Unwilling to accept the finality of terminal differentiation, Helen Blau
has honed techniques that showcase the flexibility of cells to adopt different identities.
HELEN BLAU: Director of the Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Stanford University School of MedicinePenney Gilbert
Helen Blau was born in London and holds dual citizenship in the United States and the U.K.
spent most of her
childhood in Europe.
"I loved that my family traveled so much," says Blau
, who attended summer schools in the Swiss Alps and lived with French and Austrian families.
"The experience made me adventurous, encouraged me to take risks, and exposed me to different languages and cultures-all of which shaped my development."
That same sense of unlimited possibilities ultimately guided her
"I enjoy taking on new things," says Blau
not afraid to question dogma."When I was a student-an undergraduate and then graduate student-the dogma was that once mammalian cells were differentiated, that was it.
Using a technique that involves fusing cells from two different species, Blau
found that she
could coax differentiated cells to adopt a new fate, reactivating genes that had been developmentally silenced.
discusses the mechanisms of reprogramming, the farming of seaweed, and the dance of the stem cells.
"I didn't like the idea that decisions were terminal.
So I set out to find out whether cell fate was irreversibly determined."
Not just for frogs.
As an undergraduate "I started thinking about the plasticity of cells and whether they could change their fate," says Blau
In the 1980s Blau
chose a different path to show that the cells of mammals are also plastic: melding whole cells from different species and allowing the regulatory factors present in one cell to reprogram the expression of genes in the other.
In the 1950s and '60s, a handful of investigators had used the technique to demonstrate the activity of gene repressors.
"They showed, for instance, that rat albumin was shut off when you fused a rat hepatocyte with a mouse fibroblast," says Blau
So some factor present in the fibroblast shut down the activity of a liver-specific gene like albumin.
As the fused cell divided and chromosomes were lost-interspecies hybrids suffer from serious chromosomal instability-the albumin gene would be turned back on.
"So there was clearly a repressor that was being made and then lost," says Blau
"What I wanted to do was see if, instead of repressing an active gene, you could activate a gene that was silenced.
The dogma was that you couldn't.
Some of the giants in the field had tried.
But in the system in which fused cells are allowed to divide and chromosomes can be thrown out, Blau
says, "you don't know whether you've activated a gene because you lost a repressor or because you found an activator."
To get around this confounding chromosomal conundrum, Blau
chose conditions that discouraged cell division-keeping her
culture medium mitogen-free and using muscle cells, which don't proliferate.
stacked the odds in muscle's favor, so that the resulting multinucleate hybrids, known as heterokaryons, would contain, say, three mouse muscle cells fused with a single human amniocyte (an embryonic cell isolated from amniotic fluid).
found was that the union caused the non-muscle cell to join with its muscle-cell partners in expressing muscle-specific genes.
"This was the first reprogramming of a human cell and activation of silenced human genes," says Blau
, whose Stanford
team described these and related results in Cell papers in 1983, '84, and '85.
has recently resuscitated this approach to activate the genetic program typical of induced pluripotent stem (iPS) cells.
By fusing a mouse embryonic stem cell with a human fibroblast, she
has activated the fibroblast's pluripotency program.
"It's going to help how people can look at reprogramming in a mechanistic way," she
Because the method is so rapid and efficient-75 percent of the heterokaryons show signs of reprogramming within a period of two days-it can be used to probe the series of genetic changes that pave the way to pluripotency.
Using novel bi-species RNA sequencing technologies to catalog the transcripts-and to determine whether they came from the human-fibroblast half of the heterokaryon-Blau and her
team have already identified a gene involved in DNA demethylation that's necessary for the activation of the key pluripotency genes, work described in Nature in 2010.
working toward "making the system more accessible, so people can use it to start to understand the mechanisms of reprogramming and more effectively obtain their favorite cell type."
Seeing stem cells.
"One of our goals is to see whether we can enlist stem cells that exist in the body to help repair tissues," says Blau
Muscle-a mainstay in the lab-has proven particularly challenging.
"Muscle stem cells can't be proliferated in culture because when they're put on typical plastic culture dishes they lose their 'stemness.' So we're trying to recapitulate their natural niche and ask 'How does a stem cell see the world?'" One factor is the rigidity of the micro-environment that supports the cells.
"Muscle is five orders of magnitude softer than plastic.
But when isolated stem cells are grown on a soft, hydrated gel-developed by the Blau lab-"they maintain their stem-cell function.
Using this cell-friendly hydrogel culture system, Blau
says, "we can now screen for small molecules or proteins that can influence stemness, self-renewal, expansion, and rejuvenation.
In fact, she
maintains that soon no one will want to grow their cells on tissue culture plastic.
The way the researchers monitor the properties of the cultured stem cells is via another innovative approach, this one involving bioluminescence imaging.
By labeling the stem cells with luciferase-the enzyme that gives fireflies their twinkle-Blau and her
colleagues can trace their trajectories through live animals by seeing which mice glow.
Even when the investigators introduced only a single stem cell into each mouse, Blau
says a handful "engrafted to high enough levels that we could detect them by bioluminescence imaging, which means they had expanded to make many more stem cells.
Some of the progeny of these single cell transplants had incorporated into muscle fibers, "so they met the quintessential definition of a stem cell: they not only self-renewed, they also differentiated."
"Because facts change all the time, what is really important is knowing how to communicate and be able to make a logical argument in support of a theory."
Call for rumination.
experienced a bit of culture shock when she
came to the U.S. as a graduate student at Harvard
But when it comes to bridging disciplines, Blau
doesn't stop there.
recently convinced Sebastian Thrun, the co-inventor of Google Street View, to help her
develop algorithms for tracking cell movement and division.
done all this macro-imaging, and we got him interested in micro-imaging," she
The videos of cells in culture used to develop these algorithms have attracted even more unusual trainees to Blau's
enjoys brief mini-sabbaticals-like a couple of months in Paris.
As a postdoc at the University of California, San Francisco
did some genetic counseling for families with diseases such as Duchenne muscular dystrophy.
While a graduate student, Blau sang in a band.
"You always feel that you're not spending enough time in the lab-or enough time with your children," says Blau
But making the effort can yield wide-ranging benefits.
"I think that I was a better scientist
because I had wonderful children to go home to.
And I was a better mother because not all of my dreams and goals were invested in my children.
Blau is married to Stanford psychiatrist David Spiegel.
"Choosing the right partner, one who is supportive of your career and family goals, is absolutely crucial."
Have kids, will travel.
husband have included their children in family adventures from an early age.
"They became the best travelers.
I remember when my son was 3, we arrived in Oregon and there was no bed for him.
We pulled out a drawer and put in some towels and he
said, 'This is ideal.'?" Years later, on a trip to Bali, Blau
family spent time in a village where tourists rarely ventured.