The group leader of the Cell Biology Division of the Molecular Biology Laboratory of the Medical Research Council (MRC) and part of the Cambridge Biomedical Campus in the United Kingdom; could revolutionize the study of the brain thanks to years of study and some chance. In the words of Madeline Lancaster, her attempt to grow neural stem cells failed, but she had no idea that the floating balls of cells she saw under the microscope and on her Petri dish were, in fact, miniature brain tissues.
He has done innovative work in the development of brain organoid technology that is generating significant advances in neurological development and disease research. Work in the Lancaster laboratory focuses on studying the development of the human brain using brain organoids. The laboratory uses mini-brains to study the most fundamental differences between the development of the human brain and that of other mammalian species. Its progress jeopardizes everything that comes in terms of brain studies and brings us closer to the answer to an intriguing question: what makes us human?
“I set out to grow neural stem cells on the surface of a Petri dish, but within a day I realized that something had gone wrong,” he tells Infobae exclusively in a telephone chat. The protein preparation I was using to cover the bottom of the dish was quite old, which meant that the cells did not stick together as they should, but formed floating balls. Many scientists would probably have thrown away that product, but I let it continue to grow. Very soon, I was able to see structures inside that, as a neurobiologist, I recognized as certain characteristics that you would see in the brain.”
-That is to say that, as in other famous cases of science, was chance an ingredient?
It was fortuitous, it's true, in the sense that these beings just appeared on the plate of the laboratory when I didn't expect them. The timing was also very good as the discovery happened at the beginning of my postdoctoral fellowship, which meant that I was free to explore and let the observations I could make guide me. After the initial excitement, there was a lot of work involved to turn these little balls of cells into tissues. For a year I followed my trials and errors with this development: I repeated these experiments, adding different combinations of food supplements to the cells, diligently recording the result in my laboratory book. I eventually discovered that a particular protein gel called Matrigel provided enough support to allow cells to self-organize into three-dimensional tissues.
- Are those the organoids?
- Indeed. These three-dimensional tissues are known as organoids, which literally means organ-like, but an alternative that is used in the laboratory to investigate the depths of the brain, in this case, and possible treatments against its ailments. That's exactly what these constructs are that we achieved in the laboratory: they are miniature organ tissues that resemble real ones, for example, they have the same cell types, structures and similar functions. 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 in Cambridge are now culturing mini-lung, mini-gut and mini-liver tissues.
- What are the first steps in the study of the brain?
- Studying this human organ poses a challenge. While animal models have helped us understand the fundamental mechanisms, they can only take us so far. Once again, neurons derived from human stem cells cultured in 2D have provided valuable information about themselves, but neurons do not exist in isolation, so there is a limit to what we can understand about how the brain works from these studies. Cerebral organoids give us something that looks and behaves much more like the real thing. They have allowed us to ask questions about why we are exceptionally susceptible to neurological and mental health conditions such as schizophrenia that don't seem to affect animals. And, a particular focus of my laboratory, is what makes the human brain so special.
-The next step would be to discover what differentiates us from animals: how can it be revealed?
- Understanding what sets us apart from other animals is a fundamental question. For example, we know that dolphins are smart and have big brains, but they don't have Zoom conversations! The brains of great apes are about three times smaller than ours; in fact, my recent calculations showed that they are closer in size to the brain of a mouse. We are really interested in understanding how this difference in size occurs. We grow organoids from cells of humans and our closest living relatives: chimpanzees and gorillas. We found that there were differences very early in development. Human stem cells were slower than our ape relatives in transitioning to a state that would allow neurons to grow. This very subtle variation at this key stage when cells expand exponentially has dramatic effects on the final product.
- What other differences did you detect?
-We also found that human organoids are twice the size, compared to the chimpanzee and the gorilla. This matches very well with what you see in terms of brain size. Specifically, in the cerebral cortex, the number of neurons in the human brain is twice that of the brains of great apes. To use the analogy of a computer: if you place more central processing units, you will get more computing power. I think that's probably a big part of what's going on and allowing humans to have our unique cognitive abilities.
- Is this way of investigating distancing itself from the way it was done in the past?
-Science is always about how to explore. Five hundred years ago, people mapped the world: they traveled it and translated it into increasingly accurate documents. Now we have turned inward and are trying to map what is going on inside our bodies. Every experiment is a discovery. It's really fun to look through the microscope and know that you're the first person in human history to witness a particular biological phenomenon. It's so exciting. I like to think that profound discoveries can come from unexpected observations. There is a lot of chance in science, but you also have to be open to it. In this discipline we are taught to follow the scientific method that is very important, but many people forget the first step, which is to make a good observation.
- What things are already happening with your organoids?
-I'm excited to see how organoids can help answer other research questions. For example, we are seeing increasing interest in using the tool to study the blood-brain barrier, epilepsy, and neurodegeneration.
I really want to interact with other researchers in the Cambridge community. The pandemic exposed us to more open collaborative work that science had not experienced in this way in the past. The exchange between different specialties, research centers and universities around the world intersected with bases of health banks that have been preserved for years and which, thanks to their access, allowed professionals from all disciplines to find new paths, together, using knowledge from different angles. I think it's often easy to focus on our specific field, but there's a lot we can learn from all disciplines. Often, we ask very similar questions but approach them from different angles. I think that, ultimately, we will need answers on all issues to unravel what makes us human.
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