Lab mistakes are wasting millions in research funding
Medicine starts with cells in a petri dish. But, increasingly, scientists are realizing they've been studying the wrong cells, writes Maggie Koerth-Baker.
When scientists want to study how a new drug or treatment affects the body they start with cells – disembodied pixels of humanity that can give us some idea, but not a complete picture, of what would happen in a living, breathing person. Test tube experiments, trials done “in a petri dish”, cell cultures, whatever you want to call them, this is the first line of human experimentation – we experiment on cells because its safer and (in some ways) simpler than studying whole humans. But that’s not the same as saying these studies are simple to do.
Historically, the big complication was growing the cells – coaxing them to multiply and divide outside a human body so that you had enough of them to perform and replicate experiments without having to worry about how using a different population of cells would affect the outcome. But, in the last five to 10 years, as we’ve learned more about the genetics of the cells we study, a new problem has emerged. It’s becoming apparent that the choice of specific cells used for a specific study matters a great deal – and that a lot of the research published prior to the last decade has been done with the wrong cells.
There are two things that you need to know about cancer cells. First, is that cancer isn’t just one thing. In fact, different types of cancers aren’t even a single thing unto themselves. There are many different types of lung cancers, distinguished by particular genetic mutations that affect how they grow, how deadly they are, and how easy they are to kill. The same is true of breast cancer, brain cancer, bone cancer, and on and on. This is why it’s so hard to come up with the much-vaunted “cure for cancer” – you’re not curing cancer, you’re curing lots of diseases that are all called “cancer”. But there is something that generally ties together all these disparate disorders, and that’s growth. Typically, cells can only divide 20 or 30 times before they’re burnt out. Cancer cells don’t have those kind of limitations. The whole reason they kill is because they can divide and grow, divide and grow, with nothing to check them and no way for the body to naturally kill them off.
These two facts play a major role in the story of cell cultures. The technique of growing live cell lines – identical families descended from a single cell – has been around since the late 19th century. But as recently as 30 years ago, almost all these populations were made up of cancer cells, said John Minna, distinguished chair in cancer research at the UT Southwestern Medical Center. That’s because it was only cancer cells that could grow indefinitely, one cell multiplying again and again, essentially forever. But even then, Minna said, not all cancer cells lent themselves to easy laboratory growth. “You could take 100 different lung cancers or a 100 breast cancers, and put them in culture,” he said. “But only 10-to-20 percent would grow.”
Only cancer cells could grow indefinitely and only a few of those were willing to grow in a laboratory. With no other options, scientists favored the cell families that were easiest to grow – a choice that meant there was less risk of a dead cell line mucking up your research results. Over time, certain cell lines were used so frequently that they came to be favored because of how common they were – more scientists knew more information about those cells, which made research done with them easier to replicate and prove. Even today, said Jennifer Wilding, a researcher in the department of oncology at Oxford University, scientists will typically use three or four cell lines for a study – the same ones other research groups use – chosen based on their ubiquity, rather than based on what they’re being used to study. “But that isn’t necessarily a very smart thing to do,” she said.
This is where the genetic differences between different types and subtypes of cancer become important. Say you’re trying to study a subtype of colon cancer. If the cell lines you use to research treatments for that cancer lack some of the important mutations that distinguish the subtype then all your carefully gathered data might not mean a thing.
Today, when scientists try to get tumor cells to grow in the lab, they have an 80 percent success rate, instead of 10 percent. That’s largely due to improvements in laboratory techniques, Minna said. Scientists have made many changes to the way they grow cells. For instance, one thing they do is add irradiated mouse cells to the culture. The radiation leaves the mouse cells unable to grow, but still alive – a condition that seems to turn them into a favorite food of tumor cells. “They provide some kind of nourishment that allows just about every tumor cell to grow,” he said.
Scientists also now have more luck growing non-cancerous, healthy cells. One way to do this is by manipulating telomeres, regions at the end of a chromosome that get shorter and shorter each time a cell divides and its chromosomes replicate themselves. Eventually, telomeres get too short and further cell division becomes impossible. But if you add an enzyme called telomerase to the end of the chromosome, you can artificially make the telomeres longer and effectively get them to grow forever.
Both of those developments explain why, in the last decade, the number of cell lines available to work with has grown exponentially – there are now hundreds to choose from. Scientists use all those newly available cell families in different ways. Jennifer Wilding, who primarily studies colorectal cancers, uses lots of different cell lines derived from colorectal tumors to get an idea of how a particular treatment will interact with the diversity of colorectal cancer. Instead of just 3 or 4 lines, she might test a drug on 100. “You can’t just treat one person and expect it to represent the entire disease,” she said. “If I choose a limited number of cell lines, or choose arbitrarily without knowing their genetic makeup, I'm bound to get a very biased picture.”
That’s the broad perspective. John Minna, on the other hand, is trying to figure out ways to use what’s unique about a cancer to create treatments that may only work for one cancer, or one subtype of cancers. The lung cancers associated with smoking, for instance, can have 100s or even 1000s, of mutations, and the pattern of mutations is unique to each individual patient. But if you look at all those different cancers, there are 10 or so major molecular groups -- cancers that, while not identical, are similar to each other in important ways. Minna’s goal is to build libraries of cell lines that represent all the major molecular groups in many different types of cancer. “So far, 60-70 percent of the groups are well represented,” he said. “We’ve identified the 20 or 30 percent we don’t have. We just learned that in the past year.”
Both Minna’s and Wilding’s work represents a big shift from how scientists thought about cell lines in the very recent past – when you used what would grow easily, without much regard for the specific qualities that may, or may not, have made it a good match for your research. Now, they say, as we have more cell lines to work with and as we’re able to learn more about the molecular specifics that identify those cell lines, people are starting to go back and re-evaluate old research.
What they’re finding isn’t pretty. Not only is it becoming clear that results have been skewed by the use of less-than-ideal cell lines, in many cases, the scientists weren’t even using the cell lines they thought they were using. Instead, mistakes in the laboratory meant that cell lines got mixed up with one another. A common problem: Tough, fast-growing cells finding their way into a dish of weaker-growing cells, where they quickly take over. The dish is labeled as being one thing, but the cells now growing there are totally different. HeLa, the line of cells derived from the cervical cancer tumor of an African American woman named Henrietta Lacks, are infamous for invading test tubes all over the world. “You don’t even need sloppy lab technique,” Wilding said. “All it takes is for a droplet of HeLa to fall into another culture. Then it’s survival of the fittest and HeLa is very fit.”
It can be years before a poor choice of cell line or a contaminated cell line is noticed. Today, an increasing number of journals require researchers to run DNA fingerprint analysis on the cell lines they use, and include that information in the papers they publish. That way, everyone knows if the cell line is what the researchers thought it was, and they know whether the choice of cell lines is likely to affect how the results should be interpreted. But if you’re talking about a study happened 15 years ago, or even 10, that analysis might not be a high priority on anyone’s radar. Meanwhile, the research generated by the flawed studies sits in scientific journals, altering the big picture of what we think we know about cancer and other medical problems. In 2007, the BBC estimated that contaminated cell lines, alone, were responsible for millions of wasted research dollars – money spent on studies that are now known to be, essentially, worthless.
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