"Smart" cells
Artificial proteins open a new era of smart cell therapy
Egor Morozov, iGuides.ru according to the materials UCSF
One of the problems of medicine is that many treatments are safe and effective only when they are prescribed at the right time and in very precise doses – if they are prescribed too early or too late, or in too large or too small dosages, medications may be ineffective or even harmful. And there are enough situations when doctors do not have the opportunity to find out at what time and how many medications need to be given.
However, now a team of bioengineers led by Dr. Khan El-Samad from the University of California at San Francisco and Dr. David Baker from the University of Washington has developed a remarkable solution to this problem - "smart" cells behaving like tiny autonomous robots that in the future can be used to detect tissue damage and various diseases, and also to provide assistance at the right time and in the right amount.
Surprisingly, this can be achieved without any direct human intervention thanks to the first of its kind artificial protein developed on a computer and synthesized in the laboratory, which can be used to create completely new biological circuits inside living cells. These circuits turn ordinary cells into intelligent ones, endowing them with unusual abilities.
This new protein, called LRoting Orthogonal Cage-Key pRotein, or LOCKR, is described in two articles published in the journal Nature (1, 2). And it's unlike anything biologists–or nature itself–have ever come up with.
"While many of the tools in the biotech arsenal use natural molecules that have been repurposed for use in the laboratory, LOCKR has no analogues in nature," El-Samad said. "LOCKR is a biotechnology that was conceived and implemented by people from beginning to end. This provides an unprecedented level of control over how the protein interacts with other components of the cell, and will allow us to begin to solve unsolved – and previously unsolvable – problems in biology that are important for medicine and industry."
In its structure, LOCKR resembles a closed cylinder, inside of which there is a molecular manipulator that can be designed to control almost any cellular process. In the first of two new articles, the researchers describe manipulators that can direct molecular traffic inside cells, destroy specific proteins and initiate the process of cell self-destruction.
But there is a catch – literally. The LOCKR manipulator remains hidden until the cylinder is opened. As the name of the protein implies, the cylinder remains closed until it meets a molecular "key" – a protein designed by scientists to ideally fit the "lock" of the cylinder and open it. In the absence of a key, LOCKR, in fact, does not work, and only the key can activate it.
In the background, LOCKR (yellow) is locked in a cylinder (gray), and next to it is a key (black). In the foreground, the key opens the cylinder and allows the squirrel to act.
The ability to control when the LOCKR is on or off means that it behaves similarly to an electric switch. Although switches may seem simple, even primitive, their miniature versions are the basic building blocks of all modern electronics, including the complex integrated circuits that underlie computers or smartphones. With the help of LOCKR, a protein switch, scientists can finally create biological equivalents of such chains inside cells.
"Just as integrated circuits have blown up the computer chip industry, these versatile and dynamic biological switches may soon unlock precise control over the behavior of living cells, and ultimately our health," El–Samad said.
In the second of two articles, the researchers describe an impressive demonstration of the potential of the technology for building biological circuits. Using a version of a protein called degronLOCKR, which can be turned on or off to break down the protein of interest, they created circuits that were able to dynamically regulate cellular activity in response to signals from the internal or external environment of the cell.
When biological circuits that included a genetically encoded protein sensor detected a violation of normal cellular activity, degronLOCKR reacted by destroying the proteins that control the cellular "software" that caused the violation until the cell returned to normal – this process resembles how advanced thermometers constantly measure temperature the environment and control heating, ventilation and air conditioning systems to maintain the desired temperature.
But using degronLOCKR to create new biological circuits in cells is more than just a bioengineering technique. According to Andrew Ng, Ph.D., one of the authors of the two papers, who recently completed his research in the laboratory of El Samad, the potential of the technology is almost limitless.
The principle of operation of dergonLOCKR.
"LOCKR, or more precisely, degronLOCKR, opens up a whole new field of possibilities for programming cells to treat a wide range of debilitating diseases for which safe and effective treatments are not yet available," Ng said. "With these technologies, we are limited only by our imagination."
To this end, El-Samad, Ng and their colleagues are currently creating intelligent cells based on degronLOCKR that can treat various diseases and wounds, including traumatic brain injury (TBI) - brain damage that perfectly illustrates the problem of timely and accurate drug delivery.
When the brain is seriously damaged, the body reacts by activating a strong inflammatory response. Although inflammation is an integral part of the body's recovery process, with TBI, the level of inflammation can significantly exceed the level necessary for proper wound healing. In many cases of head trauma, inflammation reaches dangerous levels that eventually lead to irreversible brain damage.
And while doctors may administer inflammation-suppressing medications to deal with this problem, they often cause inflammation to drop to such low levels that they interfere with proper brain healing. In the case of TBI, neither the body's own defense nor modern medicine can achieve the "right" level of inflammation – not too strong, not too weak, but sufficient for maximum effective healing without causing irreparable damage.
This is where degronLOCKR can help. The researchers believe that they will soon be able to turn the patient's own cells into smart ones by creating biological circuits based on degronLOCKR designed to determine the level of inflammation and modulate the activity of the immune system. It is hoped that when these engineered cells are returned to the patient's body, they will keep the inflammation in a narrow therapeutic zone.
But brain injuries are not the only case where a new protein can help. El-Samad believes that someday smart cells can be used to treat a wide range of diseases that are currently untreatable, ranging from cancer, which is immune to the latest drugs and cell therapy, to autoimmune diseases, for which there are no available treatments at all yet.
"Using degronLOCKR and similar molecules, in the future we will be able to compose increasingly complex biosystems that can lead to a new generation of smart, accurate and reliable methods of treating living cells," El-Samad said.
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