Once there was a goat living somewhere in North America. The goat, fed, kept warm, lived out its life in support of biomedical research. No one--not the company that owned it, nor the researchers who purchased compounds purified from its blood--had any idea that it was unique. But this one golden goat would end up becoming key in the development of a promising new cancer treatment and detection technology.
The story begins in 2004, before a group of cancer researchers' path even collided with this special goat. Mehmet Toner, a biomedical engineer at Massachusetts General Hospital in Boston, and Ravi Kapur, a biotech entrepreneur, had been attempting to commercialize a new system developed in Toner’s lab. It looked like a small, silver rectangle about an inch wide and two inches long. Etched into its silicon surface, barely visible to the eye, was a maze designed to thread blood around a series of microscopic posts that trapped fetal cells The device had been engineered to capture fetal cells in a pregnant woman’s blood, but it could be used to find different kinds of floating cells, too. Why not use it to catch floating cancer cells?
Finding these rogue cells--known in biology circles as circulating tumor cells, or CTCs--had long been a dream for doctors. With these cells, physicians could find evidence of cancer sweeping around a patient’s body. They might be able to monitor a patient’s response to treatment. And if researchers could study the live cancer cells in blood, as opposed to those from a needle driven into the tumor, medicine might gain deeper insights into how some cancer cells spread and take root elsewhere in a body.
When cancer cells are freed from the confines of their original home and swept along with the pulses of a heartbeat is when they become most vicious. The live tumor cells land on a new bit of tissue and form new tumors. This is called metastasis. And metastasis, or the spreading of cancer, kills nine out of 10 cancer victims.
Doctors have known that these cancers cells were drifting through patients bloodstreams for 150 years, but finding and measuring them has proven difficult. They number perhaps only one tumor cell among every billion blood cells. They easily escape detection, and so finding enough of them in a tube of blood to be useful seemed nearly inconceivable. But Toner and Kapur thought their new device might be able to pull the CTCs out of blood better than anything that had come before.
An eager new post-doc at Toner’s lab, Sunitha Nagrath, took on the project. The device worked by coating the device's miniscule posts with proteins called antibodies, which targeted one type of tumor cell. An antibody is produced by the immune system, and its entire raison d’etre is to recognize antigens, proteins on a cell’s surface. When an antibody meets a matching antigen, they zip together, like a lock into a key. If they found an antibody that targeted the tumor cells they were looking for, it would attach to the cells and they would remain stuck to the device, while the rest of the blood flowed through.
Antibodies needed for research can’t be cooked up by pouring chemicals into a vat; they must be created in the bodies of living animals. Medical companies most often use mice, rabbits, goats, pigs, donkeys, and sheep. To grow a particular antibody, an animal is injected with pieces of proteins from the antigen, inducing the animal’s immune system to create the right anitbody. The animals are then bled--many are kept alive during the process--and the antibodies are purified from the morass of liquids, cells, and proteins. (Some antibodies, once created by an animal, can be replicated in the company’s lab.)
Nagrath tested antibodies from a variety of companies. Finally, she found just the right one. It was produced by a company R&D Systems, catalog number BAF960. And it performed two crucial tasks better than the others: it found the right tumor cells, and it was sticky, gluing them tightly onto the posts. That perfect antibody came from a goat.
The experiment worked beautifully, capturing hundreds of cancer cells out of a tube of blood. Toner’s lab soon teamed up with that of Daniel Haber, director of the MGH Cancer Center, to test the system over and over. The expanding group published a paper in the prestigious journal Nature in December 2007.
Their success captured the imagination of scores of scientists, as the new approach was significantly more effective than any previous attempt. Within only a few years, dozens of teams would be developing systems to find floating tumor cells. The field, sparked by the Nature publication, would be booming.
But over the next year, something started to go wrong in Boston.
Over the course of a few months in 2008, instead of trapping primarily cancer cells, suddenly all sorts of cells were sticking to the posts. The team went into a panic. They had recently introduced a number of changes to the technology, as they expanded to testing a higher volume of samples. Could the problem be the chip itself? Had new scientists on the project introduced errors? They toiled for months to find an answer.
Then Nagrath looked more closely at the antibody, which they’d continued to order from R&D Systems. And she noticed something.
The catalog number was the same, but the batch number was different. It was from a different goat.
Here’s what they hadn’t considered. Antibodies don’t just vary from species to species. They also can vary from animal to animal, just as one human’s immune system is slightly different from another. Neither Nagrath nor anyone else on the team had realized that what made these antibodies so successful, so precise, so sticky, was the immune system of one particular goat.
After they realized the batch-number change, they tested antibodies from other goats. According to cancer biologist Shyamala Maheswaran, no animal they evaluated created these particular antibodies as well as that goat. They’d solved the question of why the technology had failed. Then a new tremor shook the team. The goat died.
Shannon Stott, a bioengineer on the team, remembers a group of about 25 researchers crowding into the cancer center’s library for their weekly Tuesday meeting in the spring of 2009. She recalls a team member--Ravi Kapur, perhaps--coming in and announcing that the goat had died of natural causes.
First, everyone thought he was kidding. Then came dread. What would they do? How could they continue with their experiments? Stott says to this day her colleagues still remember the moment they discovered the goat’s demise.
Sold vial by vial, the remaining antibodies could have fetched more than a million dollars. Kapur negotiated with R&D Systems until he bargained the price down to a bulk order of under a half-million. Then, up-front, they bought out the remaining stock of antibodies. Still today, the lab manager still has all the remaining vials under lock and key in a freezer in the cancer center. Any researcher who wants to use some of the precious cargo has to ask special permission to do so.
The team had about six to eight years of antibodies left. Obviously they needed to find a new way to detect floating cancer cells. They could no longer rely on the goat.
So they came up with a solution. In the new technology, called the CTC-iChip, the chip sheds everything but the tumor cells. It works like this: first red blood cells and platelets, the smallest of the lot, are shunted through a size filter and discarded, leaving behind mostly white blood cells and any tumor ones hiding among them.
The white blood cells are covered with minuscule metal beads coated with a cocktail of white-blood-cell-targeting antibodies. These antibodies are common in medical research, and companies easily produce them in abundance. The remaining mass of cells then winds through channels on the chip until they line up single-file. Finally, a powerful magnet drags off the bead-coated white blood cells.
Left behind are tumor cells, along with some stray white blood cells. It’s like finding the proverbial needle in a haystack, but instead of searching for a flash of metal in the sunlight, the team created a gentle breeze that lifts away all the straw.
This provides a crucial advantage. The researchers no longer need to know anything about the tumor cell, as they did when they chose an antibody to attach to one particular type of tumor cells. The remaining cells could be any kind: breast cancer, bone cancer, brain cancer. And so they no longer need those special antibodies from the unique goat.
In another technological advance, the entire system is now etched via Blu-ray technology on a clear plastic disk the size of a DVD, an angular puzzle of nearly invisible fine lines. It can be manufactured for tens of dollars per chip, reducing the cost 10 times from its predecesor. The new chip evaluates about 10 million cells per second--significantly faster than earlier versions--and completes a tube of blood in only an hour.
The team has attracted millions of dollars in funding from science institutions and cancer foundations. And they’ve partnered with Johnson & Johnson, a major international medical company, to bring the chip to market.
Within a year, the group intends to offer the newly improved CTC-iChip chip to a handful of top cancer researchers around the country. They’re hoping to receive feedback on how the scientists might best use it and how the chip can be improved. Perhaps only a few years from now, doctors may monitor the number of cancer cells in a patient’s blood to determine if a tumor is shrinking, or look for markers on those cells that will quickly alert them to the efficacy of a particular course of drugs. Toner hopes that, one day, the thin, clear disk will become a common tool for early cancer detection.
But it might never have been created without the help of a goat.
Kapur doesn’t see the story as a tale about how one animal’s immune system saved a lab-based experiment. To Kapur, the story of the goat highlights the need for academics to transform early research into something scalable, commercial--a system that doesn’t rely on a goat.
I asked Toner what would have happened if they hadn’t come across the goat’s antibodies early in the process, if the first tests hadn’t succeeded. “I’d have blamed Sunitha,” he jokes. Nagrath, now in charge of her own lab at the University of Michigan, credits her entire professional trajectory to the success of the experiments in Toner’s lab. Then Toner took a more serious tone. “We lucked out,” he says. “We lucked out because of a goat.”
[Image: Goat via Shutterstock]