dren’s hospitals. But he had little thought of becoming an academic scientist until he began a work-study job washing out
equipment in a University of Chicago biology lab. The work was
not glamorous but came with a perk: the graduate students in
the lab would let Vander Heiden make solutions for them and
show him how they did their experiments.
After graduating, he enrolled in Chicago’s MD-PhD program
and landed in the lab of Craig B. Thompson. Today Thompson is
the president and CEO of the Memorial Sloan Kettering Cancer
Center, but at the time he was studying immunology, looking at
how the body eliminated huge numbers of immune cells once
they were no longer needed.
When Vander Heiden arrived in Thompson’s lab in 1996, part
of the explanation was already understood. Those cells
would simply commit suicide, a process known
as apoptosis. It was also known that a family
of proteins named Bcl- 2 could stop a cell
from committing suicide—and that they
appeared to do so through their impact
on mitochondria, tiny organelles known
as the powerhouses of the cell for their
role in energy production.
Vander Heiden had just joined a
cutting-edge immunology lab interested
in protein signaling. Yet he had been asked
to investigate how Bcl- 2 proteins affect mitochondria, a relic of the old, outdated metabolism research. When it became clear that no one in
the lab knew much about metabolism, Vander Heiden
reread the relevant sections of his undergraduate biochemistry
textbook. He also teamed up with Navdeep Chandel, a metabolism researcher at Northwestern University who was then a graduate student in a University of Chicago cellular physiology lab.
When another lab showed that proteins released from the
mitochondria could trigger apoptosis, Vander Heiden and
Chandel got an important clue: the decision to commit suicide
could now be traced directly to the mitochondria. And yet the
deeper question of what was happening inside them remained
mysterious until the two researchers arrived at an answer,
thanks to a series of elegant experiments designed by Vander
Heiden (whom Chandel calls “a world-class experimentalist”) to
study how molecules moved through the mitochondrial mem-
brane. They discovered that the release of the mitochondrial
proteins was a sign of a failing powerhouse, a notice to the cell
that a brownout was under way so it was time to abort. But
brownouts weren’t inevitable; the Bcl- 2 proteins, like emer-
gency workers called to the scene of an imminent disaster, could
resuscitate the metabolic function of the mitochondria and keep
things from getting to that point. The suicide signal, in turn,
would never be released.
For Vander Heiden, this was a “watershed moment.” Among
other things, it meant that metabolic enzymes weren’t merely supplying energy from food. Metabolism was governing the most fundamental decision a cell has to make—whether to live or die. That
meant it had to be interwoven into the signaling cascades that
molecular biologists studied. His feeling at the time, he recalls,
Thompson, recognizing the opportunity,
shifted the focus of his lab to metabolism.
Vander Heiden, meanwhile, continued
to pursue Thompson’s broader question
of how the body eliminates unwanted
immune cells. He already knew that
growth factors, messages sent from one
cell to the next, kept cells from committing suicide, but how the signals delivered
their survival message remained unclear.
What he discovered in a series of studies
carried out in the late ’90s followed perfectly
from his previous research. Growth factors kept
cells alive by giving them permission to eat. Without
that permission, a cell soon faced an energy crisis, and the mitochondria released their death signals.
The takeaway was clear: our bodies eliminate unwanted cells
by starving them to death.
Solving the metabolism mystery
As Vander Heiden’s MD-PhD program was coming to an end, he
hadn’t yet begun to focus on cancer, but its possible links with
his research on cell suicide were intriguing. Cancer cells were
the other side of the coin—cells that were resistant to suicide,
that no longer cared about instructions from other cells. So in
2004, after completing a residency in oncology at Brigham and
Women’s Hospital in Boston, he was anxious to investigate cancer metabolism for his postdoc research.
Finding the right lab wasn’t easy. At the time, telling leading
researchers he wanted to study how cancer cells consumed glucose
was like approaching a high-tech manufacturer and announcing
you wanted to study the trucks that brought fuel to the factory.
It sounded, Vander Heiden says, “like a really ridiculous thing.”
was governing the
decision a cell has to
live or die.