On a visit to Bangalore in 1998, Robert A. Weinberg ’64, one of America’s leading cancer researchers, met a voraciously curious young doctoral student from a South Indian village so remote that he grew up without phones or television, studying by kerosene lamp. He had no Western-style last name, only a first — Mani.
Mani’s parents, rice and peanut farmers, had never been to school at all. But Weinberg sensed such scientific promise in Mani, who was then at the Indian Institute of Science, that he invited him to join his prestigious Whitehead Institute laboratory in Cambridge.
Now, Weinberg says his lab has come up with possibly its most exciting discovery since it found the first cancer gene nearly three decades ago, and much of the credit goes to that young Indian researcher, Sendurai (the name of his village) Mani.
Mani and his colleagues at the MIT-affiliated Whitehead found what appears to be a key to metastasis, the insidious process by which cancer spreads throughout the body and often kills. And, in a surprising spin-off, that same discovery also may lead to a relatively safe, simple way to transform normal adult cells into stem cells that could be used to treat other diseases.
They believe their one-step method may avoid the risk of random mutation — and possibly cancer — a stumbling block for therapies based on other recently developed techniques for creating stem cells.
The new findings by no means translate into a cure for cancer or an instant recipe for stem cell therapies, cautions Weinberg, who first came to national prominence in the 1970s for his work on genetic mutations that cause normal cells to become cancerous. But, he says, visibly struggling to convey his enthusiasm without sinking to hyperbole, “I just think this is extremely interesting.”
Other researchers who study stem cells and cancer concur, though the work is still in progress. “I think it’s fabulous,” said Michael Clarke, director of the cancer stem cell program at Stanford University. Weinberg’s lab has pinpointed a “stem cell program that cancer cells use to spread. So I think that’s incredibly important,” he said.
As Weinberg tells the tale, ensconced in a brown leather armchair near a tangled jungle of window plants in his office, metastatic cancer cells and stem cells used to occupy separate halves of his brain, with no bridge between.
But that bridge is emerging from yet a third field: the study of embryos. In earliest human life, some cells undergo a dramatic metamorphosis. From squarish, stuck-together cells of the kind that grow in sheets to form the linings of the ducts in breasts, lungs and other organs, they change into mobile, more sickle-shaped cells that can form bones and blood.
Researchers have long theorized that cancer cells may co-opt the program for that transformation, using it to gain mobility and roll out from a primary tumor to seed others elsewhere.
What Mani and his colleagues found fits into that theory and goes a step further: By exploring genes and proteins involved in metastasis, they found that when a cancer cell undergoes that square-to-sickle transformation, it also gains properties of stem cells, which can spawn vast numbers of new cells.
In particular, they found that by turning on any one of three genes, called Twist, Snail and FOXC2, they could make a cancer cell in a petri dish undergo the square-to-sickle shift. And unexpectedly, these sickle-shaped cells became far more capable of generating new tumors. Mani hopes to prove that the same thing happens in metastasis.
Their work fits into the burgeoning field of cancer stem cells, the increasingly accepted idea that tumors host a few cancer “super-cells,” which are capable of forming new tumors despite extensive cancer treatment.
But it went beyond cancer. Weinberg pushed Mani to test a seemingly logical hypothesis: Could inducing the square-to-sickle shift in normal cells turn them into normal stem cells?
Mani tested the idea in normal human breast cells left over from breast-reduction surgery. And indeed, he found that by inducing the square-to-sickle shift, those normal cells also started to resemble stem cells, becoming able to generate great numbers of copies.
Their method, if it pans out, could be easier and safer than other methods to make stem cells now in development because it would involve manipulating a cell’s biochemical environment to turn on existing genes rather than changing genes, Weinberg said.
The work suggests that it may be possible, with relatively modest manipulation, to “get what looks like a more mature cell to revert back to a stem-cell-like state,” said Dr. David Scadden, co-director of the Harvard Stem Cell Institute, who was not involved in Weinberg’s and Mani’s work. “This is fantastic because it says … that maybe cells don’t live on a one-way street.”
For all his excitement, Weinberg readily acknowledges that Mani’s line of investigation has yet to produce a “gold-standard proof” that the stem-like cells are actually stem cells. If their thinking is correct, he said, it should be possible to induce the key metamorphosis in some breast cells of one mouse, place them in another mouse’s chest and develop a breast.
The experiment worked once, he said, but his lab has been unable to replicate it, and ended up publishing its work in the leading biology journal Cell this May without that crowning proof. But “I’m not discouraged by that lack of success, though it would be nicer if it had succeeded,” Weinberg said. Such experiments take time and present technical challenges, he said.