This week we profile a recent publication in Nature from Drs. Rebecca Hodge and Trygve
Bakken in the laboratory of Dr. Ed Lein (pictured) at the Allen Institute for Brain Science.
Can you provide a brief overview of your lab’s current research focus?
My laboratory is focused on understanding the fine cellular and circuit architecture of the human brain, and what aspects of this architecture are conserved with other mammalian species versus what is specialized in human that may give rise to our particular cognitive capabilities and susceptibility to disease. As part of a big team effort in our Cell Types program, we have taken on the challenge of trying to understand the complete cellular makeup of the brain, using a wide variety of techniques including modern single cell transcriptomics, cellular physiology and anatomy, and connectivity. My team specializes in trying to apply the knowledge and methodology generated in animals used as model organisms, principally the mouse, and apply them to study the human brain. We have been quite successful in this regard, and are learning a huge amount about how the general cellular organization of the brain is highly conserved from mouse to human. On the other hand, matched or homologous cell types can have very different properties, and these differences presumably give rise to our own unique traits.
What is the significance of the findings in this publication?
The first important result is that the new technique of single nucleus transcriptomics, which measures all genes being used in single cells but can be applied to cell nuclei which are preserved in frozen tissues, opens up the study of cellular diversity in the human brain in a way that has not been possible. This is a new way of thinking about cell types in the brain, as defined by the sets of genes that given them their traits, rather than their shapes or electrical properties as has been done historically. Using this approach, we show that there are many different molecularly distinct cell types in the human cortex, and, surprisingly, that these types are largely conserved with mouse despite about 75 million years of evolution. At the same time, thousands of genes are expressed in different cells in human compared to mouse. Many of these genes are important for the function of neurons, including how they connect to other neurons and how they respond to drugs that are used to treat neuropsychiatric disorders. These differences likely contribute to challenges in using mice as model organisms and may explain why many drugs that can treat brain disorders in mice do not translate well to humans. This really highlights the need to evaluate model organisms with care and the importance of directly studying human tissue.
What are the next steps for this research?
We only looked at a single brain region in this study, so a natural extension is to extend this work to more brain regions and across human individuals. What’s more, the finding that we can align cell types across species and compare their properties opens up a huge field of comparative studies across other species. We can now ask what is truly distinctive about the human brain, and what animals are likely to be the best models for studying particular aspects of brain function. Finally, these methods are immediately applicable to start to study brain diseases and understand if particular types of cells are vulnerable in neurodegenerative diseases like Alzheimer’s or Parkinson’s disease.
The main funders of this work include:
This work was funded by the Allen Institute for Brain Science and by US National Institutes of Health grant U01 MH114812-02 to E.S.L.
