We are entering a new era in medicine as patients, health professionals, and researchers increasingly collaborate to gain new knowledge and explore new paradigms for diagnosing and treating disease. One area that exemplifies this evolution is the biobank, a repository that receives, processes, stores, and manages biospecimens for use in research. Human specimens—including blood, saliva, urine, spinal fluid, bone marrow, fresh frozen tissue, and formalin-fixed paraffin-embedded tissue—are essential for translational research. Their importance has increased significantly in the last 10 years in parallel with the drive for individualized medicine.
Many large-scale biobanking efforts are underway worldwide at institutional, national, and even international levels. When linked with subject data from questionnaires and medical records, biobanks serve as valuable resources in the study of complex diseases such as cancer, cardiovascular disease, and diabetes. Examples of these biobanks include the Personalized Medicine Research Project at Marshfield Clinic in Marshfield, Wisconsin; BioVu at Vanderbilt University School of Medicine in Nashville, Tennessee; the Mayo Clinic Biobank in Rochester, Minnesota; the Kaiser Research Program on Genetics, Environment and Health in Oakland, California; the Icelandic database by deCODE genetics in Reykjavík, Iceland; Generation Scotland Biobank in Edinburgh, Scotland; and UK Biobank in Cardiff, Wales.
Biobanks have become integral to improving population health with the goal of making medicine more effective and personalized for each one of us. All of us—participants, health professionals, researchers, and biobanks themselves—have an important role, from volunteering biospecimens to collecting consent to biospecimens processing and data accruing.
Biobanks could not operate without participants who volunteer their biospecimens and personal health information. Biobanking protocols must pay extraordinary attention to ethical guidelines and consent forms to assure participants that their specimens will be secure and their data used appropriately. Following best practices demonstrates that a biobank respects and protects the rights of participants and is committed to promoting ethically responsible research.
It is important to remember that participants with diverse ethnic and socioeconomic backgrounds have different values and opinions related to medical research. This can be a significant challenge for a biobank. It is incumbent on biobanks to invest in educating the public and engaging them in the process of shaping policy.
One area of continued debate is the use of broad consent rather than narrower, traditional approaches. The goal of broad consent is twofold: ensure participants are well informed on policies governing confidentiality and the use of their specimens at the time of consenting, and at the same time balance enough generalities around the nature of future research. Large, long-term biobanks usually use broad consent.
Many participants are also interested in the return of results and in learning about research findings. How a biobank will handle these questions must be communicated clearly at the time of consent. The biobank must also diligently follow through with agreed upon communication in order to keep participants involved.
Organizing a Biobank
At the end of the day, successful biobanks are empty, which means their biospecimens have been used for research and not stored in freezers for years without interest. But making sure a biobank has high quality samples that meet researchers' needs requires an enormous amount of support—lab and storage space, information technology expertise, robust logistics for sample movement, quality management systems, and appropriate facilities. Biobanks also depend on having the right complement of staff. In addition to trained technical lab staff, physicians, surgeons, pathologists, radiologists, nurses, and other medical staff like study coordinators all have key roles. Study coordinators in particular are essential as they are the face of the biobank when interacting with participants—recruiting them, educating them, and getting consent.
Notably, there are different models of biobanking with different aims. For example, a researcher-initiated program usually operates under traditional, study-specific consent to investigate a certain disease in a defined population. An institutional biobank may employ a dynamic consent with an access committee governing specimen use, follow-up, and contact for re-consenting participants. In contrast, broad consent may be more appropriate for a national or an international collaboration to enable wide-ranging usage of biospecimens.
Researchers have a unique role in biobanking as they shape the program by providing quality specimens and corresponding clinical data. Researchers also add more value over time if they share their data. Shared data expedites discoveries that reduce downstream cost and sample waste. Researchers are also important in helping to build trust with participants.
From a laboratorian’s perspective, two of the most important elements in a biobank are the barcode tracking system and overall quality assurance. The former is essential in order to monitor the location of each biospecimen at any given time, while quality assurance protocols safeguard sample integrity throughout the biospecimen lifecycle.
Biobanks must have detailed and carefully written standard operating procedures that all staff are trained on. A paramount metric of success for a biobank is the concept of zero sample loss: Every biospecimen coming to the repository belongs to a participant who has something to contribute to research for a healthier future. These precious specimens must not be compromised or lost.
Dealing With Preanalytical Challenges
Since the success of a biobank depends on the quality of its biospecimens, preanalytical issues are particularly important. Processing protocols developed in the laboratory have a major impact on all downstream analyses. Biobanking must be a well-controlled, well-documented process end-to-end. The expectation is that all samples will be handled and processed the same way with any deviations recorded. The most important factors that create challenges in biobanking processes are summarized in Table 1.
The Life of a Biospecimen
The life of a biospecimen begins when a participant signs a consent form and his or her sample is collected (Table 2). Depending on sample type, samples are stabilized at an ambient, refrigerated, or frozen temperature before being routed to the biobank for timely processing. Collection is defined as those specimens obtained from one participant at a given time or visit. The biobank then receives and accessions each collection into the laboratory information management system (LIMS).
Even before recruitment, biobank staff collect study-specific information for processing and storage. This information creates the study in the LIMS and is then activated for sample receipt. Samples arrive with study-specific information and are labeled with a participant identifier. The biobank scans each specimen and follows processing instructions in the LIMS and performs the required fractionation and aliquoting. All aliquots are created in smaller volumes (such as 1 mL in matrix tubes with a two-dimensional barcode at the bottom). Each aliquot from a participant gets a unique repository identification code in the LIMS before it is stored. During their long lifespan in the biobank, specimens' storage temperature is monitored closely. Facilities have redundant backups to maintain constant conditions.
Our Experience With a Large-Scale Biorepository
The Mayo Clinic has a long history of biological specimen and data banking. Since 1907, Mayo Clinic has archived all tissue slides and formalin-fixed, paraffin-embedded blocks and made them available to clinicians to assist in patient care and to researchers with appropriate institutional approval. Investigator-initiated, disease-specific collections are too many to list.
In 2009, the Mayo Clinic Center for Individualized Medicine initiated a large scale biorepository, the Mayo Clinic Biobank, to support a wide array of health-related research studies, especially those with the potential to improve patient care, by recruiting 50,000 subjects. Unlike the clinical biobank paradigm, the Mayo Clinic Biobank is not focused on a specific disease category.
From the beginning, we engaged community members to get recommendations about biobank procedures and guiding principles, including: strong privacy protections, convenient recruitment, data sharing, limited options for return of research results, long-term community oversight, and an easy-to-understand consent document. A key outcome of this engagement was the recommendation to establish a community advisory board.
The Mayo Clinic Biobank is an opt-in biobank. This means that participants actively agree in written, informed consent to permit use of samples and/or data in multiple studies, provide access to data from a questionnaire and from their medical record (both past and future), provide blood samples drawn specifically for the biobank, and permit access to stored clinical samples. They also agree to permit sharing of de-identified data with other researchers through secured computer databases such as the National Library of Medicine’s database of Genotypes and Phenotypes (dbGaP). Participants also agree to future contact for additional studies.
Our consent document covers privacy protections, the risks involved in participating, and the potential for receiving results from projects that use the biobank. It also provides two checkboxes—included at the suggestion of the community advisory board—allowing the participant the option of 1) not allowing access to stored clinical specimens for research, and 2) not allowing family members access to samples after their death.
Standard blood collection at our institution includes three 10 mL tubes with ethylenediaminetetraacetic acid (EDTA), a 10 mL tube without additives, and a 4.5 mL tube with sodium citrate. Blood samples are fractionated and DNA is extracted from 4 mL of EDTA blood on automated platforms. Unique identification numbers are assigned to each individual container received or created, and barcoded labels are adhered to each container. All demographics are disassociated from the sample record after 3 days to make patient information secure. Over 1.25 million aliquots have been prepared and stored for future use in a robotic freezer at -80°C.
Our Biobank Access Committee reviews investigators' requests to access samples and data to ensure adherence to our principles, including scientific excellence, alignment with institutional goals, and potential to improve patient care.
The Biobank Access Committee, in collaboration with the community advisory board, has developed a policy for determining whether research results, including incidental findings, warrant being offered to biobank participants. An ad hoc panel of experts reviews results that are potentially clinically meaningful, such as genetic test results with known clinical utility, to determine whether knowledge of the research results would affect clinical care of biobank participants. If the panel decides that the results are valuable for clinical care, the biobank contacts participants and offers genetic counseling to help them decide whether they want to learn their results. We offer to those who so chose a second appointment with a genetic counselor at which time the research results are disclosed. If results will be used for clinical decision making, the genetic counselor facilitates confirmation of the research results in a CLIA-approved lab.
In June 2016, the National Institutes of Health announced that Mayo Clinic Biobank would be the central repository for processing and storing biospecimens from 1 million participants in the All of Us Research Program (https://allofus.nih.gov). This will be the largest national biospecimen resource focused on precision medicine.
We all have an important role in making biobanks a success. Biobanks that have rich corresponding data on a large number of participants provide critical information and infrastructure support for clinical research. In order to deliver on the promise of biobanking and accelerate translation of research discoveries into more personalized and effective patient care, it takes the unique expertise of laboratorians, clinicians, researchers, and many others all working toward a common goal.
Mine S. Cicek, PhD, is assistant professor of laboratory medicine and pathology at Mayo Clinic in Rochester, Minnesota, and director of biospecimens accessioning and processing core laboratory in the biorepository program at Mayo’s Center for Individualized Medicine. +Email: [email protected]