The Science of Siblings

When you meet Vishwanath “Vishu” Lingappa ’75, one of the first things you notice is his voice. In a blog for National Geographic, Carl Zimmer calls it a “radio-talk-show-host” voice. Other descriptions could equally well apply. It is a CEO’s voice and an orator’s voice. A simple interview with Lingappa has more dramatic pianissimos and booming crescendos than a Beethoven symphony.

Most of all, though, it is a big brother’s voice, loud and encouraging and demanding at the same time.

“I have a favorite story about Vishu,” says his brother, Jairam ’80. “As kids, when we were watching TV and got to a commercial break, he would say ‘Jai! I’ll bet you can’t make me a peanut-butter-and-jelly sandwich and milk and bring it back upstairs in less than a minute!’ ”

As the youngest sibling, Jai always looked up to his big brother. He would race downstairs to make the sandwich. He didn’t realize that as soon as he left the room, Vishu would stop counting and then start again when he heard Jairam approaching. “Sixty-one! Sixty-two!” Vishu would say as Jairam burst into the room. “You almost made it! Next time you’ll do it!”

In a literal way, Vishu has always been there for Jairam and his sister Jaisri ’79. When Jaisri and Jairam were undergraduates at Swarthmore, he arranged for them to work in his Ph.D. mentor’s laboratory at Rockefeller University during the summer. When Jairam decided to go to medical school after getting a doctorate in biophysics, he chose the University of California–San Francisco (UCSF), where Vishu was an attending physician, and Jaisri was a resident. The three Lingappa siblings lived in the same house, and their weekly discussions of cases from the New England Journal of Medicine were the stuff of local legend.

In the competitive and individualistic world of academia, it is a rare thing for three siblings to stick together the way that the Lingappas have. Not only have they stayed close physically (Jairam and Jaisri now live in Seattle and teach at the University of Washington), they work in similar fields: Vishu and Jaisri focus on understanding how a host cell’s proteins get co-opted by viruses after infection, while Jairam uses human genetics to understand how viruses might enter the host in the first place. All have been involved with Vishu’s company, Prosetta Biosciences, either as founders or scientific advisers. Now 12 years old, the company is closing in on a new class of drugs that would be effective against multiple viral diseases. 

“If we are right that we have found the next generation of drug targets, it will change the face of the pharmaceutical industry,” Vishu says. He’s using his full-on CEO voice now—the one he used this winter to clinch the latest round of capital funding for his company. Viruses, beware! In the power of three Lingappas, you have found a worthy adversary.

From Geneva to Sri Lanka … to Swarthmore

Vishu was born in 1954 to parents who had a remarkable story of their own. B.T. and Yamuna Lingappa had met in India, after she wrote and published a story about two star-crossed lovers searching for knowledge. B.T., a great believer in the power of education, admired the story and became her pen pal. Before long, Yamuna was traveling hundreds of miles to meet him, and eventually they married. In the India of the late 1940s, it was absolutely unheard-of—a marriage for love, between people from two different Brahmin subcastes.

“There was a big hullaballoo in the extended families,” Jairam says. The Lingappas moved to the United States to pursue doctoral degrees. After graduate school at Purdue (where Vishu was born) and postdoc positions at the University of Michigan and Michigan State (where Jaisri and Jairam were born, respectively), they settled down in Worcester, Mass., to teach and do research at Holy Cross College.

But their days of wandering were not quite over. In 1969 and 1970, their sabbatical year, B.T. and Yamuna spent 13 months traveling the globe with Vishu, Jaisri, and Jairam. It was a formative experience for the younger Lingappas.

The first stop was Geneva, for five months. “My parents, in their brilliant and maverick way, decided not to send us to an international school but to place us in a French-speaking local school,” Jaisri says—even though she and Jairam spoke not a word of French. “We had to learn very quickly.” 

The next stop was Turkey—and another eye-opening lesson outside the classroom. “Right next door to the hotel was a Turkish sweet shop,” Jairam says. “The owner lavished us with sweets, until the very last night, when he found out we were Americans, and he abruptly wouldn’t let us back into the store. It taught us how much politics impacts our lives, how the U.S. is regarded both positively and negatively abroad.”

India came next. “We wandered all over the subcontinent, from Kashmir to Sri Lanka,” Vishu says. For the first time, the Lingappa children were confronted with the enormous economic disparity between their homeland and the homeland of their relatives.

“I remember taking a rickshaw one time,” Jaisri says. “Back then, it was the equivalent of a taxi. But it showed you how human life was devalued, with people treated as almost beasts of burden. The person pulling our rickshaw did not look well. Mother asked him some questions and found out that he had a fever, and she helped him get medical care.”

“It just didn’t seem right,” she says. “We had so many experiences like that, where it was clear that a small intervention could make a big difference. How powerless we felt … That experience made all three of us activists.”

Of course, the ’60s were a time of social upheaval in America. In 1967, Vishu’s parents appointed him the family’s representative to the historic march on the Pentagon to protest the Vietnam War.

“That was when I first saw the name of Swarthmore,” Vishu says. “There was a small contingent from Harvard and a small contingent from Stanford, and then there was a very large contingent from Swarthmore.” Curious about this small college with an outsized antiwar movement, Vishu read up on Swarthmore’s Quaker heritage, and Swarthmore moved to the top of the list when he applied to colleges.

Swarthmore was the second transformative experience of Vishu’s life. “Never again in my life did I have to work half as hard as I did at Swarthmore—and I’m a guy who still works 12 hours a day, seven days a week,” Vishu says. “I was miserable for the first two years, until I figured the place out,” he says. “Then it became enormously fun and one of the most intellectually pleasant experiences I’ve ever had.”

Three professors had a lifelong impact on him: philosophy professor Richie Schuldenfrei, Russian professor Thompson Bradley, and biology professor Bob Savage. From Schuldenfrei, Vishu learned to challenge the “naïve reductionism” that pervades modern science—the view that the whole is nothing more than the sum of the parts. Without the ability to see the bigger picture, he believes that he would not have discovered the new drug targets that Prosetta is working on.

Following a moral compass

From Bradley, Vishu says he learned a “moral compass,” and he learned to take a historical approach. In biology, this means paying attention to evolution. “Anything that we discover in biology today, evolution has already figured out, and 100 times more,” he says. 

“It also means recognizing, as scientists rarely do, that history doesn’t end with us,” Vishu adds. In the early 2000s, scientists were proclaiming the human genome as the be all and end all of medical knowledge. In fact, as they soon discovered, the genome is only the beginning. You can’t understand anything in a cell without proteomics—the study of how proteins change their shapes to perform various tasks. And Lingappa has gone a step beyond that. While most biologists focus on individual proteins, he studies groups of proteins. Where most scientists try to simplify, Vishu complicates, not for the sake of complication but to follow the golden thread laid down by evolution.

After Swarthmore, Vishu joined the laboratory of a future Nobel Prize-winner, Günter Blobel, at Rockefeller University. There he learned Blobel’s technique of “functional reconstitution of protein biogenesis in cell-free systems.” That mouthful of words means simply recreating in a test tube the hard-to-decipher events that occur in the crowded interior of a cell. In a living cell, many processes happen too fast for scientists to see, as if powered by jet fuel. The same reactions happen more slowly and inefficiently in a test tube, as if they are powered by a sputtering kerosene lamp. This inefficiency is actually a boon for the researcher. The ability to slow reactions down and observe the intermediate steps helped Vishu discover the multiprotein complexes that lie at the heart of his current research.

Listening to Little Sister

Until the 1990s, the main influences on Vishu’s career were older people: his parents, Schuldenfrei, Bradley, Savage, Blobel. But there was one more piece that still had yet to fall into place, and it came from his younger sister. 

Jaisri had followed in Vishu’s footsteps to a great degree—going to Swarthmore, taking classes with Schuldenfrei, Bradley, and Savage, working in Blobel’s lab next to Vishu, and learning the power of cell-free systems. But she didn’t plan to follow him into cell biology. She intended to go into neurology instead. Then, in 1987, she had a life-changing experience of her own. She moved to San Francisco and found herself at the epicenter of the AIDS epidemic.

“I spent the first half of my internship giving out death sentences,” she says. That’s what AIDS was back then: a 100 percent fatal disease for which no treatment was known. But halfway through her internship, a new drug came out—AZT—and changed the whole equation. “Suddenly people were surviving,” she says. “There was hope and a sense of what science can do.” Her plans went out the window. Now Jaisri wanted to understand how HIV worked.

She zeroed in on one particular part of HIV’s life cycle. Like any virus, HIV consists of RNA (its genetic code) enclosed within a protective shell, called a capsid. The capsid is assembled from a single type of protein—2,000 or so bricks assembled into a sphere. But what does the assembling? According to conventional wisdom, backed up by experiments, the process is spontaneous: Get enough copies of the protein and the RNA together, and the virus will self-assemble with no additional input of energy.

To Jaisri, this idea of spontaneous generation didn’t sound right. Maybe it could happen in the artificial setting of a recombinant DNA lab but not in a real cell. The inside of a cell is a fantastically busy place—think of Grand Central Station or the streets of Mumbai. How can 2,000 copies of a protein find one another within this chaotic environment? 

Surely, she thought, they needed help from the cell itself. To prove it, she showed that a reduction in the cell’s fuel supply (called ATP) would slow the process down. The experiments used cell-free systems, where the reactions were already slow in the first place. Her apprenticeship in Vishu’s lab was already paying dividends.

At first no one believed her idea that capsid assembly in the cell was not spontaneous, except Vishu. Even Jaisri wasn’t entirely sure. The first few experiments gave negative or ever- so-slightly positive results, the kind that leave a researcher wondering if she is chasing a will-o’-the-wisp. But Vishu was always 10 steps ahead of her. “I could bring him data, and he would make me see it in a completely different way,” she says. She learned that negative data doesn’t necessarily mean the effect isn’t there: You just have to ask the question a different way. It was the same lesson she had learned at Swarthmore, from Savage’s biology courses.

Even after she had established to her satisfaction that the virus tapped into the cell’s fuel supply, “she had a really hard time publishing it,” says Mike McCune, a professor at UCSF who is on Prosetta’s board of directors. “Now it’s accepted, but at the time, some of the giants of the field didn’t accept it.”

One reason Vishu welcomed her idea was that it fit right into his own hypotheses, which are still controversial. He introduced a concept known as “protein bioconformatics,” which says that the same protein can do different things, depending on what shape it assumes. An important corollary of this idea is that what are currently called “misfolded” proteins may actually represent (or have represented in the evolutionary past) alternatively folded forms with different functions.

In the Lingappa model as applied to virology, the virus pulls together what Vishu calls “assembly machines” and what the rest of the profession calls “RNA granules.” These are complex sets of proteins that the cell temporarily uses to build its own structures. Think of auto parts lying around a garage, which the cell puts together to make an engine. Now think of the process gone horribly awry. The virus enters the cell and combines these parts in a way they were never intended to go. It turns the cell’s assembly machine into a misshapen creature—call it a Transformer—that is, nevertheless, very good at doing what the virus wants it to (finding viral proteins and chaperoning them into a capsid). When the job is finished, the virus releases the pieces of the Transformer back into the cell, and nobody can tell the Transformer was ever there.

In the slowed-down world of the test tube, the Lingappas have seen this process. They have seen the partially assembled capsids and the Transformers and shown that they consume the cell’s fuel.

Finding the latchkey

Why does it matter that capsid assembly is energy-dependent and chaperone-dependent? It means that if you can create a drug that latches on to the Transformer during the brief period when it is active, you can stop the viral assembly in its tracks. The drug won’t have side effects on healthy cells, because when the assembly machines are in their normal (non-Transformer) shape the drug won’t bind to them. And the virus won’t develop resistance because, unlike every other antiviral drug ever developed, it doesn’t attack the virus. It only latches onto the cell’s own proteins and prevents their misuse by the virus. The virus simply can’t use the cell’s machinery for its own nefarious ends—like a bank robber who can’t find a teller.

Prosetta is now in hot pursuit of drugs that will bind to the aberrant assembly machines. It’s not easy, because they are so fragile, but “Vishu has figured out how to isolate them in a test tube so that they’re stable and druggable,” McCune says. 

Last year Vishu and several colleagues (including Vishu’s daughter Usha and Jaisri) published an article in the Proceedings of the National Academy of Sciences about a drug active against the rabies virus that he hopes to have ready for clinical trials in about a year. This wasn’t headline news, because rabies vaccines already exist and are very effective. But maybe it should have been headline news. Rabies is the most lethal virus known, with essentially a 100 percent fatality rate.

“It makes Ebola look like a walk in the park,” Vishu says. Though it may seem like a thing of the past, rabies kills more than 50,000 people a year—and probably a lot more, because most of the victims live in poor societies with inadequate disease-reporting systems. Prosetta’s drug could be the first one to treat rabies after symptoms start.

But the rabies drug is only the beginning. Perhaps the most exciting feature of the new drugs is their versatility. For example, one drug can target all flaviviruses—a family that includes dengue, yellow fever, West Nile virus, and hepatitis C. Contrast this with the limited repertoire of conventional antivirals such as Tamiflu, and you begin to understand why Vishu expects to reshape the pharmaceuticals business. It’s the lesson of evolution again. Viruses can easily make small changes to develop resistance to a drug. But mutating into a whole new viral family is highly implausible. “I’m not expecting them to develop resistance in my lifetime or my kids’ lifetimes,” he says.

Science and Service

When Vishu told his colleagues in 2002 that he was resigning his academic position at UCSF to start a company, they were incredulous. But it was important for him not to have a fallback position. “I was prepared to put it all at risk,” he says. And it turned out to be a smart move. “Savvy investors realize they’re investing in a person,” he explains. “If that person is willing to put it all on the line, they’re either crazy, or they’re a good bet. The big question for the investor is whether they’re crazy or not.”

So far Vishu has done a pretty good job of convincing people that he’s sane. Prosetta’s seed money has come from wealthy donors, and this year for the first time he took his case to institutional investors. That’s a sign that the financial community is starting to see the company as a less speculative venture.

Yet the money is only the means, not the end. Deep in his heart, the idealist endures. In the early 1980s, Vishu wrote, “Science in a capitalist society is a reflection of capitalism itself—shackled by the same fetters on creativity and justice that burden society as a whole.” He still stands by those words. He dreams of equality and justice, especially for those who don’t have access to health care. He hasn’t forgotten the rickshaw driver in India or the 50,000 victims of rabies. But his methods have changed. He has started a nonprofit foundation and funded it with Prosetta stock. Someday, if Prosetta has been successful, he plans to dedicate those resources to combat the inequities in our society, starting with health care.

“The whole Lingappa family has always been committed to two passions, science and service,” says McCune. “That’s why I wanted to join Prosetta. It’s so different from the other biotechnology companies. Vishu isn’t interested in making money. He is interested in making people healthy.”