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Medicine has a problem "Goldilocks". Many therapies are safe and effective only when they are given at the right time and in very specific doses – given too soon or too late, too much or too little, drugs can be ineffective, even harmful. But in many situations, doctors have no way of knowing when and how to do it.
Today, a team of bioengineers led by Hana El-Samad, Ph.D. of the University of San Francisco, and David Baker, PhD of the University of Washington, have come up with a Remarkable solution to this problem: "smart" cells behaving like tiny autonomous robots that, in the future, can be used to detect damage and diseases and to provide help at the right time and in the appropriate quantities.
Surprisingly, this can be accomplished without any direct human intervention thanks to a unique, computer-designed and synthesized laboratory-based artificial protein that can be used to create new biological circuits within living cells. . These circuits transform ordinary cells into smart cells with remarkable capabilities.
This new protein, formerly known as the orthogonal lock-key p-protein protein, or LOCKR, is described in a pair of articles published July 24 in the journal Nature. And this is unlike anything biologists – or nature itself – ever imagined.
"While many biotechnology arsenal tools use natural molecules that have been reused for the lab, LOCKR has no equivalent," said El-Samad, a professor of biochemistry and biology. biophysics to the Kuo family of UCSF and co-lead author of the new studies. "LOCKR is a biotechnology designed and developed by humans from start to finish, which allows unprecedented control over how the protein interacts with other cell components and will allow us to begin to tackle unresolved problems – and previously – insoluble – biology issues with important implications for medicine and industry. "
In its structure, LOCKR resembles a barrel that, once opened, reveals a molecular arm that can be designed to control virtually all cellular processes. In the first of two new articles, the researchers describe arms capable of directing the molecular traffic inside the cells, degrading specific proteins and initiating the cell's self-destruction process.
But there is a trap – literally. LOCKR's arm remains hidden until the barrel is opened. As the name of the protein suggests, the barrel remains closed until it encounters a molecular "key" – a protein designed by scientists to integrate it perfectly into the "lock" of the protein. barrel – who opens it. In the absence of key, LOCKR is actually disabled and the key turns it on.
The ability to control when LOCKR is "on" or "off" means that it behaves much like an electrical switch. Although the switches may seem simple, even the most primitive and miniaturized switches are the cornerstone of all modern electronics, including complex integrated circuits powering computers, iPhones and all other smart gadgets. With LOCKR, a switch-like protein, scientists can finally build the biological equivalent of such circuits in cells.
"In the same way that integrated circuits have allowed the explosion of the computer chip industry, these versatile and dynamic biological switches could soon enable precise control of the behavior of living cells and ultimately our health." "said El-Samad, also a researcher Chan Zuckerberg Biohub.
In the second of two documents, the researchers describe an impressive demonstration of the potential of circuit design technology. Using a version of the tool called degronLOCKR, which can be turned on and off to degrade a protein of interest, they have built circuits that can dynamically regulate cell activity in response to signals from the internal and external environment of the cell.
When the circuits, which included a genetically encoded sensor, detected a disruption of normal cell activity, degronLOCKR reacted by destroying the proteins that drive the cellular "software" responsible for the disturbance, until the cell returns to normal – a process reminiscent The thermostats continuously detect room temperature and direct HVAC systems to shut down or turn on to maintain the desired temperature.
But using degronLOCKR to build new biological circuits like this one in cells is more than just a bioengineering engineering trick. According to Andrew Ng, PhD, co-first author of the two studies who just completed his Ph.D. in the laboratory of El-Samad, the potential of this technology is virtually unlimited.
"LOCKR, and more specifically, degronLOCKR, opens up a whole new field of possibilities for programming cells to treat a wide range of debilitating conditions for which safe and effective treatments are not yet available," said Ng, who worked with El-Samad through the UC Berkeley-UCSF Postgraduate Program in Bioengineering. "With these technologies, we are only constrained by our imagination."
To this end, El-Samad, Ng and their collaborators are now building smart cells based on degronLOCKR that could treat a variety of diseases and conditions, including traumatic brain injury (TBI), a disease typical of the medical problem in medicine.
When the brain undergoes a traumatic injury, the body reacts by activating a vigorous inflammatory response. Although inflammation is an essential part of the body's healing process, in TBI, inflammation levels can far exceed what is needed, or even be in good health. In many cases of TBI, inflammation reaches dangerous levels that leave the brain permanently damaged.
Although doctors can administer medications to manage this situation, they often cause inflammation to fall to such a low level that it prevents brain healing. With TBI, neither the body's own defenses nor modern medicine can achieve the correct "right" level of inflammation – neither too high nor too low, but sufficient to allow maximum healing without causing permanent damage .
That's where degronLOCKR can help. The researchers believe that they will soon be able to turn a patient's cells into smart cells by installing degronLOCKR-based circuits designed to detect inflammation and modulate the immune system's activity. . The hope is that when these modified cells are put back into the patient's body, they will maintain inflammation well in the narrow therapeutic area.
But TBI is not the only condition that scientists tackle with this technology. El-Samad believes that smart cells could one day be used to treat a wide range of currently incurable diseases, ranging from insensitive cancers to the latest drugs and cell therapies to autoimmune diseases for which no treatment is yet available.
"By using degronLOCKR and similar molecules planned for future development, we will be able to compose increasingly sophisticated circuits, which could pave the way for a new generation of intelligent, accurate and robust live cell therapies", said El-Samad.
Other authors of the first article include Robert A. Langan, Scott E. Boyken, Marc J. Lajoie, Zibo Chen, Stephanie Berger and Vikram Khipple Mulligan at the Institute for Protein Design at the University of Washington; Jennifer A. Samson and John E. Dueber of UC Berkeley; Galen Dods, Alexandra M. Westbrook and Taylor H. Nguyen of UCSF; and Walter R. P. Novak at Wabash College. Taylor H. Nguyen, Mariana Gómez-Schiavon and Galen Dods of UCSF; Robert A. Langan and Scott E. Boyken at the Institute for Protein Design at the University of Washington; Jennifer Samson, Lucas M. Waldburger and John E. Dueber of UC Berkeley.
The research was funded by the Washington Research Foundation, the Burroughs Wellcome Fund, a BER IDAT grant from the Department of Energy (DEWAC02W05CH11231), support from the National Institute of General Medical Sciences (ALSW ENABLE (GM124169W01) ) and the Advanced Defense Research Projects Agency (HR0011W16W2W).
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