Inside Salk; Salk Insitute

The power of connections

If the United States can be described as the "melting pot" of countries, the Salk Institute might be called the “reaction flask” of scientific institutes: its mix of scientists from varying fields produces surprising–and even life-changing–results.

From left: Reuben Shaw and Alan Saghatelian

Since its inception, the Institute has demonstrated that intellectual collisions between scientists from different fields can spark remarkable discoveries. Bringing together first-rate researchers in physics, behavioral psychology, genetics, plant science and other fields has led to everything from cancer drugs to a new understanding of the biological basis of language.

Now, Salk is doubling down on this strategy. Rapid technological advances are allowing scientists to connect across fields in ways that were never before possible. With this rise in technological capability has come a new generation of scientists who are experts in working across multiple fields. In recent months, the Salk Institute has recruited a new batch of such researchers to tackle major problems in biology from entirely new perspectives.

These incoming experts in chemistry, computer science and imaging aren’t just providing savvy technical know-how to other labs, but are offering unique approaches that, when partnered with traditional biology, could help solve fundamental problems in human health.

Consider Alan Saghatelian, for instance. Saghatelian joined Salk last summer, bringing with him a perspective from outside molecular biology that is already yielding new insights ranging from cancer research to DNA visualization.

Saghatelian first began to move into the field of biochemistry while a chemistry undergraduate at the University of California, Los Angeles. He approached his fourth year wanting to do more than just develop new methods to create chemicals.

“In chemistry, you engineer a molecule and you’re done. In biology, you make discoveries and it becomes a first step in a long journey,” says Saghatelian. “I didn’t want to be the guy waiting for someone to make a cool discovery and then make the drug. I wanted to be part of the discovery to help uncover the unknown.”

Eventually, Saghatelian found himself in a unique position to contribute to that discovery process. He became an expert in mass spectrometry, a technology that charts the weight of molecules and can reveal the thousands of molecules present in cell or tissue samples. While many scientists use mass spectrometry routinely, Saghatelian is pushing this technology to new limits to solve problems for which no other solution exists.

Capturing small molecules for big answers

Tiny molecules can provide a completely different view of biology from the more common sequencing methods (which focus on DNA and RNA) and may help uncover new avenues to treat disease. Even so, many of these small molecules are still relatively unknown.

Leveraging his chemistry background and the latest mass spectrometry technologies, Saghatelian is taking a closer look at small molecules. By seeing how they change between samples–for example, between cancerous and noncancerous tissues–he can find molecules of interest that could point to potential treatments for disease.

Identifying and synthesizing a previously unknown small molecule is slow and difficult, but there have been payoffs. As an assistant professor at Harvard University, Saghatelian partnered with a local medical center to discover an entirely new class of lipids, called FAHFAs. The group found that, when they administered FAHFAs to mice with the equivalent of type 2 diabetes, the elevated blood sugar in the mice dropped. The lipids also show up in normal human tissue and less so in at-risk patients, hinting at their use for a potential diabetes therapy.

In a collaboration that spins off of his research in metabolism, Saghatelian is also partnering with Salk Professor Reuben Shaw to look for weaknesses in cancer. Shaw’s lab has been able to show that genes that are critical in cancer are also key players in metabolism. Shaw and Saghatelian are trying to use the links between cancer genes and metabolism to identify specific small molecules that cancer cells need to grow.

Now, they will use mass spectrometry to detect and quantify thousands of small molecules in cells where cancer genes are turned on in the hopes of uncovering–and eventually blocking–the molecules and pathways cancer uses to grow.

“Alan has cutting-edge techniques to discover brand new natural lipids in our bodies that regulate metabolism and may fight diabetes,” says Shaw. “But these same methods can be used to study what lipids and other metabolites are different between cancers with one type of gene mutation versus the same type of cancer, but bearing a different gene mutation.” By decoding the metabolic changes in closely related cancers, they may be able to discover opportunities for new precision cancer treatments and cancer diagnostics.

In another collaboration–spurred on after informal conversations– Saghatelian is partnering with Associate Professor Clodagh O’Shea to better image critical protein-protein and protein-DNA interactions within living cells.

“The idea came about right at that bleeding edge of biology and chemistry,” says O’Shea, holder of Salk’s William Scandling Developmental Chair. O’Shea–who also works with Saghatelian to tag cancer-killing viruses with small molecules–credits many factors to these and other exciting collaborations that are commonplace at the Salk Institute. “You don’t have 10 researchers in the same field competing against each other. Instead, you have the best-of-the-best from their respective fields working together. Everyone here is a singularity, experts in their particular areas, but with converged themes,” she says.

Saghatelian is also working with other Salk labs to understand jumping genes and genetic mosaicism; distinguish how stem cells may differ from each other more than expected; find out how cells in the brain known as astrocytes contribute to Alzheimer’s disease; and uncover the connection between metabolism and the cancer gene p53, to name a few.

“The integration of mass spectrometry into the Salk will enable new questions to be asked and answered in all fields, including cancer, metabolism and neurodegenerative disease,” says Saghatelian. “These exciting collaborations are just the beginning.”

From left: Ullas Pedmale and Saket Navlakha

Connecting the dots between biology and computing

What does stomach flu have in common with an anti-government hacker? What can Google’s server system teach us about how the brain handles sleep deprivation? And how can a classic game theory quandary explain plant growth?

Assistant Professor Saket Navlakha is exploring such questions by striving to uncover algorithms in nature–strategies of how molecules, cells and organisms solve computational problems without a central commander. Discovering shared principles can help advance the fields of both computer science and biology, leading to improved computing algorithms and a better understanding of large, distributed biological systems.

While computer science and biology have had a long history of collaboration, computer scientists working in biology have typically been limited to analyzing troves of experimental information (e.g., imaging or sequencing data) to uncover patterns. Now, computing experts are doing more than just mining information, says Navlakha. Advances in “big data” and jumps in technology in the last few years have triggered this shift.

“There’s been a resurgence of computer science interfacing with biology because now we can really manipulate biological systems in ways we couldn’t before,” says Navlakha, who began his research in computing and graph theory but moved to exploring biological networks at the encouragement of his advisor at the University of Maryland, College Park. “We can get into finer details of biological processes instead of staying at a broad, abstract level.”

Armed with new algorithmic and computational technologies, Navlakha, who recently joined the Salk Institute, has already begun to explore potential collaborations that cover the spectrum of biological questions. Like Saghatelian, Navlakha’s expertise can apply to virtually all areas of biology, from protein interactions to disease outcomes, plant growth to brain development.

Groundbreaking work by Salk Assistant Professor Janelle Ayres, for example, suggests that killing a pathogen with antibiotics might not be the most efficient way to treat an infection. Rather, she predicts that developing therapeutics aimed at the collateral damage done to an organism (rather than the pathogen itself) would lead to new infectious disease treatments that pathogens will not evolve resistance to.

In conversations with Ayres, Navlakha saw parallels in how governments or companies handle security breaches by hackers. When faced with a digital invasion, organizations must decide if they will use their resources to aggressively go after the hackers (pathogens) or focus on stabilizing their system and minimizing collateral damage. The two researchers began to collaborate to develop computational analyses that encompass the principles of both host-pathogen interactions and hacker defense.

“My lab has the expertise to experimentally test our predictions at the level of a single individual and within model populations, but it will be important to predict within an epidemiological context how our approaches to treating infectious diseases will impact the emergence and spread of resistant pathogens,” says Ayres. “In our collaboration with the Navlakha lab, we will be able to execute such computational analyses.”

Navlakha adds, “We’re interested in seeing if there are analogies in the way tradeoffs are made in host-pathogen interactions that might be similar in network engineering and security.” Finding such parallels could also help both fields develop efficient ways to deal with cyber or biological invasions.

“The ability to participate in interdisciplinary collaborations with such ease is the beauty of Salk,” says Ayres. “It is only through such collaborations that science can be pushed into new and unexpected directions, which ultimately leads to the most exciting discoveries.”

In addition to this work, Navlakha plans to connect with neuroscientists to explore intriguing parallels between the brain and computers. When you do a search on Google, a central commander selects one of thousands of servers with a low activity load to take on that request. By evenly distributing requests for work, the system is able to quickly provide accurate answers to users. The brain also does its own “load balancing” (called homeostasis) to generate responses in a timely manner. The brain, however, does all of this without a central commander.

“Every neuron is active on its own, but emergently from the brain’s actions you get a very robust and load-balanced system,” says Navlakha. “It would be really cool to study this process of how neurons solve the load-balance problem and use that insight to improve the fault tolerance and performance of distributed networks, like the Internet.”

A better understanding of how load balancing in the brain works could point to ways to alleviate disturbances, which often happen in mental illness and potentially even in sleep deprivation, where overworked neurons are not able to rebalance work loads. To explore this and other questions related to the brain, Navlakha has begun conversations on potential neuroscience collaborations with Salk faculty, such as Kenta Asahina, Xin Jin and Charles Stevens.

Navlakha is also talking with Salk’s plant biologists to try to better understand how plants cooperate or compete for available sunlight. In economics, a hypothetic scenario called the prisoner’s dilemma explores the payoffs of cooperation versus competition. If two suspects are arrested for a crime, kept in separate rooms and individually asked who was responsible, they can each choose to stay loyal and not give up any information (cooperate) or betray each other (compete). If both remain loyal to each other (cooperate) by staying silent, they get light sentences; but if both blame each other (compete), they are deemed liars and given a medium sentence. Finally, if only one points the finger and the other stays silent, the betrayer (competitor) goes free while the betrayed (cooperator) gets a long sentence.

While talking with Salk plant researcher Joanne Chory, Navlakha discovered that plants have a similar quandary. If two plants are growing in the same space, a few outcomes can occur: both might grow normally and share the sunlight (cooperate); both could grow aggressively in hopes of shading the other plant (compete); or one could grow more aggressively than the other, dooming the smaller plant. Competing uses up precious resources the plants have, so it’s not always in their best interest to grow aggressively.

“When I first met Saket last year, my lab had been studying shade avoidance for about 10 years,” says Chory, a Howard Hughes Medical Institute investigator and the Howard H. and Maryam R. Newman Chair in Plant Biology. “We had learned quite a bit about the process–just enough to know that we had reached a bottleneck. We needed help because our models for how plants alter their growth rates in the shade were becoming more complex when ideally they should become simpler.”

Chory and her postdoctoral researcher, Ullas Pedmale, met with Navlakha to discuss how to analyze the large amounts of gene expression data the lab had gathered and derive a network model for how plants grow. “Saket’s questions about whether plants cooperate or compete got us to think about shade avoidance in a totally different way,” says Chory.

By studying how and why plants cooperate or compete with each other for sunlight in the framework of the prisoner’s dilemma, Navlakha hopes to quantify how nature evolved these strategies in plants. Such an understanding could provide valuable knowledge to the field of agriculture by suggesting which species to plant next to each other–and at what times and conditions–to control growth yields.

“The big theme of all of these collaborations is in trying to develop a computational understanding of life,” says Navlakha.

Dmitry Lyumkis

Unraveling structures to combat disease

If Saghatelian’s small molecules are equivalent to a 6-foot human, the protein complexes Dmitry Lyumkis studies, termed macromolecules, are on the order of several White Houses stacked next to each other.

For a long time, understanding the active areas of these macromolecules– which can have anywhere from just a few to as many as several hundred intermingled proteins on average–was limited by imaging technology. But a recent breakthrough in the resolution of a specialized microscopy has catapulted forward the imaging of large macromolecules, which could speed up drug discovery related to a number of diseases. Lyumkis, a scientist who came to the Institute under a new cross-disciplinary initiative called the Salk Fellows Program, brings this technology and expertise to explore key macromolecular complexes related to human disease.

Established in 2014, the Salk Fellows Program aims to specifically encourage connections across fields. “The interdisciplinary partnerships among the Fellows and faculty that the program facilitates will continue to add to our environment of innovative collaborations and create future intellectual leaders in the biological sciences,” says Salk Professor Inder Verma, who is, along with Professors Fred Gage and Ronald Evans, currently leading this program.

Lyumkis, the inaugural Helmsley-Salk Fellow, uses a cutting-edge technology that images large proteins and macromolecular complexes in more resolution than ever before to build three-dimensional models of the imaged objects. The resulting recreations provide a better understanding of protein function and sometimes reveal long sought-after clues in structural biology.

“An image is worth a thousand words,” says Lyumkis. “Apart from understanding how the complexes work from a basic research perspective, imaging these structures can make it much easier to generate drugs that target proteins of interest.” He is discussing potential collaborations with multiple Salk laboratories that can benefit from the technology. In particular, he plans to work with other Salk researchers to target a macromolecule that plays a major role in different types of cancer and inflammatory disease. If Lyumkis can uncover its structure, he and collaborators can test mutations in areas where the subunits interact to develop targeted therapies for cancer.

From left: Senior Director of the Biophotonics Core James Fitzpatrick; Salk Fellow Dmitry Lyumkis; and Senior Director of IT Operations Frank Dwyer in Salk’s Computing Core. The computational power and server set-up needed to successfully image molecules requires collaboration across departments.

“Though we’ve had this breakthrough in resolution, there’s still a lot to be improved in the technology,” says Lyumkis, who is improving the existing methods for analyzing the image data and building more accurate three-dimensional representations of typically heterogeneous objects. “My long-term goal is to spearhead methods that will allow us to solve increasingly more complicated molecular structures that may contain many different mobile components, and then apply these tools to better understand and potentially treat human disease.”

The second Fellow in the program, Jesse Dixon, who will join the Institute in August 2015, is also looking at large molecular structures. He will work with Salk researchers to more closely examine the three-dimensional packaging of DNA that O’Shea and others are interested in, and determine what those structures mean for basic biological processes, cancer and evolution. Both fellows are supported by the Leona M. and Harry B. Helmsley Charitable Trust through the Helmsley Center for Genomic Medicine at Salk.

“Salk is a wonderful example of the benefits of collaboration among researchers, where we share equipment, infrastructure and ideas,” says Verma, who is also the American Cancer Society Professor of Molecular Biology and the Irwin and Joan Jacobs Chair in Exemplary Life Science. “More importantly, collaborations across fields can expand scientific endeavors and, as we have seen time and time again, pave the way for new discoveries.”