When it comes to biology, fiction often predates reality, sometimes by centuries. Mary Shelley’s Frankenstein epitomizes how much one novel has infiltrated science throughout time. For example, earlier this year, Science created a fun infographic depicting which 21st century technologies could give birth to a modern day Victor Frankenstein. A combination of transplants, lab-grown and mechanical organs, along with bionics round out the magazine’s homage to the book’ s 200th anniversary.
Since the first paper describing a brain organoid—a miniature, simplified version of a human organ—published in 2013, many new technologies, from organs-on-a-chip to organoids, have continued biomedical science down the innovative path that some still liken to Shelley’s work. No longer the stuff of Gothic novels, these methods and technologies have the potential to replace some animal models currently used in studying new drugs and developing personalized approaches for cancer treatment.
Though many teams contribute to innovation in the laboratory, there are salient differences in the technologies from which mini-organs spring. Ken Zaret, PhD, director of the Institute for Regenerative Medicine at Penn, explains that organoids are simply miniature versions of immature organs. Where an organ-on-a-chip involves cells grown on an engineered structure under controlled conditions, organoids, eventually the size of a grain of sand and viable for up to a year, are created when immature cells are manipulated into different organ tissue types before being spun in a bioreactor where they take on a three-dimensional form.
For Zaret, the most important aspect of taking cell culture from 2-D to 3-D is the ability to model disease diagnosis and treatment.
For example, internationally renowned neuroscientists, Guo-li Ming, MD, PhD, and Hongjun Song, PhD, moved to Penn in 2017 to continue their work with brain organoids. Well known for their research on the molecular mechanisms underlying early brain development and brain-based disorders such as schizophrenia and autism, Song investigates how neural cells are born, and Ming focuses on pre-birth cell development. Their work has been instrumental in advancing our knowledge about the Zika virus. Using organoids, the pair found that the virus targets brain stem cells, decreasing cell replication and mimicking microcephaly, a condition in which a newborn baby’s head is significantly smaller than normal. The approach cemented the potential of using organoids to ask questions about brain diseases.
Their work uses brain organoids, sometimes called mini-brains, because “cells don’t function in isolation,” Song said. “They are a better mimic of human biology compared to other technologies.” At 100 days, brain organoids resemble the organization of cells in human fetuses in the late second trimester.
Song is now working with Penn neurosurgeon Donald O’Rourke, MD to make organoids from glioblastoma cells donated by cancer patients. They use them to test different immunotherapies against each patient’s own unique cancer cell-derived organoid. In addition, they use a glioblastoma organoid fused to one made from normal brain cells to study the migration of cancer cells into normal brain tissue for a front-seat view of how a cancer metastasizes.
Another Penn neurosurgeon, Isaac Chen, MD, aims to use cerebral organoids to find a way to restore vision in his patients. His lab generated mini-brains from a human embryonic stem cell line and transplanted them into the brains, specifically the visual cortex, of 11 rats. At the Society for Neuroscience meeting in November 2017, Chen described that when light was aimed into the rat’s eye or when the regions in the brain responsible for vision were electrically stimulated, neurons in the organoid fired, signaling that the cells were communicating with the rat’s own brain cells.
As more organoid-based studies in tissues from the neck to the mid-section of the human body take shape, Penn researchers could soon create their own map of how this technology is changing our understanding of chronic and deadly conditions. In addition to the brain, researchers across Penn Medicine – often in collaboration with colleagues at Penn Vet and other Penn schools – are using mini-organs to evaluate treatment options and drug development for diseases in nearly every system of the body, including esophageal cancer, oropharyngeal squamous cell carcinomas, and lung diseases, as well as a rare disease called dyskeratosis congenita, which causes stem cells to fail, leading to a host of serious conditions, including acute intestinal inflammation.
“Since we can’t do genetic experiments in humans, organoids are one of our best methods to assess the behavior of human lung cells,” said Edward E. Morrisey, PhD, a professor of Cell and Developmental Biology, and director of the Penn Center for Pulmonary Biology, whose lab is looking for compounds to treat such conditions as idiopathic pulmonary fibrosis, whose cause is poorly understood.
From this flurry of research, there’s no doubt that organoids are helping to accelerate lab research to clinical practice. But at the same time, in 2017 when a researcher from the Salk Institute in San Diego reported that his lab had transplanted a brain organoid into a mouse brain, some ethical hackles were raised anew.
“People are more worried about if [brain organoids] reach a certain level — if it’s really like a human brain. We’re not there; we’re very far from there,” Song said in a recent Washington Post article. “But the question people ask is, ‘Do they have consciousness?’ The biggest problem I have so far is I think, as a field, we don’t know: What is consciousness? What is pain?”
While the future of organoids in biomedical research has many unanswered questions, their utility to more efficiently and ethically research and test new drugs in a personalized way for an array of diseases is a safe bet.