“HowLoud” Campaign Makes a Sound Point

As we explored in our Spring 2015 article Good Vibrations, noise can beneficial in certain scientific contexts but is far less welcome in more mundane situations.

KPCC’s AirTalk program recently featured an interview with Brendan Farrell, a former Caltech postdoctoral student in computing and mathematical sciences, about his Kickstarter campaign that aims to map the noise levels of Southland communities. Farrell got the idea for the site, called HowLoud, after he went seeking a new apartment in a quiet location — only to realize there were no good, accurate data on how quiet a given apartment might be.

HowLoud is an attempt to provide that information: it seeks to scientifically quantify noise levels in the region and also provide an easy way for consumers to compare various locations. The system quantifies noise from traffic, airports, and businesses on a 100-point scale, with quieter areas receiving higher scores.

As Farrell explained on AirTalk, “We wanted to create a user-friendly consumer tool. We’ve taken a lot of the traditional acoustical engineering tools and used [computer modeling] on a massive scale, so we have a huge 3-D model of all of Los Angeles County and Orange County. And we have the traffic in there and just use physics to propagate the noise this traffic creates throughout the region.”

The HowLoud Kickstarter page tells more about the project and about how to get involved.
The HowLoud Kickstarter page tells more about the project and about how to get involved.


The HowLoud Kickstarter project—run by a team including Farrell and four mapping and mathematical modeling experts—has been featured in several media outlets and is well on its way to reaching its goal.

The rest of the KPCC interview can be found online.

Freezing a Bullet (+)

X-Ray Vision, an article in our Spring 2015 issue, examined the central role Caltech has played in developing a powerful technique for revealing the molecular machinery of life. In May, chemist André Hoelz, who was featured in the article, published a new paper describing how he used the technique to reveal how protein-synthesizing cellular machines are built.

Crystal structure of the assembly chaperone of ribosomal protein L4 (Acl4) that picks up a newly synthesized ribosomal protein when it emerges from the ribosome in the cytoplasm, protects it from the degradation machinery, and delivers it to the assembly site of new ribosomes in the nucleus.   Credit: Ferdinand Huber/Caltech
Crystal structure of the assembly chaperone of ribosomal protein L4 (Acl4) that picks up a newly synthesized ribosomal protein when it emerges from the ribosome in the cytoplasm, protects it from the degradation machinery, and delivers it to the assembly site of new ribosomes in the nucleus.
Credit: Ferdinand Huber/Caltech

Ribosomes are vital to the function of all living cells. Using the genetic information from RNA, these large molecular complexes build proteins by linking amino acids together in a specific order. Scientists have known for more than half a century that these cellular machines are themselves made up of about 80 different proteins, called ribosomal proteins, along with several RNA molecules and that these components are added in a particular sequence to construct new ribosomes, but no one has known the mechanism that controls that process.

Now researchers from Caltech and Heidelberg University have combined their expertise to track a ribosomal protein in yeast all the way from its synthesis in the cytoplasm, the cellular compartment surrounding the nucleus of a cell, to its incorporation into a developing ribosome within the nucleus. In so doing, they have identified a new chaperone protein, known as Acl4, that ushers a specific ribosomal protein through the construction process and a new regulatory mechanism that likely occurs in all eukaryotic cells.

The results, described in a paper that appears online in the journal Molecular Cell, also suggest an approach for making new antifungal agents.

The work was completed in the labs of André Hoelz, assistant professor of chemistry at Caltech, and Ed Hurt, director of the Heidelberg University Biochemistry Center (BZH).

“We now understand how this chaperone, Acl4, works with its ribosomal protein with great precision,” says Hoelz. “Seeing that is kind of like being able to freeze a bullet whizzing through the air and turn it around and analyze it in all dimensions to see exactly what it looks like.”

That is because the entire ribosome assembly process—including the synthesis of new ribosomal proteins by ribosomes in the cytoplasm, the transfer of those proteins into the nucleus, their incorporation into a developing ribosome, and the completed ribosome’s export back out of the nucleus into the cytoplasm—happens in the tens of minutes timescale. So quickly that more than a million ribosomes are produced per day in mammalian cells to allow for turnover and cell division. Therefore, being able to follow a ribosomal protein through that process is not a simple task.

Hurt and his team in Germany have developed a new technique to capture the state of a ribosomal protein shortly after it is synthesized. When they “stopped” this particular flying bullet, an important ribosomal protein known as L4, they found that its was bound to Acl4.

Hoelz’s group at Caltech then used X-ray crystallography to obtain an atomic snapshot of Acl4 and further biochemical interaction studies to establish how Acl4 recognizes and protects L4. They found that Acl4 attaches to L4 (having a high affinity for only that ribosomal protein) as it emerges from the ribosome that produced it, akin to a hand gripping a baseball. Thereby the chaperone ensures that the ribosomal protein is protected from machinery in the cell that would otherwise destroy it and ushers the L4 molecule through the sole gateway between the nucleus and cytoplasm, called the nuclear pore complex, to the site in the nucleus where new ribosomes are constructed.

“The ribosomal protein together with its chaperone basically travel through the nucleus and screen their surroundings until they find an assembling ribosome that is at exactly the right stage for the ribosomal protein to be incorporated,” explains Ferdinand Huber, a graduate student in Hoelz’s group and one of the first authors on the paper. “Once found, the chaperone lets the ribosomal protein go and gets recycled to go pick up another protein.”

The researchers say that Acl4 is just one example from a whole family of chaperone proteins that likely work in this same fashion.

Hoelz adds that if this process does not work properly, ribosomes and proteins cannot be made. Some diseases (including aggressive leukemia subtypes) are associated with malfunctions in this process.

“It is likely that human cells also contain a dedicated assembly chaperone for L4. However, we are certain that it has a distinct atomic structure, which might allow us to develop new antifungal agents,” Hoelz says. “By preventing the chaperone from interacting with its partner, you could keep the cell from making new ribosomes. You could potentially weaken the organism to the point where the immune system could then clear the infection. This is a completely new approach.”

Co-first authors on the paper, “Coordinated Ribosomal L4 Protein Assembly into the Pre-Ribosome Is Regulated by Its Eukaryote-Specific Extension,” are Huber and Philipp Stelter of Heidelberg University. Additional authors include Ruth Kunze and Dirk Flemming also from Heidelberg University. The work was supported by the Boehringer Ingelheim Fonds, the V Foundation for Cancer Research, the Edward Mallinckrodt, Jr. Foundation, the Sidney Kimmel Foundation for Cancer Research, and the German Research Foundation (DFG).

—Kimm Fesenmaier

Small Wonder (+)

Turning big things into small packages is useful enough when you’re packing for a long car trip, but when you’re packing for a voyage into space, where weight and volume are at a premium, it’s absolutely essential.

That’s why a team at Caltech’s Space Structures Laboratory has developed an efficient new packing technique that can be used to minimize the space required to store structures with large surface areas. Such structures potentially include solar sails—used to propel spacecraft—prior to their deployment in space.

The technique, called “slip wrapping,” is demonstrated online in a new video.

In addition to being useful for packaging solar sails, the technique may help package other structures including drag sails, photovoltaic arrays, and thermal shields—all of which are large, but thin, when deployed.

Graduate student Manan Arya; Nicolas Lee, the W. M. Keck Institute for Space Studies Postdoctoral Scholar in Aerospace; and Sergio Pellegrino, the Joyce and Kent Kresa Professor of Aeronautics and Professor of Civil Engineering, conceived the technique.

Pellegrino’s work was previously featured in the Winter 2013 issue of E&S; see “Using Space Wisely” on page 14. Lee is funded as a Keck Institute for Space Studies (KISS) Prize Postdoctoral Fellow; KISS is a “think and do tank” that aims to develop revolutionary concepts and technology for future space missions (see March 2015 issue of E&S for a recent feature on KISS).

A paper on this technique was presented at the American Institute of Aeronautics and Astronautics’ SciTech 2015 in Kissimmee, Florida, in January. It can be downloaded from pellegrino.caltech.edu/publications.html

—Jon Nalick

Dedication of Advanced LIGO (+)

In the Winter 2015 issue of E&S, we examined some of the visualizations created by the most sensitive detectors in the world—those associated with the Laser Interferometer Gravitational-Wave Observatory, or LIGO. Here we take a look at the next step in the LIGO story.

The Advanced LIGO Project, a major upgrade that will increase the sensitivity of the Laser Interferometer Gravitational-wave Observatories instruments by a factor of 10 and provide a 1,000-fold increase in the number of astrophysical candidates for gravitational wave signals, was officially dedicated May 19 in a ceremony held at the LIGO Hanford facility in Richland, Washington.

LIGO was designed and is operated by Caltech and MIT, with funding from the National Science Foundation (NSF). Advanced LIGO, also funded by the NSF, will begin its first searches for gravitational waves in the fall of this year.

Researchers installing some of the small suspended LIGO mirrors in the vacuum system. Credit: Courtesy of LIGO Laboratory
Researchers installing some of the small suspended LIGO mirrors in the vacuum system.
Credit: Courtesy of LIGO Laboratory

The dedication ceremony featured remarks from Caltech president Thomas F. Rosenbaum, the Sonja and William Davidow Presidential Chair and professor of physics; Professor of Physics Tom Soifer (BS ’68), the Kent and Joyce Kresa Leadership Chair of Caltech’s Division of Physics, Mathematics and Astronomy; and NSF director France Córdova (PhD ’79).

“We’ve spent the past seven years putting together the most sensitive gravitational-wave detector ever built. Commissioning the detectors has gone extremely well thus far, and we are looking forward to our first science run with Advanced LIGO beginning later in 2015.  This is a very exciting time for the field,” says Caltech’s David H. Reitze, executive director of the LIGO Project.

“Advanced LIGO represents a critically important step forward in our continuing effort to understand the extraordinary mysteries of our universe,” says Córdova. “It gives scientists a highly sophisticated instrument for detecting gravitational waves, which we believe carry with them information about their dynamic origins and about the nature of gravity that cannot be obtained by conventional astronomical tools.”

“This is a particularly thrilling event, marking the opening of a new window on the universe, one that will allow us to see the final cataclysmic moments in the lives of stars that would otherwise be invisible to us,” says Soifer.

Predicted by Albert Einstein in 1916 as a consequence of his general theory of relativity, gravitational waves are ripples in the fabric of space and time produced by violent events in the distant universe—for example, by the collision of two black holes or by the cores of supernova explosions. Gravitational waves are emitted by accelerating masses much in the same way as radio waves are produced by accelerating charges, such as electrons in antennas. As they travel to Earth, these ripples in the space-time fabric bring with them information about their violent origins and about the nature of gravity that cannot be obtained by other astronomical tools.

Although they have not yet been detected directly, the influence of gravitational waves on a binary pulsar system (two neutron stars orbiting each other) has been measured accurately and is in excellent agreement with the predictions. Scientists therefore have great confidence that gravitational waves exist. But a direct detection will confirm Einstein’s vision of the waves and allow a fascinating new window into cataclysms in the cosmos.

LIGO was originally proposed as a means of detecting these gravitational waves. Each of the 4-km-long L-shaped LIGO interferometers (one each at LIGO Hanford and at the LIGO observatory in Livingston, Louisiana) use a laser split into two beams that travel back and forth down long arms (which are beam tubes from which the air has been evacuated). The beams are used to monitor the distance between precisely configured mirrors. According to Einstein’s theory, the relative distance between the mirrors will change very slightly when a gravitational wave passes by.

The original configuration of LIGO was sensitive enough to detect a change in the lengths of the 4-km arms by a distance one-thousandth the size of a proton; this is like accurately measuring the distance from Earth to the nearest star—3 light years—to within the width of a human hair. Advanced LIGO, which will utilize the infrastructure of LIGO, will be 10 times more sensitive.

Included in the upgrade were changes in the lasers (180-watt highly stabilized systems), optics (40-kg fused-silica “test mass” mirrors suspended by fused-silica fibers), seismic isolation systems (using inertial sensing and feedback), and in how the microscopic motion (less than one billionth of one billionth of a meter) of the test masses is detected.

The change of more than a factor of 10 in sensitivity also comes with a significant increase in the sensitive frequency range. This will allow Advanced LIGO to look at the last minutes of the life of pairs of massive black holes as they spiral closer, coalesce into one larger black hole, and then vibrate much like two soap bubbles becoming one. It will also allow the instrument to pinpoint periodic signals from the many known pulsars that radiate in the range from 500 to 1,000 Hertz (frequencies that correspond to high notes on an organ).

Advanced LIGO will also be used to search for the gravitational cosmic background—allowing tests of theories about the development of the universe only 10-35 seconds after the Big Bang.

LIGO research is carried out by the LIGO Scientific Collaboration (LSC), a group of some 950 scientists at universities around the United States and in 15 other countries. The LSC network includes the LIGO interferometers and the GEO600 interferometer, located near Hannover, Germany, and theand and the LSC works jointly with the Virgo Collaboration—which designed and constructed the 3-km-long Virgo interferometer located in Cascina, Italy—to analyze data from the LIGO, GEO, and Virgo interferometers.

Several international partners including the Max Planck Institute for Gravitational Physics, the Albert Einstein Institute, the Laser Zentrum Hannover, and the Leibniz Universität Hannover in Germany; an Australian consortium of universities, led by the Australian National University and the University of Adelaide, and supported by the Australian Research Council; partners in the United Kingdom funded by the Science and Technology Facilities Council; and the University of Florida and Columbia University, provided significant contributions of equipment, labor, and expertise.

—Written by Kathy Svitil

The Meteorite from Mars (+)

When a meteorite plowed into the earth near the Moroccan town of Tissint in 2011, it provided scientists with intriguing new clues to the evolution of our solar system.

Nanomineralogist Chi Ma, who studied samples of the meteorite firsthand, identified two new minerals from the meteorite, as we reported in our Spring 2015 issue of E&S, in the article “They Came From Outer Space.

But Ma is far from alone in his interest in this out-of-this-world object. Natural History Museum of London meteorite expert Caroline Smith discusses why in this four-minute video, highlighting the significance of the meteorite’s discovery. She notes it is one of only 130 meteorites on Earth known to have originated from Mars.

Smith says the find was a rare one because witnesses actually saw the meteor that heralded its fall to Earth. (Strictly speaking, a meteor is the flash or streak of light resulting from interplanetary debris burning up in the atmosphere. A meteoroid is the solid debris that originates in space before its impact with the earth’s surface. A meteoroid that survives impact with Earth’s surface is called a meteorite. Hence, the Tissint sample, is a meteorite.)

Having witnesses who saw the meteorite’s fall to Earth made it easy to locate quickly. And that, as Smith notes in the video, is crucial because, “if you’re interested in studying organic molecules . . . you want to get your hands on the least contaminated meteorites.” The longer the meteorite lays around, the more Earth stuff it’s likely to accumulate.

Ma says finds like the Tissint meteorite keep him constantly energized and surprised. For most people, the Next Big Thing in their careers seldom just falls from the sky. But for Ma, it just might.

—Written by Jon Nalick

Endnotes (+)

What Started for You at Caltech?

In our Spring 2015 issue, we asked alumni to share what originated for them at Caltech, and printed only a few of the responses we received. Here are several more, some of which were edited for grammar, spelling, length, and clarity.

The idea that I could study anything I want. The experience of pushing yourself to the limit, and then some more.

Caltech taught me how to think and consequently write. Without those talents my life would be in turmoil.

I got in the habit of doing exercises and have continued to do so. I am 73 years old now and in much better health than most of my peers. Had I not signed up for body building about 55 years ago I suspect I would not be nearly as healthy today. Thanks, Caltech!

I learned that science isn’t about carrying around a collection of facts and formulas. Instead, science is a process of learning to think, to deconstruct a problem, to solve it, and to put the solution into context.

A lifelong appreciation for the musical works of Richard Wagner.

I started running because of Caltech. And even though I’m still not all that fast and have never come close to winning a race (or even finishing in the top half), I’ve been running ever since.

It helped lead to my 1965 selection as one of the first scientist astronauts for the Apollo Program. Ultimately, I became the Lunar Module Pilot on Apollo 17 in December 1972 and the last of 12 men to step on the Moon and the only scientist to explore it.

Through exploration of different sciences and listening to societal problems, I realized that my interest was to bring science together to solve those problems.

It started my competitive swimming career.

My Caltech education proved invaluable in 1981 when I was invited to join the staff of the National Academy of Sciences Office of International Affairs, where I worked on projects ranging from a conference on chemistry and world food supplies, to biofuels in Brazil, to industrial energy efficiency in India.

Finding the Value of X-rays (+)

In researching our article on X-ray crystallography (“X-ray Vision“) we came across this 1940s-era General Electric film, Taking the X Out of X-rays, which discusses the origins of X-ray research and the technology that made it possible.

The nine-minute black-and-white video explains what X-rays are, how they work, and the basics of X-ray photography and fluoroscopy. The information is still relevant 70 years later, long after most of us have lost the sense of wonder about the hidden world these rays reveal. But for the film’s presenter, that sense of wonder is fresh and exciting. He marvels, “Rays, which are themselves invisible, can reveal objects that are otherwise also invisible.”

Throop Rocks (+)

Photo by Katie Neith

At first glance, the Throop Memorial Garden looks to be just what it says it is—a lush plot of greenery and water features that offer respite from the sun for turtles, koi, and people alike. But a closer look at the plaques attached to large boulders on the east edge of the tiny campus park reveal that some of the hardscaping also serves as an exhibit of local geological history. Where Throop Hall—Caltech’s first building—once stood proud, rocks representing nearly 2 billion years of the binding of minerals and mineraloids in the San Gabriel Mountains now dot the gently sloped hillside. Grouped according to type and age, the eight different types of rocks that can be found in the garden include 1.7 billion-year-old ancient gray gneisses from Brown Mountain, distinctive pink granite that once underlaid Echo Mountain, and mystery boulders initially found in the Arroyo Seco that, according to the plaque, were “clearly transported there by man,” and whose original sources and ages are unknown.

Photo by Van Urfalian

JPL—The Suicide Squad’s First Mission (+)

"Suicide Squad" members, from left: Rudolph Schott, Amo Smith, Frank Malina, Ed Forman, and Jack Parsons.
“Suicide Squad” members, from left: Rudolph Schott, Amo Smith, Frank Malina, Ed Forman, and Jack Parsons.
Photo courtesy JPL

“The Rocketmen” video, one chapter in a documentary series about the early days of JPL, focuses on the origin of the rocketry pioneers known on campus as the “Suicide Squad” for their dangerous experiments.

The group was highlighted in the Spring 2014 issue of E&S in an article titled “Launch Points,” and JPL’s three-minute video offers even more interesting details about it.

The video covers the group’s first rocket motor test in 1936, conducted in a remote part of the Arroyo Seco on Halloween. JPL historian Erik Conway notes onscreen that the initial efforts fizzled when the fuse sputtered out. “On the fourth try, the motor ignited and the oxygen line whipped around, started shooting fire, and they all ran away,” Conway says, adding that the group considered the experiment a success in part because “they learned a number of things not to do.”

A Lifetime of Crystallography (+)

Chemist Dick Marsh, a Techer through and through, has witnessed the evolution of X-ray crystallography (see “X-Ray Vision“) since the era of Linus Pauling.

Dick Marsh in 2012 Photo courtesy of the American Crystallographic Association
Dick Marsh in 2012

He studied applied chemistry at Caltech, receiving his undergraduate degree in 1943. He then joined the Navy, where his job was to degauss ships so they wouldn’t trigger magnetic mines.

After the war, he enrolled in graduate school at Tulane University, but when he tried to sign up, most of the classes were already filled. The registrar found one available class—at Sophie Newcomb College, the women’s college next door. The class was on X-ray crystallography, the study of crystals and their structure using X-ray diffraction.

As he wrote later in an essay for the American Crystallographic Association, he had never heard of X-ray crystallography. But the class changed his life, as he credits his instructor, Rose Mooney, for inspiring him to become a crystallographer.

(As a side note, according to Marsh’s essay, Mooney had been accepted to Caltech’s graduate program a few years prior. She didn’t know Caltech didn’t allow women at the time and the university didn’t know “R.C.L. Mooney” was a woman. Marsh wrote that Linus Pauling would help arrange a research assistantship for her and help transfer her to the University of Chicago, where she got her PhD.)

Marsh later transferred to UCLA for his PhD and returned to Caltech as a postdoc in 1950, focusing on the structures of smaller molecules. It was the heyday of structural chemistry. People from all over the world were flocking to Pasadena to work with Pauling, Marsh says.

Dick Marsh and Linus Pauling at Pauling’s 85th birthday celebration.

The first paper he published at Caltech was with Pauling, in which they used crystallography to find the structure of a molecule called chlorine hydrate. Pauling was extremely cogent and articulate, Marsh recalls. After solving a molecular structure, Marsh would show the results to Pauling, who would take a look and speak into a recording device, dictating an entire paper from start to finish for his secretary to type out.

Through his more than six-decade career at Caltech, Marsh has seen how computers have revolutionized the field. “When I started, I had a slide rule and a pencil,” he says. Now, in his role as senior research associate in chemistry, emeritus, he still goes to work every day. Solving chemical structures is a great puzzle, he says, and it’s the joy of cracking these riddles that keeps him going. Asked if he has any favorite discoveries after all these years, he can’t choose. “They’ve all been fun,” he says.

–Marcus Woo

Photos courtesy of the American Crystallographic Association


Blasts from the Past (+)

Our “Launch Points” article about JPL’s origins and history focused on some of its most important milestones. Magazine space considerations, however, meant that we had to omit many other equally interesting and noteworthy stories.Space_Suit_1.tif

Luckily, JPL, in its own version of Throwback Thursday, posts an archival photo and caption each month on its website highlighting events that range from historically significant to scientifically important to just plain quirky.

Among our favorites is the photo chosen for July 2010, which features engineer Allyn B. “Hap” Hazard in a 1960 image wearing a space suit he designed. The photo appeared in Life and other magazines at the time.

Caltech Biochemist Sheds Light on Structure of Key Cellular ‘Gatekeeper’ (+)

Credit: Lance Hayashida/Caltech Office of Strategic Communications and the Hoelz Laboratory/Caltech
Click image to enlarge
Credit: Lance Hayashida/Caltech Office of Strategic Communications and the Hoelz Laboratory/Caltech

Facing a challenge akin to solving a 1,000-piece jigsaw puzzle while blindfolded—and without touching the pieces—many structural biochemists thought it would be impossible to determine the atomic structure of a massive cellular machine called the nuclear pore complex (NPC), which is vital for cell survival.

But after 10 years of attacking the problem, a team led by André Hoelz, assistant professor of chemistry, recently solved almost a third of the puzzle. The approach his team developed to do so also promises to speed completion of the remainder.

In an article published online February 12 by Science Express, Hoelz and his colleagues describe the structure of a significant portion of the NPC, which is made up of many copies of about 34 different proteins, perhaps 1,000 proteins in all and a total of 10 million atoms. In eukaryotic cells (those with a membrane-bound nucleus), the NPC forms a transport channel in the nuclear membrane. The NPC serves as a gatekeeper, essentially deciding which proteins and other molecules are permitted to pass into and out of the nucleus. The survival of cells is dependent upon the accuracy of these decisions.

Understanding the structure of the NPC could lead to new classes of cancer drugs as well as antiviral medicines. “The NPC is a huge target of viruses,” Hoelz says. Indeed, pathogens such as HIV and Ebola subvert the NPC as a way to take control of cells, rendering them incapable of functioning normally. Figuring out just how the NPC works might enable the design of new drugs to block such intruders.

“This is an incredibly important structure to study,” he says, “but because it is so large and complex, people thought it was crazy to work on it. But 10 years ago, we hypothesized that we could solve the atomic structure with a divide-and-conquer approach—basically breaking the task into manageable parts—and we’ve shown that for a major section of the NPC, this actually worked.”

To map the structure of the NPC, Hoelz relied primarily on X-ray crystallography, which involves shining X-rays on a crystallized sample and using detectors to analyze the pattern of rays reflected off the atoms in the crystal.

It is particularly challenging to obtain X-ray diffraction images of the intact NPC for several reasons, including that the NPC is both enormous (about 30 times larger than the ribosome, a large cellular component whose structure wasn’t solved until the year 2000) and complex (with as many as 1,000 individual pieces, each composed of several smaller sections). In addition, the NPC is flexible, with many moving parts, making it difficult to capture in individual snapshots at the atomic level, as X-ray crystallography aims to do. Finally, despite being enormous compared to other cellular components, the NPC is still vanishingly small (only 120 nanometers wide, or about 1/900th the thickness of a dollar bill), and its highly flexible nature prohibits structure determination with current X-ray crystallography methods.

To overcome those obstacles, Hoelz and his team chose to determine the structure of the coat nucleoporin complex (CNC)—one of the two main complexes that make up the NPC—rather than tackling the whole structure at once (in total the NPC is composed of six subcomplexes, two major ones and four smaller ones, see illustration). He enlisted the support of study coauthor Anthony Kossiakoff of the University of Chicago, who helped to develop the engineered antibodies needed to essentially “superglue” the samples into place to form an ordered crystalline lattice so they could be properly imaged. The X-ray diffraction data used for structure determination was collected at the General Medical Sciences and National Cancer Institutes Structural Biology Beamline at the Argonne National Laboratory.

With the help of Caltech’s Molecular Observatory—a facility, developed with support from the Gordon and Betty Moore Foundation, that includes a completely automated X-ray beamline at the Stanford Synchrotron Radiation Laboratory that can be controlled remotely from Caltech—Hoelz’s team refined the antibody adhesives required to generate the best crystalline samples. This process alone took two years to get exactly right.

Hoelz and his team were able to determine the precise size, shape, and the position of all atoms of the CNC, and also its location within the entire NPC.

The CNC is not the first component of the NPC to be fully characterized, but it is by far the largest. Hoelz says that once the other major component—known as the adaptor–channel nucleoporin complex—and the four smaller subcomplexes are mapped, the NPC’s structure will be fully understood.

The CNC that Hoelz and his team evaluated comes from baker’s yeast—a commonly used research organism—but the CNC structure is the right size and shape to dock with the NPC of a human cell. “It fits inside like a hand in a glove,” Hoelz says. “That’s significant because it is a very strong indication that the architecture of the NPC in both are probably the same and that the machinery is so important that evolution has not changed it in a billion years.”

Being able to successfully determine the structure of the CNC makes mapping the remainder of the NPC an easier proposition. “It’s like climbing Mount Everest. Knowing you can do it lowers the bar, so you know you can now climb K2 and all these other mountains,” says Hoelz, who is convinced that the entire NPC will be characterized soon. “It will happen. I don’t know if it will be in five or 10 or 20 years, but I’m sure it will happen in my lifetime. We will have an atomic model of the entire nuclear pore.”

Still, he adds, “My dream actually goes much farther. I don’t really want to have a static image of the pore. What I really would like—and this is where people look at me with a bit of a smile on their face, like they’re laughing a little bit—is to get an image of how the pore is moving, how the machine actually works. The pore is not a static hole, it can open up like the iris of a camera to let something through that’s much bigger. How does it do it?”

To understand that machine in motion, he adds, “you don’t just need one snapshot, you need multiple snapshots. But once you have one, you can infer the other ones much quicker, so that’s the ultimate goal. That’s the dream.”

Along with Hoelz, additional Caltech authors on the paper, “Architecture of the Nuclear Pore Complex Coat,” include postdoctoral scholars Tobias Stuwe and Ana R. Correia, and graduate student Daniel H. Lin. Coauthors from the University of Chicago Department of Biochemistry and Molecular Biology include Anthony Kossiakoff, Marcin Paduch and Vincent Lu. The work was supported by Caltech startup funds, the Albert Wyrick V Scholar Award of the V Foundation for Cancer Research, the 54th Mallinckrodt Scholar Award of the Edward Mallinckrodt, Jr. Foundation, and a Kimmel Scholar Award of the Sidney Kimmel Foundation for Cancer Research.

Written by Jon Nalick