CIMBio Course Fills Urgent Need
By Mika Ono
The Scripps Research Institute's Center for Integrated Molecular
Biosciences (CIMBio) was abuzz with activity last week, as
some 80 people spilled out of conference rooms, microscopy
suites, and laboratories as part of an intensive, nine-day
course entitled "A Practical Course in Molecular Microscopy."
"This course in cryo-electron microscopy addresses a desperate
need," says Associate Professor Clint Potter. "The field is
taking off and there simply aren't many ways to be trained
in the technique."
Organized by Potter, Associate Professor Bridget Carragher,
and Professor Ron Milligan under the auspices of the National
Resource for Automated Molecular Microscopy at CIMBio, the
course aims to offer students a thorough grounding in all
aspects of molecular structural determination by cryo-electron
microscopy.
Forty participants—Ph.D. candidates, postdocs, and
a few senior scientists—and 36 instructors—many
of whom are pioneers in the field—traveled from labs
around the world to attend the course. Dozens of support staff
and scientists from Scripps Research also participated.
The schedule of classes was not for the fainthearted.
Students spent mornings in lectures—on topics such
as "Fundamentals of Image Analysis and Averaging," "Introduction
to 2D Crystal Analysis," and "Imaging: Recording and Assessment."
They spent afternoons in hands-on workshops on sample preparation,
use of the electron microscope, and evaluation and analysis
of the images. They spent evenings in poster sessions, additional
workshops, and sessions tailored to address individual research
projects.
"These are 13-hour days," notes Potter, "and for some people
they're longer, because they stay up late chatting. I'm expecting
we'll all look pretty bad by the end of it."
But, as the course progressed, enthusiasm among the participants
seemed unflagging.
"I am pretty tired," admitted Gary Ren, a research associate
in the Yeager lab, a few days in to the proceedings. "It's
incredibly exciting, though. This is a precious time and I
want to make the most of it."
Naked and Cold
Why all the interest in cryo-electron microscopy?
The technique sits squarely between the established fields
of x-ray crystallography, on the one hand, which can solve
protein structures to exquisitely high resolution, and cell
biology, on the other, which focuses on the larger picture
of where those proteins are in a cell.
"With cryo-EM, we can look at how solved protein structures
perform critical tasks within a cell, such as transportation
and replication," says Carragher. "That's what the technique
is all about from our perspective—putting together the
parts of a working machine."
Milligan notes that cryo-electron microscopy is currently
the only technique that can be used to directly visualize
macromolecular machines within a cell.
"You simply can't grow crystals of things whose conformation
changes by the second," he notes. "So, over the last 30 years,
methodologies of looking at these pieces frozen in their native
state, naked and cold, have developed."
According to Milligan, cryo-electron microscopy has come
into its own during the last few years. Many top universities
have hired cryo-electron microscopists. Cryo-electron microscopy
has been recognized by granting agencies as an important technology.
And an increasing number of researchers are trying to break
into the field.
"It's a vibrant area," observes Millgan.
While interest in cryo-electron microscopy is burgeoning
among scientists worldwide, training opportunities have remained
limited. While scientists present papers at conferences, rarely
can they address the issues of technique in these forums.
"Conferences are about results, not technique," states Carragher.
"In general, [at conferences technique] is just the thing
you do in your lab—but sometimes it's what makes the
difference between success and failure."
Potter adds, "There's not much [about cryo-EM technique]
written down. One of the problems in our field is that there
has not been a general protocol. A lot of experimental technique
is lore passed from scientist to scientist."
A Course is Born
Up until now, one training ground for cryo-electron microscopy
technique has dominated the field—a course held every
other year at the European Molecular Biology Laboratory in
Heidelberg, Germany.
"Almost everyone in the field started at Heidelberg or has
taught there," says Carragher. "Because cryo-EM is complex,
it's hard to get started [in it] without going to a course
and meeting the people."
In recent years, however, the Heidelberg course has become
chronically oversubscribed.
So, the CIMBio team decided to fill the gap with a course
of its own, offered in the off years for the Heidelberg course
and aimed primarily at scientists in the United States and
Pacific Rim to balance the Heidelberg course's European thrust.
The idea for a new course was met with overwhelming support
from other researchers in the field. When the team contacted
the world's leading cryo-electron microscopists about teaching
at the course—for free—all accepted the invitation.
Personnel from several of the other national resource centers
around the country also offered to give lectures and demonstrations.
Funding to cover the expenses of food, busing, and faculty
travel came from both public and private sources. Two National
Institutes of Health grants, and a donation from the Agouron
Institute supported the venture. Participants paid a registration
feel of $350. And several private firms—FEI Co., Gatan
Inc., and Tietz Video and Image Processing Systems—also
helped out.
"Manufacturers have been very supportive, not only by cutting
checks, but also by donating equipment and resources," says
Potter.
To hear Potter and Carragher tell it, getting people to
apply to the course was probably the easiest part of the process.
"We did very little advertising and got a huge response,"
says Potter. "We put out one e-mail, received 80 applications,
and closed the course in June."
The team originally planned to offer 24 places to those
most qualified and most needing the training, but, as Carragher
admits, "We weren't very good at saying 'no,' so we squeezed
up to 36 by the time the course started and then added four
more on the first day!"
CIMBio Can Take It
Potter, Carragher, and Milligan's time during the last two
months has been dominated by grappling with arranging the
logistics of the course.
"It's been a lot of work," notes Potter.
"A huge effort involving many people," seconds Carragher.
"We are grateful to the dozens of support staff and scientists
at Scripps who generously donated their time and attention."
Thankfully, the CIMBio building at Scripps Research, which
opened early last year, has also made their job a little easier.
"Having so many people in your building for 10 days is no
joke," says Carragher. "There aren't many buildings that can
take it, but CIMBio can. We have a fantastic microscopy suite—one
of the best there is."
In the CIMBio Building are six rooms for microscopes, which
are mounted on three-foot-thick concrete slabs isolated from
the building's foundation to protect the instrumentation from
vibrations. The rooms are climate-controlled with low humidity
to prevent contamination of samples by water vapor, and are
sound-proofed so that outside noise does not cause minute
movement.
"We also have a large lecture room, facilities with computers,
and lab space with an open configuration," says Potter. "We
had this course in the back of our minds when we were designing
the building."
After nine long days of lectures, workshops, microscopy
work, and discussions, however, the building was becoming
part of the background for most of the course participants.
The value of what they were learning, however, was still
front and center.
"The course has been offering a wonderful survey of current
methods, excellent exposure to ground-breaking research, and
an ideal combination of lectures and hands-on experience,"
said one participant, too shy to be identified by name. "In
addition, there's been a very nice atmosphere to get to know
each other."
"Some of the instructors here are pillars of the field,"
enthused Christopher Ackerson, a Ph.D. candidate at Stanford
University. "The roster is impressive."
One instructor, Alok Mitra from the University of Aukland,
added, "The students have been surviving—and that is
saying a lot!"
So, was all the work organizing the course worthwhile?
Potter didn't hesitate with a resounding "Yes!"
Carragher seemed to agree, pointing to the remarkable cross-fertilization
and interaction that had taken place among the scientists:
"At least one exchange will result in a publication in the
near future!"
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