Tuesday, October 20, 2015
Dabney Hall, Lounge – Dabney Hall

Bringing Joy into Your Teaching: A Workshop by Chris Duffy

Monday, October 19, 2015
Guggenheim 101 (Lees-Kubota Lecture Hall) – Guggenheim Aeronautical Laboratory

The Future of Teaching and Learning at Caltech: An Innovation Showcase

Monday, October 19, 2015 to Friday, October 23, 2015

TeachWeek Caltech

Wednesday, October 21, 2015
Keck Center

Engaging Students Beyond Their Field

Tuesday, October 21, 2014
Keck Center

Engaging Students Beyond Their Field

Thursday, October 22, 2015

Confessions of a Converted Lecturer: TeachWeek Keynote by Eric Mazur

An Antibody That Can Attack HIV in New Ways

Proteins called broadly neutralizing antibodies (bNAbs) are a promising key to the prevention of infection by HIV, the virus that causes AIDS. bNAbs have been found in blood samples from some HIV patients whose immune systems can naturally control the infection. These antibodies may protect a patient's healthy cells by recognizing a protein called the envelope spike, present on the surface of all HIV strains and inhibiting, or neutralizing, the effects of the virus. Now Caltech researchers have discovered that one particular bNAb may be able to recognize this signature protein, even as it takes on different conformations during infection—making it easier to detect and neutralize the viruses in an infected patient.

The work, from the laboratory of Pamela Bjorkman, Centennial Professor of Biology, was published in the September 10 issue of the journal Cell.

The process of HIV infection begins when the virus comes into contact with human immune cells called T cells that carry a particular protein, CD4, on their surface. Three-part (or "trimer") proteins called envelope spikes on the surface of the virus recognize and bind to the CD4 proteins. The spikes can be in either a closed or an open conformation, going from closed to open when the spike binds to CD4. The open conformation then triggers fusion of the virus with the target cell, allowing the HIV virus to deposit its genetic material inside the host cell, forcing it to become a factory for making new viruses that can go on to infect other cells.

The bNAbs recognize the envelope spike on the surface of HIV, and most known bNAbs only recognize the spike in the closed conformation. Although the only target of neutralizing antibodies is the envelope spike, each bNAb actually functions by recognizing just one specific target, or epitope, on this protein. Some targets allow more effective neutralization of the virus, and, therefore, some bNAbs are more effective against HIV than others. In 2014, Bjorkman and her collaborators at Rockefeller University reported initial characterization of a potent bNAb called 8ANC195 in the blood of HIV patients whose immune systems could naturally control their infections. They also discovered that this antibody could neutralize the HIV virus by targeting a different epitope than any other previously identified bNAb.

In the work described in the recent Cell paper, they investigated how 8ANC195 functions—and how its unique properties could be beneficial for HIV therapies.

"In Pamela's lab we use X-ray crystallography and electron microscopy to study protein–protein interactions on a molecular level," says Louise Scharf, a postdoctoral scholar in Bjorkman's laboratory and the first author on the paper. "We previously were able to define the binding site of this antibody on a subunit of the HIV envelope spike, so in this study we solved the three-dimensional structure of this antibody in complex with the entire spike, and showed in detail exactly how the antibody recognizes the virus."

What they found was that although most bNAbs recognize the envelope spike in its closed conformation, 8ANC195 could recognize the viral protein in both the closed conformation and a partially open conformation. "We think it's actually an advantage if the antibody can recognize these different forms," Scharf says.

The most common form of HIV infection is when a virus in the bloodstream attaches to a T cell and infects the cell. In this instance, the spikes on the free-floating virus would be predominantly in the closed conformation until they made contact with the host cell. Most bNAbs could neutralize this virus. However, HIV also can spread directly from one cell to another. In this case, because the antibody already is attached to the host cell, the spike is in an open conformation. But 8ANC195 could still recognize and attach to it.

A potential medical application of this antibody is in so-called combination therapies, in which a patient is given a cocktail of several antibodies that work in different ways to fight off the virus as it rapidly changes and evolves. "Our collaborators at Rockefeller have studied this extensively in animal models, showing that if you administer a combination of these antibodies, you greatly reduce how much of the virus can escape and infect the host," Scharf says. "So 8ANC195 is one more antibody that we can use therapeutically; it targets a different epitope than other potent antibodies, and it has the advantage of being able to recognize these multiple conformations."

The idea of bNAb therapeutics might not be far from a clinical reality. Scharf says that the same collaborators at Rockefeller University are already testing bNAbs in a human treatment in a clinical trial. Although the initial trial will not include 8ANC195, the antibody may be included in a combination therapy trial in the near future, Scharf says.

Furthermore, the availability of complete information about how 8ANC195 binds to the viral spike will allow Scharf, Bjorkman, and their colleagues to begin engineering the antibody to be more potent and able to recognize more strains of HIV.

"In addition to supporting the use of 8ANC195 for therapeutic applications, our structural studies of 8ANC195 have revealed an unanticipated new conformation of the HIV envelope spike that is relevant to understanding the mechanism by which HIV enters host cells and bNAbs inhibit this process," Bjorkman says.

These results were published in a journal article titled "Broadly Neutralizing Antibody 8ANC195 Recognizes Closed and Open States of HIV-1 Env." In addition to Scharf and Bjorkman, other Caltech coauthors include graduate student Haoqing Wang, research technician Han Gao, research scientist Songye Chen, and Beckman Institute resource director Alasdair W. McDowall. Funding for the work was provided by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health; the Bill and Melinda Gates Foundation; and the American Cancer Society. Crystallography and electron microscopy were done at the Molecular Observatory at Caltech, supported by the Gordon and Betty Moore Foundation.

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Partnership with Heritage Medical Research Institute Will Augment Translational Medicine Research

A new partnership will support translational sciences and health technology at Caltech thanks to a three-year commitment from Heritage Medical Research Institute (HMRI), a nonprofit founded and led by Caltech trustee Richard N. Merkin.

With this gift, the Institute and HMRI have created the Heritage Research Institute for the Advancement of Medicine and Science at Caltech. Eight Caltech faculty members from three academic divisions have been selected for the inaugural cohort of Heritage researchers, with a ninth yet to be named. These scientists and engineers—who will hold the title of Heritage Principal Investigators—will receive salary and research support as well as opportunities to learn from and collaborate with each other and with practicing physicians in the local community.

"Dick Merkin's insights into the changing landscape of modern medicine, his devotion to supporting young talent, and his exceptional generosity have come together to create an innovative program to advance translational research," says President Thomas F. Rosenbaum, holder of the Sonja and William Davidow Presidential Chair and professor of physics. "The generous support of HMRI, through Dick's vision, will provide the freedom and resources for faculty from across the divisions to tackle difficult science and engineering problems for the betterment of the human condition."

As a physician and a healthcare executive, Merkin has witnessed the rapid evolution of medicine and patient care in recent decades—and says he sees monumental changes on the horizon.

"I think some of the greatest breakthroughs this century will occur in biology, and I think Caltech is particularly positioned to be a leader in this area," Merkin says. "Our biggest problems are our biggest opportunities, and Caltech is gifted in looking at the world not as it is, but as it could be."

Caltech is uniquely suited to accelerating progress due to its highly collaborative environment, Merkin adds. The convergence of multidisciplinary science and technology, he says, is driving innovation at an exponential rate, particularly in the areas of implantable sensors and precision medicine.

Many of Caltech's new Heritage Principal Investigators have already deepened our understanding of how the human body works—from the microbes in our gut to the chemicals in our brain—and are advancing the study of diseases such as diabetes, autism, and cancer. As a trustee and benefactor, Merkin has been energized by the potential impact of their investigations.

"The most imaginative scientists on the globe are concentrated at Caltech," Merkin says. "They are dedicated to understanding the world around us. Just being able to interact with so many passionate, hardworking, and brilliant people is inspiring. I'm very grateful to be part of the Institute." 

Adds Stephen Mayo, the William K. Bowes Jr. Leadership Chair of the Division of Biology and Biological Engineering and Bren Professor of Biology and Chemistry: "As a valued friend of the Institute and a physician, Richard Merkin knows that the treatments of tomorrow begin in the lab today. This gift will embolden the Heritage Principal Investigators—some of whom are in the early stages of their careers—to pursue their most promising ideas and, in turn, quicken the pace of discovery in the biosciences."

A graduate of the University of Miami, Merkin began his career as a physician before creating what is now known as Heritage Provider Network (HPN) in 1979. Merkin serves as HPN's president and chief executive officer and has overseen its growth into one of California's largest healthcare provider networks. In 2012, Fast Company magazine named HPN one of the most innovative healthcare companies for embracing techniques such as data mining and predictive modeling to better the well-being of patients and improve the nation's healthcare system.

Merkin's philanthropy focuses on medical research, the arts, and children, with a special emphasis on the people of Southern California. He has served on the Caltech Board of Trustees since 2007 and also sits on the boards of the Los Angeles County Museum of Art and United Friends of the Children, as well as educational institutions, including the Keck School of Medicine of USC and Alliance College-Ready Public Schools. The latter runs 27 charter schools in the greater Los Angeles area, including one site named after him—the Richard Merkin Middle School. 

In 2003, Merkin founded HMRI, a nonprofit that also has supported the Dana Farber Cancer Institute and the Prostate Cancer Foundation. In deciding where to direct HMRI's research funds, making a pledge to Caltech made sense for Merkin.

"Watching the Institute's stewardship of resources as a trustee makes me very comfortable investing as a benefactor," Merkin says. "Supporting Caltech and its faculty and students is a much broader investment in a better future—not just for the local community, not just for the United States, but, really, for the world."

Marisa Demers
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Developmental Biologist Eric H. Davidson Passes Away

Eric Harris Davidson, Caltech's Norman Chandler Professor of Cell Biology, passed away on Tuesday, September 1, 2015. He was 78 years old.

Davidson, a developmental biologist, was a pioneer researcher and theorist of the gene regulatory networks that perform complex biological processes, such as the transformation of a single-celled egg into a complex organism. His work helped to reveal how the DNA sequences inherited in the genome are used to initiate and drive forward the sequence of steps that result in development.

His research emphasized quantitative understanding of biological mechanisms and the logic functions encoded in genetic networks, and focused on the question of how the genomic DNA could encode not only protein sequences but also the complex "software" needed for differentiating cell types in the right places and proportions to make complex animals.

Davidson initially focused on quantitative methods for analyzing genome functions. In 1969, he and his longtime colleague, molecular biophysicist Roy Britten, published the first model of a gene regulatory network, a web of interacting regulatory genes. This network included both regulatory DNA sequences—segments of DNA at each gene that set the conditions for when and where that gene will be turned on or off—and genes that code for molecules that bind to the regulatory DNA of other genes to turn them on or off. These gene regulatory networks have since been shown experimentally to control the process of development.

In 1971, Britten and Davidson published a landmark paper concluding that the evolution of an animal's body plan depends on changes in how genes are regulated during development. This concept was the foundation for the field of evolutionary developmental biology.

For the last forty years, Davidson's work centered on the purple sea urchin, Strongylocentrotus purpuratus, whose range includes the waters off Caltech's Kerckhoff Marine Biology Laboratory in Corona del Mar, California.

Inherent in the idea of gene regulatory networks was the concept that genome sequences that provided information about how genes should be expressed would be as important as the genome sequences that coded for the proteins themselves. Although non-protein-coding DNA was long considered to be "junk," Davidson recognized that the key regulatory code resided in this genetic material. In 2006, Davidson co-led a group of 240 researchers from more than 70 institutions that sequenced the purple sea urchin's genome. In 2008, a consortium of institutions led by Davidson's lab characterized the 23,000 genes of that genome.

In parallel, the Davidson group systematically created a comprehensive functional testing strategy to detect all of the control connections between the genes involved in the key events in the earliest stages of sea urchin embryo development, and to determine how the activity of each gene affected the ability of every other gene in that part of the embryo to be expressed. The network model, first described in 2002 and elucidated and extended over the next 13 years, revealed that the regulatory networks governing high-level processes such as the formation of a specific type of cell are built from gene circuits that can have striking similarities even when the identities of the genes in the circuits are different. These circuits can be viewed as a few dozen types of modules that perform specific functions. Because similar modular systems appear to exist in flies, frogs, chicks, mice, and zebrafish, they may be a universal feature of higher organisms.

The work, Davidson noted at the time, allows scientists to tinker with and re-engineer genetic networks, a process that simulates the genetic changes that accompany the evolution of organisms in real life. "The evolution of animals is due to changes in the structure of these gene regulatory networks, so this work provides us with an opportunity to study evolution in a new and decisive way," he said.

In 2012, Davidson's laboratory devised the first complete computational model of one of those networks, consisting of about 50 genes. Each gene was modeled as an on/off switch. The initial state of each switch was set, and the model was allowed to run. The team found that the predicted final state of the network matched results in normal and genetically manipulated sea urchins, validating a powerful tool for understanding gene regulatory networks in a way not previously possible.

"Eric's early recognition that 'biological engineering' would be a powerful approach for elucidating fundamental biological principles is an excellent example of his ability to foresee important advances in science," says Stephen Mayo, the Bren Professor of Biology and Chemistry and William K. Bowes Jr. Leadership Chair for the Division of Biology and Biological Engineering.

"Eric was a great man whose work on gene regulatory networks was paradigm shifting and has had tremendous impact in multiple fields of biology," says Marianne Bronner, the Albert Billings Ruddock Professor of Biology at Caltech. "He will be sorely missed as a colleague and friend."

Davidson was born on April 13, 1937, in New York, New York, and earned his bachelor of arts degree from the University of Pennsylvania in 1958 and his doctorate from Rockefeller University in 1963. He worked as a postdoctoral researcher and then as a member of the Rockefeller faculty before coming to Caltech as a visiting assistant professor of biology in 1970. He became a Caltech associate professor in 1971, a professor in 1974, and was named Chandler Professor in 1982. 

He was a member of the National Academy of Sciences and a fellow of the American Association for the Advancement of Science. In 2011, he was awarded the International Prize for Biology by the Japan Society for the Promotion of Science. He was also the recipient of the Lifetime Achievement Award from the Society for Developmental Biology and the A.O. Kovalevsky Medal from the St. Petersburg Society of Naturalists.

He authored six books, ranging from his classic 1968 monograph, Gene Activity in Early Development, to Genomic Control Processes, published this year and coauthored with Caltech research assistant professor Isabelle Peter.

Davidson had varied interests including history; American football (he played in the 1990s on Caltech's team); and the traditional music of the Appalachian Mountains, which he himself performed, playing the clawhammer banjo with the Iron Mountain String Band. 

He is survived by his daughter, Elsa Davidson Bahrampour. 

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Making Nanowires from Protein and DNA

The ability to custom design biological materials such as protein and DNA opens up technological possibilities that were unimaginable just a few decades ago. For example, synthetic structures made of DNA could one day be used to deliver cancer drugs directly to tumor cells, and customized proteins could be designed to specifically attack a certain kind of virus. Although researchers have already made such structures out of DNA or protein alone, a Caltech team recently created—for the first time—a synthetic structure made of both protein and DNA. Combining the two molecule types into one biomaterial opens the door to numerous applications.

A paper describing the so-called hybridized, or multiple component, materials appears in the September 2 issue of the journal Nature.

There are many advantages to multiple component materials, says Yun (Kurt) Mou (PhD '15), first author of the Nature study. "If your material is made up of several different kinds of components, it can have more functionality. For example, protein is very versatile; it can be used for many things, such as protein–protein interactions or as an enzyme to speed up a reaction. And DNA is easily programmed into nanostructures of a variety of sizes and shapes."

But how do you begin to create something like a protein–DNA nanowire—a material that no one has seen before?

Mou and his colleagues in the laboratory of Stephen Mayo, Bren Professor of Biology and Chemistry and the William K. Bowes Jr. Leadership Chair of Caltech's Division of Biology and Biological Engineering, began with a computer program to design the type of protein and DNA that would work best as part of their hybrid material. "Materials can be formed using just a trial-and-error method of combining things to see what results, but it's better and more efficient if you can first predict what the structure is like and then design a protein to form that kind of material," he says.

The researchers entered the properties of the protein–DNA nanowire they wanted into a computer program developed in the lab; the program then generated a sequence of amino acids (protein building blocks) and nitrogenous bases (DNA building blocks) that would produce the desired material.

However, successfully making a hybrid material is not as simple as just plugging some properties into a computer program, Mou says. Although the computer model provides a sequence, the researcher must thoroughly check the model to be sure that the sequence produced makes sense; if not, the researcher must provide the computer with information that can be used to correct the model. "So in the end, you choose the sequence that you and the computer both agree on. Then, you can physically mix the prescribed amino acids and DNA bases to form the nanowire."

The resulting sequence was an artificial version of a protein–DNA coupling that occurs in nature. In the initial stage of gene expression, called transcription, a sequence of DNA is first converted into RNA. To pull in the enzyme that actually transcribes the DNA into RNA, proteins called transcription factors must first bind certain regions of the DNA sequence called protein-binding domains.

Using the computer program, the researchers engineered a sequence of DNA that contained many of these protein-binding domains at regular intervals. They then selected the transcription factor that naturally binds to this particular protein-binding site—the transcription factor called Engrailed from the fruit fly Drosophila. However, in nature, Engrailed only attaches itself to the protein-binding site on the DNA. To create a long nanowire made of a continuous strand of protein attached to a continuous strand of DNA, the researchers had to modify the transcription factor to include a site that would allow Engrailed also to bind to the next protein in line.

"Essentially, it's like giving this protein two hands instead of just one," Mou explains. "The hand that holds the DNA is easy because it is provided by nature, but the other hand needs to be added there to hold onto another protein."

Another unique attribute of this new protein–DNA nanowire is that it employs coassembly—meaning that the material will not form until both the protein components and the DNA components have been added to the solution. Although materials previously could be made out of DNA with protein added later, the use of coassembly to make the hybrid material was a first. This attribute is important for the material's future use in medicine or industry, Mou says, as the two sets of components can be provided separately and then combined to make the nanowire whenever and wherever it is needed.

This finding builds on earlier work in the Mayo lab, which, in 1997, created one of the first artificial proteins, thus launching the field of computational protein design. The ability to create synthetic proteins allows researchers to develop proteins with new capabilities and functions, such as therapeutic proteins that target cancer. The creation of a coassembled protein–DNA nanowire is another milestone in this field.

"Our earlier work focused primarily on designing soluble, protein-only systems. The work reported here represents a significant expansion of our activities into the realm of nanoscale mixed biomaterials," Mayo says.

Although the development of this new biomaterial is in the very early stages, the method, Mou says, has many promising applications that could change research and clinical practices in the future.

"Our next step will be to explore the many potential applications of our new biomaterial," Mou says. "It could be incorporated into methods to deliver drugs into cells—to create targeted therapies that only bind to a certain biomarker on a certain cell type, such as cancer cells. We could also expand the idea of protein–DNA nanowires to protein–RNA nanowires that could be used for gene therapy applications. And because this material is brand-new, there are probably many more applications that we haven't even considered yet."  

The work was published in a paper titled, "Computational design of co-assembling protein-DNA nanowires." In addition to Mou and Mayo, other Caltech coauthors include former graduate students Jiun-Yann Yu (PhD '14) and Timothy M. Wannier (PhD '15), as well as Chin-Lin Guo from Academia Sinica in Taiwan. The work was funded by the Defense Advanced Research Projects Agency Protein Design Processes Program, a National Security Science and Engineering Faculty Fellowship, and the Caltech Programmable Molecular Technology Initiative funded by the Gordon and Betty Moore Foundation.

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