When Madeline Lancaster’s attempt to grow neural stem cells ‘failed’ she had no idea that the floating balls of cells she saw in her petri dish, resolutely not doing what she wanted them to do, were in fact miniature brain tissues. They would revolutionise our ability to study the early stages of brain development and take us closer to answering: what makes us human?
I’d set out to grow neural stem cells on the surface of a Petri dish but within a day, I’d realised something had gone wrong. The protein preparation I was using to coat the bottom of the dish was quite old, which meant that the cells were not sticking as they were meant to, instead they formed these floating balls.
A lot of people would probably have just thrown these balls of cells away, but I let them continue growing. Quite soon, I could see structures inside them that as a neurobiologist I recognised as certain features you would see in the brain.
It was serendipitous in the sense that these beings just sort of appeared in the dish when I wasn’t expecting them. The timing was also very nice as the discovery happened early on in my postdoctoral fellowship, which meant that I was free to explore and let whatever observations I might make guide me.
After the initial excitement, there was a lot of hard work involved to develop these small balls of cells into tissues. Over the next several months to a year, I would repeat these experiments, adding different combinations of ‘food’ supplements to the cells, diligently recording the outcome in my lab book. Eventually I discovered that a particular protein gel called Matrigel provided enough support to allow the cells to self-organise into three-dimensional tissues.
These three-dimensional tissues are known as organoids – literally meaning ‘organ-like.’ And that’s exactly what they are – they are miniature organ tissues that resemble actual organs, for example they have the same cell types, similar structure and function. Depending on the type of stem cells used different organoids develop. In my case I used neural cells to grow brain-organoids or ‘mini-brains’ as they are sometimes called, but others across Cambridge are now growing mini-lung, mini-gut, and mini-liver tissues.
Studying the human brain poses a challenge. While animal models have helped us to understand the fundamental mechanisms, they can only take us so far. Again, human stem-cell-derived neurons grown in 2D have provided valuable insights about the cells themselves, but neurons don’t exist in isolation and so there’s a limit to how much we can understand about the way the brain works from these studies.
Brain-organoids give us something that looks and behaves a lot more like the real thing. They have allowed us to ask questions about why we are uniquely susceptible to neurological and mental health conditions like schizophrenia that don’t appear to affect animals. And, a particular focus of my lab, is what makes the human brain so special.
Understanding what sets us apart from other animals is such a fundamental question. For example, we know dolphins are smart and have big brains but they’re not having Zoom conversations!
Great apes’ brains are around three times smaller than ours – in fact my recent calculations showed they are closer in size to a mouse’s brain! We’re really interested in how this difference in size comes about.
We grew organoids from the cells of humans and our closest living relatives: chimpanzees and gorillas. We found that there were differences very early on in development. The human stem cells were slower than our ape relatives to transition into a state that would allow neurons to grow. This very subtle variation at this key stage when cells are expanding exponentially has dramatic effects on the end-product.
We also found that human organoids are double the size, compared with the chimpanzee and the gorilla. This matches very nicely with what you see in terms of brain size. Specifically, in the cerebral cortex, the number of neurons in the human brain is double that of the brains of great apes.
To use the analogy of a computer – if you put in more central processing units, you're going to get more computing power. I think that's probably a big part of what's going on and enabling humans to have our unique cognitive capabilities.
Science is like exploring. Five-hundred years ago people were mapping the world. Now we’ve turned inward and are trying to map out what's going on inside our bodies. Every experiment is a discovery. It's great fun to look down the microscope and know that you're the first person in the history of humankind to witness a particular biological phenomenon. It’s so thrilling.
I like to think that profound discoveries can come from unexpected observations. There’s a lot of serendipity in science, but you also have to be open to it. In science we’re taught to follow the scientific method which is very important, but a lot of people forget about the very first step, which is to make an observation.
I’m excited to see how organoids can help answer other research questions. For instance, we’re seeing more and more interest in using the tool to study the blood-brain barrier, epilepsy and neurodegeneration.
I’ve recently become a Fellow at Clare Hall. I’m really looking forward to interacting with other researchers in the Cambridge community. I think it’s often easy to become focused on our specific field but there’s so much we can learn from all the disciplines. Often, we are asking very similar questions but coming at it from different angles. I think ultimately we will need answers from all subjects to unravel what makes us human.
Madeline Lancaster is a Group Leader at the Medical Research Council (MRC) Laboratory of Molecular Biology in Cambridge and an Official Fellow at Clare Hall.
This profile is part of This Cambridge Life – stories from the people who make Cambridge University unique.
Words: Charis Goodyear. Photography: Lloyd Mann.
