A Harvard-led team has developed a method for keeping human brain organoids alive and developing for years, opening new possibilities for studying brain development, neurological disease and potential treatments.
A team led by Paola Arlotta of Harvard University has developed a new method for keeping human brain organoids alive in laboratory culture for up to five years, a breakthrough that could significantly extend the period over which scientists can study the development of the human brain.
The research, published in Nature, is less a single discovery than a new scientific technique that could enable many others. Brain organoids do not resemble fully formed human brains, but they reproduce different types of brain cells, their gene expression and some stages of their organisation. They have become an important tool for investigating an organ that remains exceptionally difficult to study directly.
The new technique addresses one of the central limitations of existing brain organoids. Until now, researchers could largely reproduce only embryonic stages of human brain development, equivalent to the first months of life in the womb. Cells grown in laboratory conditions, particularly vulnerable neurons, deteriorated before they could develop much further.
Arlotta’s team developed a culture method that allowed neurons to continue maturing for years rather than months. The researchers also conducted a separate experiment in which young and mature brain cells were combined in the same organoid. The experiment showed that cells retain a record of the time that has passed. Young cells were able to reprogramme older ones, which skipped intermediate stages of development and generated a type of neuron in two weeks that would normally take months to develop.
The ability to observe brain development over a much longer period could be particularly important for understanding diseases whose effects emerge only after birth. Noelia Antón-Bolaños, a co-author of the study who carried out the work at Harvard and now leads her own laboratory at Utrecht University in the Netherlands, pointed to Huntington’s disease as an example.
Although Huntington’s disease is associated with a mutated gene present from birth, its symptoms generally appear during adulthood. This has made it difficult to observe what happens at cellular level during the earliest stages of development. Long-lived organoids could allow researchers to examine those stages directly and determine whether particular types of cells begin to change long before clinical symptoms emerge.
The researchers also found that the cells maintained a human-specific internal biological clock even outside the body. Through epigenetics, which examines chemical marks that accumulate on DNA with age, scientists can track this clock and determine how long cells have been developing.
That finding is significant because human neurons take years to mature fully, making the process difficult to reproduce using animals. The organoids, according to the study, faithfully recorded the passage of time at an epigenetic level. A two-year-old organoid could therefore provide a model for investigating aspects of brain development occurring at a comparable stage in a human child.
The potential applications extend beyond basic research. Antón-Bolaños said the ability of mature cells to respond to younger cells raised the possibility that researchers could eventually identify the signals responsible for generating new neurons more rapidly. Such knowledge could, in the future, contribute to approaches aimed at slowing neurodegenerative processes.
The technology could also improve the study of conditions in which timing is crucial. Sandra Acosta, a professor at the University of Barcelona and leader of the Research Group in Neurological Disease Models, highlighted the importance of preserving the timing of human brain development. In epilepsy research, for example, scientists need to generate particular neurons at the correct stage of development if they are to reproduce the disease accurately.
The scale of the new resource is also substantial. The researchers will make available more than 424,000 analysed cells, 110 organoids and records tracking DNA ageing over five years, allowing other scientists to investigate the data without having to reproduce the entire experiment themselves.
The breakthrough does not mean that scientists can recreate a complete human brain in a laboratory. Instead, it extends the period during which key aspects of human brain development can be observed. By allowing researchers to follow cells for years rather than months, the organoids expand the territory in which scientists can search for answers to some of the most difficult questions surrounding human neurological disease.
