects Research: Guidelines and Key Legislation

The Belmont Report (Ethical Framework): Established the foundational principles for human subjects research: - Respect for Persons (Autonomy): Recognizes individuals as autonomous agents and provides protections for those with diminished autonomy. - Beneficence: The obligation to do no harm, maximize potential benefits, and minimize risks. - Justice: Ensures fairness in the distribution of research benefits and burdens; to each what they are owed.
International Guidelines vs. US Law: - The Nuremberg Code and the Declaration of Helsinki are international guidelines but are not legally binding laws in the US.

United States Laws Protecting Patients and Research Participants

HIPAA (Health Insurance Portability and Accountability Act of 1996): - Protects the privacy and security of patient health information. - Limits restrictions health insurers can place based on pre-existing conditions. - Ensures health insurance continuity during job changes or losses. - Caveat: HIPAA does not cover direct-to-consumer (DTC) genetic testing or other non-"covered entities."
GINA (Genetic Information Nondiscrimination Act of 2009): - Prohibits employers from using genetic information for job decisions. - Prohibits health insurers from using genetic information to determine coverage. - Protections: Only applies to asymptomatic individuals. - Caveats: Does not apply to life insurance, disability insurance, long-term care insurance, the US military, or employers with fewer than $15$ employees.
The Common Rule (45 CFR 46): - Federal guidelines for human participation in research originally published in 1991 with a major revision in 2018. - Establishes policies for Institutional Review Boards (IRBs) and procedures for informed consent. - Uses the Belmont Report as its underlying framework.

Informed Consent Procedures and Requirements

Purpose of Informed Consent: - Autonomy: Preserves the ability of patients to make their own decisions. - Protection from Paternalism: Prevents groups or individuals from limiting autonomy for what is perceived as the subject's "own good." - Medical Paternalism: Specifically when healthcare providers make choices for patients without consent or against the patient's wishes.
Key Features per the Common Rule (Subpart A): 1. Disclosure: Adequate information must be provided to make an informed decision. 2. Comprehension: The researcher must ensure the subject understands the information. 3. Voluntariness: The decision must be voluntary and free from coercion.
Mandatory Information for Subjects (45 CFR 46.116): - A statement that the study involves research, its purpose, duration, and procedures (identifying experimental ones). - Description of reasonably foreseeable risks or discomforts. - Description of reasonably expected benefits to the subject or others. - Disclosure of alternative procedures or treatments that might benefit the subject. - Statement on the extent of identifying record confidentiality. - For research with more than minimal risk: Explanation of compensation and available medical treatments if injury occurs. - Contact information for questions about rights or research-related injury. - Statement that participation is voluntary, refusal involves no penalty, and the subject may withdraw at any time.

Case Studies in Bioethics and Genomics

Moore vs. Regents of the University of California (1990): - Background: John Moore was a hairy cell leukemia patient at UCLA Medical Center in the 1970s. His doctor and UCLA patented a cell line derived from Moore's white blood cells without his knowledge. - Legal Action: Moore sued based on property rights, claiming he did not consent to the research use of his cells. - Court Decision: The court ruled that the cells were distinct from Moore’s body because they were altered in the lab. The court feared that granting patients ownership rights would restrict research and lead to the selling of body parts. - Outcome: Acknowledged issues with consent but denied Moore property rights over the samples.
Henrietta Lacks and HeLa Cells: - Background: Henrietta Lacks (1920–1951) had her cells taken without her consent. George Gey developed the HeLa cell line, which was shared globally for 24 years before her family was notified. - Impact: HeLa cells were essential for many biomedical advances. - Legal Status: A lawsuit was settled in 2023; a Novartis lawsuit was settled in February 2026.
Havasupai Tribe Diabetes Research: - Background: In 2004, lawsuits were filed after ASU researchers used blood samples (initially taken for diabetes research) for unauthorized studies on migration, inbreeding, and schizophrenia. - Settlement (2010): Included $700,000$ , the return of blood samples, and a ban on the researchers from the reservation.

Modern Genomics Research and Biobanks

Current Programs: - All of Us Research Program (NIH): Inviting one million people across the US to build a diverse health database exploring biology, lifestyle, and environment. - 23andMe: Collaborates with pharmaceutical companies for clinical trials, focusing on lifestyle, environment, and genetic insights like Type 2 Diabetes and lactose intolerance.
The Biobanking Process: - Obtain informed consent → Collect biospecimens → Process and store in biobank → Samples made available for research.
Ethical Questions for Biobanks: 1. Are current consent methods adequate for potential psychological risks? 2. Is re-contacting participants for multiple uses of samples possible or required? 3. Are anonymization procedures sufficient to prevent re-identification and genetic discrimination? 4. Is there an obligation to return clinically significant results found during research? 5. Is it fair for researchers to profit from human-derived samples?
Revised Common Rule Solutions: - Future Use Statements: Consent must choose between a) Future research may occur after removing identifiers, or b) No future research will be done. - Broad Consent: Allows samples to be used for multiple studies without re-consenting for each, provided a general description of the research is given.
UCLA Health Universal Consent: - Uses an opt-in/opt-out process for leftover biological samples (blood, urine, tissue). - Offers options to hear about other research opportunities and to receive actionable genetic results (via the ATLAS Genetic Screening Program).

Genes as Commodities: Patenting and the Myriad Case

Current Ownership Status: Individuals do not have ownership rights over biological samples given for research (Moore vs. UC Regents); ownership resides with researchers/institutions (Washington v. Catalona).
Patent Definition and Criteria: - Rights: Exclusive rights to a process or product (US Constitution Art 1, Sec 8) for usually $20$ years. - Criteria (35 U.S.C. 101): Must be new/novel, useful, non-obvious, and NOT a product of nature.
The Myriad Case (Association for Molecular Pathology vs. Myriad Genetics, 2013): - Background: Myriad Genetics patented BRCA1 (1994) and BRCA2 (1995), gaining a monopoly on diagnostic testing and research for these genes. - Implications: Restricted variant databases and limited research on BRCA associated cancers (which exhibit incomplete penetrance and are autosomal recessive). - Supreme Court Ruling (9-0): Ruled that naturally occurring DNA sequences cannot be patented. The isolation method was deemed routine and not "new."
Expertise and Policy (Shobita Parthasarathy): - Suggests that the bioethics community initially supported gene patents because the scientific community viewed them as necessary for innovation. - Argues that "technical expertise does not equal social wisdom" and that policy should include alternative voices (citing Tuskegee and the Flint water crisis) to provide contextual understanding of marginalized communities.