The greatest conversation of a human being is within himself. A person is made up of about 30 trillion cells: neurons in the brain, red blood cells, adipocytes in fat… The scientific community thought for decades that each of these cells threw their garbage out in a few balls of about 100 millionths of a millimeter, but the error was huge. Swedish scientist Jan Lötvall’s team discovered 15 years ago that these expelled vesicles, called exosomes, were not bags of debris, but packages of genetic information traveling through the body. It was a remote communication system between human cells. A team from Harvard University (USA), headed by the Spanish biologist Rubén García and the American doctor Ronald Kahn, has now illuminated the ins and outs of this enormous internal conversation.
Exosomes are leading a revolution in medicine. Healthy cells send messages of all kinds through these vesicles, but so do sick cells. Malignant cancer cells, for example, use this remote communication pathway to prepare for the colonization of other organs: the dreaded metastasis. Intercepting these messages and deciphering them would make it possible to diagnose diseases much sooner than now, from simple blood or urine samples. The problem is that it is not about gossiping about the dialogue between two cells. It is a gibberish of 30 billion. And each cell emits thousands of vesicles every day.
Rubén García, a 35-year-old biologist raised in the Madrid municipality of Alcorcón, describes it as a kind of microscopic post office, in which cells send marked packages. “Perhaps some vesicles of a cell carry a specific load that goes to the liver and other vesicles are destined to go to the muscle and carry another totally different content. This is the current hypothesis, but there is still no evidence”, explains the researcher.
García’s team has studied cells from five tissues – liver, muscle, blood vessels, white fat and brown fat – and has verified that each type sends packets with a characteristic content. The messages are written in the same language: microRNA, small molecules that are like words of about 20 chemical letters. Harvard scientists have discovered specific syllables that determine whether these words have to leave the cell or stay in it. “Each type of cell has its own codes,” says García.
The new results suggest that it is possible to intercept a cellular message in a blood test and find out what type of cell has sent it, according to Peruvian biologist Morayma Temoche. “It could help detect cancer in early stages and determine which tissue is involved,” says the researcher, who has not participated in the study. Temoche, from the US biotech company Metagenomi, received her doctorate two years ago at the University of Berkeley, in the laboratory of Randy Schekman, winner of the 2013 Nobel Prize in Medicine for her discoveries on vesicle trafficking. MicroRNAs have already been used in recent years as biomarkers for the diagnosis of some tumors, but their usefulness has been reduced by the complexity and errors of the technologies.
Could help detect cancer in early stages and determine which tissue is involved
Morayma Temoche, biologist
For Temoche, the sequences of letters now detected in the microRNAs “work like a postal code”, which determines whether the message is sent or remains in the cell. If these codes are generalizable, the biologist argues, the discovery would be “a turning point”, by allowing scientists to prepare packages of therapeutic messages by adding the necessary sequence of letters.
Rubén García compares the gallbladder system with “a large distribution company, like Amazon.” In this example, the objects for sale would be the microRNAs, which would be packaged in the exosomes and would carry a “bar code” to identify their direction. “One of the biggest challenges for the coming years is to find out which brands, which destination labels, carry these exosomes to transport their content to one organ and not another,” says Garcia, who plans to move this year to the National Center for Biotechnology, in Madrid, to investigate it.
Garcia still works at the Joslin Diabetes Center at Harvard Medical School in Boston. Her laboratory, led by Ronald Kahn (Louisville, 78 years old), already showed in 2017 that fat cells release a large number of microRNA vesicles that circulate in the blood and can regulate glucose metabolism in the liver. . In his new study, published Dec. 22 in the journal NatureGarcía and colleagues show in human cell cultures that it is possible to control this hepatic management of sugars by genetically modifying the barcode of the fat microRNAs.
One of the biggest challenges is figuring out what destination tags those exosomes carry to transport their contents to one organ and not another.
Ruben Garcia, biologist
The Harvard group is now exploring potential treatments for diabetes and other metabolic diseases, Kahn explained in a statement. “We can genetically engineer microRNA in easily accessible subcutaneous fat to improve metabolism in the liver, which is a more difficult target for direct gene therapy. And if something goes wrong, we can always remove the fat, but you can’t remove the liver,” Kahn argued.
Garcia also believes that his research lays the groundwork for new strategies. “This system can be manipulated to make the microRNAs that interest you go more or less to the vesicles, using this means of communication to change the genetic expression of the target cells and, presumably, their behavior,” explains the Spanish biologist. “Tissue could be obtained from a patient, modified in such a way that the microRNAs of interest are loaded into their vesicles and, when put back into the patient, it constitutes a constant source of that microRNA, sent in vesicles to the organs wherever it is needed. necessary, for example to those affected by a tumor or another illness”, hypothesizes García.
The Spanish biologist recalls the pioneering work of Francisco Sánchez Madrid and María Mittelbrunn, two Spanish scientists who in 2013, at the National Center for Cardiovascular Research, discovered the first shared codes in the microRNA emitted by a type of human white blood cell. García’s team has identified more exit codes for the cells and, for the first time, has revealed the existence of codes so that the message does not leave. “These sequences that remain in the cell can also be of great clinical use”, emphasizes the Harvard researcher.
Some drugs already use microRNA-like molecules to treat some diseases. Inclisiran, from the Swiss pharmaceutical company Novartis, reduces the amount of cholesterol in the blood, by inhibiting the cellular production of a protein that increases these levels. García believes that it is possible to modify this type of therapeutic molecules, adding barcodes so that they remain longer in the desired cells. “They could be a kind of effect enhancer over time, so that the drug needs to be injected less and less frequently,” he surmises.
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George Holan is chief editor at Plainsmen Post and has articles published in many notable publications in the last decade.