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Horizon Discovery
Horizon Discovery

Master of Fate

While tracing the tricky and sometimes surprising paths of multipotent cells in the skin, mammary gland, and heart, Cédric Blanpain has repeatedly turned the stem cell field on its head.
 

By | July 1, 2013

CÉDRIC BLANPAIN
Professor of Stem Cell and Developmental Biology, Interdisciplinary Research Institute, Université Libre de Bruxelles - Brussels, Belgium
COURTESY OF CÉDRIC BLANPAIN
Cédric Blanpain is nothing if not dogged. During his first year of a 7-year medical school program at the Université Libre de Bruxelles (ULB) in Belgium, the 18-year-old did a rotation in a molecular biology lab and decided that he wanted a career in research. Yet, first, Blanpain finished his med school stint and completed a 2-year residency in internal medicine, though he never subsequently worked as a practicing physician.

“It was a lot of effort, being on call often and working 80 hours per week, while knowing that in the end I would never end up a general practitioner, but I wanted to finish what I started,” says Blanpain. In fact, he was so determined that even after completing a 4-year PhD, Blanpain went back to medicine for a year to get his board certification, which required returning to work in the intensive-care unit and riding along in ambulances to horrible accidents. “It was extremely stressful. It was awful, to be honest,” he admits.

Yet once his medical requirements were completed, Blanpain poured his tenaciousness into research, in 2002 starting a postdoc in the lab of Elaine Fuchs at Rockefeller University, one of the few labs then studying stem cells. There, Blanpain published papers in Science, Cell, and Genes and Development, among others. Today, this stem-cell aficionado operates his own lab at ULB, studying mechanisms that regulate the fate of stem cells during normal growth and in cancer. And his medical training wasn’t all for naught: “During any project that has medical implications, I know what I’m doing, what we should follow up on, and the needs of the doctor and patient,” he says.
Here, Blanpain traces his own history, from early work on frog bladders, to an almost-but-not-really cure for baldness, to the fine art of watching cells differentiate in vivo.

Blanpain Begins

Thanks, Mom. “My mom is a medical doctor, and I used to read and discuss medical articles with her, so that’s why I was really interested in medicine. I started medical school with the idea of becoming a psychiatrist. I was 18 years old and fascinated by questions that many teenagers ask: What is consciousness? What is emotion? But I realized that, in terms of science, this field was much less developed than basic biochemistry, physiology, and cellular biology.”

Full bladder. Instead of psychiatry, Blanpain found himself drawn toward cell biology after a rotation in a research lab. “Before aquaporins were discovered, which won the Nobel Prize, we were looking for a channel that promotes water flow across the membrane—we were looking for the aquaporin. We used this cool system, the bladder of Xenopus. The bladder can reabsorb water, and it’s easy to weigh the thing. So we were convinced there were water channels there if we could purify them, but we were chasing this water channel at the wrong size. The idea was good and the protocol was good, but we couldn’t purify it. Still, it was a really fascinating project.”

“That was a question I’d had since back in my first year of medical school: Why isn’t the same oncogene found in every tumor, and why do certain tissues form tumors and not others?”

No entry. In 1997, Blanpain completed his medical residency and joined the ULB lab of Marc Parmentier, who had recently cloned and identified a receptor for HIV entry into human cells. “It was really a major breakthrough. He showed that a mutation in the gene CCR5 can cause complete resistance to HIV infection for people who are homozygous for this mutation. It completely opened up the idea of this gene as a main target for HIV therapies. During my thesis, I tried to understand how the virus interacts with this receptor, how we can block it, and the importance of endocytosis for HIV entry. It was a hot topic in the late 1990s.” During his 4 years as a graduate student, Blanpain published 10 papers as a first author, including the first identification of a CCR5 chemokine antagonist—a molecule that could bind the HIV receptor and prevent HIV entry without causing inflammation; and the mechanism by which a novel antibody blocks HIV entry into a cell.

Brave new cell. “After my PhD, I wanted to do a new line of research, something completely novel. And, at least in Europe, there were few people working on stem cells. Before 2000 was really the early days of stem cells; only the hematopoietic stem cell people were making much progress. So in the last year of my PhD, I went to the first Keystone meeting on stem cells, met the people who comprised the field, and applied to several of those labs. I chose to go to Elaine Fuchs’s lab—she was just about to move to Rockefeller University, and New York was a fantastic city. Elaine’s lab was amazing, with a lot of top people, and Elaine was a fantastic mentor. She taught me so many things that I still use every day. It was among the best times in my life.”

Imaging inactivity. Blanpain’s first publication from Fuchs’s lab was a Science paper, a landmark study in which, for the first time, the team showed it was possible to isolate stem cells based on their quiescence. “At the time, there was no way to isolate stem cells; we had no markers. But we knew they were cycling less frequently than other cells. Then, another postdoc had the brilliant idea to generate a way of marking slow cycling cells with a fluorescent label.” Since its publication, the paper has been cited more than 1,000 times.

Panning for gold. “But though it was a fascinating technique, this label, histone H2B–green fluorescent protein, wasn’t really convenient to look at stem cells under every type of condition, like knockout mice. I thought we needed to establish a gold standard marker to isolate these cells.” Blanpain came up with a method to isolate hair-follicle stem cells using a combination of monoclonal antibodies. Those stem cells, once isolated, were able to re-form the whole structure of the skin—the first demonstration that such stem cells are multipotent. “In that paper, we showed that we could re-form a tuft of hair on the backs of nude mice. The picture of that made it around the world, and I received many e-mails from people saying, ‘I’m completely bald, I see that you can regenerate hair. I would like to try that on myself.’ We had to tell them we work with mouse stem cells, and so far can’t do that on humans, especially for conditions such as baldness.”

Blanpain's Plan

Fresh start. In 2006, Blanpain wrapped up his postdoc with Fuchs and headed back to his native Belgium to start a lab at his alma mater, Université Libre de Bruxelles. “One of the things no one was doing in the field was trying to define the cellular origin of skin cancer. We knew which mutations cause cancer, but in which cell type mutations accumulate to give rise to cancer was completely unknown. That was a question I’d had since back in my first year of medical school: Why isn’t the same oncogene found in every tumor, and why do certain tissues form tumors and not others?” His team first expressed oncogenes in different skin cell types, then used a lineage-tracing approach to fluorescently mark the cells and follow their fate, monitoring which became cancerous and which did not. “We realized, as we had been expecting, that not all cells are sensitive to oncogene expression, and only certain cell populations progress to form skin cancer.”

Origins. “We found something else really interesting. Textbook chapters about cancer often say that a tumor arises from one cell type because it expresses the same marker as that cell type—the tumor and cells look alike. But when we did this analysis, we realized that many of the cells from which cancer originates do not express the markers they will express once they form a tumor. So using the expression of certain markers as a surrogate way to extrapolate to the origin of cancer was misleading. Instead, we identified the cellular origin of basal cell carcinoma, the most frequent tumor in humans, and the cellular origin of this tumor was not at all what we expected based on cellular markers.” This finding graced the cover of Nature Cell Biology in March 2010.

Cornering cancer. “Another major area we work on is cancer stem cells. When a tumor is formed, how does the tumor grow? Is it through the presence of rare stem cells, like in a normal tissue, or is it just a stochastic choice that dictates which cells contribute to tumor formation?” A traditional technique to identify cancer stem cells is to sort a tumor into different cell populations, then transplant those populations into immunodeficient mice. When a certain population of cells gives rise more frequently to tumors, scientists deduce those are the cancer stem cells. “From this experiment, you can learn what cells can do, but you cannot learn what cells naturally do,” says Blanpain. “We decided to have a brand new look at how tumors grow by using a lineage-tracing experiment. We labeled cells within a normal intact tumor, then looked at the fate of each of many individual tumor cells. We saw some cells that give rise to hundreds of cancer cells within a few weeks, while other cells contribute very little. With physicist Ben Simons at the University of Cambridge, we modeled these data in a Nature paper last year and gave a value to the probability and frequency of renewal of various types of cells in the tumor.” That study also landed Blanpain on the list of Nature’s top 10 scientists who mattered in 2012.

Breast test. “In the mammary field, people have purified cells and shown that a single cell can re-form the mammary gland, exactly what I did as a postdoc for the hair follicle. Like us, they concluded that the mammary gland is maintained by multipotent cells. For the same reason that we did lineage tracing in the skin—to find out where cancer arises and how it grows—we decided to also look for the cellular origin of cancer in the mammary gland, and generated a mouse model to do lineage tracing. When we did that, we were hoping to find multipotent stem cells, but each time we did the tracing, we only saw unipotent stem cells. We wondered if, in vivo, these cells are unipotent, and only upon transplantation do they gain broader differentiation potential. The answer was yes: the same cells that are unipotent in lineage become multipotent upon transplantation. Now people think completely differently about cancer in the mammary gland.” Knowledge of how these stem cells differentiate in mammary tissue will hopefully help researchers determine if these cells or others are at the origin of breast cancers.

“We saw some cells that give rise to hundreds of cancer cells within a few weeks, while other cells contribute very little.”

Side project. “We have one project completely unrelated to all the others. When I was still a postdoc, a grad student contacted me to ask if I’d be his mentor for a project. I said, “Why not?” He wanted to study the specification of cardiac cells during development. I figured cell-fate decision should be similar whether in the skin or cardiac lineage. We used embryonic stem cells to understand that model. When you let ESCs differentiate, a fraction of them differentiate into cardiac cells, a little foci of beating cells in the dish. We then found one gene, Mesp1, that was promoting almost all the ESCs into the cardiovascular lineages. That was really a major discovery in the field. Mesp1 was by far the most potent cardiac-inducing factor ever found. We’ve since made progress in that and identified new markers to isolate progenitors in cardiac differentiation, and we’re now repeating all this in vivo.”

Blissful Blanpain

Digging diversity. “I now have a lab of almost 40 people, and there’s more than 12 different nationalities. That’s exceptional in terms of cultural and ideas exchange. We have French, Belgian, Italian, Spanish, Greek, Chinese, Singaporean, American students, and more.”

Love at first rotation. “I met my wife on her first day of rotation in the medical school. I was a young resident, she was a med student, and it was happily ever after.”

Homebody. “I started my lab back at ULB for several reasons. Mainly, we’re family oriented. I wanted my kids to know their grandparents, uncles, aunts, and cousins. All my family lives in Belgium, so we wanted to be near them.”

Travel fatigue. “I give many talks. I think I’ve given more than 100 talks over the last 5 years. Traveling was always something that I loved. When I was a student, during each vacation I would do a big backpacking trip, to India, Thailand, South America, Mexico, Indonesia, and more. So I love traveling, but traveling to give a talk—flying 8 hours, sleeping, giving a talk, then back on a plane—is much less fun. There are too many meetings. I think I need to learn to travel less.”

Family ties. “I have two boys, ages 6 and 8. My oldest son is already completely crazy about science. He already has a microscope at home, and is making many discoveries.”

Bookworm. “I love reading novels. I like novels from many different countries, especially Spanish writers and South American writers. One of the best is Gabriel García Márquez. One Hundred Years of Solitude is one of my favorite books.”


Greatest Hits

• With Marc Parmentier, identified the first chemokine antagonist of an HIV receptor and defined
   how a novel antibody blocks HIV entry into a cell.

• With Elaine Fuchs, developed a marker to identify hair-follicle  stem cells and identified
   multipotent hair-follicle stem cells.

• Using lineage tracing, determined that some cell types within a tissue are more sensitive to oncogene
   expression than others within the same tissue.

• Pinpointed the cellular origin of basal cell carcinoma, the most common human cancer.

• Published the first experimental evidence for the existence of cancer stem cells in an intact solid tumor.

• Discovered unipotent stem cells that maintain the mouse mammary gland.

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