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Nanoparticle-Based Cancer Therapies Shown to Work in Humans

A team of researchers led by Caltech scientists has shown that nanoparticles can function to target tumors while avoiding adjacent healthy tissue in human cancer patients.

"Our work shows that this specificity, as previously demonstrated in preclinical animal studies, can in fact occur in humans," says study leader Mark E. Davis, the Warren and Katharine Schlinger Professor of Chemical Engineering at Caltech. "The ability to target tumors is one of the primary reasons for using nanoparticles as therapeutics to treat solid tumors."

The findings, published online the week of March 21 in the journal Proceedings of the National Academy of Sciences, demonstrate that nanoparticle-based therapies can act as a "precision medicine" for targeting tumors while leaving healthy tissue intact.

In the study, Davis and his colleagues examined gastric tumors from nine human patients both before and after infusion with a drug—camptothecin—that was chemically bound to nanoparticles about 30 nanometers in size.

"Our nanoparticles are so small that if one were to increase the size to that of a soccer ball, the increase in size would be on the same order as going from a soccer ball to the planet Earth," says Davis, who is also a member of the City of Hope Comprehensive Cancer Center in Duarte, California, where the clinical trial was conducted.

The team found that 24 to 48 hours after the nanoparticles were administered, they had localized in the tumor tissues and released their drug cargo, and the drug had had the intended biological effects of inhibiting two proteins that are involved in the progression of the cancer. Equally important, both the nanoparticles and the drug were absent from healthy tissue adjacent to the tumors.

The nanoparticles are designed to be flexible delivery vehicles. "We can attach different drugs to the nanoparticles, and by changing the chemistry of the bond linking the drug to the nanoparticle, we can alter the release rate of the drug to be faster or slower," says Andrew Clark, a graduate student in Davis's lab and the study's first author.

Davis says his team's findings suggest that a phenomenon known as the enhanced permeability and retention (EPR) effect is at work in humans. In the EPR effect, abnormal blood vessels that are "leakier" than normal blood vessels in healthy tissue allow nanoparticles to preferentially concentrate in tumors. Until now, the existence of the EPR effect has been conclusively proven only in animal models of human cancers.

"Our results don't prove the EPR effect in humans, but they are completely consistent with it," Davis says.

The findings could also help pave the way toward more effective cancer drug cocktails that can be tailored to fight specific cancers and that leave patients with fewer side effects.

"Right now, if a doctor wants to use multiple drugs to treat a cancer, they often can't do it because the cumulative toxic effects of the drugs would not be tolerated by the patient," Davis says. "With targeted nanoparticles, you have far fewer side effects, so it is anticipated that a drug combination can be selected based on the biology and medicine rather than the limitations of the drugs."

These nanoparticles are currently being tested in a number of phase-II clinical trials. (Information about trials of the nanoparticles, denoted CRLX101, is available at www.clinicaltrials.gov).

In addition to Davis and Clark, other coauthors on the study, entitled "CRLX101 nanoparticles localize in human tumors and not in adjacent, nonneoplastic tissue after intravenous dosing," include Devin Wiley (MS '11, PhD '13) and Jonathan Zuckerman (PhD '12); Paul Webster of the Oak Crest Institute of Science; Joseph Chao and James Lin at City of Hope; and Yun Yen of Taipei Medical University, who was at City of Hope and a visitor in the Davis lab at the initiation of the clinical trial. The research was supported by grants from the National Cancer Institute and the National Institutes of Health and by Cerulean Pharma Inc. Davis is a consultant to and holds stock in Cerulean Pharma Inc. 

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Quintessentially Caltech

How best to recognize Caltech's own Ahmed Zewail, the Linus Pauling Professor of Chemistry and professor of physics, and director of the Physical Biology Center for Ultrafast Science and Technology, who has served on Caltech's faculty for 40 years? President Thomas F. Rosenbaum had the answer: what he would later call a "quintessentially Caltech conference."

And so, on Friday, February 26, more than 1,000 people gathered to hear exceptional researchers, including 5 Nobel Laureates, from across disciplines consider our future as part of the full-day "Science and Society" conference that honored the career of Zewail, whom Rosenbaum called "a wizard of scientific innovation."

Read the full story and view the slideshow

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Quintessentially Caltech

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Caltech: A Personal Perspective

Ahmed Zewail, Nobel Laureate
Linus Pauling Professor of Chemistry and Professor of Physics, Caltech

Zewail provided an overview of his journey from a young child in Egypt to Caltech Nobel laureate. On the day he won the 1999 Nobel Prize in Physics, he recalled, Caltech president David Baltimore came to Zewail's house, but he refused to open the door. "We thought he was paparazzi," Zewail admitted.

Credit: Chris Sabanpan

The End of Disease?

Roger Kornberg, Nobel Laureate
Mrs. George A. Winzer Professor in Medicine, Stanford, School of Medicine

As advanced as we think we are, Kornberg said, scientists today understand less than 1 percent of human biology. Attracting more young people to the field of medical research is therefore critical. "Young scientists are the most likely to discover something," he said. "And numbers matter."

Credit: Chris Sabanpan

The Future of Medicine

David Baltimore, Nobel Laureate
Caltech President Emeritus
Robert Andrews Millikan Professor of Biology, Caltech

The human body can survive a maximum of roughly 120 years, according to Baltimore. He predicted a future in which scientists work to push that envelope, using gene editing "to liberate us from the process of aging" and "to perfect the human body, whatever that means."

Credit: Chris Sabanpan

The Future of Quantum Physics

H. Jeff Kimble, Member, National Academy of Sciences
William L. Valentine Professor and Professor of Physics, Caltech

Kimble's lecture about the future of quantum physics included predictions about quantum computing, quantum simulation, and quantum metrology. "Science helps hold us together and appreciate our sameness rather than our differences," he said.

 

Credit: Chris Sabanpan

Time, Einstein, and the Coolest Stuff in the Universe

William Phillips, Nobel Laureate
Physicist, National Institute of Standards and Technology
Distinguished University Professor, University of Maryland

In a hands-on demonstration, Phillips put on a pair of lab goggles and dunked a variety of items—a rose, a racquetball, several inflated balloons—into a vat of liquid nitrogen to help demonstrate his overall point: that we can create super-accurate atomic clocks by cooling down atoms to astoundingly low temperatures.

Credit: Chris Sabanpan

Inequality and World Economics

A. Michael Spence, Nobel Laureate
Philip H. Knight Professor and Dean, Emeritus
Stanford University Graduate School of Business

Spence discussed a number of global economic trends—including the decline in middle-class jobs and the rise of job-eliminating technologies—in a lecture that considered the disparities between rich and poor. "I'm a little worried about what's going on in the global economy right now and I tend to be an optimist," he said.

Credit: Chris Sabanpan

The Future of Space Exploration

Charles Elachi, NASA Outstanding Leadership Medal Recipient
Caltech Vice President
Director, Jet Propulsion Laboratory

Elachi said he believes we will establish a space station on Mars and that humans will begin visiting the planet by 2030. But, he noted, "It's important that we take care of our own planet. It's the only thing we have, at least for now."

 

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How best to recognize Caltech's own Ahmed Zewail, the Linus Pauling Professor of Chemistry and professor of physics, and director of the Physical Biology Center for Ultrafast Science and Technology, who has served on Caltech's faculty for 40 years? President Thomas F. Rosenbaum had the answer: what he would later call a "quintessentially Caltech conference."

And so, on Friday, February 26, more than 1,000 people gathered to hear exceptional researchers, including 5 Nobel Laureates, from across disciplines consider our future as part of the full-day "Science and Society" conference that honored the career of Zewail, whom Rosenbaum called "a wizard of scientific innovation."

The speakers lectured on a broad spectrum of topics, ranging from space travel to global economic inequality to what happens when five inflated balloons are stuffed into a vat of liquid nitrogen. Their talks were moderated by Nathan Gardels, editor in chief of The WorldPost, and Peter Dervan, the Bren Professor of Chemistry, who noted while introducing Zewail that they have been close friends ever since their early days starting as assistant professors together at Caltech.

"What an extraordinary day," Rosenbaum said at the conclusion of the event, held in Beckman Auditorium. "It's unusual to find a series of talks at this incredibly high level of excellence—intellectually deep and pedagogically engaging."

As many of the speakers pointed out, Zewail's list of accomplishments is staggering. He has authored some 600 articles and 16 books and was sole recipient of the 1999 Nobel Prize for his pioneering work in femtochemistry. In the post-Nobel era, he developed a new field dubbed four-dimensional electron microscopy. He has been active in global affairs, serving as the first U.S. Science Envoy to the Middle East and helping establish the Zewail City of Science and Technology in Cairo, which he hopes to turn into "the Caltech of Egypt."

"Ahmed is a very special kind of scientist," said Fiona Harrison, chair of Caltech's Division of Physics, Mathematics and Astronomy, during the conference's introductory remarks. She noted the "incredible breadth of his research" and cited a colleague's observation that "Ahmed is someone who never has average goals."

Jackie Barton, chair of Caltech's Division of Chemistry and Chemical Engineering, praised Caltech for taking a chance on Zewail four decades ago, when he was a young scientist. "He had this vision," she said. "The vision was to watch the dynamics of chemical reactions, to watch reactions happening on a faster and faster time scale, indeed to watch the making and breaking of chemical bonds."

She added: "He has this intuitive sense of the dynamical motions of atoms and molecules, their coherence, or lack thereof, as the case may be. And then he has this extraordinary attention to every detail, so that he's able to meld together theory and experiment and understand that dance, that choreography of atoms and molecules as they carry out a reaction."

To further honor Zewail, Caltech presented him with a rare book of Benjamin Franklin's speeches and scientific research—on lightning rods and the aurora borealis, among other phenomena—that is signed by Rosenbaum and all of Caltech's former presidents. Caltech Provost Ed Stolper noted that it is the only book authored by Franklin that was published during his lifetime.

As Stolper noted in his introductory remarks, the gift is a fitting one for Zewail, who has come to embody the ideal of Caltech, a place "where scientists and engineers are limited only by their imagination." He added Ahmed is one of the few scientists that, like Benjamin Franklin and Linus Pauling, not only excelled in science but has made a broader impact on society through his writings and actions.

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New CCE Leadership Chair Honors the Past and Supports the Future

A new leadership chair in Caltech's Division of Chemistry and Chemical Engineering (CCE) will amplify the Institute's support of its scholars' freedom to pursue the most interesting and challenging lines of inquiry. Established through a $10 million gift from a couple who wish to remain anonymous, the chair will be named in honor of the late Norman Davidson, a longtime Caltech faculty member whose scientific contributions represented in part the beginnings of molecular biology. 

"Through this gift, CCE can maintain its excellence and move forward in new frontiers in chemistry," says Jacqueline K. Barton, Caltech's Arthur and Marian Hanisch Memorial Professor of Chemistry and inaugural holder of the Norman Davidson Leadership Chair.

Read the full story at giving.caltech.edu

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A new leadership chair in the Division of Chemistry and Chemical Engineering (CCE) will amplify the Institute’s support of its scholars’ freedom.

Caltech Names Six Distinguished Alumni

Caltech has announced that Eric Betzig (BS '83), Janet C. Campagna (MS '85), Neil Gehrels (PhD '82), Carl V. Larson (BS '52), Thomas J. "Tim" Litle IV (BS '62), and Ellen D. Williams (PhD '82) are this year's recipients of the Distinguished Alumni Award.

First presented in 1966, the award is the highest honor the Institute bestows upon its graduates. It is awarded in recognition of a particular achievement of noteworthy value, a series of such achievements, or a career of noteworthy accomplishment. Presentation of the awards will be given on Saturday, May 21, 2016, as part of Caltech's Seminar Day.

The 2016 Distinguished Alumni Award recipients are

Eric Betzig (BS '83, Physics)

Physicist; Group Leader, Janelia Research Campus, Howard Hughes Medical Institute

Betzig is being recognized for his groundbreaking contributions to microscopy. He pioneered a method known as single-molecule microscopy, or "nanoscopy," which allows cellular structures at the nanoscale to be observed using optical microscopy. For the work, he shared the Nobel Prize in Chemistry in 2014.

Janet C. Campagna (MS '85, Social Science)

CEO, QS Investors

Campagna is being recognized for her contributions to quantitative investment and for her leadership in the financial industry. Campagna is the founder of QS Investors, LLC, a leading customized solutions and global quantitative equities provider. She is responsible for all business, strategic, and investment decisions within QS Investors. 

Neil Gehrels (PhD '82, Physics)

Chief of the Astroparticle Physics Laboratory, NASA's Goddard Space Flight Center

Gehrels is being recognized for his scientific leadership in the study of gamma ray bursts as well as for his significant contributions to high-energy astrophysics, infrared astronomy, and instrument development.

Carl V. Larson (BS '52, Mechanical Engineering)

Larson is being recognized for his accomplished career in the electronics industry. Over the course of three decades, Larson has held numerous and diverse leadership roles in fields ranging from engineering to marketing. He is also being celebrated for his sustained commitment to the research, students, and alumni of Caltech.

Thomas J. "Tim" Litle IV  (BS '62, Engineering and Applied Science)

Founder and Chairman, Litle & Co.

Litle is being recognized for his revolutionary contributions to commerce. Through innovations such as the presorted mail program he developed for the U.S. Postal Service and the three-digit security codes on credit cards, Litle has made global business more efficient and secure.

Ellen D. Williams (PhD '82, Chemistry)

Director, Advanced Research Projects Agency-Energy (ARPA-E)

Williams is being recognized for her sustained record of innovation and achievement in the area of structural surface physics. She founded the Materials Research Science and Engineering Center at the University of Maryland and was the chief scientist for BP. She now serves as director of the Advanced Research Project Agency (ARPA-E) in the U.S. Department of Energy.

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The awardees range from the class of 1952 to the class of 1983, across a wide range of divisions.

Counting Molecules with an Ordinary Cell Phone

Diagnostic health care is often restricted in areas with limited resources, because the procedures required to detect many of the molecular markers that can diagnose diseases are too complex or expensive to be used outside of a central laboratory. Researchers in the lab of Rustem Ismagilov, Caltech's Ethel Wilson Bowles and Robert Bowles Professor of Chemistry and Chemical Engineering and director of the Jacobs Institute for Molecular Engineering for Medicine, are inventing new technologies to help bring emerging diagnostic capabilities out of laboratories and to the point of care. Among the important requirements for such diagnostic devices is that the results—or readouts—be robust against a variety of environmental conditions and user errors.

To address the need for a robust readout system for quantitative diagnostics, researchers in the Ismagilov lab have invented a new visual readout method that uses analytical chemistries and image processing to provide unambiguous quantification of single nucleic-acid molecules that can be performed by any cell-phone camera.

The visual readout method is described and validated using RNA from the hepatitis C virus—HCV RNA—in a paper in the February 22 issue of the journal ACS Nano.

The work utilizes a microfluidic technology called SlipChip, which was invented in the Ismagilov lab several years ago. A SlipChip serves as a portable lab-on-a-chip and can be used to quantify concentrations of single molecules. Each SlipChip encodes a complex program for isolating single molecules (such as DNA or RNA) along with chemical reactants in nanoliter-sized wells. The program also controls the complex reactions in each well: the chip consists of two plates that move—or "slip"—relative to one another, with each "slip" joining or separating the hundreds or even thousands of tiny wells, either bringing reactants and molecules into contact or isolating them. The architecture of the chip enables the user to have complete control over these chemical reactions and can prevent contamination, making it an ideal platform for a user-friendly, robust diagnostic device.

The new visual readout method builds upon this SlipChip platform. Special indicator chemistries are integrated into the wells of the SlipChip device. After an amplification reaction—a reaction that multiplies nucleic-acid molecules—wells change color depending on whether the reaction in it was positive or negative. For example, if a SlipChip is being used to count HCV RNA molecules in a sample, a well containing an RNA molecule that amplified during the reaction would turn blue; whereas a well lacking an RNA molecule would remain purple.

To read the result, a user simply takes a picture of the entire SlipChip using any camera phone. Then the photo is processed using a ratiometric approach that transforms the colors detected by the camera's sensor into an unambiguous readout of positives and negatives.

Previous SlipChip technologies utilized a chemical that would fluoresce when a reaction took place within a well. But those readouts can be too subtle for detection by a common cell-phone camera or can require specific lighting conditions. The new method provides guidelines for selecting indicators that yield color changes compatible with the color sensitivities of phone cameras, and the ratiometric processing removes the need for a user to distinguish colors by sight.

"The readout process we developed can be used with any cell-phone camera," says Jesus Rodriguez-Manzano, a postdoctoral scholar in chemical engineering and one of two first authors on the paper. "It is rapid, automated, and doesn't require counting or visual interpretation, so the results can be read by anyone—even users who are color blind or working under poor lighting conditions. This robustness makes our visual readout method appropriate for integration with devices used in any setting, including at the point of care in limited-resource settings. This is critical because the need for highly sensitive diagnostics is greatest in such regions."

The paper is titled "Reading Out Single-Molecule Digital RNA and DNA Isothermal Amplification in Nanoliter Volumes with Unmodified Camera Phones." In addition to Rodriguez-Manzano, Mikhail Karymov is also a first author. Other Caltech coauthors include Stefano Begolo, David Selck, Dmitriy Zhukov, and Erik Jue. The work was funded by grants from the Defense Advanced Research Projects Agency, the National Institutes of Health, and an Innovation in Regulatory Science Award from the Burroughs Wellcome Fund. Microfluidic technologies developed by Ismagilov's group have been licensed to Emerald BioStructures, RainDance Technologies, and SlipChip Corp., of which Ismagilov is a founder.

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The new visual readout method to count individual nucleic-acid molecules within a sample can be performed by any cell-phone camera.
Monday, February 29, 2016

Modeling molecules at the microscale

Considering the Future

Science and Society conference to honor Nobel Laureate Ahmed Zewail

Can we find life on other planets? Can we bridge the economic divide between rich and poor? Can we engineer the human body to live longer than our genes currently allow, and should we even attempt such a thing?

On February 26, some of the nation's leading scientists and researchers—including five Nobel laureates, two of whom are from Caltech—will gather at Caltech to discuss some of the most perplexing questions facing humanity. During a one-day conference titled "Science and Society," they will address an eclectic mix of topics ranging from current efforts to reduce global poverty to the mechanical workings of clocks so accurate that they lose less than a second every 300 million years.

The conference has been organized in honor of Ahmed Zewail, Caltech's Linus Pauling Professor of Chemistry and professor of physics, who was the sole recipient of the 1999 Nobel Prize in Chemistry for his development of the field of femtochemistry. Zewail, who also serves as director of Caltech's Physical Biology Center for Ultrafast Science and Technology, has lived the concept that science should drive the betterment of society, not only in his academic life, but in his advocacy as a U.S. science envoy to the Middle East and scientific advisor to the United Nations, and as a leader within his native Egypt, as exemplified by the role he played both during and after the Egyptian revolution of 2011.

"Science plays a vital role in helping people live better lives and helping humanity understand its place in the universe, and it's a rare treat for so many distinguished people to gather in one place to discuss these fascinating topics," says Zewail. "The theme that will shine through in this conference is that a passion for science, combined with a sense of optimism, can make the almost-impossible possible."

The conference, which will be held in Beckman Auditorium, will include speakers from Caltech, Stanford, the University of Maryland, and the Jet Propulsion Laboratory. Caltech's president, Thomas F. Rosenbaum, and provost, Edward Stolper, as well as Jacqueline Barton, chair of the Division of Chemistry and Chemical Engineering, and Fiona Harrison, the Kent and Joyce Kresa Leadership Chair of the Division of Physics, Mathematics and Astronomy, will open the conference; Rosenbaum will also provide concluding remarks at the end of the day.

The other speakers will include Caltech Nobel laureate David Baltimore, who will talk about "The Future of Medicine" and the CRISPR technology that is now teaching scientists how to "edit" a person's genes, an undertaking that raises a host of ethical questions. "Since medicine has brought us from a life expectancy of 45 years to one of 77 in the last century, it is reasonable to expect medicine will be able to extend it to 85 or even 100," says Baltimore, the Robert Andrews Millikan Professor of Biology. "But to go much beyond that, we would need to think about altering our genes. Should we think about that?"

William Phillips, a physicist at the National Institute of Standards and Technology and a Nobel laureate, will give a talk titled "Time, Einstein, and the Coolest Stuff in the Universe." His discussion will focus on how scientists are using supercold atoms to "allow tests of some of Einstein's strangest predictions" and to create supremely accurate atomic clocks, which, he says, "are essential to industry, commerce, and science." Phillips is also a Distinguished University Professor at the University of Maryland, College Park.

JPL director Charles Elachi will predict—in his talk about "The Future of Space Exploration"—that, during the next decade, we will establish permanent scientific stations on Mars and engage in a search for present or past ocean life on the moons of Europa, Enceladus, and Titan. Elachi believes that, in the near future, "we will also be imaging and characterizing planets around neighboring stars to see if we are alone."

Roger Kornberg, Nobel laureate and the Mrs. George A. Winzer Professor in Medicine at the Stanford School of Medicine, will discuss "The End of Disease." His talk will look at the challenges faced by the scientific community from both "biomedical and political myopia," while also considering the capacity and power of physics, chemistry, and biology to bring modern medicine forward.

A. Michael Spence, a Nobel laureate from the Stanford Graduate School of Business who will speak on "Inequality and World Economics," believes the integration of the world economy has helped reduce global income inequality on a "massive scale." Nonetheless, he says, the economic divide between rich and poor is getting larger within many countries, including virtually all developed nations. In his lecture, Spence says, he will try "to unpack the contributing factors to this inequality, its results, and how to respond effectively to this trend."

And Caltech's H. Jeff Kimble, the William L. Valentine Professor and professor of physics, will be focusing on "startling advances in quantum physics"—specifically, how the complex correlations that arise among many strongly interacting quantum objects has and can continue to shape computation, communication, and the health of physics and society more generally. 

Visit the Science and Society Conference website for more information about the event and to register and receive updates.

Written by Alex Roth

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On February 26, some of the nation's leading scientists and researchers will gather at Caltech to discuss some of the most perplexing questions facing humanity.

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