Banking is about generating returns. In finance, savers earn interest on money invested, while in medical research, samples stored in a biobank yield returns in the form of scientific dividends.
In both cases, the magnitude of potential returns depends on the size of the investment made. In research, investment equates to both the quality of samples and the manner in which they are stored.
Tissue, cellular, and other biological samples are vital to medical research and drug development. Everything from biomarker analysis through tumor characterization depends on the ability to carry out experiments in the lab.
But experimentation is of value only if the samples are representative of the organ or cell in its natural state. Cell lines adapted to survive in laboratory conditions are of little value when it comes to predicting how their wild-type relatives will react when exposed to a drug candidate.
As a result, the manner in which biological samples are stored is critical to maintaining their value.
Source of Concern
One of the challenges facing the biobanking sector is that biospecimens come from an ever-expanding range of sources. This diversity needs to be kept in mind when deciding how samples are stored, says Dianne Chadwick, Ph.D., manager of biobank operations at the University Health Network in Toronto, Canada.
“Traditional biospecimens are bulk tissues and blood derivatives—such as serum, plasma, and buffy coat—that are snap frozen or formalin fixed and paraffin embedded (FFPE). These are nonviable and unenriched, thus limiting analysis and interpretation,” Dr. Chadwick points out.
She contrasts this with what she calls “next-generation biospecimens,” which are those that come from a more disparate range of cellular and tissue sources that are often taken at multiple time points.
“Next-generation biospecimens will likely be enriched for analysis by next-generation technologies. Tissues may be microdissected into cell subpopulations, such as tumor and microenvironment, and plasma samples may be enriched for circulating DNA, such as tumor DNA in cancer patients,”Dr. Chadwick adds. “Enriched derivatives may be analyzed by next-generation technologies such as whole-genome sequencing [WGS], RNAseq, or single-cell sequencing so that viable cells may be used to establish organoid cultures and tested for drug sensitivity.”
Increased volume is one of the major differences researchers face when storing next-generation samples, according to Dr. Chadwick, who explains that larger specimens are needed to facilitate useful experimentation: “Low analyte quantities mean large quantities of biofluids are needed for analysis until more sensitive assays are developed. And patient specimens need to be processed within minutes, either in the biopsy suite or operating room to avoid sample degradation.”
Keeping up with the ever-growing range of sample types, and experiments in which they are assessed, is an ongoing battle for biobanks. Dr. Chadwick says engagement with scientists is vital to understanding their needs and ensuring appropriate storage capacity does not become a limiting factor.
“For biobanks to remain relevant, we need to engage the research community early and often to be sure that we are meeting their biospecimen needs,” she declares “and we need to develop creative solutions with multidisciplinary input from scientists, pathologists, interventional radiologists, surgeons, and internists to obtain, process, and store these valuable specimens.”
In oncology, circulating tumor cells (CTCs) provide a good example of a new sample type that poses a challenge for traditional material handling and biobanking methodologies.
The experimental utility of such samples is not in doubt. Several labs have shown that CTC enumeration and molecular characterization may be valuable predictors of patient outcome and response to therapeutic intervention. However, working with CTCs is difficult, says Rebecca Sandlin, Ph.D., instructor in surgery at Harvard Medical School and Massachusetts General Hospital, and an investigator at the center for engineering in medicine at Massachusetts General Hospital.
“CTCs are extremely rare, and only recently have technologies been developed that are capable of isolating these cells from patient blood,” Dr. Sandlin explains, adding that traditional methods of preparing cells for biobanking have proved hard to apply.
“In cryogenic storage, we must cool a cell from room temperature down to –196°C in liquid nitrogen,” she notes. “During this process, ice nucleation occurs and can damage cells by either mechanical or solution effects. To minimize damage, we treat cells with cryoprotectants such as dimethylsulfoxide.
“However, cryoprotectants are often very toxic, and thus the loading protocol must be carefully developed. Then, other parameters such as the cooling rate need to be optimized. Once this is figured out, we need to optimize our methods for thawing the cells and removing the cryoprotectant.
“Overall, the process of optimizing a cryopreservation procedure can be quite challenging. However, this optimization approach is not possible for CTCs due to their heterogeneity and extreme rarity.”
The End of the Biobanking Ice Age?
To address the difficulties in storing CTCs, Dr. Sandlin and her team have developed a methodology based on a process called vitrification, in which samples are solidified using a super-cooled liquid.
“Unlike standard cryopreservation methods where cells are slowly cooled,” she says “vitrification is an ‘ice free’ method of cryopreservation achieved by loading high concentrations of toxic cryoprotectants followed by rapidly cooling cells through the glass transition.” And rapid cooling is no exaggeration. Cells preserved using Dr. Sandlin’s approach are first loaded into 0.2-mm-diameter silica capillaries and then cooled at a rate equivalent to 250,000°C/min by being submerged in liquid nitrogen.
There are numerous advantages of preserving precious, rare cells using this approach, according to Dr. Sandlin: “Because cooling is so rapid, we can vitrify cells with lower concentrations of cryoprotectants, so there is less concern regarding toxicity.”
She adds that, “Because ice crystallization is completely avoided, this approach may be gentler to CTCs.”
Another recent development in the biobanking sector is collaborative biobanking, whereby industry, academia, and government set up shared facilities. The idea is to provide storage capacity to researchers and firms that are unable or unwilling to invest in the development of a biobank.
In 2006, for example, the Wellcome Trust, the Medical Research Council, and the Department of Health established the UK Biobank, in which a range of biological samples from 500,000 people are stored.1 The overall aim of the project is to improve the diagnosis and treatment of diseases; however, the UK Biobank also has funding to allow for the storage of biological samples on behalf of other researchers and organizations.
The collaborative biobanking approach is well suited to researchers working in the field of personalized medicines, according to Dina Avery, Ph.D., assistant professor and regulatory affairs specialist at the University of Alabama.
“It is great that we see more high-quality biobanking infrastructures geared toward personalized precision medicine approaches,” Dr. Avery says. “In addition, we see more multi-institutional, multidisciplinary biobanking collaborations leading the way to provide novel personalized medicine approaches to advance prognosis, prevention, diagnosis, and treatment of disease.”
It is important that collaborative biobanking develops into an ecosystem that reflects the diverse aims of all parties that need to store samples for research purposes, she adds.
“Given different stakeholders and missions, it is unlikely that one-size policies will fit all biobanks, but attention to organizational diversity is critical for the promotion of appropriate and effective biobank governance,” Dr. Avery insists.
The importance of enabling a wide range of biobanking options was highlighted by Simeon-Dubach et al. in research published last year in Biopreservation and Biobanking (published by Mary Ann Liebert, Inc.).2
The researchers looked at various business models being used to provide sample storage capacity for academia and industry, and found that sustainability is best achieved by tailoring capacity to the specific application.
The authors wrote that, “Most experts recommend that biobanks be set up and run in a similar manner to small- and medium-sized business enterprises.
“However, taking into account the incredible diversity in biobanking, running a biobank like such businesses may make sense to a medium-large biobank, but may be less applicable in a number of aspects for a small, mono-user-type collection.”
2. Simeon-Dubach D, Goldring K, Henderson MK. Trends in Biobanking Business Planning: Initial Results of a Survey of Biobankers. Biopreserv. Biobank. 2017; 15(1): 72–74. doi:10.1089/bio.2016.0080.