Doubts cast over ‘wild’ claim that magnetic control can turn on genes

This is a major breakthrough if it actually works: South Korean researchers say they have developed a magnetically controlled switch to turn on genes inside cells, which could lead to transformative medical treatments. But others say the results, which were published in a major journal, are implausible and that the paper has problems, such as one image being an inverted version of another.

The key question now is whether independent groups are able to replicate this result. One of the critics, physicist Andrew York, thinks this should have been tried before the paper was published. “This claim is so strong, so wild, so revolutionary, that you really should send a sample to another lab, ask them to check: ‘Yes, we see it too,'” says York, who works for a research organization in the United States but spoke as an individual. “I believe the document has been under review for three years. That’s plenty of time to send samples to friendly laboratories.”

Lead researcher Jongpil Kim of Dongguk University in Seoul says his team works with several biotechnology companies and other research institutes. “We expect these collaborative datasets to be disclosed in subsequent publications. »

There are already ways to control various biological processes with light, using a technique called optogenetics, based on proteins that respond to light. Once cells are genetically modified to produce this type of protein, light can be used, for example, to turn on nerve cells. Optogenetics is widely used in research, for example to treat certain types of blindness.

The huge disadvantage of optogenetics is that light cannot penetrate deep into the body. So, various teams around the world are trying to find ways to control biological processes with capable signals, such as a magnetic field. This would have many applications in medicine, as well as research. For example, it would make it possible to modify the body’s cells to produce a therapeutic protein, then control when, where and how much of it is produced using magnetic signals.

In an article published in the prestigious journal CellKim’s team claims to have made something called magnetogenetics real, by developing a switch capable of activating genes in genetically modified cells when triggered by a specific magnetic signal that can reach any part of the human body. Additionally, Kim says this signal had no detectable effects of any kind in the mice it was tested on, unless the switch was genetically modified, suggesting it should be safe for medical use.

Specifically, Kim’s team applied a 4-kilohertz electromagnetic square wave with a force of 2 millitesla to the cells that was turned on and off 60 times per second, or at 60 hertz. By interacting with a protein called cytochrome b5, the paper says, this signal induced an oscillation of calcium ions over a period of just under a minute. In other words, calcium ions moved back and forth across the cell every 50 seconds or so.

How the electromagnetic signal affects cytochrome b5 and triggers the oscillation is unclear. “The precise biophysical mechanism is still being studied,” says Kim.

This oscillation somehow triggers the “on switch,” or promoter sequence, for a gene called LGR4said the team. Promoter sequences activate any genes they are inserted in front of, so if that promoter sequence is placed in front of other genes, they can also be activated by magnetism, meaning they act like a magnetically activated genetic switch. The paper describes this switch working in mice and human cells of different types, as well as in whole mice.

It would be a huge breakthrough if confirmed, York says. “This changes everything about how mammalian systems respond to electromagnetic fields.” But to him it makes no sense that a 60 Hz signal would cause an oscillation with a period of almost a minute. “The biological answer is incredibly implausible,” York says.

Kim says the oscillation period is not determined by the frequency of the signal. “Subsequent oscillations are governed by independent internal signaling processes within the cell rather than by the frequency of the external stimulus,” he says.

The magnitude of the calcium oscillation is also very important, York says. “This is an incredibly physiologically significant response. It’s like saying the temperature changes 10 degrees.” This should affect a wide range of biological processes in cells, York says, but the paper claims that it only activates a single gene with no other observable effects.

Kim rejects this. “The magnitude of our observed signal is relatively modest and remains within a physiologically manageable range,” he says.

In one experiment, the researchers linked their electromagnetic switch to a gene for a luminescent protein. Adam Cohen of Harvard University noted that Figure S1J in the paper appears to show that the modified cells begin to luminesce several hours before the switch is even turned on. But Kim says it’s a “computational artifact caused by the curve-smoothing process.”

On a website called PubPeer, a commenter named Yong‐Chang Zhou posted that in the paper’s Figure S5P, one image appears to be an inverted version of another. “Mirroring is not something that normally happens when you take multiple photos of the same sample,” explains Elisabeth Bik, who specializes in discovering scientific errors.

“We identified a write error in Figure S5P where a control image was duplicated during data entry. [quality control] process. We are currently undergoing a formal correction in Cell to replace it with the correct raw data. This oversight does not affect the scientific conclusions of the study,” says Kim.

New scientist asked the editor of Cell for comment, but has not yet received a response.