Biologists Deliver Neutralizing Antibodies that Protect Against HIV Infection in Mice

Process represents novel approach to HIV prevention

PASADENA, Calif.—Over the past year, researchers at the California Institute of Technology (Caltech), and around the world, have been studying a group of potent antibodies that have the ability to neutralize HIV in the lab; their hope is that they may learn how to create a vaccine that makes antibodies with similar properties. Now, biologists at Caltech led by Nobel Laureate David Baltimore, president emeritus and Robert Andrews Millikan Professor of Biology, have taken one step closer to that goal: they have developed a way to deliver these antibodies to mice and, in so doing, have effectively protected them from HIV infection. 

This new approach to HIV prevention—called Vectored ImmunoProphylaxis, or VIP—is outlined in the November 30 advance online publication of the journal Nature.

Traditional efforts to develop a vaccine against HIV have been centered on designing substances that provoke an effective immune response—either in the form of antibodies to block infection or T cells that attack infected cells. With VIP, protective antibodies are being provided up front.

"VIP has a similar effect to a vaccine, but without ever calling on the immune system to do any of the work," says Alejandro Balazs, lead author of the study and a postdoctoral scholar in Baltimore's lab. "Normally, you put an antigen or killed bacteria or something into the body, and the immune system figures out how to make an antibody against it. We've taken that whole part out of the equation."

Because mice are not sensitive to HIV, the researchers used specialized mice carrying human immune cells that are able to grow HIV. They utilized an adeno-associated virus (AAV)—a small, harmless virus that has been useful in gene-therapy trials—as a carrier to deliver genes that are able to specify antibody production. The AAV was injected into the leg muscle of mice, and the muscle cells then put broadly neutralizing antibodies into the animals' circulatory systems. After just a single AAV injection, the mice produced high concentrations of these antibodies for the rest of their lives, as shown by intermittent sampling of their blood. Remarkably, these antibodies protected the mice from infection when the researchers exposed them to HIV intravenously.

The team points out that the leap from mice to humans is large—the fact that the approach works in mice does not necessarily mean it will be successful in humans. Still, the researchers believe that the large amounts of antibodies that the mice were able to produce—coupled with the finding that a relatively small amount of antibody has proved protective in the mice—may translate into human protection against HIV infection.


The paper also notes that in the mouse model, VIP worked even in the face of increased exposure to HIV. To test the efficacy of the antibody, the researchers started with a virus dose of one nanogram, which was enough to infect the majority of the mice who received it. When they saw that the mice given VIP could withstand that dose, they continued to bump it up until they were challenging them with 125 nanograms of virus.

"We expected that at some dose, the antibodies would fail to protect the mice, but it never did—even when we gave mice 100 times more HIV than would be needed to infect 7 out of 8 mice," says Balazs. "All of the exposures in this work were significantly larger than a human being would be likely to encounter."

He points out that this outcome likely had more to do with the properties of the antibody that was tested than the method, but adds that VIP is what enabled the large amount of this powerful antibody to circulate through the mice and fight the virus. Furthermore, VIP is a platform technique, meaning that as more potent neutralizing antibodies are isolated or developed for HIV or other infectious organisms, they can also be delivered using this method.

"If humans are like mice, then we have devised a way to protect against the transmission of HIV from person to person," says Baltimore. "But that is a huge if, and so the next step is to try to find out whether humans behave like mice."

He says the team is currently in the process of developing a plan to test their method in human clinical trials. The initial tests will ask whether the AAV vector can program the muscle of humans to make levels of antibody that would be expected to be protective against HIV.


The study, "Antibody-based Protection Against HIV Infection by Vectored ImmunoProphylaxis," was funded by the Bill and Melinda Gates Foundation, the National Institutes of Health, and the Caltech-UCLA Joint Center for Translational Medicine. Caltech biology researchers Joyce Chen, Christin M. Hong, and Lili Yang also contributed to the paper, as well as Dinesh Rao, a hematologist from the University of California, Los Angeles. 

Katie Neith

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Caltech Researchers Find Pulsating Response to Stress in Bacteria



In their experiment, the researchers studied how a bacterial species called B. subtilis responds to a stressful environment—for example, one without food. In such conditions, the single-celled organism activates a large set of genes that help it deal with hardship, by aiding cell repair for instance. Previously, biologists had thought the bacteria would handle stress by turning on the relevant genes and simply leaving them on until the stress goes away.

Instead, the researchers found that B. subtilis continuously flips these genes on and off. When faced with more stress, it increases the frequency of these pulses. The pulsating action is like switching your heater on full blast for a brief period every few minutes, and turning it on and off more frequently if you want the house to be warmer.

"It's a very different view of how a cell can respond to a particular stress," says James Locke, a postdoctoral scholar at Caltech. Locke and graduate student Jonathan Young are the lead authors on a paper describing this work, which was published in the October 21 issue of Science.

To make their finding, the researchers introduced a chemical to B. subtilis that inhibits the production of ATP, the energy-carrying molecules of cells. The team found that the stress induced by this chemical triggers interactions within a set of genes—collectively called a genetic circuit. This circuit, which contains a set of positive and negative feedback loops, generates sustained pulses of activity in a key regulatory protein called σB  ("sigma B"). The researchers attached fluorescent proteins to the circuit, causing the cells to glow green when σB was activated. By making movies of the flashing cells, the team could then study the dynamics of the circuit.

The key to this pulsating mechanism is the variability inherent in how proteins are made, the researchers say. The number of copies of any specific protein in a given cell fluctuates over time. The bacterial gene circuit amplifies these molecular fluctuations, also called noise, to generate discrete pulses of σB activation. The stress also activates another key protein that modulates the pulse frequencies.

By turning a steady input (the stress) into an oscillating output (the activation of σB) the genetic circuit is analogous to an electrical inverter, a device that converts direct current (DC) into alternating current (AC), explains Michael Elowitz, professor of biology and bioengineering at Caltech, Howard Hughes Medical Institute investigator, and coauthor of the paper. "You might think you need some kind of elaborate circuitry to implement that, but the cell can do it with just a few proteins, and by taking advantage of noise."

This work provides a blueprint for how relatively simple genetic circuits can generate complex and dynamic behaviors in individual cells, the researchers say. "We're excited to think that similar mechanisms may occur in other cellular processes," Locke says. "It'd be interesting in the future to see which aspects of this circuit architecture also appear in more complex systems, such as mammalian cells.”

"With this work and recent work in other systems, we're starting to get a glimpse of just how dynamic cellular control systems really are," Elowitz adds. "That's something that was very difficult to see in the past."

The other authors of the Science paper, "Stochastic pulse regulation in bacterial stress response," are research technicians Michelle Fontes and Maria Jesus Hernandez Jimenez. The research was funded by the National Institutes of Health, the National Science Foundation, the Packard Foundation, the International Human Frontier Science Organization, and the European Molecular Biology Organization.

Marcus Woo

Switching Senses

Caltech biologists find that leeches shift the way they locate prey in adulthood

PASADENA, Calif.—Many meat-eating animals have unique ways of hunting down a meal using their senses. To find a tasty treat, bats use echolocation, snakes rely on infrared vision, and owls take advantage of the concave feathers on their faces, the better to help them hear possible prey. Leeches have not just one but two distinct ways of detecting dinner, and, according to new findings from biologists at the California Institute of Technology (Caltech), their preferred method changes as they age.

Medicinal leeches, like many aquatic animals, use water disturbances to help them find a meal. Juvenile leeches eat the blood of fish and amphibians, while adults opt for blood meals from the more nutritious mammals. Since it was known that leeches change their food sources as they develop, the Caltech team wanted to know if the way they sense potential food changed as well. Their findings are outlined in a paper now available online in the Journal of Experimental Biology.

The group set up experiments to test how much leeches rely on each of the two sensory modalities they use to find food: hairs on their bodies that can note disturbances in the water made by prey moving through it and simple eyes that can pick up on the passing shadows that those waves make. They monitored both juvenile and adult leeches as they reacted to mechanical waves in a tank of water or to passing shadows, as well as to a combination of the two stimuli. The leeches in both age groups responded in similar ways when only one stimulus was present. But when both waves and shadows existed, the adult leeches responded solely to the waves. 

"We knew that there was a developmental switch in what kind of prey they go after," says Daniel Wagenaar, senior author of the paper and Broad Senior Research Fellow in Brain Circuitry at Caltech. "So when we saw a difference in the source of disturbances that the juveniles go after relative to the adults, we thought 'great—it's probably matching what we know.'"

However, the team was very surprised to see that the individual sensory modalities aren't modified during development to help decipher different types of prey. The leech's visual system doesn't really change as the animal matures; neither does the mechanical system. What does change, however, is the integration of the visual and mechanical cues to make a final behavioral decision.

"As they mature, the animals basically start paying attention to one sense more than the other," explains Cynthia Harley, lead author of the study and a postdoctoral scholar in biology at Caltech. She says that the team will now focus their studies on the adult leeches to learn more about how this sensory information is processed both at the behavioral and cellular levels.

Paper coauthor Javier Cienfuegos, now a freshman at Yale, contributed to the study while a high school student at the Polytechnic School, which is located next to Caltech's campus. He ran about half of the experimental trials and was "instrumental in the success of the study," says Harley.

The research outlined in the paper, "Developmentally regulated multisensory integration for prey localization in the medicinal leech," was funded by the Burroughs Wellcome Fund and the Broad Foundations.

Katie Neith

Building Better HIV Antibodies

Caltech biologists create neutralizing antibody that shows increased potency


Current advances in isolating antibodies from HIV-infected individuals have allowed for the discovery of a large number of new, broadly neutralizing anti-HIV antibodies directed against the host receptor (CD4) binding site—a functional site on the surface of the virus that allows for cell entry and infection. Using a technique known as structure-based rational design, the team modified one already-known and particularly potent antibody—NIH45-46—so that it can target the binding site in a different and more powerful way. A study outlining their process was published in the October 27 issue of Science Express.


By conducting structural studies, the researchers were able to identify how NIH45-46 interacted with gp120—a protein on the surface of the virus that's required for the successful entry of HIV into cells—to neutralize the virus. Using this information, they were able to create a new antibody (dubbed NIH45-46G54W) that is better able to grab onto and interfere with gp120. This improves the antibody's breadth—or extent to which it effectively targets many subtypes of HIV—and potency by an order of magnitude, according to Ron Diskin, a postdoctoral scholar in Bjorkman's lab at Caltech and the paper's lead author.





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Caltech Neuroscientists Record Novel Responses to Faces from Single Neurons in Humans

Finding offers new insights into neural basis of social perception

PASADENA, Calif.—Responding to faces is a critical tool for social interactions between humans. Without the ability to read faces and their expressions, it would be hard to tell friends from strangers upon first glance, let alone a sad person from a happy one. Now, neuroscientists from the California Institute of Technology (Caltech), with the help of collaborators at Huntington Memorial Hospital in Pasadena and Cedars-Sinai Medical Center in Los Angeles, have discovered a novel response to human faces by looking at recordings from brain cells in neurosurgical patients.

The finding, described in the journal Current Biology, provides the first description of neurons that respond strongly when the patient sees an entire face, but respond much less to a face in which only a very small region has been erased.

"The finding really surprised us," says Ueli Rutishauser, first author on the paper, a former postdoctoral fellow at Caltech, and now a visitor in the Division of Biology. "Here you have neurons that respond well to seeing pictures of whole faces, but when you show them only parts of faces, they actually respond less and less the more of the face you show. That just seems counterintuitive."

The neurons are located in a brain region called the amygdala, which has long been known to be important for the processing of emotions. However, the study results strengthen a growing belief among researchers that the amygdala has also a more general role in the processing of, and learning about, social stimuli such as faces.

Other researchers have described the amygdala's neuronal response to faces before, but this dramatic selectivity—which requires the face to be whole in order to elicit a response—is a new insight. 

"Our interpretation of this initially puzzling effect is that the brain cares about representing the entire face, and needs to be highly sensitive to anything wrong with the face, like a part missing," explains Ralph Adolphs, senior author on the study and Bren Professor of Psychology and Neuroscience and professor of biology at Caltech. "This is probably an important mechanism to ensure that we do not mistake one person for another and to help us keep track of many individuals."

The team recorded brain-cell responses in human participants who were awaiting surgery for drug-resistant epileptic seizures. As part of the preparation for surgery, the patients had electrodes implanted in their medial temporal lobes, the area of the brain where the amygdala is located. By using special clinical electrodes that have very small wires inserted, the researchers were able to observe the firings of individual neurons as participants looked at images of whole faces and partially revealed faces. The voluntary participants provided the researchers with a unique and very rare opportunity to measure responses from single neurons through the implanted depth electrodes, says Rutishauser.  

"This is really a dream collaboration for basic research scientists," he says. "At Caltech, we are very fortunate to have several nearby hospitals at which the neurosurgeons are interested in such collaborative medical research." 

The team plans to continue their studies by looking at how the same neurons respond to emotional stimuli. This future work, combined with the present study results, could be highly valuable for understanding a variety of psychiatric diseases in which this region of the brain is thought to function abnormally, such as mood disorders and autism.

Other Caltech authors on the paper are Oana Tudusciuc, a postdoctoral scholar in neuroscience and psychology, and Dirk Neumann, visiting associate in biology. Medical collaborators on the study include Adam Mamelak, a neurosurgeon at Cedars-Sinai; and Huntington Memorial Hospital's Christopher Heller, neurosurgeon; Ian Ross, neurosurgeon; Linda Philpott, neuropsychologist; and William Sutherling, medical director of the Epilepsy and Brain Mapping Program. The work in the paper "Neuronal responses selective for whole faces in the human amygdala," was supported by the National Science Foundation, the Pfeiffer Family Foundation, and the Gordon and Betty Moore Foundation.

Katie Neith

Four Caltech Researchers Given NIH Director's Awards

Research projects will explore membrane proteins, brain activity, genetic programming, and signaling molecules

PASADENA, Calif.—Four members of the California Institute of Technology (Caltech) faculty have been named among the researchers being given National Institutes of Health (NIH) Director's Awards. The awards are administered through the NIH's Common Fund, which provides support for research deemed to be both innovative and risky.

"The NIH Director's Award programs reinvigorate the biomedical work force by providing unique opportunities to provide research that is neither incremental nor conventional," said James M. Anderson, director of the Division of Program Coordination, Planning,  and Strategic Initiatives, which guides the Common Fund's High-Risk Research program. "The awards are intended to catalyze giant leaps forward for any area of biomedical research, allowing investigators to go in entirely new directions."

There are three types of NIH Director's Awards: the Pioneer Award, the New Innovator Award, and the Transformative Research Projects Award. This year, Caltech scientists were given two of 13 Pioneer Awards; two other Caltech researchers were among the 49 scientists given New Innovator Awards.

NIH Pioneer Awards

William Clemons Jr., assistant professor of biochemistry, and Thanos Siapas, professor of computation and neural systems, were each presented with an NIH Pioneer Award to promote what the Institutes call "pioneering and possibly transforming approaches" to key challenges in biomedical and behavioral research. 

Clemons' project will focus on membrane proteins. "Membrane proteins are an abundant and important class of molecules that play critical roles in medicine," he says. "But progress in understanding these molecules has been hindered by an inability to obtain them in significant quantities. Our goal is to examine the biological principles that cause these limitations, and discover new methods to overcome them. This award will allow us to explore these ideas in ways that aren't possible through traditional funding methods." 

Clemons received his BS from Virginia Tech in 1995, and his PhD from the University of Utah in 2000, spending time at the Laboratory of Molecular Biology in Cambridge, UK. After a postdoctoral fellowship at Harvard Medical School, he arrived at Caltech in 2005.

Siapas will use his Pioneer Award to develop neural probes for large-scale recordings of brain activity. "Brain functions such as perception, learning, and memory arise from the coordinated activation of billions of neurons distributed throughout the brain," Siapas says. "While we know a lot about the properties of individual neurons, much less is known about how assemblies of neurons interact to perform computations. Our goal is to develop large-scale, multielectrode arrays that will enable the monitoring of many neurons simultaneously across different brain areas. We hope that such arrays will expose new fundamental insights into brain activity, and will find application in the study of animal models of brain disorders."

Siapas received his BS, MS, and PhD degrees from the Massachusetts Institute of Technology in 1990, 1992, and 1996, respectively. He came to Caltech in 2002, and was named a full professor in 2010.

NIH New Innovator Awards

Long Cai, assistant professor of chemistry, and Lea Goentoro, assistant professor of biology, were each given the New Innovator Award, which the NIH says is meant to both stimulate highly innovative research and support promising new investigators.

Cai and his colleagues are working to use single-molecule microscopy to help them better understand the genetic programs in individual cells. "Our idea is to label the molecules individually," says Cai. "Then we can identify where these molecules are in the cell and how many of them are there, by single-molecule counting. "

"The goal is to monitor individual cells to find out how they work," he adds. "This may provide valuable information about rogue cells that are involved in cancer and other diseases."

Cai received his BA and PhD from Harvard in 2001 and 2006, respectively, and joined the Caltech faculty in 2010.

Goentoro will be exploring the ways in which cellular signaling molecules respond to their environment. "Have you ever noticed how we can easily whisper to each other in a quiet room, but we have to shout if we're standing on a busy road?" she asks. "In perceiving the world, our sensory systems automatically change their detection sensitivity according to the ambient condition, a phenomenon known as Weber's Law. We have found evidence to suggest that each cell in our body uses this same principle in perceiving signaling molecules in its surroundings. We will use the Innovator Award to explore this relative perception in cells, the underlying mechanism, and how it goes wrong in diseases."

"I am very grateful for the award," Goentoro adds. "It will give us precious freedom to explore ideas we are very curious about."

Goentoro's BS was awarded by the University of Wisconsin, Madison, in 2001, and she got her PhD from Princeton University in 2006. She has been at Caltech since July of this year.

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