Over the past few years, many studies have found that tumors harbor a vast array of bacteria, fungi and viruses. The surprising findings have led many scientists to rethink the nature of cancer.
The medical possibilities are exciting: If tumors shed their unique microbes into the bloodstream, could they serve as an early marker of disease? Or can antibiotics shrink tumors?
In 2019, a start-up mined these findings to develop microbe-based tests for cancer. This year, regulators agreed to prioritize the company’s upcoming trial because of its commitment to saving lives.
But now several research groups have cast doubt on three of the most famous studies in the field, reporting that they were unable to replicate the results. So-called tumor microbes, critics say, are likely mirages or the result of contamination.
“They just found things that weren’t there,” said Steven Salzberg, an expert in analyzing DNA sequences at Johns Hopkins University, who published one of the recent critiques.
The authors of the work defended their data and pointed to recent studies that reached similar conclusions. The expanding debate reflects the tension between the potentially powerful applications that can come from understanding tumor microbes, and the challenge of deciphering their true nature. Independent experts say the current controversy is an example of the growing pains of a young but promising field.
Biologists have known for decades that at least some microbes play a role in cancer. The most notable example is a virus known as HPV, which causes cervical cancer by infecting cells. And some strains of bacteria drive other cancers in organs such as the intestine and stomach.
Over the decades, these links have been slowly elucidated, as scientists lacked the technology available today. The search accelerated dramatically once researchers learned how to pull DNA fragments from tumors. They then used computers to determine whether the genetic material came from human cells or from other species.
In 2019, a team of scientists at New York University School of Medicine used these techniques in a pancreatic cancer study they published in the journal Nature. In many tumors, they found DNA fragments from several different types of fungi. Further research led them to conclude that fungi drive the growth of tumors.
These remarkable results caught the attention of Dr. Peter Allen, a surgeon at Duke University School of Medicine, who began looking for microbes in pancreatic tumors from his own patients.
But after searching 140 tumors, Dr. Allen and his colleagues could not find significant amounts of DNA from any microbes, including fungi. “We didn’t find any real signatures,” he said.
They then reviewed the original study, whose genetic data had been uploaded to a public database. The team of Dr. Allen didn’t find an appreciable amount of fungal DNA in that data, either. they published they discovered in Nature on August 2.
The New York University researchers defended their work. “My group still stands by what we found,” said Deepak Saxena, one of the authors of the original study. He pointed to other data consistent with his results.
In August, for example, researchers based at Tokyo Medical and Dental University reported finding fungi in pancreatic tumors from 78 of 180 patients. And patients with tumors that contained fungi were at greater risk of dying in the three years after their surgery, the study found.
Other researchers ask in a 2020 report on Science by a team at the Weizmann Institute of Science in Israel. Examining 1,500 tumors from seven types of cancer, the study found that each type of tumor had a unique set of bacteria, with breast cancer harboring a particularly rich variety.
But Jacques Neefjes, a microbiologist at Leiden University in the Netherlands, and his colleagues could not detect bacteria inside cancer cells using some of the Weizmann team’s methods in their own collection of 129 samples of breast cancer. “We haven’t found a single case,” he said.
In January, the group of Dr. Neefjes published a summary of their findings, which Science attached to the Israeli paper. They argued that the bacteria found by Weizmann’s team were byproducts of infections and were in fact not a normal part of breast cancer tumors.
Ravid Straussman, the head of Weizmann’s research, said that his group conducted further research and that “the results clearly confirm the presence of bacteria in cancer cells.” He also said it was impossible to verify the claims from Dr.’s team. Neefjes because they provided some details about their own experiment.
In a third studypublished in Nature in 2020, researchers from the University of California, San Diego analyzed the government’s database of tumor DNA, called the Cancer Genome Atlas, and trained a computer to identify microbial DNA sequences from 18,000 tumors. The computer learned to distinguish 33 different types of cancer based on their unique combinations of microbes.
“It looks like an incredible proof of concept,” said Abraham Gihawi, a postdoctoral researcher at the University of East Anglia.
But Dr. changed his mind. He and his colleagues took a closer look at microbes that supposedly favor certain types of cancer. They seem completely out of place. Adrenal gland tumors appear to host a virus previously known only to infect shrimp in the Gulf of Mexico. Bacteria known only to grow in seaweed seem to favor bladder cancer.
“This is a sure sign that something is going wrong,” Dr. Gihawi and his colleagues wrote in a letter that they published on August 9 in the journal Microbial Genomics. They considered seaweed bacteria and other out-of-place “nonsense”.
In a subsequent study with Dr. Salzberg, the researchers reanalyzed the data for themselves. “We showed that paper was wrong,” said Dr. Salzburg. The second analysis was accepted by the journal mBio, he said.
Taught by Dr. Salzberg and his colleagues have several possible reasons for the seemingly inexplicable results. To identify microbial DNA from tumors, for example, one must first remove as much of the human sequence as possible. Critics say the San Diego team left some human order behind.
Critics also argue that errors can occur when scientists compare tumor sequences with microbial DNA to find matches because some of that data is contaminated with human DNA. That’s how DNA from a human cancer cell can appear to resemble DNA from a seaweed microbe.
The San Diego team, led by Rob Knight, has respond in length to these criticisms. said Dr. Knight that he and his colleagues used the best resources they could for their 2020 paper, and they continued to improve their methods for the one paper they produced. published last year in the journal Cell with the group of Dr. Straussman.
In that study, they used new techniques to remove more human DNA from their analysis. To predict different types of cancer, they considered only bacteria with DNA to pass a very strict inspection. “You still get signatures that are specific to the type of tumor,” said Dr. Knight.
In 2019, Dr. Knight founded a company called Micronoma to develop cancer tests based on his microbe findings. (Dr. Straussman serves on its scientific advisory board.) To date, the company has raised $17.5 million from private investors.
In January, Micronoma received a “Breakthrough Device” designation from the Food and Drug Administration for a lung cancer test, which will accelerate its development for a clinical trial. Sandrine Miller-Montgomery, Micronoma’s chief executive, said the trial will begin in 2024.
“These criticisms have not led to any change in our company’s plans,” said Dr. Miller-Montgomery.
Dr. Sven Borchmann, a physician-scientist at the University of Cologne, questioned whether the San Diego team was trying to turn its findings into a medical diagnosis too quickly, instead of doing more experiments to find out what it really means. say the results. “I think they’re too quick to focus on application instead of understanding,” he said.
However, suspected Dr. Borchmann that the team of Dr. Knight has found a number of species that will hold up to scrutiny, despite recent challenges. “It doesn’t invalidate the whole claim,” he said.
Qin Ma, a computational biologist at Ohio State University, agreed that the new criticisms of the three papers do not change the overall weight of evidence gathered in recent years. “Everyone agrees that microbes exist in tumors and are important,” he said.
But Dr. Ma and others recognized that the field is still searching for a standard set of tools that will provide highly accurate results. The current debate is moving the field toward that goal, they say.
“I wouldn’t be surprised if the disagreement causes both camps to change and push the science further,” said Dr. Arturo Casadevall, a microbiologist at the Johns Hopkins University School of Medicine who was not involved in any of the studies. “This is a story of the scientific process at work.”