Puzzle Maker: Building a Chemical from the Ground Up

For chemists like Sarah Reisman, professor of chemistry at Caltech, synthesizing molecules is like designing your own jigsaw puzzle. You know what the solved puzzle looks like—the molecule—and your job is to figure out the best pieces to use to put it together.

"We look at the molecule we want to build and think about how to cut it up into pieces. When we are in the lab, the question is: do your puzzle pieces go back together?" says Reisman.

Synthesizing molecules is a vital part of many chemical manufacturing industries, from producing fuels to dyes used in flatscreen TVs with organic light-emitting diode (OLED) displays. Scientists also create molecules from scratch to better understand how they work, as well as to design new drugs.

Reisman's team has been busy trying to crack the puzzle of the insecticide ryanodine, a complex molecule first isolated from a tropical plant in the 1940s. Ryanodine paralyzes insects by binding to a class of calcium-channel receptors called ryanodine receptors. In humans, these receptors play critical roles in muscle and neuronal function. Mutations in the genes that encode ryanodine receptors can lead to disease, including certain types of heart arrhythmias and possibly Alzheimer's disease.

As a stepping stone on the path to synthesizing ryanodine, Reisman, along with graduate student Kangway Chuang and postdoctoral researcher Chen Xu, first targeted a similar molecule, ryanodol. Ryanodol previously has been made by two other research groups: In the late 1970s, a research team made ryanodol in 41 steps, and in 2014, another team synthesized the chemical in 35 steps.

Now, reporting in the journal Science, Reisman's team has devised a route to synthesize ryanodol in just 15 steps. This significantly cuts the time required to make ryanodol, and presumably also ryanodine, which Reisman's team will try to synthesize next.

"Once you have the platform for making both of these molecules, it opens up a lot of possibilities," says Reisman. "In general, it is important that we know how to put molecules together. Without this, it's tough to think about how to study the biological function of molecules and develop new drugs."

Ryanodol and ryanodine belong to a class of molecules called terpenes. These are naturally occurring molecules that commonly contain between 10 and 30 carbon atoms. For example, 10-carbon terpenes include R-carvone, the molecule behind the flavor in spearmint leaves; and pinene, which is derived from pine trees and is the primary chemical in the paint solvent turpentine. The antimalarial drug artemisinin, derived from the wormwood shrub, is a 15-carbon terpene.

Ryanodol and ryanodine are some of the more chemically complex 20-carbon terpenes, with five different carbon rings and many carbon–oxygen bonds.

"The simplest forms of terpenes give you fragrances and flavors, but as you build upon the structure, you get more interesting biological compounds like ryanodol and ryanodine," says Reisman.

There are two big challenges in the synthesis of ryanodol. First, chemists have to build the five rings that make up the carbon backbone of the molecule, and second, they have to precisely decorate seven of the carbons with "OH" (or hydroxyl) groups, the chemical structure found in alcohols. Previous syntheses of ryanodol required multiple chemical reactions to introduce the OH groups, adding extra steps. Reisman's synthesis develops new reactions that brings in two or three alcohols at a time—a key discovery of the new synthesis that makes it more efficient. 

The Reisman team began with a simple commercially available terpene, then attached two of the OH groups. They then built up four of the five carbons rings in a series of reactions. Next, the team brought in two more OH groups, and a precursor to an OH group, again in a single step. The fifth and final ring was formed in two steps using conditions developed in a previous synthesis, which also introduced the remaining two OH groups.

"Five of the oxygen atoms are brought in with just two reactions. That is the key to streamlining the synthesis," says Reisman. "It's like building from Legos using the larger pieces instead of the small ones. You get there faster."

Reisman's team is now working on the final piece of the puzzle: creating ryanodine from ryanodol. They think the solution not only will help them to make ryanodine but also aid in the synthesis of new, designer analogues. This will lead to more precise studies of the ryanodine receptors and the possible development of drugs that can target them.

The Science study, entitled "A 15-Step Synthesis of (+)-Ryanodol," is also authored by Kangway V. Chuang and Chen Xu of Caltech. Reisman is a Heritage Principal Investigator, and the research is funded by the National Science Foundation, Shenzhen UV-ChemTech Inc., the National Institutes of Health, Eli Lilly, and Novartis.

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Designing Ultrasound Tools with Lego-Like Proteins

Ultrasound imaging is used around the world to help visualize developing babies and diagnose disease. Sound waves bounce off the tissues, revealing their different densities and shapes. The next step in ultrasound technology is to image not just anatomy, but specific cells and molecules deeper in the body, such as those associated with tumors or bacteria in our gut.

A new study from Caltech outlines how protein engineering techniques might help achieve this milestone. The researchers engineered protein-shelled nanostructures called gas vesicles—which reflect sound waves—to exhibit new properties useful for ultrasound technologies. In the future, these gas vesicles could be administered to a patient to visualize tissues of interest. The modified gas vesicles were shown to: give off more distinct signals, making them easier to image; target specific cell types; and help create color ultrasound images.

"It's somewhat like engineering with molecular Legos," says assistant professor of chemical engineering and Heritage Principal Investigator Mikhail Shapiro, who is the senior author of a new paper about the research published in this month's issue of the journal ACS Nano and featured on the journal's cover. "We can swap different protein 'pieces' on the surface of gas vesicles to alter their targeting properties and to visualize multiple molecules in different colors."

"Today, ultrasound is mostly anatomical," says Anupama Lakshmanan, a graduate student in Shapiro's lab and lead author of the study. "We want to bring it down to the molecular and cellular level."

In 2014, Shapiro first discovered the potential use of gas vesicles in ultrasound imaging. These gas-filled structures are naturally occurring in water-dwelling single-celled organisms, such as Anabaena flos-aquae, a species of cyanobacteria that forms filamentous clumps of multicell chains. The gas vesicles help the organisms control how much they float and thus their exposure to sunlight at the water's surface. Shapiro realized that the vesicles would readily reflect sound waves during ultrasound imaging, and ultimately demonstrated this using mice.

In the latest research, Shapiro and his team set out to give the gas vesicles new properties by engineering gas vesicle protein C, or GvpC, a protein naturally found on the surface of vesicles that gives them mechanical strength and prevents them from collapsing. The protein can be engineered to have different sizes, with longer versions of the protein producing stronger and stiffer nanostructures.

"The proteins are like the framing rods of an airplane fuselage. You use them to determine the mechanics of the structure." Shapiro says.

In one experiment, the scientists removed the strengthening protein from gas vesicles and then administered the engineered vesicles to mice and performed ultrasound imaging. Compared to normal vesicles, the modified vesicles vibrated more in response to sound waves, and thus resonated with harmonic frequencies. Harmonics are created when sound waves bounce around, for instance in a violin, and form new waves with doubled and tripled frequencies. Harmonics are not readily created in natural tissues, making the vesicles stand out in ultrasound images.

In another set of experiments, the researchers demonstrated how the gas vesicles could be made to target certain tissues in the body. They genetically engineered the vesicles to display various cellular targets, such as an amino acid sequence that recognizes proteins called integrins that are overproduced in tumor cells.

"Adding these functionalities to the gas vesicles is like snapping on a new Lego piece; it's a modular system," says Shapiro.

The team also showed how multicolor ultrasound images might be created. Conventional ultrasound images appear black and white. Shapiro's group created an approach for imaging three different types of gas vesicles as separate "colors" based on their differential ability to resist collapse under pressure. The vesicles themselves do not appear in different colors, but they can be assigned colors based on their different properties.

To demonstrate this, the team made three different versions of the vesicles with varying strengths of the GvpC protein. They then increased the ultrasound pressures, causing the variant populations to successively collapse one by one. As each population collapsed, the overall ultrasound signal decreased in proportion to the amount of that variant in the sample, and this signal change was then mapped to a specific color. In the future, if each variant population targeted a specific cell type, researchers would be able to visualize the cells in multiple colors.

"You might be able to see tumor cells versus the immune cells attacking the tumor, and thus monitor the progress of a medical treatment," says Shapiro.

The ACS Nano paper, entitled "Molecular Engineering Of Acoustic Protein Nanostructures," was funded by the National Institutes of Health, the Defense Advanced Research Projects Agency, the Heritage Research Institute for the Advancement of Medicine and Science at Caltech, and the Burroughs Wellcome Fund. Other Caltech authors include graduate student Arash Farhadi, undergraduate Suchita Nety, research assistant Audrey Lee-Gosselin, and postdoctoral scholars Raymond Bourdeau and David Maresca.

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Wednesday, August 24, 2016
JPL

JPL Postdoc Research Day - Poster Session

Ahmed Zewail, 1946–2016

Ahmed Zewail, the Linus Pauling Professor of Chemistry, professor of physics, and director of the Physical Biology Center for Ultrafast Science and Technology at Caltech, passed away on Tuesday, August 2, 2016. He was 70 years old.

Zewail was the sole recipient of the 1999 Nobel Prize in Chemistry for his pioneering developments in femtoscience, making possible observations of atoms in motion on the femtosecond (10-15 seconds) time scale. These developments led to the establishment of the discipline of femtochemistry. More recently, he and his group developed "4D" electron microscopy for the direct visualization in the four dimensions of space and time of materials and biological behaviors.

For his contributions to science and for his public service, Zewail received honors from around the globe. Fifty honorary degrees in the sciences, arts, philosophy, law, medicine, and humane letters were conferred on him, including those from Oxford University, Cambridge University, Peking University, École Normale Supérieure, Yale University, University of Pennsylvania, and Alexandria University.

Zewail was decorated with the Order of the Grand Collar of the Nile, Egypt's highest state honor, and was named to the Order of Légion d'Honneur by the President of France, among other state honors. He was an elected member of academies and learned societies including the National Academy of Sciences, the Royal Society of London, the American Philosophical Society, the French Academy, the Russian Academy, the Chinese Academy, and the Swedish Academy. Postage stamps have been issued in commemoration of his contributions to science and humanity.

"Ahmed was the quintessential scholar and global citizen," says Caltech president Thomas F. Rosenbaum, the Sonja and William Davidow Presidential Chair and professor of physics. "He spent a lifetime developing instruments that interrogate nature in fundamentally new ways, and defining new directions that cut across the physical and biological sciences. Ahmed's fervor for discovery never abated and he serves as an inspiration to colleagues and generations of students. The Caltech community deeply mourns his loss."

"Ahmed Zewail was a great man for chemistry, for science, and for society. All of us at Caltech grieve his loss," says Jacqueline K. Barton, Arthur and Marian Hanisch Memorial Professor of Chemistry and Norman Davidson Leadership Chair of the Division of Chemistry and Chemical Engineering.

Among the more than 100 international prizes and awards, he was the recipient of the Albert Einstein World Award, the Benjamin Franklin Medal, the Leonardo da Vinci Award, the Robert A. Welch Award, the Wolf Prize, the King Faisal Prize, the Othmer Gold Medal, and the Priestley Gold Medal. In his name, international prizes have been established in Amsterdam, Cairo, Detroit, Trieste, and Washington, D.C.; in Cairo, the AZ Foundation provides support for the dissemination of knowledge and for merit awards in arts and sciences.

Following the 2011 Egyptian revolution, the government established Zewail City of Science and Technology as the national project for scientific renaissance, and Zewail became its first chair of the Board of Trustees.

In 2009, President Barack Obama appointed Zewail to the Council of Advisors on Science and Technology, and in the same year he was named the first U.S. Science Envoy to the Middle East. Subsequently, in 2013, Secretary General of the United Nations Ban Ki-moon invited Zewail to join the U.N. Scientific Advisory Board. In Egypt, he served in the Council of Advisors to the President.

Zewail was the author of some 600 articles and 14 books, and was known for his effective public lectures and writings not only on science but also in global affairs. For his leadership role in these world affairs, he received, among others, the "Top American Leaders Award" from The Washington Post and Harvard University.

Born in 1946 in Damanhur, Egypt, Zewail received his early education in Egypt and earned his BS and MS degrees from Alexandria University in 1967 and 1969. He received a PhD from the University of Pennsylvania in 1974 and completed an IBM postdoctoral fellowship at UC Berkeley before joining the faculty at Caltech in 1976 as an assistant professor. He became an associate professor in 1978 and a professor in 1982. He was Linus Pauling Professor of Chemical Physics from 1990–97, was named professor of physics in 1995, and was named Linus Pauling Professor of Chemistry in 1997.

Zewail is survived by his wife, Dema Faham, and his four children, Maha, Amani, Nabeel, and Hani. 

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The Linus Pauling Professor of Chemistry, professor of physics passed away on Tuesday, August 2, 2016. He was 70 years old.
Thursday, August 11, 2016
Center for Student Services 360 (Workshop Space) – Center for Student Services

Teaching Statement Workshop 2: Peer Review

Friday, July 29, 2016

25 Years of Directed Evolution - Arnold Lab Reflections Symposium

Special Delivery

From the exploration of other planets to the meanderings of single cells through our bloodstream and into our tissues, Caltech and JPL researchers are thinking about transportation in unexpected ways. They're using transformative delivery methods to land on Mars, collect data in hard-to-reach locales, and shepherd drugs to the brain.

For example, chemical engineer Mark Davis is building on his experience with nanomaterials to create a nanoparticle delivery vehicle that would encapsulate chemotherapeutics and carry them to where they are supposed to go in the body. These nanoparticles should stay in the blood until they reach a tumor and then release their payload, thus allowing the drugs to destroy solid tumors while sparing healthy tissue.

Lance Christensen, a senior atmospheric scientist at JPL, invents tunable laser spectrometers that basically sniff the atmosphere for trace measurements of gases. Such spectrometers can be carried on drones to measure the abundance of atmospheric gases such as methane, water vapor, and carbon dioxide.

And then there's geochemist Ken Farley, the project scientist for Mars 2020, the new rover mission. He is helping define the science goals for the Mars 2020 mission and determining how to pack an assembly of all-new scientific instruments onto an existing rover. And he has to do all this in time to meet the "very hard" launch date of 2020—when Mars and Earth are closest in orbit to each other.

The overall focus for all of these researchers is to better be able to ask big questions about the origins of life, to monitor the earth's emissions and overall health, and even to treat some of the most devastating diseases we encounter. For more about their efforts, read Special Delivery on E&S+.

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Jack Roberts's Online Success

At 98 years of age, John D. "Jack" Roberts, Caltech Institute professor of chemistry, emeritus, recently became a best-selling online author.

On June 8, Roberts turned 98; just a few days later, his textbook, Basic Principles of Organic Chemistry, surpassed 500,000 file downloads. He wrote the first edition with his protégé Marjorie C. Caserio in 1964. The second edition, created in 1977, is now available online for free at the Caltech Library, where it has been doing brisk business: since December 2012, when accurate records of the book's popularity began being maintained, more than 502,000 copies have been downloaded.

Roberts, a proponent of open access to scholarly material, has worked with the Caltech Library for the last decade to make five of his previously published textbooks freely available.

"Since being included in CaltechAUTHORS in September 2011, Basic Principles of Organic Chemistry has accounted for more than 10 percent of all file downloads," says George Porter, Caltech's engineering librarian. "This is more than twice the download activity of CaltechAUTHORS' second most highly used resource."

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2016 Distinguished Alumna: Ellen D. Williams (PhD ’82, Chemistry)

The 2016 Distinguished Alumni Awards were presented on Saturday, May 21, during the 79th annual Seminar Day. Each week, the Caltech Alumni Association will share a story about a recipient.

In early March of this year, Ellen Williams stood before an audience of more than 2,000 researchers, entrepreneurs, and policymakers gathered in Washington, D.C., to discuss the future of energy. 

"We are living in a time as dynamic as when Thomas Edison and his contemporaries experimented with electricity," she declared as master of ceremonies for the Energy Innovation Summit, a conference that included as speakers luminaries such as former Vice President Al Gore and U.S. Secretary of Energy Ernest Moniz. "Drawing upon the science and engineering developments of recent decades, and supported by stunning advances in computational capability, today's innovators are pushing the boundaries of what is possible with energy."

Williams should know. As the director for the Advanced Research Project Agency–Energy (ARPA-E), which hosted the summit, she heads an organization that has invested more than $1.3 billion in hundreds of energy-related projects. Her position at the forefront of energy research is the culmination of a long career at the intersection of cutting-edge science, industry, and public policy.

Read the full story on the Caltech Alumni Association website

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Williams received the award for her sustained record of innovation and achievement in the area of structural-surface physics.
Wednesday, August 24, 2016
Center for Student Services 360 (Workshop Space) – Center for Student Services

CTLO's Summer Short Course for Faculty: (Re)Designing Your Class

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