John H. Richards, 1930–2015

John H. ("Jack") Richards, a professor of organic chemistry and biochemistry at Caltech whose research was focused on gaining a molecular understanding of the mechanisms of protein function, passed away on Thursday, April 23, 2015. He was 85 years old.

Richards used altered proteins obtained from the deliberate mutation of DNA—a process called site-directed mutagenesis—in combination with recombinant and cloning techniques, as well as chemically synthesized polypeptides (chains of amino acids) and their derivatives, to study the mechanisms by which proteins act as catalysts to perform the chemical reactions necessary to life. Among the proteins of particular interest to Richards were proteolytic enzymes that break apart other proteins; enzymes called lactamases that endow some microorganisms with antibiotic resistance; and DNA polymerases, the enzymes that build DNA molecules by assembling nucleotides.

Richards also worked in collaboration with Harry Gray, the Arnold O. Beckman Professor of Chemistry, and Jay Winkler, member of the Beckman Institute and faculty associate in chemistry, examining how proteins transport the electrons that are the cell's energy currency, including a class of copper-containing proteins called azurins that power certain types of bacteria. As Gray recalls, "Jack, Jay Winkler, and I worked closely together for over 25 years. He was the perfect collaborator, generous with his time. He taught Jay and me and our students the biology we needed to attack problems in biological inorganic chemistry. His work on engineering blue copper proteins opened the way for experiments in the Beckman Institute Laser Resource Center that shed light on the factors that control electron flow in respiration and photosynthesis."

According to colleague Douglas Rees, the Roscoe Gilkey Dickinson Professor of Chemistry at Caltech and an investigator with Howard Hughes Medical Institute, Richards was a "visionary" who helped drive the integration of chemistry and biology at the heart of contemporary biochemistry.

"What most struck me about Jack is he had this real style," Rees recalls. "He wasn't the sort of guy who was just going to crank through and try to wear some problem down. He liked coming up with a really clever, elegant solution to a problem. And early on, at a time when I think a lot of chemists were typically not very interested in biological problems, Jack had this fascination with biology and chemical mechanisms. He appreciated how the future of biology was rooted in chemistry, and he was the leader of the modern era of biochemistry in the chemistry division here."

Richards was born on March 13, 1930, in Berkeley, California, and earned a BA from UC Berkeley in 1951. As a Rhodes Scholar, he traveled to England to attend the University of Oxford, from which he obtained a BSc in 1953. He then returned to UC Berkeley for his graduate studies, earning a PhD in 1955.

After two years as an instructor at Harvard University, Richards came to Caltech in 1957 as an assistant professor. He spent the rest of his career at the Institute, with promotions to associate professor in 1961 and to professor in 1970. He was named a professor of organic chemistry and biochemistry in 1999. Richards was the chair of the faculty from 1991 to 1993. 

"Jack Richards was part of the fabric of Caltech and interdisciplinary science for more than 50 years," says Jacqueline K. Barton, the Arthur and Marian Hanisch Memorial Professor and chair of the Division of Chemistry and Chemical Engineering.

Over his career, Richards also served in a number of corporate and governmental advisory roles, including as a member of the board of the Huntington Medical Research Institute since 1999 and as a member of the Department of Energy's Basic Energy Science Advisory Committee (2001–13).

From 1985 to 2007, Richards was a corporate scientific adviser to the biotechnology company Applied Biosystems, now a part of Life Technologies. Applied Biosystems was the first company to commercially produce an automated DNA sequencing instrument—technology that was pioneered at Caltech by Leroy Hood (BS '60, PhD '68).

Richards also embraced his role as an educator and acted as a mentor to generations of undergraduate and graduate students, as well as to faculty, during his nearly six decades at Caltech. "He really liked being with students and was stimulated by that interaction," Rees recalls. "He was able to teach up to the very end. I think that meant a lot to him."

"Jack was a co-advisor for my thesis work and an incredible mentor. He joyously encouraged and supported risk taking and strongly influenced my entry into the protein engineering field," says Stephen Mayo (PhD '88), Caltech's William K. Bowes Jr. Leadership Chair of the Division of Biology and Biological Engineering and Bren Professor of Biology and Chemistry. "Jack's advice and mentorship didn't stop after I completed my degree. He was a great sounding board for discussing research directions, and he provided incredibly clear career advice that was often delivered with humorous anecdotes that made our sometimes intense discussions easier. I owe Jack a great deal and will miss him as a mentor and colleague but, most importantly, as a friend."

"It's hard to imagine the sort of changes that you would see in this, in any place, over 58 years," Rees adds. "It's a long baseline. But he liked brainstorming about new ideas and technologies. He was a key part of the biochemistry subgroup. If we were grappling with some issue and trying to figure out what the most prudent course of action was, he would often look at it from his unique perspective, and we would say, you know, that's right. He could really unite us. He leaves a hole."

Richards is survived by his second wife, Minnie McMillan, professor of molecular microbiology and immunology and professor of neurology at the University of Southern California's Keck School of Medicine. Richards also leaves behind four daughters from his first marriage (to Marian King), Kathleen Fraga of Grass Valley, California; Jennifer Welton of Belgrade, Montana; Julia Hart of Clayton, California; and Cynthia Clapp of Corvallis, Oregon; and four grandchildren.

He will be buried in Nevada City, California, where his grandfather and favorite uncle lived.

Writer: 
Kathy Svitil
Writer: 
Exclude from News Hub: 
No
News Type: 
In Our Community

“Freezing a Bullet” to Find Clues to Ribosome Assembly Process

Researchers Figure Out How Protein-Synthesizing Cellular Machines Are Built in Stepwise Fashion

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).

 

Writer: 
Kimm Fesenmaier
Writer: 
Exclude from News Hub: 
No
Short Title: 
Figuring Out How Ribosomes Are Made
News Type: 
Research News

JCAP Receives a 5-Year, $75M Funding Renewal

On Monday, April 27, the Department of Energy (DOE) announced a five-year, $75 million renewal of the Joint Center for Artificial Photosynthesis (JCAP). JCAP's mission is to explore the science and technology of artificial photosynthesis to harness solar energy for the production of fuel.

JCAP is the nation's largest research program dedicated to the development of an artificial solar-fuel generation technology. Established in 2010 as a DOE Energy Innovation Hub, JCAP aims to create a low-cost generator to make fuel from sunlight 10 times more efficiently than plants. Such a breakthrough would have the potential to reduce our country's dependence on oil and enhance energy security.

The Hub is directed by Caltech, but it has its primary sites both at Lawrence Berkeley National Laboratory (LBNL) and at Caltech. JCAP brings together more than 150 scientists and engineers from Caltech and LBNL, and also draws on the expertise and capabilities of key partners at UC Irvine, UC San Diego, and the SLAC National Accelerator Laboratory at Stanford.

The funding renewal announcement was made at LBNL by Franklin Orr, under secretary for science and energy at DOE.

"JCAP's work to produce fuels from sunlight and carbon dioxide holds the promise of a potentially revolutionary technology that would put America on the path to a low-carbon economy," said Orr in a DOE press release. "While the scientific challenges of producing such fuels are considerable," the released noted, "JCAP will capitalize on state-of-the-art capabilities developed during its initial five years of research, including sophisticated characterization tools and unique automated high-throughput experimentation that can quickly make and screen large libraries of materials to identify components for artificial photosynthesis systems."   

"We are honored and delighted to receive renewed support from the Department of Energy for JCAP," says JCAP director Harry A. Atwater, Howard Hughes Professor of Applied Physics and Materials Science at Caltech. "Thanks to this renewal, JCAP will continue to push the scientific frontiers of artificial photosynthesis, with an emphasis on selective carbon dioxide reduction under mild temperature and pressure conditions. Carbon dioxide reduction is at the core of natural photosynthesis, and understanding the science and technology of this reaction is also central to society's efforts to mitigate carbon dioxide emission. It is an enormous challenge, but just the sort of problem that is worthy of sustained scientific investment. We are excited for the work ahead."

In its first five years of research, JCAP has made significant advances in a number of areas, including the automated and rapid discovery and characterization of new catalysts and light absorbers, the development of techniques for protecting the light-absorbing components in solar-fuels generators, and the creation of experimental protocols for objective evaluations of the activity and stability of materials. All of these technologies are critical to the development of solar-driven water splitting and the reduction of carbon dioxide to produce fuel.

For more information about JCAP, please visit http://solarfuelshub.org/.

Frontpage Title: 
JCAP Funding Renewed
Listing Title: 
JCAP Funding Renewed
Writer: 
Exclude from News Hub: 
No
Short Title: 
JCAP Funding Renewed
News Type: 
Research News
Tuesday, May 19, 2015
Guggenheim 101 (Lees-Kubota Lecture Hall) – Guggenheim Aeronautical Laboratory

Science in a Small World - Short Talks

Tuesday, May 19, 2015
Dabney Hall, Garden of the Associates – The Garden of the Associates

Science in a Small World - Poster Session #2

Tuesday, May 19, 2015
Dabney Hall, Garden of the Associates – The Garden of the Associates

Science in a Small World - Poster Session #1

Five from Caltech Elected to American Academy of Arts and Sciences

The American Academy of Arts and Sciences has elected five Caltech community members as academy fellows. They are faculty members Michael B. Elowitz, professor of biology and bioengineering and an investigator with the Howard Hughes Medical Institute; Mory Gharib (PhD '83), Hans W. Liepmann Professor of Aeronautics and Bioinspired Engineering, director of the Ronald and Maxine Linde Institute of Economic and Management Sciences, and vice provost; and Linda C. Hsieh-Wilson, professor of chemistry; and Caltech trustees James Rothenberg and Maria Hummer-Tuttle. The American Academy is one of the nation's oldest honorary societies. Members are accomplished scholars and leaders representing diverse fields including academia, business, public affairs, the humanities, and the arts.

 

Michael B. Elowitz was noted for his work that "helped to initiate synthetic biology." Elowitz studies genetic circuits—interacting genes and proteins that enable cells to sense environmental conditions and to communicate. He and his group build simplified synthetic genetic circuits and study their effects in bacteria, yeast, and mammalian cells. He has received numerous honors in recognition of his work, including a MacArthur Fellowship in 2007.
 

Mory Gharib and his group use nature's own design principles—apparent in fins, wings, blood vessels, and more—as inspiration for a myriad of inventions. They have studied fluid flows inside the zebrafish heart to develop efficient micropumps and more efficient artificial heart valves, and cactus spine to develop arrays of nanoneedles, based on carbon nanotubes, for painless drug delivery. Gharib holds nearly 100 patents, and was elected to the National Academy of Engineering in 2015.

Linda C. Hsieh-Wilson was noted for her pioneering work in the new fields of chemical glycobiology and chemical neurobiology. Her work combines organic chemistry and neurobiology in order to understand how carbohydrates contribute to fundamental brain processes such as cell growth and neuronal communication, neural development, and memory at the molecular level. She and her group discovered a means for suppressing tumor-cell growth by blocking the attachment of certain sugars to proteins, restricting delivery of certain carbohydrates to proteins within the tumor.

Maria Hummer-Tuttle, a lawyer, was a partner and chair of the management committee and co–managing partner of Manatt, Phelps and Phillips in Los Angeles. She currently serves on the boards of Caltech, the J. Paul Getty Trust, the W. M. Keck Foundation, the Suu Foundation, and the Foundation for Art and Preservation in Embassies. Hummer-Tuttle is president of the Hummer Tuttle Foundation, serves on the advisory board of the USC Center on Public Diplomacy at the Annenberg School as well as on the program advisory committee of the Annenberg Retreat at Sunnylands, and is a member of the Pacific Council on International Policy, the Council on Foreign Relations, and the Getty Conservation Institute Council.

Jim Rothenberg is chairman of the Capital Group Companies, Inc. In addition to his service on the Caltech board, he serves on the boards of Capital Research and Management Company, the Capital Group Companies, Inc., and American Funds Distributors, Inc. In addition, he is a portfolio counselor for the Growth Fund of America, as well as vice chairman of the Growth Fund of America and Fundamental Investors. A chartered financial analyst, he was named to the Harvard Corporation as the treasurer of Harvard University in 2004. He also serves as a director of Huntington Memorial Hospital in Pasadena.

Elowitz, Gharib, and Hsieh-Wilson join 83 current Caltech faculty as members of the American Academy. Also included in this year's list are five alumni: Robert Cohen (MS '70, PhD '72), St. Laurent Professor of Chemical Engineering at MIT and codirector of the DuPont-MIT Alliance; Alexei Filippenko (PhD '84), professor of astronomy at UC Berkeley; Katherine Hayles (MS '69), professor of literature at Duke University; Michael Snyder (PhD'83), professor and chair of genetics at Stanford University; and Donald Truhlar (PhD '70), professor of chemistry at the University of Minnesota.

Founded in 1780 by John Adams, James Bowdoin, John Hancock, and other scholar-patriots, the academy aims to serve the nation by cultivating "every art and science which may tend to advance the interest, honor, dignity, and happiness of a free, independent, and virtuous people." The academy has elected as fellows and foreign honorary members "leading thinkers and doers" from each generation, including George Washington and Ben Franklin in the 18th century, Daniel Webster and Ralph Waldo Emerson in the 19th, and Albert Einstein and Woodrow Wilson in the 20th.

A full list of new members is available on the academy website at https://www.amacad.org/content/members/members.aspx.

The new class will be inducted at a ceremony on October 10, 2015, in Cambridge, Massachusetts.

Frontpage Title: 
American Academy Elects Five from Caltech
Listing Title: 
American Academy Elects Five from Caltech
Contact: 
Writer: 
Exclude from News Hub: 
No
Short Title: 
American Academy Elects Five from Caltech
News Type: 
In Our Community
Teaser Image: 

Chemists Create “Comb” that Detects Terahertz Waves with Extreme Precision

Light can come in many frequencies, only a small fraction of which can be seen by humans. Between the invisible low-frequency radio waves used by cell phones and the high frequencies associated with infrared light lies a fairly wide swath of the electromagnetic spectrum occupied by what are called terahertz, or sometimes submillimeter, waves. Exploitation of these waves could lead to many new applications in fields ranging from medical imaging to astronomy, but terahertz waves have proven tricky to produce and study in the laboratory. Now, Caltech chemists have created a device that generates and detects terahertz waves over a wide spectral range with extreme precision, allowing it to be used as an unparalleled tool for measuring terahertz waves.

The new device is an example of what is known as a frequency comb, which uses ultrafast pulsed lasers, or oscillators, to produce thousands of unique frequencies of radiation distributed evenly across a spectrum like the teeth of a comb. Scientists can then use them like rulers, lining up the teeth like tick marks to very precisely measure light frequencies. The first frequency combs, developed in the 1990s, earned their creators (John Hall of JILA and Theordor Hánsch of the Max Planck Institute of Quantum Optics and Ludwig Maximilians University Munich) the 2005 Nobel Prize in physics. These combs, which originated in the visible part of the spectrum, have revolutionized how scientists measure light, leading, for example, to the development of today's most accurate timekeepers, known as optical atomic clocks.

The team at Caltech combined commercially available lasers and optics with custom-built electronics to extend this technology to the terahertz, creating a terahertz frequency comb with an unprecedented combination of spectral coverage and precision. Its thousands of "teeth" are evenly spaced across the majority of the terahertz region of the spectrum (0.15-2.4 THz), giving scientists a way to simultaneously measure absorption in a sample at all of those frequencies.

The work is described in a paper that appears in the online version of the journal Physical Review Letters and will be published in the April 24 issue. The lead author is graduate student and National Science Foundation fellow Ian Finneran, who works in the lab of Geoffrey A. Blake, professor of cosmochemistry and planetary sciences and professor of chemistry at Caltech.

Blake explains the utility of the new device, contrasting it with a common radio tuner. "With radio waves, most tuners let you zero in on and listen to just one station, or frequency, at a time," he says. "Here, in our terahertz approach, we can separate and process more than 10,000 frequencies all at once. In the near future, we hope to bump that number up to more than 100,000."

That is important because the terahertz region of the spectrum is chock-full of information. Everything in the universe that is warmer than about 10 degrees Kelvin (-263 degrees Celsius) gives off terahertz radiation. Even at these very low temperatures molecules can rotate in space, yielding unique fingerprints in the terahertz. Astronomers using telescopes such as Caltech's Submillimeter Observatory, the Atacama Large Millimeter Array, and the Herschel Space Observatory are searching stellar nurseries and planet-forming disks at terahertz frequencies, looking for such chemical fingerprints to try to determine the kinds of molecules that are present and thus available to planetary systems. But in just a single chunk of the sky, it would not be unusual to find signatures of 25 or more different molecules.

To be able to definitively identify specific molecules within such a tangle of terahertz signals, scientists first need to determine exact measurements of the chemical fingerprints associated with various molecules. This requires a precise source of terahertz waves, in addition to a sensitive detector, and the terahertz frequency comb is ideal for making such measurements in the lab.

"When we look up into space with terahertz light, we basically see this forest of lines related to the tumbling motions of various molecules," says Finneran. "Unraveling and understanding these lines is difficult, as you must trek across that forest one point and one molecule at a time in the lab. It can take weeks, and you would have to use many different instruments. What we've developed, this terahertz comb, is a way to analyze the entire forest all at once."

After the device generates its tens of thousands of evenly spaced frequencies, the waves travel through a sample—in the paper, the researchers provide the example of water vapor. The instrument then measures what light passes through the sample and what gets absorbed by molecules at each tooth along the comb. If a detected tooth gets shorter, the sample absorbed that particular terahertz wave; if it comes through at the baseline height, the sample did not absorb at that frequency.

"Since we know exactly where each of the tick marks on our ruler is to about nine digits, we can use this as a diagnostic tool to get these frequencies really, really precisely," says Finneran. "When you look up in space, you want to make sure that you have such very exact measurements from the lab."

In addition to the astrochemical application of identifying molecules in space, the terahertz comb will also be useful for studying fundamental interactions between molecules. "The terahertz is unique in that it is really the only direct way to look not only at vibrations within individual large molecules that are important to life, but also at vibrations between different molecules that govern the behavior of liquids such as water," says Blake.

Additional coauthors on the paper, "Decade-Spanning High-Precision Terahertz Frequency Comb," include current Caltech graduate students Jacob Good, P. Brandon Carroll, and Marco Allodi, as well as recent graduate Daniel Holland (PhD '14). The work was supported by funding from the National Science Foundation.

Writer: 
Kimm Fesenmaier
Frontpage Title: 
“Combing” Through Terahertz Waves
Listing Title: 
“Combing” Through Terahertz Waves
Contact: 
Writer: 
Exclude from News Hub: 
No
Short Title: 
“Combing” Through Terahertz Waves
News Type: 
Research News

Understanding the Earth at Caltech

Created by: 
Teaser Image: 
Listing Title: 
Understanding the Earth at Caltech
Frontpage Title: 
Understanding the Earth at Caltech
Slideshow: 
Credit: Courtesy J. Andrade/Caltech

The ground beneath our feet may seem unexceptional, but it has a profound impact on the mechanics of landslides, earthquakes, and even Mars rovers. That is why civil and mechanical engineer Jose Andrade studies soils as well as other granular materials. Andrade creates computational models that capture the behavior of these materials—simulating a landslide or the interaction of a rover wheel and Martian soil, for instance. Though modeling a few grains of sand may be simple, predicting their action as a bulk material is very complex. "This dichotomy…leads to some really cool work," says Andrade. "The challenge is to capture the essence of the physics without the complexity of applying it to each grain in order to devise models that work at the landslide level."

Credit: Kelly Lance ©2013 MBARI

Geobiologist Victoria Orphan looks deep into the ocean to learn how microbes influence carbon, nitrogen, and sulfur cycling. For more than 20 years, her lab has been studying methane-breathing marine microorganisms that inhabit rocky mounds on the ocean floor. "Methane is a much more powerful greenhouse gas than carbon dioxide, so tracing its flow through the environment is really a priority for climate models and for understanding the carbon cycle," says Orphan. Her team recently discovered a significantly wider habitat for these microbes than was previously known. The microbes, she thinks, could be preventing large volumes of the potent greenhouse gas from entering the oceans and reaching the atmosphere.

Credit: NASA/JPL-Caltech

Researchers know that aerosols—tiny particles in the atmosphere—scatter and absorb incoming sunlight, affecting the formation and properties of clouds. But it is not well understood how these effects might influence climate change. Enter chemical engineer John Seinfeld. His team conducted a global survey of the impact of changing aerosol levels on low-level marine clouds—clouds with the largest impact on the amount of incoming sunlight Earth reflects back into space—and found that varying aerosol levels altered both the quantity of atmospheric clouds and the clouds' internal properties. These results offer climatologists "unique guidance on how warm cloud processes should be incorporated in climate models with changing aerosol levels," Seinfeld says.

Credit: Yan Hu/Aroian Lab/UC San Diego

Tiny parasitic worms infect nearly half a billion people worldwide, causing gastrointestinal issues, cognitive impairment, and other health problems. Biologist Paul Sternberg is on the case. His lab recently analyzed the entire 313-million-nucleotide genome of the hookworm Ancylostoma ceylanicum to determine which genes turn on when the worm infects its host. A new family of proteins unique to parasitic worms and related to the early infection process was identified; the discovery could lead to new treatments targeting those genes. "A parasitic infection is a balance between the parasites trying to suppress the immune system and the host trying to attack the parasite," Sternberg observes, "and by analyzing the genome, we can uncover clues that might help us alter that balance in favor of the host."

Credit: K.Batygin/Caltech

Earth is special, not least because our solar system has a unique (as far as we know) orbital architecture: its rocky planets have relatively low masses compared to those around other sun-like stars. Planetary scientist Konstantin Batygin has an explanation. Using computer simulations to describe the solar system's early evolution, he and his colleagues showed that Jupiter's primordial wandering initiated a collisional cascade that ultimately destroyed the first generation population of more massive planets once residing in Earth's current orbital neighborhood. This process wiped the inner solar system's slate clean and set the stage for the formation of the planets that exist today. "Ultimately, what this means," says Batygin, "is that planets truly like Earth are intrinsically not very common."

Credit: Nicolás Wey-Gόmez/Caltech

Human understanding of the world has evolved over centuries, anchored to scientific and technological advancements and our ability to map uncharted territories. Historian Nicolás Wey-Gόmez traces this evolution and how the age of discovery helped shape culture and politics in the modern era. Using primary sources such as letters and diaries, he examines the assumptions behind Europe's encounter with the Americas, focusing on early portrayals of native peoples by Europeans. "The science and technology that early modern Europeans recovered from antiquity by way of the Arab world enabled them to imagine lands far beyond their own," says Wey-Gómez. "This knowledge provided them with an essential framework to begin to comprehend the peoples they encountered around the globe."

Body: 

At Caltech, researchers study the Earth from many angles—from investigating its origins and evolution to exploring its geology and inner workings to examining its biological systems. Taken together, their findings enable a more nuanced understanding of our planet in all its complexity, helping to ensure that it—and we—endure. This slideshow highlights just a few of the Earth-centered projects happening right now at Caltech.

Exclude from News Hub: 
Yes

Inhibitor for Abnormal Protein Points the Way to More Selective Cancer Drugs

Nowhere is the adage "form follows function" more true than in the folded chain of amino acids that makes up a single protein macromolecule. But proteins are very sensitive to errors in their genetic blueprints. One single-letter DNA "misspelling" (called a point mutation) can alter a protein's structure or electric charge distribution enough to render it ineffective or even deleterious.

Unfortunately, cells containing abnormal proteins generally coexist alongside those containing the normal (or "wild") type, and telling them apart requires a high degree of molecular specificity. This is a particular concern in the case of cancer-causing proteins.

"With present technologies, developing a drug that will target only the mutant version of a protein is difficult," notes Blake Farrow, a graduate student in materials science at Caltech and a Howard Hughes Medical Institute Fellow. "Most anticancer agents indiscriminately attack both mutant and healthy proteins and tissues."

Farrow is part of a Caltech-led team that recently created a new type of highly selective molecule that can actively distinguish a mutated protein from the wild type by binding only the mutated protein.

The work was described in a paper that appeared in Nature Chemistry on April 13.

The project was begun by Kaycie Deyle (PhD '14), now a postdoctoral fellow at École Polytechnique Fédérale de Lausanne, and utilized a number of novel technologies, including click chemistry and protein-catalyzed capture (PCC). Click chemistry is a technique for rapidly and reliably constructing molecular assemblies from modular components. PCC screening, which was developed by the Caltech researchers, uses click chemistry to reveal which of several candidate molecules will bind (and "click") most strongly to a given region of a specific protein.

As a test case, the researchers investigated a point mutation called E17K, which occurs in a specific region of Akt1, a protein hundreds of amino acids long. Akt1 plays a key role in cell growth and proliferation, and its E17K mutation is closely linked to an increase in the development of tumors and the survival of cancer cells.

Using a synthesized fragment of the cancer-causing form of Akt1, the researchers replaced an amino acid close to the E17K mutation with a structure that could act as a "click handle." The goal was to create a short molecule that could wedge itself into the folds of the protein, binding to the E17K mutation at one end and "clicking" to the handle at the other.

Candidate molecules were constructed by splicing amino acids together into short chains five amino acids long, which is just enough to reach from the click handle to the mutation site. With almost two dozen amino acids to choose from for each of the five slots, the researchers were faced with over a million possible configurations.

A multistep PCC screening process narrowed this large number of candidates down to one combination that bound to the mutant version of the protein 10 times more strongly than to the wild type. The code letters representing the five amino acids making up the molecule gave it its informal name: "yleaf."

Next, a second PCC screening process was used to find amino acid chains that could be used to extend the yleaf molecule, giving it the ability to grip multiple naturally occurring features of the Akt1 molecule, rather than requiring a click handle to be artificially inserted. Testing of this wider-wingspan yleaf showed that not only did it bind almost exclusively to its intended target (and nowhere else, including the unmutated form of Akt1), but also that in doing so it inhibited the protein's activity and hence could be expected to impair its ability to support tumor growth. In fact, the extended yleaf molecule inhibited the mutated protein a thousand times better than it did the wild-type form.

James Heath, the Elizabeth W. Gilloon Professor and Professor of Chemistry at Caltech and corresponding author of the paper, says this selective inhibitor strategy "is certainly a very important first step" toward new cancer drug modalities. With additional design considerations to facilitate passage through the cell membrane, compounds of this sort could become the basis of new drugs for targeting and inhibiting abnormal protein molecules in living cells, he says.

In addition to Farrow, Deyle, and Heath, other authors on the Nature Chemistry paper, "A protein-targeting strategy used to develop a selective inhibitor of the E17K point mutation in the PH domain of Akt1," are Michelle Wong, Aiko Umeda, Arundhati Nag, and Samir Das from Caltech; Ying Qiao Hee and Jeremy Work, who contributed to the work at Caltech as a Summer Undergraduate Research Fellow and an Amgen Scholar, respectively; Bert Lai from Indi Molecular; and Steven W. Millward from the University of Texas MD Anderson Cancer Center. The work was supported by the Institute for Collaborative Biotechnologies, the National Cancer Institute, the Defense Advanced Research Projects Agency and the Jean Perkins Foundation. Research was performed in collaboration with Indi Molecular (founded by Heath), which seeks to commercialize PCC technology.

Tags: 
Frontpage Title: 
Creating Targeted Cancer Drugs
Listing Title: 
Creating Targeted Cancer Drugs
Writer: 
Exclude from News Hub: 
No
Short Title: 
Creating Targeted Cancer Drugs
News Type: 
Research News

Pages

Subscribe to RSS - CCE