The Center for Alternatives to Animal Testing (CAAT) at the Johns Hopkins Bloomberg School of Public Health pioneered mass-produced standardized human BrainSpheres (or “mini-brains”) three years ago. Today, in a paper published in Nature’s online journal Scientific Reports, a multidisciplinary team from four institutions has shown how these mini-brains can be used in brain cancer research.
Thomas Hartung, director of CAAT, sees this as a breakthrough in the study of human cell models of disease. “Only recently have stem cell technologies allowed us to reproduce human biology. Now, with the development of 3D organoids like our BrainSpheres, we are using them to model diseases.”
Taking a tumor from a patient and culturing it to optimize treatments rarely succeeds. Tumors outside of healthy tissue are not the same, and it is difficult to produce standardized cultures to compare treatments. Often, this requires using mice without an immune system—so-called “nude” mice—but this is costly, time-consuming, and often of limited relevance, as a tumor in mouse tissue is not the same as a tumor in a human tissue. Adding a few cells of the tumor to the developing mini-brains, however, allows mass-production of human tumor tissue. Combined with innovative automated histopathology from MicroMatrices in Dundee, Scotland, the University of Dundee, and Perkin Elmer, the reaction of both the tumor and the healthy brain tissue to treatment options can be monitored at the same time.
The collaboration with neurosurgeons at the Mayo Clinic and Johns Hopkins utilized this model to study glioblastoma, a devastating childhood brain tumor found mostly in children but one that sometimes affects adults. “In principle, any tumor and any host tissue can be matched with the mushrooming of new 3D tissue models from stem cells,” says Hartung, who initiated the research. His center has been advocating for the use of such alternatives to animal testing for 37 years. Most recently, they showed that their BrainSpheres can be used to model viral infections and neurodevelopmental processes. “These are proofs-of-principle that 21st century human cell-based technologies can succeed where animal models fail.”
The successful collaboration of clinicians, pharmacologists, toxicologists, and pathologists is an example of “translational medicine,” i.e., the bidirectional collaboration of clinicians and pre-clinical research. In the future, the team hopes that patient-specific decisions can be supported by testing a patient’s tumor with some of the more than 200 chemotherapies available.
“If you have only one or two chances, you want the best therapy possible,” says Hartung. “It was the personal experience of my sister’s goddaughter, who died a few years ago from glioblastoma, which prompted this new use of our mini-brain technology. So, something sad and devastating can bring some light for others.”
BrainSpheres (mini-brains) are created from induced pluripotent stem cells (IPSC). Like embryonic stem cells, which can form any tissue of the human body, IPSC are derived from a tiny piece of human skin donated by a patient or healthy donor. These cells are genetically reprogrammed to return to an embryonic state, in which they can be maintained for many years. Whenever needed, they can be stimulated to form other tissues, including brain tissues. The CAAT team published the technology for mass production of mini-brains in 2017 (A Human Brain Microphysiological System derived from iPSC to study central nervous system toxicity and disease. ALTEX 2017, 34:362-376. doi: 10.14573/altex.1609122.). Adding a few glioblastoma cells from a patient at an early stage of mini-brain engineering generates the formation of tumors within the organoid. After a few weeks, chemotherapies and their effects on both tumors and healthy brain tissue can be evaluated. This new method—presented for the first time in this publication—can accelerate evaluations by pathologists. The researchers demonstrated this for the well-established chemotherapy agent temozolomide (TMZ) as well as for an experimental treatment, doxorubicin (DOX), that is not yet used in patients.
The study results indicated the system could predict a clinical response to TMZ and also demonstrated anti-tumor efficacy with DOX. Furthermore, it was also observed that DOX acted via selective killing of tumor cells (apoptosis) with little or no effect on normal brain cells. This system can be adapted for use with publicly available libraries of glioblastoma patient-derived cell lines, paving the way for the creation of a more efficient discovery platform for new therapies, ultimately offering a more personalized approach by matching patients to therapies that are more likely to be clinically effective.
Contact: Michael Hughes (firstname.lastname@example.org)
Center for Alternatives to Animal Testing (CAAT)
Simon Plummer, Stephanie Wallace, Graeme Ball, Roslyn Lloyd, Paula Schiapparelli, Alfredo Quiñones-Hinojosa, Thomas Hartung & David Pamies “A Human iPSC-derived 3D platform using primary brain cancer cells to study drug development and personalized medicine.”
Scientific Reports, volume 9, Article number: 1407 (2019)
Available at: https://www.nature.com/articles/s41598-018-38130-0
About CAAT: The Johns Hopkins Center for Alternatives to Animal Testing (CAAT), founded in 1981, is part of the Johns Hopkins University Bloomberg School of Public Health, with a European branch (CAAT-Europe) located at the University of Konstanz, Germany. CAAT promotes humane science by supporting the creation, development, validation, and use of alternatives to animals in research, product safety testing, and education. The center seeks to effect change by working with scientists in industry, government, and academia to find new ways to replace animals with non-animal methods, reduce the numbers of animals necessary, or refine methods to make them less painful or stressful to the animals involved.