▎ WuXi AppTec content team editor
Recently, the top scientific magazine "Nature" released an annual list of noteworthy technologies, and the authors said that these tools are expected to have a significant impact on scientific research this year. Today, WuXi AppTec's content team will share the highlights with readers by clicking "Read more" at the end of the article to browse the full english text.
Complete sequencing of the human genome
When the Telomere-to-Telomere (T2T) research project was launched in 2019, nearly one-tenth of the human genome (mainly heterochromatin and other complex regions) was still unsequenced or had more errors. Last May, the T2T project first reported on the end-to-end sequence of the human genome, adding nearly 200 million new base pairs to the widely used Human Genome Atlas (GRCh38), writing the final chapter for the Human Genome Project.
Originally released in 2013, GRCh38 could not conclusively map highly repetitive genomic sequences due to the limitations of the short-read sequencing technique used, including telomeres at both ends of chromosomes and centromeres that regulate the distribution of newly replicated DNA in cell division.
Long-read sequencing technology has brought a breakthrough to sequencing these regions, which can sequence fragments of tens of thousands to hundreds of thousands of base pairs in length at once, allowing scientists in the T2T project to discover small variations in long repetitive sequences. These tiny fingerprint-like variants allow them to trace different repeat sequences to sequence the remaining genomes.
Image credit: 123RF
Oxford Nanopore Technology (ONT) technology platform is also able to capture multiple DNA modifications that regulate gene expression, allowing T2T scientists to depict epigenetic markers at the genome scale.
Currently, one of T2T's collaborating institutions, the Human Pangenome Reference Consortium, is committed to sequencing the genomes of hundreds of donors around the world to generate a more representative genome map that reflects the diversity of human alleles. The organization's goal is to capture 97 percent of human allele diversity. Scientists say that using the recent whole genome sequencing technology, it is expected to generate a whole genome map of all vertebrate species on The Earth in the future.
Resolve protein structure
Protein structure determines protein function, but it is not easy to resolve protein structure. Over the past two years, advances in experimental technology and computing have given researchers complementary tools to resolve protein structures at unprecedented speed and resolution.
The AlphaFold2 artificial intelligence algorithm, developed by DeepMind, relies on deep learning strategies to predict protein structure based on its amino acid sequence. A paper published last July showed that it was able to predict 98.5 percent of human protein structures. At the same time, the RoseTTAFold software system built by Professor David Baker's team at the University of Washington Protein Design Institute also showed the same ability as AlphaFold2 in predicting protein structure.
At the same time, the development of cryo-electron microscopy (Cryo-EM) technology has allowed researchers to experiment with the structure of the most challenging proteins and complexes. In 2020, advances in cryo-EM hardware and software allowed both teams to resolve protein structures at a level of clarity of less than 1.5, capturing the location of individual atoms. These studies show that it is possible to resolve complex protein structures with clarity close to the atomic level.
More and more experimental scientists see AlphaFold2 and cryo-EM as complementary tools, and computer models can help with the analysis and reconstruction of cryo-EM data, which can find structures that are not yet tactile by computational predictions. Scientists hope to use machine learning techniques in the future to assist cryo-EM to resolve conformational changes as proteins interact with other molecules, as well as their natural behavior in frozen cell sections.
Quantum simulation
Quantum computers process data through units called qubits, and a classical binary bit can only represent a single binary value, such as 0 or 1, meaning it can only be in one of two possible states. However, a qubit can represent an arbitrary superposition of a 0, a 1, or a combination of 0 and 1, possibly a 0 and a 1. Due to its unique physical properties, quantum computers have super computing power.
Technological advances in recent years have rapidly improved the stability and functionality of qubit hardware, while increasing the number of qubits contained in quantum computers from dozens to hundreds. Pioneers in this field have set up companies to develop simulators based on quantum computers. Industry insiders estimate that quantum simulators are expected to be commercialized within the next year or two. Professor Jaewook Ahn, a physicist at the Korea Advanced Institute of Science and Technology, likens it to the planes originally built by the Wright brothers. "The first aircraft they built didn't have any advantage in terms of transportation." He said, "Yet it eventually changed the world!" ”
Precision genome editing
Most genetic diseases require genetic correction, and Dr. Ruqian Liu and his team, a chemical biologist at Harvard University, have developed two techniques that can accurately edit genomes. Using CRISPR to precisely target the characteristics of specific sequences in the genome while limiting Cas9's cleavage of DNA, they developed a single-base editor capable of converting cytosine (C) to thymine (T), or adenine (A) to guanine (G). The new generation of prime editing will not only convert any base into other types of bases, but also insert DNA sequences precisely into the genome.
▲ The pilot editing system can not only perform any conversion between bases, but also insert or delete specific DNA sequences (Image source: Prime Medicine official website)
Single-base editing technology first appeared in a scientific paper in 2016, and now the in-research therapies based on this technology are about to enter the clinical development stage. Beam Therapeutics, co-founded by Dr. Liu Ruqian, received permission from the U.S. FDA last November to launch clinical trials to evaluate the efficacy and safety of its base-editing therapy BEAM-101 in the treatment of patients with sickle cell anemia.
Lead editing is still in its infancy, but iterative systems with higher performance are emerging. Liu's team's latest pilot edit was able to increase the length of inserted DNA to thousands of base pairs, equivalent to the length of a complete gene. Dr. Liu said this could provide a safer, more tightly regulated gene therapy strategy. At present, the efficiency of pilot editing is still not very high, but Dr. Liu Pointed out, "In some cases, we know that if you replace only 10% or even 1% of the genes, you can reverse the disease." ”
▲ Dr. Ruqian Liu looks ahead to the future of gene editing at the 2020 WuXi AppTec Global Forum