Next Generation Biorepositories for Transformative Medicine

S Dravida, Founder CEO Transcell Biologics

V Vellanki, Intern Transcell Biolife

Aman Iqbal, Scientist Healthcare Entrepreneur

A biorepository is a biobank that collects processes stores and distributes biological materials to support future scientific investigation Next generation biobanks with inbuilt capacities to store clinical grade biosamples derived therapy grade cells donor or patients clinical data acquired cellular sequence data are forecast to lead in offering biobank derived transformative medicine The biobanking industrys future looks bright with deep entry barriers owing to the intellectual property surrounding the applications A new order of the ages

For centuries naturalist collected and curated various flora and fauna from around the world with the idea that these collections would provide important information about natural world. Biobanking was started with a similar purpose like collection of biospecimen as an inventory to be utilised for scientific research. The modern era of biobanking can be traced to have originated during the Cold War by anthropologists who had begun to collect and store blood and tissue samples from indigenous communities. They collected the samples fixated on the fact that these samples contained vital clues about genetic ancestry and human evolution. Biobanking in it’s various forms is an activity involving the collection of biospecimen and associated data and their storage for differing lengths of time before use. In some cases, biospecimens are immediately used, but in others, they're stored typically for the term of a specified project or in perpetuity until the materials are declared to be of little value with applications. The field of biobanking has further changed over the past thirty years. It went from predominantly university-based repositories that were developed for research needs of specific projects into institutional and government supported repositories, commercial biorepositories, population-based, disease-oriented biobanks and lastly, virtual biobanks. The information related to stored biospecimen have increased in complexity from basics data sets like date of collection, disease diagnosis, to extensive information sets like phenotype, clinical history, genomics, proteomics of the biosample.

Cryopreservation technology

Cryopreservation is a procedure that preserves organelles, cells, tissues, other biological materials by cooling to very low temperatures (-20 deg C and more). Viable tissues, derived stem cells, cells which have great potential for use in clinical research, medical applications, cannot be stored viable just by cooling or freezing for a long time as ice crystal formation gives osmotic shock causing membrane damage during freezing and thawing leading to cell death. The use of cryoprotective agents and temperature control equipment are necessary evils for the successful cryopreservation of cells or tissues to retain viability intended for applications. The methods and variety of cryoprotectants used in cryopreservation of biological samples may vary depending on the type of biosample and type of utility for which the biosample is cryopreserved giving room for intellectual property and technical know how in this space.

Freezing of biological material is a preclinical step that determines heterogeneity and decentralisation of biobanking. Storing temperature conditions at the time of collection and during maintenance are pre-analytical features affecting basic data heterogeneity. Presently, the standard temperature for storage of tissues and cells are between − 80 °C and − 150 °C (recommend liquid nitrogen, in particular the vapour phase stage (−150 °C) over the liquid phase (−196 °C)) while ultra-low temperatures preserve the integrity of proteins, DNA, RNA, and cellular components.

Biobank residing data sets

Collection of stem cells and tissues derived from samples present an enormous data source. Besides analysing cellspecific genotypes that can be used for cell-based therapies (described later), there is also the opportunity to carry out whole genome sequencing for each individual sample. Depending on the background of the individual, one can get a very good sense of the genetic makeup of others from the same background giving rise to a genetic pool that will allow for the development of genotypic specific personalised medicine as described later. When you take the individual tissues and grow them into 3D organoids, one can screen a library of drugs (small molecules and biologics) giving rise to genotypic and phenotypic specific drug combinations personalised for each individual. Now imagine taking every single tissue from the biobank, growing it into 3D organoids and carrying out ultra-high throughput screening can provide us terra bytes of data that allows us to aid our understanding of complex epigenetic-genetic interplay to develop precision medicine.

Large scale biospecimen banking in conjunction with highly annotated clinical data for each biospecimen is crucial to identifying optimal patient demographics, therapeutic approaches for specific patient subgroups, and laying the foundation for novel discoveries based on interrogation of the big data derived from this approach. However, to protect patient identity and confidentiality it is necessary to de-identify the biospecimen. This task can be accomplished via a Clinical Data Warehouse (CDW) using bar codes linked to patient Medical Record Numbers (MRNs), and MRNs linked to patient Electronic Medical Records (EMR). The biobank itself remains blind to patient identity but is able to access patient medical records and demographics. Biospecimen, if collected and stored properly, may be used for both therapy and research. That is, large samples such as cord blood or adipose tissue may be later removed and used for patient treatment. However, if multiple small aliquots of the specimen are also stored those “bullets” can be used for research and interrogative purposes to determine patient qualifications for trials and improved outcomes from such trials, along with providing specimens for research interrogation that produces big data that can be the source of novel discoveries and additional therapies.

Preserving all the way

With incredible advancements in the technologies to do with collection and storage of human samples to obtain important results in the field of medical research, today one can collect, store, preserve tissues, stem cells, cells, DNA, proteins, subcellular components for ever, retrieve whenever needed integrating standard procedures for the coordination of sample collection and usage.

Cell lines

The history of cell line biobanking started with generation of the HeLa cell line in 1951 at Johns Hopkins Hospital. The HeLa cell line is used worldwide in research laboratories as it offers an optimal and stable model system for in vitro research experiments while scientific results have been gained with vital advantages for global health like the development of polio vaccines. The evolution of cell line biobanks highlights the importance of standardising technical procedures; data reproducibility in medical research. Major cell line repositories include: Japanese Cancer Research Resources Bank, ATCC (USA), Leibniz-Institute DSMZ, European Collection of Cell Cultures, Korean Cell Line Bank.

Specimen/Tissues

The first specimen biobanks started as university-based repositories with attached hospitals and research institutes for specific research projects. They were established by clinical researchers with access to patient populations that took advantage of the availability of ‘left over’ aliquots or biosamples that were going to be discarded were stored for either immediate or future use. Automated sample processing, the dawn of World Wide Web revolutionised the management use specimen from biobanks eventually. One such success story in utilising specimen from biobanks is the development of trastuzumab antibody (Herceptin), one of the drugs effectively used to treat specific subtypes of breast cancer.

Stem cell biobanking

In multicellular organisms like humans, stem cells are undifferentiated cells that can differentiate into various types of cells and self-renew. They are found in embryos, foetus and adults with different properties in each. They are named as: Embryonic stem cells, Fetal stem cells, Hematopoietic stem cells, Mesenchymal stem cells, Tissue specific stem cells, Induced Pluripotent stem cells. There are five known types of sources to harvest stem cells: 1. Biopsy 2. Biological discards 3. Embryos 4. Foetus 5. Cadaver.

Cord Blood biobanking for Hematopoietic stem cells; Peripheral blood/Bone marrow banking for both Hematopoietic and Mesenchymal stem cells; Amniotic/Cord tissue banking for Mesenchymal stem cells; Tissue banking for derived epithelial stem cells, endothelial stem cells; induced pluripotent stem cell banking are some of the popular concepts. These concepts are regulated operating entities to do with collection, processing, cryopreserving and retrieving the stem cell units from the repositories for applications. Before the advent of stem cell biobanking concept that allows partial or complete evaluation of the genome, epigenome, transcriptome, metabolome, and proteome components of the biospecimen stored, and Formalin-Fixed Paraffin Embedded (FFPE) tissue was the specimen usually collected in biobanking databases were used in research programs. The “next generation” era has exposed several disadvantages in the use of FFPE tissue for molecular/genetics and protein studies paving way to cryoprotectants used cryopreserved tissues for better-quality of the derived components that includes cells for clinical applications like clinical trials and cell therapies.

Biobanked Stem cells for cell therapies/regenerative medicine (Autologous and Allogenic):

Stem cells have the remarkable potential to be developed into many different cell types in the body during early life and growth. In addition, in many tissues they serve as a sort of internal repair system, dividing essentially without limit to replenish other cells as long as the person or animal is still alive. When a stem cell divides, each new cell has the potential either to remain a stem cell or become another type of cell with a more specialized function, such as a muscle cell, a red blood cell, or a brain cell. One of the key orthologous applications of biobanking is the opportunity to harvest stem cells for regenerative medicine. Research in the last couple of decades have allowed researchers around the world to transform mouse stem cells into variety of human cells like neurons, skin cells for grafting, and many more. Stem Cell Therapy (SCT) is the treatment of various disorders, non-serious to life threatening, by using stem cells. These stem cells can be procured from a lot of different sources and used to potentially treat more than 80 disorders, including neuromuscular and degenerative disorders.

Hematopoietic disorders (e.g. leukaemia, thalassemia, aplastic anemia, MDS, sickle cell anemia, storage disorders etc.) affect the bone marrow and manifest with various systemic complications. Stem cells from a donor (either from cord blood or bone marrow) are known to reconstitute the defective bone marrow and permanently overcome the disorder.

Degenerative disorders arise from degeneration or wear and tear of bone, cartilage, muscle, fat or any other tissue, cell or organ. This could occur due to a variety of reasons, but it's normally the process known as ageing, or 'getting old' that is the biggest cause. The disorders have a slow and insidious onset but once contracted, can be long-standing, pain-staking and lifelong. These disorders can affect any organ of the body. The common degenerative disorders are diabetes, osteoarthritis, stroke, chronic renal failure, congestive cardiac failure, myocardial infarction, Alzheimer's disease, Parkinson's disease etc.

Although stem cells are often used in therapy immediately upon isolation, in many circumstances the stem and progenitor cells will be harvested, processed and banked frozen until a later time. Biobanking is a convenient alternative to same-day therapeutic use, in that it allows for patient recovery (e.g., from liposuction or surgery), provides time to identify the best treatment options, and may allow for multiple interventions without additional patient inconvenience or risk.

Biobanking can be advantageous in both the autologous and allogeneic settings, to reduce costs, to personalise therapies if needed, and to reduce patient inconvenience. In the autologous setting the collection and banking of biospecimen can inconvenience the patient only once, with multiple aliquots being set aside for future use. The biospecimen can be collected when the patient is at their youngest and healthiest, so that the cells are most optimal for use in therapy at any time in future. In addition, it reduces the concerns about disease transmission and immune rejection. In the allogeneic setting it can permit selection of the most ideal biospecimen donor when personalised therapies are not needed. Young and healthy donors free of disease or other medical issues can be utilised, biospecimen expanded into hundreds if not thousands of therapeutic aliquots, and then placed at various banking sites around the country (or world) where they can be immediately available when needed. Creation of large autologous biospecimen banks (e.g., cord blood banks) can also permit clinical trial tailoring to specific patients with certain diseases or indications that shortens time to treatment, rapidly fills patient recruitment quotas and increases the probability of positive treatment outcomes.

Biobanked Stem cells for precision medicine and predicting health signatures

Human specimens and derived cells with associated clinical and phenotype data make it possible to analyse large cohorts with large-scale genome sequencing leading to the identification of several novel molecular alterations in cancer, and tumour subtypes are classified according to distinct genomic alterations, letting a precision medicine approach for patient care.

Likewise, cryopreserved donor or patient’s biosample derived cell specific genotypes analysed provide predictive health signatures of an individual which is different from diagnostics. Biobank derived predictive health signatures are more authentic with associated data points to offer the services related to the donor/patient’s life style to prevent or prolong the contraction.

Biobanked Stem cells in drug discovery

The evolution and heterogeneity of biosamples composing the biobanks go hand in hand with the development of highly sensitive, high-throughput methods in discovery and development of new drugs or re-purposing drugs utilising the phenotypically responsive platforms derived out of stored biosamples — Phenotype--based drug discovery— A next generation approach. The complexity of the molecular patterns of diseases provides multiple opportunities for targeted therapeutic intervention, tailored to suit the particular characteristics of the disease. Developing and evaluating such novel therapies demands access to well designed and structured collections of biosamples and derived selective components. Therefore, harmonising biobanking procedures to develop innovative solutions supporting biobank’s operability directed to developing new drugs effectively reaching out to the largest possible number of patients is one of the next gen scenarios.

Biobanked Stem cells in Standard Care

Hematopoietic Stem cell Transplantations (HSCT) is regulated as Standard Care in practising treatments for blood and blood related disorders worldwide while blood stem cells are harvested from clinical sources like cord blood, bone marrow and peripheral blood. Autologous, Allogenic and tandem transplantations are part of Standard Care while cryopreserving the harvested and formulated stem cells is a necessary component in imparting HSCT highlighting the role of Biobank in Standard Care.

Blood biobanking

Blood is known as one of the most common biospecimens with utility well established. It is collected in sterile tubes containing preservatives or additives specific to application and blood fraction need (serum, plasma, white blood cells, red cells). The optimal temperature for blood component storage varies between low (− 20 °C) and ultra-low temperature (− 80 °C) for short- and long-term, respectively for maintaining the integrity and stability of every blood component.

DNA/RNA banking

Fresh frozen tissue is found to be ideal specimen for DNA/RNA extraction as genetic material is reduced or degraded in FFPE tissue due to cross-links between nucleic acids induced by formalin and the time interval between tissue resection and fixation. Molecular analysis is majorly dependent on the collection / extraction/storage modalities of DNA and RNA molecules. DNA is more stable than RNA and is preserved at −80 °C for longer periods.

Genomic biobanks and meta-analysis of genomic data promises to reveal the genetic underpinnings of health and disease. Data sets associated with biobanks can aid in the building of country and population specific health programs either to prevent or combat epidemics and pandemics.

As the field of biobanking evolves in the coming decade, it is impossible to ignore bioethics and compliance associated with it. The intent is to protect the donors or patients from disclosures of their personal health information. Every country/geography sets standards and regulations in order to ensure privacy and security dealing with data residing in biobanks.

The progress of individual in relation to translational medicine will be an unsolved issue of conceptual interpretation of the human genome data, modern research in chemical biology, molecular, cell biology, biotechnology and other allied branches impossible without biobanking and using different types of biological materials. Establishing functional dynamic biobanks of the human material should be connected with the need of solving a range of social, medical and humanitarian issues.

Transformative medicine that starts and ends with patients is known as the future of global healthcare while Biobanks can step up to transformational role in offering predictive diagnostics, personalized medicine — a one stop hub from womb-to-tomb offering transformative medicine.

--Issue 39--

Author Bio

S Dravida

S Dravida is the Founder CEO of Transcell Biologics (www.transcellbio.science). She is a Technocrat innovating new vistas in the fields of adult stem cell technologies and commercialization

V Vellanki

V Vellanki is pursuing B.S Finance and Economics at Penn State University. He is an Intern at Transcell Biolife (www.transcell.in) a next gen biobank with a vision to become an epicenter offering transformative medicine in Asia

Aman Iqbal

Aman Iqbal is a Scientist and Healthcare entrepreneur. He is a technology and healthcare visionary, and is passionate about the role of data in automating various industries including healthcare.

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