By Krista Conger, Stanford
University
Dogged by challenges
‘Somewhat mind-boggling’
June 4, 2018 -- Human
immune cells in blood can be converted directly into functional neurons in the
laboratory in about three weeks with the addition of just four proteins,
researchers at the Stanford University
School of Medicine have found.
The dramatic transformation does not require the cells to
first enter a state called pluripotency but instead occurs through a more direct
process called transdifferentiation.
The conversion occurs with relatively high efficiency —
generating as many as 50,000 neurons from 1 milliliter of blood — and it can be
achieved with fresh or previously frozen and stored blood samples, which vastly
enhances opportunities for the study of neurological disorders such as
schizophrenia and autism.
“Blood is one of the easiest biological samples to
obtain,” said Marius
Wernig, MD, associate professor of pathology and a member of Stanford’s Institute for Stem Cell
Biology and Regenerative Medicine. “Nearly every patient who walks into a
hospital leaves a blood sample, and often these samples are frozen and stored
for future study. This technique is a breakthrough that opens the possibility
to learn about complex disease processes by studying large numbers of
patients.”
A paper describing the findings was published online June
4 in the Proceedings of the National Academy
of Sciences. Wernig is the senior author. Former postdoctoral scholar
Koji Tanabe, PhD, and graduate student Cheen Ang are the lead authors.
Dogged by challenges
The transdifferentiation technique was first developed in
Wernig’s laboratory in 2010 when he and his colleagues showed that they could
convert mouse skin cells into mouse neurons without first inducing the cells to
become pluripotent — a developmentally flexible stage from which the cells can
become nearly any type of tissue. They went on to show the technique could also
be used on human skin and liver cells.
But each approach has been dogged by challenges,
particularly for researchers wishing to study genetically complex mental disorders,
such as autism or schizophrenia, for which many hundreds of individual,
patient-specific samples are needed in order to suss out the relative
contributions of dozens or more disease-associated mutations.
“Generating induced pluripotent stem cells from large
numbers of patients is expensive and laborious. Moreover, obtaining skin cells
involves an invasive and painful procedure,” Wernig said. “The prospect of
generating iPS cells from hundreds of patients is daunting and would require
automation of the complex reprogramming process.”
Although it’s possible to directly convert skin cells to
neurons, the biopsied skin cells first have to be grown in the laboratory for a
period of time until their numbers increase — a process likely to introduce
genetic mutations not found in the person from whom the cells were obtained.
The researchers wondered if there was an easier, more
efficient way to generate patient-specific neurons.
‘Somewhat mind-boggling’
In the new study, Wernig and his colleague focused on highly
specialized immune cells called T cells that circulate in the blood. T cells
protect us from disease by recognizing and killing infected or cancerous cells.
In contrast, neurons are long and skinny cells capable of conducting electrical
impulses along their length and passing them from cell to cell. But despite the
cells’ vastly different shapes, locations and biological missions, the
researchers found it unexpectedly easy to complete their quest.
“It’s kind of shocking how simple it is to convert T
cells into functional neurons in just a few days,” Wernig said. “T cells are
very specialized immune cells with a simple round shape, so the rapid
transformation is somewhat mind-boggling.”
The resulting human neurons aren’t perfect. They lack the
ability to form mature synapses, or connections, with one another. But they are
able to carry out the main fundamental functions of neurons, and Wernig and his
colleague are hopeful they will be able to further optimize the technique in
the future. In the meantime, they’ve started to collect blood samples from
children with autism.
“We now have a way to directly study the neuronal
function of, in principle, hundreds of people with schizophrenia and autism,”
Wernig said. “For decades we’ve had very few clues about the origins of these
disorders or how to treat them. Now we can start to answer so many questions.”
Other Stanford co-authors are postdoctoral scholars Soham
Chanda, PhD, and Daniel Haag, PhD; undergraduate student Victor Olmos;
professor of psychiatry and behavioral sciences Douglas Levinson,
MD; and professor of molecular and cellular physiology Thomas Südhof, MD.
The research was supported by the National Institutes of Health (grants MH092931
and MH104172), the California Institute for
Regenerative Medicine, the New York Stem Cell
Foundation, the Howard Hughes Medical
Institute, the Siebel Foundation and the Stanford Schizophrenia Genetics
Research Fund.
Stanford’s Department
of Pathology also supported the work.
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