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Editor | Xi The cell therapy system developed by synthetic biology has broad prospects for disease treatment
.
The principle is to assemble the drug protein expression control switch in the cell, and the cell regulates and releases the drug protein under the action of the external stimulus signal
.
Applying the cell therapy system to diabetes, oral small molecules can be used as exogenous stimulating signals to regulate insulin expression and avoid the pain caused by insulin injection
.
At present, most drug protein regulatory switches are designed based on transcription level regulation.
Exogenous stimulation signals first need to stimulate transcription factors, transcribing and processing drug protein genes into mRNA, and then translating the drug protein
.
This regulation process is relatively complicated and the protein expression time is relatively slow, which limits the application of cell therapy systems in diabetes and other diseases
.
Therefore, the development of rapid protein expression regulation systems is a research hotspot in synthetic biology
.
On November 15, 2021, Liu Tao's team from Peking University and Ye Haifeng's team from East China Normal University published a research paper entitled Genetic code expanded cell-based therapy for treating diabetes in mice in Nature Chemical Biology
.
The article uses gene codon expansion technology to develop a non-natural amino acid-regulated insulin cell therapy system (Noncanonical Amino acids (ncAAs)-triggered Therapeutic Switch, NATS), which proves that the system can quickly regulate protein expression at the translation level (Figure 1)
.
This research complements the protein regulatory switch tool library in synthetic biology, and also provides new ideas for the application and innovation of gene codon expansion technology
.
Figure 1 The NAST system quickly regulates protein expression at the translation level.
Codon expansion technology can recognize the aminoacyl tRNA synthetase and tRNA molecule pairs of ncAA through evolution, and insert ncAA into the protein during the process of translating mRNA containing ectopic amber codons
.
The most important application of gene codon expansion technology is the site-specific modification of proteins.
Liu Tao's team focused on the protein translation mechanism of this technology and established a drug protein regulatory system that regulates protein translation
.
The researchers inserted drug protein genes containing ectopic amber codons and aminoacyl tRNA synthetase and tRNA molecule pairs into the genome of mammalian cells to construct a NATS system cell line (Figure 2a)
.
In normal culture medium, the ribosome of NATS cells translates into ectopic amber codons due to the lack of ncAA, which leads to the termination of translation
.
In the medium containing ncAA, NATS cells can use ncAA to translate drug proteins (Figure 2b)
.
Figure 2 On-off regulation of NATS system The protein expression activated by NATS system has obvious concentration-dependent and reversible regulation of ncAA
.
Only 1 minute of contact between ncAA and cells is enough to activate the NATS system: this is not achieved by the classic transcriptional level regulation system
.
In order to achieve oral ncAA to regulate the expression of the target protein in animals, the researchers first did ncAA pharmacokinetic experiments and proved that ncAA can be absorbed by mice orally
.
Transplantation of human cells into mice after in vitro transformation needs to overcome immune rejection.
For this reason, the researchers chose two cell embedding methods for clinical research, wrapping NATS cells selectively permeating membranes for cell transplantation
.
The selective permeation membrane only allows proteins and other biological macromolecules and small molecules to pass freely, while isolating mouse immune cells, so that NATS cells can survive in the mouse body and secrete the target protein into the blood
.
The blood sugar of diabetic patients fluctuates with the eating situation, and accurate and timely blood sugar control can greatly reduce the incidence of diabetes complications
.
The insulin expression system regulated by the transcription level needs at least 4 hours to lower the blood sugar of mice, which is difficult to meet the requirements for rapid blood sugar control
.
In order to study the speed of lowering blood sugar of the translational level control system, the researchers administered a single dose of ncAA gavage to diabetic mice transplanted with NATS cells.
The results showed that 90 minutes after oral administration of ncAA, the increased serum insulin levels and The blood glucose level was significantly reduced, which proved the speed advantage of the translation level regulating protein expression
.
Diabetes is a chronic disease that requires lifelong medication.
In order to prove the long-term therapeutic effect of NATS cells, the researchers monitored the insulin and blood sugar levels of diabetic mice for one month and found that NATS cells can continuously control blood sugar in mice
.
At the same time, the researchers added ncAA to mouse feed to make "ncAA biscuits", which can control blood sugar by mice directly eating, which improves the convenience of administration
.
Moreover, in the long-term toxicity experiment, ncAA did not cause abnormalities in mice
.
The NATS system developed in this article transcends the traditional transcription level regulation, directly controls protein expression in the translation stage, increases the speed of protein regulation, expands the regulatory tools of synthetic biology for cell therapy, and provides diabetes and other diseases that require immediate intervention.
A new treatment strategy
.
This article applies gene codon expansion technology to cell therapy for the first time.
It is hoped that in the future, scientists can further develop the application of gene codon expansion technology in disease treatment
.
The first authors of the article are PhD students Chen Chao and Huang Yujia from Peking University, and PhD student Yu Guiling from East China Normal University
.
The corresponding authors are researcher Liu Tao from the School of Pharmacy of Peking University and Professor Ye Haifeng from the School of Life Sciences, East China Normal University
.
Original link: https:// Platemaker: Notes for reprinting on the eleventh [Non-original article] The copyright of this article belongs to the author of the article, personal forwarding and sharing are welcome, and it is prohibited without permission Reprinted, the author has all legal rights, offenders must be investigated
.
.
The principle is to assemble the drug protein expression control switch in the cell, and the cell regulates and releases the drug protein under the action of the external stimulus signal
.
Applying the cell therapy system to diabetes, oral small molecules can be used as exogenous stimulating signals to regulate insulin expression and avoid the pain caused by insulin injection
.
At present, most drug protein regulatory switches are designed based on transcription level regulation.
Exogenous stimulation signals first need to stimulate transcription factors, transcribing and processing drug protein genes into mRNA, and then translating the drug protein
.
This regulation process is relatively complicated and the protein expression time is relatively slow, which limits the application of cell therapy systems in diabetes and other diseases
.
Therefore, the development of rapid protein expression regulation systems is a research hotspot in synthetic biology
.
On November 15, 2021, Liu Tao's team from Peking University and Ye Haifeng's team from East China Normal University published a research paper entitled Genetic code expanded cell-based therapy for treating diabetes in mice in Nature Chemical Biology
.
The article uses gene codon expansion technology to develop a non-natural amino acid-regulated insulin cell therapy system (Noncanonical Amino acids (ncAAs)-triggered Therapeutic Switch, NATS), which proves that the system can quickly regulate protein expression at the translation level (Figure 1)
.
This research complements the protein regulatory switch tool library in synthetic biology, and also provides new ideas for the application and innovation of gene codon expansion technology
.
Figure 1 The NAST system quickly regulates protein expression at the translation level.
Codon expansion technology can recognize the aminoacyl tRNA synthetase and tRNA molecule pairs of ncAA through evolution, and insert ncAA into the protein during the process of translating mRNA containing ectopic amber codons
.
The most important application of gene codon expansion technology is the site-specific modification of proteins.
Liu Tao's team focused on the protein translation mechanism of this technology and established a drug protein regulatory system that regulates protein translation
.
The researchers inserted drug protein genes containing ectopic amber codons and aminoacyl tRNA synthetase and tRNA molecule pairs into the genome of mammalian cells to construct a NATS system cell line (Figure 2a)
.
In normal culture medium, the ribosome of NATS cells translates into ectopic amber codons due to the lack of ncAA, which leads to the termination of translation
.
In the medium containing ncAA, NATS cells can use ncAA to translate drug proteins (Figure 2b)
.
Figure 2 On-off regulation of NATS system The protein expression activated by NATS system has obvious concentration-dependent and reversible regulation of ncAA
.
Only 1 minute of contact between ncAA and cells is enough to activate the NATS system: this is not achieved by the classic transcriptional level regulation system
.
In order to achieve oral ncAA to regulate the expression of the target protein in animals, the researchers first did ncAA pharmacokinetic experiments and proved that ncAA can be absorbed by mice orally
.
Transplantation of human cells into mice after in vitro transformation needs to overcome immune rejection.
For this reason, the researchers chose two cell embedding methods for clinical research, wrapping NATS cells selectively permeating membranes for cell transplantation
.
The selective permeation membrane only allows proteins and other biological macromolecules and small molecules to pass freely, while isolating mouse immune cells, so that NATS cells can survive in the mouse body and secrete the target protein into the blood
.
The blood sugar of diabetic patients fluctuates with the eating situation, and accurate and timely blood sugar control can greatly reduce the incidence of diabetes complications
.
The insulin expression system regulated by the transcription level needs at least 4 hours to lower the blood sugar of mice, which is difficult to meet the requirements for rapid blood sugar control
.
In order to study the speed of lowering blood sugar of the translational level control system, the researchers administered a single dose of ncAA gavage to diabetic mice transplanted with NATS cells.
The results showed that 90 minutes after oral administration of ncAA, the increased serum insulin levels and The blood glucose level was significantly reduced, which proved the speed advantage of the translation level regulating protein expression
.
Diabetes is a chronic disease that requires lifelong medication.
In order to prove the long-term therapeutic effect of NATS cells, the researchers monitored the insulin and blood sugar levels of diabetic mice for one month and found that NATS cells can continuously control blood sugar in mice
.
At the same time, the researchers added ncAA to mouse feed to make "ncAA biscuits", which can control blood sugar by mice directly eating, which improves the convenience of administration
.
Moreover, in the long-term toxicity experiment, ncAA did not cause abnormalities in mice
.
The NATS system developed in this article transcends the traditional transcription level regulation, directly controls protein expression in the translation stage, increases the speed of protein regulation, expands the regulatory tools of synthetic biology for cell therapy, and provides diabetes and other diseases that require immediate intervention.
A new treatment strategy
.
This article applies gene codon expansion technology to cell therapy for the first time.
It is hoped that in the future, scientists can further develop the application of gene codon expansion technology in disease treatment
.
The first authors of the article are PhD students Chen Chao and Huang Yujia from Peking University, and PhD student Yu Guiling from East China Normal University
.
The corresponding authors are researcher Liu Tao from the School of Pharmacy of Peking University and Professor Ye Haifeng from the School of Life Sciences, East China Normal University
.
Original link: https:// Platemaker: Notes for reprinting on the eleventh [Non-original article] The copyright of this article belongs to the author of the article, personal forwarding and sharing are welcome, and it is prohibited without permission Reprinted, the author has all legal rights, offenders must be investigated
.
