For thousands of years, human have been trying to understand a fundamental question about ourselves – What is inside our brain and how does it work? This many centuries-long topic continues to puzzle the world today, but thanks to global science collaboration and cutting-edge technologies, we are one step closer to demystify the most sophisticated organ in our body.

Among the greatest talents in the field of brain science, an internationally renowned neurobiologist and biophysicist, and a leading scientist in brain research in China, Academician of the Chinese Academy of Sciences, Professor Mu-ming Poo has devoted himself to the research of brain science for many years. 

In 2021, Professor Mu-ming Poo led a team that cooperated with BGI Group and used BGI's spatio-temporal omics technology, Stereo-seq, to promote the research of the brain. 

He also joined the SpatioTemporal Omics Consortium (STOC) initiated by BGI-Research and other institutions in 2022 as a core member to collaborate with more than 190 top scientists from 30 countries to answer some key questions in brain science.

In a recent interview, he shared his insights on brain science, spatio-temporal omics, and other areas.

Professor Mu-ming Poo, Academician of the Chinese Academy of Sciences (CAS), Scientific Director of Institute of Neuroscience, CAS, and CAS Center for Excellence in Brain Science and Intelligence Technology, and Paul Licht Distinguished Professor in Biology Emeritus at University of California, Berkeley.

Q. Why is brain science so important?

Brain science is a cutting-edge field in life sciences. But our current understanding of the brain is quite limited, with many unanswered questions.  

We all know that humans are the most intelligent of all species, but why have humans developed such complex and capable brains while other animals have not? This is a great question.

There is little difference in structure between human fertilized eggs and fertilized eggs of other animals, only a little difference in size. So, why can human fertilized eggs differentiate into brains? How does the brain form during human development? How does the brain’s complex network structure work? Why can the brain process information and generate such advanced intelligence? These are questions people are curious about.

The human brain is probably the most complex biological tissue system. Therefore, the working principle of the brain, its structure, and how it functions are all important frontier issues, that may not even be resolved this century.

Q: Why is brain research so difficult? 

To truly understand the complexity of the brain, we first need to understand its structure, particularly the connections between individual nerve cells, which are also known as networks. Networks are the necessary structures for processing information.

By depicting the connections at the cell level, we can generate a connection map, which we call a mesoscopic neural connection map. Only by understanding this structure at the mesoscopic level can we know how the network processes information. 

The first technical difficulty is distinguishing the various cell types in each brain area. A big difference between brain tissue and other tissues is that brain tissue has a particularly large number of cell subtypes - hundreds, even thousands of them. From mice to monkeys to humans, the study of subtypes is a very popular field in life sciences. We need to determine the type of cell, and then we can label the cell, trace its projections and connections, and finally construct a map.

The second technical difficulty is the tracking map, which shows long-range neural connections distributed between various brain regions. To do a tracking map, it must have the resolution of the cell level and be able to track long-range connections. This technology is very complex.

Q: What effect do you think the emergence of spatio-temporal omics will have on life sciences research?

A major contribution of spatio-temporal omics is the addition of space and time factors. The various omics studies we have been doing are based on a fixed sampling time without detailed cell spatial distribution information. But all transcriptomes and proteomes are dynamic, develop in a special status of spatial distribution, and change over time. Only by knowing these changes can we understand the true meaning of these omics.

For example, if you want to use transcriptome information to distinguish cell types - if the transcriptome changes over time, does the cell type also change over time? Therefore, if you want to define whether a cell belongs to a certain type, it is not enough to just look at the transcriptome at one time point. We must also know whether the transcriptome is stable. If the change in the transcriptome pattern is only a temporary change, it can only be considered as a temporary state of the cell, not a real cell type.

In this sense, there is no way to truly classify cells if the time factor is not added or the transcriptome at each time point not be clarified.

Cell classification is the first step for us to study biological tissues. The most critical thing is how many stable cell types there are. Without a clear classification, our understanding of the complex systems of living things is very difficult.

The emergence of spatio-temporal omics not only solves the differences in spatial distribution, but also changes in time. In fact, various omics studies generally have not considered the factor of space. The single-cell transcriptomes we make are all on disrupted cells and we have to analyze them one by one. The spatial location of these cells in the tissue needs to be clarified as well.

Therefore, I think that the technology for spatio-temporal transcriptome research is a major progress in the field of biology. 

Focusing on the field of brain science, the first direction in which spatio-temporal omics can make significant contributions is to clearly distinguish hundreds of different cell subtypes in the brain, and to clarify the distribution of various subtypes in brain tissue.

Q: In May 2022, the SpatioTemporal Omics Consortium (STOC) was established. So far, more than 190 top scientists from 30 countries have joined. As a core member, could you please introduce the original intention of joining this consortium and your expectations for its future development?

Like the Human Genome Project, one of the most important goals of the STOC is to unite scientists. With STOC, it is those scientists who are interested in spatio-temporal omics research across the globe. 

The research on brain science, such as the structure and function of the human brain, is several orders of magnitude more difficult than the Human Genome Project, so we need cooperation from all over the world.

Spatio-temporal omics is a necessary means for us to study the brain. In the development of this technology, we also need the joint effort of scientists in relevant fields around the world. In the international cooperation of biological research, there are already good precedents, and BGI has made many remarkable achievements in this regard. This was also the basis to establish an international consortium such as the STOC.

I believe that in the field of biological research, especially the research related to diseases, the competition is far less than the cooperation, and the information obtained is publicly available all over the world. So, on this basis, everyone can work together to do this work, and it is a win-win for everyone. 

Q: How will brain science research develop in the next 5 to 10 years? 

From the developments in brain science over the past century, 5 to 10 years is a very short time. At present, our understanding of major issues in brain science is still very superficial. To really understand the structure and function of the brain is something that may take decades or even a century.

Human interest in brain science stems from curiosity. Why is our brain so complicated? How did intelligent objects like the brain emerge? It is a research discipline driven by curiosity to understand nature.

But we are now facing a very serious problem in society with the extent of brain diseases such as autism in childhood, depression in middle age, and degenerative diseases in old age such as Alzheimer's, Parkinson's, and others.

According to statistics from the World Health Organization, the social burden of brain diseases has reached 28% of the global social burden of various diseases, exceeding the burden of cardiovascular disease and cancer.

Therefore, under such a heavy social burden, if we cannot solve the problem of diagnosis and treatment of brain diseases, our medical system could collapse. Because of the urgency of the problem, we cannot wait until brain science has figured it out how to solve the problem - it will be too late.

The current development direction, including that undertaken by the China Brain Project, is to apply the results and some basic understanding to the diagnosis and treatment of brain diseases as soon as possible. 

For example, we now have technology that can diagnose whether a person's cognitive decline is abnormally greater than the normal population. After the diagnosis is made, we need to develop some technologies that can intervene early and prevent the evolution and occurrence of the disease before it reaches a critical condition. 

To give another example, we still don't understand what depression is all about because we haven't figured out the network structure of the brain. But if we can develop a regulation technology that changes the macroscopic activity state of the brain, and make it advance to a normal state, then maybe we'll be able to curb and alleviate depression.

If you want to talk about the development in the next 5 to 10 years, I think it will be the development in this field.