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Celebrating DNA Double Helix's 70th at CPL's 3rd Anniversary——Part V: Genomic medicine, genomic neurobiology and technology, and closing remarks


A two-day international scientific symposium to celebrate the 70th anniversary of the discovery of DNA's double helix structure, the most profound biological discovery of the last century, concluded in Beijing on Oct 22, 2023.

The symposium, which also marked the third anniversary of Changping Laboratory, focused on recent advances in life sciences reflecting the living legacy of the DNA double helix. Topics presented and discussed in the symposium included  DNA sequencing, gene editing, central dogma, DNA and immunology, epigenetics, genomics, genomic medicine and genomic neurobiology and technology.

Session VII: Genomic Medicine

Dissecting Biochemical Pathways of Regulated Cell Death

Professor Wang introduced the biochemical pathways of aging in the mammalian reproductive system. He illustrated the pathways of programmed cell apoptosis and necrosis, providing an overview of his team's research on regulating the signaling pathways of programmed cell death.

Next, he delved into the discovery of the protein kinase RIP3 and associated MLKL, elucidating the molecular mechanisms that underlied programmed cell necrosis. Their research involving the deletion of RIP3 and MLKL genes in male and female mice revealed that RIP3, as opposed to MLKL, played a pivotal role in overseeing the aging process of the male and female reproductive systems. Specifically, RIP3 was found to oversee programmed necrosis in male mice by influencing spermatogonial stem cells, and in female mice, it regulated apoptosis in ovarian granulosa-luteal cells. In summary, the research outlined how RIP3 governed the aging of the mammalian reproductive system.

2.Presentation by Dennis Lo

Creating a Paradigm Shift in Prenatal Diagnostics using Circulating DNA

Professor Lo developed an interest in prenatal testing when he was a medical student at the University of Oxford. He dreamt about the possibility of testing fetal DNA and chromosomes just from a peripheral blood sample from the pregnant mother. He made a breakthrough in 1997 when he boiled maternal blood plasma and showed that he was able to observe a Y-chromosomal DNA PCR signal in samples obtained from pregnant women carrying male fetuses.He then spent many years trying to translate this discovery into a new platform for non-invasive prenatal testing (NIPT). He showed that fetal trisomy 21 could be detected from maternal plasma by single molecule PCR and random massively parallel sequencing. The latter method has now been used worldwide by millions of pregnant women every year.

Professor Lo has also pioneered the cell-free DNA approach to many other branches of medicine, including post-transplantation monitoring and the detection of multiple types of cancer, culminating in the first generation of multi-cancer early detection (MCED) tests.

3.Presentation by Jie Qiao

Searching for Keys from the Genome: Thirty Years of PGT

Professor Qiao reviewed the development and applications of Preimplantation Genetic Testing (PGT) over the past 30 years, highlighting the role of genomic sequencing technology in advancing PGT and reproductive health. Embryo developmental abnormalities can lead to adverse pregnancy outcomes, but PGT, coupled with assisted reproductive techniques, allowed for the selection of healthy embryos through genetic analysis before implantation into the mother's uterus. It increased the chances of having healthy offspring. Based on the pioneering research conducted by many teams represented by Qiao’s on human pre-implantation and post implantation embryonic development and gamete development, which elucidates the dynamic regulatory mechanisms of cell fate determination and embryonic development from multiple perspectives such as genetics and epigenetics, laying a solid theoretical foundation for PGT application.

Moreover, the advent of single-cell sequencing technology has further accelerated the clinical application of PGT. A significant milestone was achieved in 2014 when the world's first test-tube baby screened for single-gene genetic diseases using MALBAC genomic amplification and high-throughput sequencing was born at Peking University Third Hospital. This marked China's advance in PGT technology on a global scale. At Present, NGS-PGT can diagnose hundreds of single-gene diseases, multiple gene mutations, single-gene testing with HLA typing analysis, and cases involving incomplete pedigrees or de novo mutations. Furthermore, non-invasive Preimplantation Genetic Testing (niPGT) based on cell-free DNA (cfDNA) has been developed, taking PGT toward the goal of being non-invasive, safe, and accurate.

4.Presentation by Zemin Zhang

Tumor Heterogeneity at the Microenvironment Level and its Implication in Personalized Immunotherapy

To unravel the heterogeneity of the tumor microenvironment at the single-cell level, Professor Zhang's team integrated single-cell transcriptome data from various cancer types. They constructed tissue distribution and gene expression profiles of various cell types, including myeloid cells, T cells, NK cells, and others involved in tumor infiltration. Several cell subtypes and states related to tumor development were identified, such as LAMP3+ dendritic cells, SPP1+ macrophages, and tumor-associated NK cells (TaNK), and their interactions were revealed. These findings contributed to the development of potential targets for tumor immunotherapy.

Based on the heterogeneity of the tumor microenvironment among different patients, patients have been further categorized. The Zhang lab found that patients may possess different dominant immune evasion mechanisms. In line with this, the team proposed the possibility of developing personalized tumor treatments by tailoring different strategies based on the composition of a patient's cell types and states.

5.Presentation by Yunlong Cao

Broad-spectrum SARS-CoV-2 Therapeutics and Prophylactics designed based on Viral Evolution Prediction

In this report, investigator Yunlong Cao systematically introduced the work conducted by his group about SARS-CoV-2 evolution prediction and the development of broadly neutralizing antibodies. He pointed out that SARS-CoV-2 is undergoing continuous evolution, giving rise to numerous immune-evasive mutants. Furthermore, the pace of viral mutation surpasses that of vaccine and antibody drug development. To address this issue, they reported a series of pioneering efforts on predicting the evolutionary trends of SARS-CoV-2. They developed a high-throughput deep mutational scanning (DMS) technique to systematically analyze the antibody escape sites of SARS-CoV-2 receptor-binding domain (RBD). With the characterization of thousands of SARS-CoV-2-specific monoclonal antibodies isolated from convalescent and vaccinated individuals, they successfully predicted the prevalence of various mutant strains, including BQ.1.1, CH.1.1, and XBB subvariants. Currently, this approach has been widely applied in monitoring the emergence of concerning mutations of SARS-CoV-2 by the community. Subsequently, Cao introduced their rational identification of a broad-spectrum neutralizing antibody, SA55, which was isolated from individuals who had recovered from SARS in 2003 and received three doses of CoronaVac, by high-throughput single-cell V(D)J sequencing and DMS epitope mapping. SA55 has already been transferred to SINOVAC for clinical development. Finally, he provided insights into future strategies for the development of broad-spectrum COVID vaccines, emphasizing the feasibility of designing broad-spectrum vaccines based on the prediction of RBD mutational hotspots.

Session VIII: Genomic Neurobiology and Technology

1.Presentation by Tom Maniatis

The Protocadherin Gene Cluster: A Bar Code Generator for Single Neuron Self-Recognition in the Mammalian Brain

Professor Maniatis discussed the mechanisms by which clustered Pcdh genes regulate the distribution of serotonergic neurons in the brain. He emphasized the importance of individual neurons accurately distinguishing "self" from "non-self", and mechanisms that prevent neurites from the same neuron to form synaptic connections.  Through their research, Professor Maniatis's team discovered that the protocadherin (Pcdh) gene cluster, divided into Pcdh-α, Pcdh-β, and Pcdh-γ regions, provide a "bar code" for single neuron self-recognition. Subsequent studies revealed the function of Pcdhs in the wiring of olfactory sensory neurons (OSN) and serotonergic neurons, highlighting the role of Pcdhs' diversity in the assembly of cell surface molecules. In cases of diversity loss, OSNs failed to correctly connect in the brain, leading to an inability for mice to distinguish different odors. Through extensive research, Professor Maniatis's team identified a single gene within the Pcdh cluster, Pcdh-α-ac2, responsible for the ability of serotonergic neurons to assemble in a tiled pattern throughout the brain, ensuring the even distribution of serotonin. Deleting Pcdh-α-ac2 caused serotonergic neurons to become entangled, resulting in depressive symptoms in mice. These studies provided new insights into the study of brain diseases, suggesting that abnormalities in neuronal wiring may be related to various neurological disorders.

2.Presentation by Don Cleveland

Designer DNA Drug Therapy for Neurodegenerative Disease

Professor Cleveland discussed the molecular mechanisms underlying various gene mutations associated with neurodegenerative diseases and the use of antisense oligonucleotides (ASOs) in treating these conditions. Professor Cleveland's team discovered that ASOs can enter neurons and selectively pair with mRNA, resulting in RNA degradation and the inhibition of gene expression. Leveraging this feature, the team designed various ASO-based therapeutic strategies to address neurodegenerative diseases caused by gain-of-function gene mutations. He then provided examples of recent research achievements by his team. For instance, around 2% of individuals with Amyotrophic Lateral Sclerosis (ALS) develop the disease due to the toxic effects of functionally mutated SOD1 genes. ASO-SOD1 was effective in reducing SOD1 expression. Similarly, Parkinson's disease caused by activating mutations in the LRRK2 gene could be targeted with ASO-LRRK2. Additionally, Alzheimer's disease related to the accumulation of misfolded Tau protein could be addressed with ASO-Tau. Professor Cleveland also shared applications of ASOs in guiding normal gene expression in ALS and Frontotemporal Dementia (FTD). For example, ASO drugs could partially replace the function of TDP-43, restoring normal splicing of STMN2 pre-mRNA and thereby normalizing the synthesis of Stathmin-2 protein. In conclusion, Professor Cleveland summarized the progress and prospects of DNA drugs in treating neurodegenerative diseases within the nervous system.

3.Presentation by Joseph Ecker

What Lies Above? Mapping the Human Brain Epigenome

Professor Ecker highlighted the potential impact of DNA methylation in brain cells on human cognitive abilities. He discussed how this specific DNA methylation in the brain primarily occurred at CH sites and was closely associated with synaptic events, particularly around birth. Employing snm3C-seq technology, which allowed for the simultaneous measurement of DNA methylation and chromatin conformation in individual cells, with a focus on CH methylation, Professor Ecker's team was able to classify neurons based on their epigenetic profiles. Furthermore, they discovered that the absence of a DNA methyltransferase enzyme called DNMT3A led to abnormal CH methylation, impacting synaptic connectivity between neurons and the formation of long-term memories. These studies unveiled the critical role of CH methylation in the brain, providing new insights into the mechanisms and potential treatments for cognitive function and neurodegenerative diseases.

4.Presentation by Xiaoqun Wang

Human Brain Genomics: A Journey through Development, Evolution and Disease

Professor Wang's presentation primarily focused on the classification, distribution, and development of neural progenitor cells, including radial glial cells (RG cells), intermediate progenitor cells (IPC) and outer radial glial cells (oRG). Through techniques such as single-cell sequencing and spatial transcriptomics, Professor Wang's team decoded the molecular characteristics of various types of neural progenitor cells and cell lineages during human brain development in different regions. They explored the transformation of neuroepithelial cells (NE cells) into RG cells and the critical signaling pathways involved in this process. Using the gene TMEM14B, which plays a significant role in cortical neurogenesis, Professor Wang introduced the cell types and gene expression profiles of human brain progenitor cells. This shed light on the diversity and evolution of gene expression in these cells. The team also utilized animal models and human-vascularized brain organoids to investigate the mechanisms of brain developmental disorders.

5.Presentation by Hesheng Liu

Advances in Functional Brain Imaging Technology

Professor Liu introduced a precise, personalized brain functional parcellation technology based on MRI and its clinical applications, as well as a novel MRI technology for the recording of neural activities in vivo. Professor Liu started with an introduction of the research history of human brain functional mapping and traditional approaches to brain parcellation, demonstrating individual differences among adults, newborns, and rhesus monkeys. He then introduced the Personalized Brain Functional Sectors (pBFS) developed by his team, which divides the individual cerebral cortex into 213 functional regions with high intra-individual reproducibility and high sensitivity to individual differences. The precision of pBFS was rigorously validated by invasive functional mapping techniques including electrical cortical stimulation and lesion-based mapping. This technology shows great potential in guiding precise neuromodulation treatments for various brain disorders including aphasia and depression. In addition, in response to the limited temporal resolution of the traditional functional MRI, Liu lab has developed a novel technology called TRIGGER, which utilizes specially optimized high signal-to-noise ratio magnetic resonance sequences, and can record neural activity of the awake human brain with a high temporal and spatial resolution of 5 mm and 1.4 ms. Its capability of detecting neural electrical activity was further validated by frog leg electrical stimulation experiments.


Closing Remarks by Sunney Xie