Hopkins Medicine Magazine - go home
Current Issue Past Issues Talk to Us About the Magazine Search
an online version of the magazine Fall 2007
Features
Desert Bloom, illustration by Stephanie Dalton Cowan
 
  Akhilesh Pandey’s quest to pin down the entire human proteome knows no bounds. Then there’s the money thing.

BY RAMSEY FLYNN
PHOTOS BY MIKE CIESIELSKI
 
 
 
 

His office here is comically unadorned. It’s one of the standard 10-by-12 units rimming the research building’s fifth floor, blessed with a view onto East Monument Street that this globetrotting researcher couldn’t care less about. A bulletin board leans against a spare chair. Two printers lie at odd angles on the floor, dusty. The only visual clue to a regular human presence is the black guitar case tucked into a far corner.

“One of my failed experiments,” says Akhilesh Pandey, suddenly breaking into a high-pitched laugh amplified by the metallic filing cabinets that flank his spartan computer desk.

Say what you will about his manically unquenchable vision, but this is a man who can laugh at himself. This is a good thing in that Pandey—modest workspace aside—is possessed by a gigantic idea. He has challenged himself to take the lead in collecting and enhancing all of the world’s far-flung information about human proteins into one iron-clad database, with each entry judiciously annotated by expert biologists—all of it accessible to anyone in the world at the click of a mouse.

It’s a mission vastly more daunting than the once unthinkable mapping of the human genome, but it’s also widely regarded by top scientists as the most worthy of next big frontiers. Genes code for proteins, but those proteins—the dynamic machines responsible for tissue function or malfunction—remain tantalizingly under-charted, untapped when it comes to advancing the human condition.

While humans possess about 25,000 genes (just over a third more than those for the simple roundworm), scientists now believe that each human gene can express hundreds of different proteins over time. This suggests the human proteome is composed of millions of individual proteins, many of which interact with each other in complex systems in nearly constant motion. This makes proteins moving targets, often compelling their pursuers to visualize them as if with movie cameras.

Many of the world’s most elite scientists are now lusting for the full proteomic road map. They know the human proteome is bursting with coveted biomarkers for cancers, cardiac abnormalities, brain disorders, and other problems that can affect most every tissue in the human organism. If scientists can know the proteome intimately, many believe, they can detect, predict, and disrupt an untold number of human disorders.

Clearly, someone has to chase each protein down and define it with authority, so why not this hyperkinetic 41-year-old Brahmin from India?

When Pandey first started chatting up his grand idea among scientist friends back in 2001, his advisers thought it too absurdly ambitious. It appeared to require a dedicated squadron of pricey researchers armed with a deep knowledge of exquisitely sensitive protein-scanning mass spectrometers and so little professional ego that no rising Western scientists in their right minds would conceivably join him. A government might have to fund it, but the cash-strapped NIH had become increasingly shy about major new projects. And private investors? They barely understood the genome project in its early days; why would they invest in a ballyhooed “next frontier,” with no demonstrable financial return?

“Fair enough,” said Pandey, who’d established a lifelong skill at finding his way around seemingly impossible obstacles.

And so Pandey took matters into his own hands. He broke out his personal Visa card in May 2002 and leased 2,000 square feet of prime office space for a low price back in Bangalore. For his scientists, he tapped another credit card to fund a line of salaries, again exploiting the modest costs required by young scientists in India. Then he needed high-capacity computer equipment, which required more credit cards. His credit lines soon extended to the max on seven different cards, at up to $20,000 each. His family and friends became worried sick. They didn’t understand what Akhilesh was up to, but they knew he was devilishly smart. As his pie-in-the-sky idea briefly teetered near the breaking point in 2005—deepening to $200,000 in debt with no compelling income plan in place—Akhilesh’s businessman brother, Ajay, extended his own credit cards to the older brother he so deeply admired. This put Ajay in for $50,000.

Today, Pandey is the founder and director of a 40-person enterprise based in Bangalore (and partly operated from his Hopkins office in Baltimore) that has quietly carved out a niche for building the most credible online archive of carefully annotated protein data available—plumbing the intricacies of over 20,000 human proteins and drawing nearly 1 million hits every month—and it’s all still free at the click of a mouse. It’s called the Institute of Bioinformatics (IOB), and it produces a database called the Human Protein Reference Database. The rapid emergence of this Hopkins affiliate has put Pandey on the hook for more than $350,000 in annual salaries and leasing costs.

As Pandey energetically shuttles back and forth between Bangalore and his 10-person proteomics wet lab here at Hopkins’ Institute of Genetic Medicine—where he collaborates with other departments in searching out biomarkers for pancreatic and breast cancers—one has to wonder: What is Pandey’s plan for paying off those screaming credit cards once and for all?

 

*****

 

 

HIS FRIENDS AND FAMILY MEMBERS think Akhilesh Pandey has always needed to change the world. His brother says the drive was innate but further magnified by their upbringing in a military family where self-discipline and skill

1 1 1
youth magazine
Out of India: Proteomics visionary Akhilesh Pandey emerged from military brat to global research through a circuitous route. His rise to prominence started after a national youth magazine hailed his rise to India’s top academic standing at 15.
were the two things a young man could control amid constantly changing schools and regular uprootings. Their father was a career lawyer in the Indian Air Force who demanded that all three younger Pandeys exhibit “officer-like qualities,” which Ajay says meant to be “large in thinking” and to show leadership in all pursuits.

Despite his willingness to challenge his father’s wisdom on certain habits—such as the senior Pandey’s parsimonious ways—Akhilesh nevertheless thrived on his father’s call to large thinking: He drove himself to the top spot on entrance exams for India’s elite National Defense Academy. The feat landed Akhilesh on the cover of an Indian youth magazine when he was just 15, which served as advance billing for his arrival at the military’s medical school in Pune two years later. In 1984, some 45,000 aspiring candidates from all across India applied for the school’s 156 slots. One went to Pandey just for the asking; his entry scores were that strong.

Medical school classmate Arun Malhotra recalls how Pandey displayed a natural desire to question the received cultural wisdom. When Pandey was tasked with representing his class’s dining interests, he proposed upgrades for meal offerings, assigning the cadets themselves to gather the freshest meats, vegetables, fruits, and spices at local markets.

“He made it a cooperative,” says Malhotra. “He changed the whole damn system.” The change boosted quality and cut costs by half, says Malhotra, but the entrenched cafeteria food-buyers didn’t welcome the loss of income. Several of them roughed up Pandey, locking him into his dorm room in an attempt to get him to back down. The young rebel refused to submit.

“It was a mini-test of character,” recalls classmate Vasanth Kumar.

Pandey considered such small rebellions a form of patriotism. He believed in India’s military culture but also felt honor-bound to keep raising its standards. He saw a life in military medicine as selflessly anti-profit. He liked the idea that he’d have fixed hours, providing equal and affordable care to all comers. He spoke of such virtues with a messianic zeal.

Then came the switch. It began in the third year of medical school as Pandey and several dorm mates talked about their ideal military career paths. Suddenly, Pandey leaped into the “large thinking” so ingrained by his father. Clinical medicine sounded boring to him now. Where was the excitement in applying the things they’d learned by rote? How could they improve medicine? Pandey wanted to blaze new trails in medical science. Didn’t the Indian Army have a medical research wing he could join?

The dorm mates looked flummoxed. “That’s not going to happen,” said Malhotra, who came from a long line of Indian Army generals

1 1 1
Heart
During his time as a medical student at an armed forces medical school outside of Pune, Pandey sometimes took rides with classmates atop passenger trains.

“If you want to do that sort of work, you’ll have to go somewhere else.”

Pandey was taken aback. But before the week was out, he was making new life plans. His dorm mates were right. He needed to leave the Army, and fast. That meant he needed to break the 20-year contract he’d signed with the Army at 17, which would cost a bundle of money that his family didn’t have. He first shared the breakaway plan with his mother, then a high school principal, enjoining her to soften up dad. His father had finally made retirement, which came with the traditional reward of a house and car. Now the younger Pandey eyed the gleaming new Suzuki family sedan with an entirely different purpose: to help pay his ticket west.

 

Heart
The Pandey family’s Suzuki sedan, above, was sold to buy out the younger Akhilesh’s military contract for a future in medical research.

 

*****

 

 

ONCE FIRMLY PLANTED IN THE U.S. IN AUGUST 1990 at the age of 23, Pandey seized upon American medical education like a man possessed. He found his way into a doctoral program in the laboratory of Vishva Dixit at the University of Michigan, then into a clinical pathology residency at

1 1 1
Heart
A young Pandey outside the medical school graduation building.
Harvard’s Brigham and Women’s Hospital, then to the lab of Harvey Lodish at MIT’s Whitehead Institute for Biomedical Research for post-doctoral training.

By 2000, Pandey was eager to begin doing something with all of this knowledge. At the time, the Human Genome Project was closing in on a rough draft of a single individual’s genomic sequence, with two primary groups of scientists now racing to define the foundational blueprint of human life. But Pandey and his advisers peered into the early results and began to wonder. All agreed that knowing the entire human genome was an undeniably magnificent thing. It gave modern scientists tremendous insights into new ways to identify harmful mutations, or to harness codes that could improve the human condition. But what about the layer of human factors below all that? What about the tissues for which those strings of Gs, Cs, As, and Ts provided marching orders?

Scientists knew the DNA dictated the basic course of proteins, but they also knew the myriad forms of proteins were only thinly understood. Some scientists specialized in divining the inner workings of these endlessly adumbrating micro-structures, but only a handful had the instinct for taking a step back from their microscopes and leaping off into large thinking, the big picture.

Pandey wanted to know the emerging next field from the ground up. He turned his sights across the Atlantic, joining the lab of Matthias Mann at the University of Denmark for a three-year plunge into a field of study that had only recently been given a name. If the study of genes was called genomics, then the complementary study of proteins should echo the field from which it stemmed: proteomics.

Since its emergence as a field unto itself in the late 1990s, “proteomics” has generally come to mean the study of proteins coded by genes. And, in the same way that all of the genes in a single organism came to be known as its “genome,” all proteins comprising a single organism are known as its “proteome.”

As Pandey probed ever deeper into the rapidly expanding field, he became frustrated over how all of its published data seemed so scattered. Shouldn’t there be a master reference, a field guide? He was certainly aware of how one visionary scientist from a previous generation had summoned the conviction to gather the most authoritative data about genetics into a tome known widely as Mendelian Inheritance in Man. That scientist was a larger-than-life figure who’d established his career in Baltimore: Victor A. McKusick.

McKusick first printed his catalog in 1966 and kept it constantly updated. With a growing team of associates assisting in the endeavor, the catalog eventually migrated to the Internet under the editorship of scientists at the McKusick-Nathans Institute of Genetic Medicine at Johns Hopkins. In 2002, Akhilesh Pandey looked back across the Atlantic. He was impressed that McKusick was still in business, still participating in the care and feeding of his baby, now surrounded by a top-flight community of deeply engaged scientists. Pandey wanted in.

 

*****

 

 

THE MCKUSICK-NATHANS INSTITUTE GENETIC Medicine liked the idea of linking up with Pandey’s quest to extend genetics to its next level, offering him a faculty appointment even before his time was up in Denmark.

1 1 1
Heart
The staff at Pandey’s Institute of Bioinformatics, arrayed outside the building in a Bangalore technical park that shelters the operation’s headquarters.
In his emerging bid to establish himself as a new leader in proteomics’ vanguard, Pandey’s new appointment gave him needed traction. Soon after his 2002 launch of the IOB in Bangalore, the newly minted Hopkins professor won $1 million grants from the NIH two years in a row. Hopkins added another $100,000 earmarked just for the IOB, and key disease categories expressed interest in paid consultations by Pandey’s IOB team and his 10-person proteomics wet lab here at the Institute of Genetic Medicine. Developers of the latest costly technology in mass spectrometers cut deals in exchange for the team’s data-rich feedback.

But even with his Baltimore-Bangalore combination, Pandey’s small army has been mapping the human proteome largely in obscurity. That’s partly, he says, because much of the world does not yet understand the work’s import. “We are the underground underdogs,” he smiles.

“Underdogs” is an apt descriptor. Other groups have also joined the chase in recent years—including private firms like Myriad Proteomics, a Utah-based enterprise that enjoyed the deep financial support of partners like Hitachi Ltd. and the Oracle Corporation. When they first got together in 2001, the group planned to put up to half a billion dollars behind the effort, with the intent of harvesting the new frontier for drug discovery. In short order, Myriad learned there was little commercial demand for their information, so they reconstituted themselves as the very sort of drug discovery firm they’d once targeted as clients.

But it’s not like some of the world’s most accomplished scientists don’t want the information that Pandey and his friends are so happy to provide. The best researchers are eating it up. One of Pandey’s most satisfied customers is Jef Boeke, who directs the High-Throughput Lab at the Institute for Basic Biomedical Sciences here.

Boeke’s primary interest is in yeast, which shares a number of proteins with the human proteome and serves as a simple model for many human disease mechanisms. Boeke can get protein data from other providers, he says, but it’s not always free. And those providers also don’t annotate the data, or even inspect its accuracy after it’s culled from protein-related research papers by automated computer software programs. Boeke says he and his colleagues like Pandey’s information for its human touch, the palpable intelligence so readily apparent in the entries’ footnotes.

When his group draws from Pandey’s database, says Boeke, they can track the data’s original sources and proceed on the confidence that the formulas have been procured and codified by biologists.  

“Genomic and protein data are exploding,” says Boeke, whose lab’s appetite for definitive information sometimes surges ahead of the databases that purport to hold it all. None of which argues against the transcendent value of Pandey’s mission. Senior scientists here know it’s got to be done, and they hope Pandey can pull off the feat. “I think it will become a basic tool just like the genome database,” says Hopkins’ Bert Vogelstein, the most cited scientist in modern research papers. “We know a lot about the DNA. We know a lot about the RNA. There’s still hardly anything about the protein constituents itself, so that’s where the action lies.”

“I think Akhilesh has done a phenomenal thing,” says Hopkins research vice dean Chi Dang. He predicts that new insights into the human proteome will catapult scientists beyond the narrow view offered through their microscopes and into an entirely new bioscape of ever-changing protein relationships—all ripe with untold bounty for improving human health.

“The trouble,” says Dang, is that Pandey must find an enduring source of money—one that “can fund his staff into perpetuity.”

 

*****

 

 

FOR HIS MORNING LAB MEETING on an October Monday at Hopkins,

1 1 1
Heart
Current members of The Pandey Lab recently assembled around their director at Hopkins. Clockwise from left: Students Dhanashree Kelkar, Sutopa Dwivedi, Arivusudar Marimuthu, Min-Sik Kim, Kumaran Kandasamy, Manoj Kashyap, Jun Zhong and postdoctoral fellows Raghothama Chaerkady and Yi Yang.
Akhilesh Pandey takes his place at the head of the conference room table clad in a black mock turtleneck. His team is an entirely foreign-born blend of Asian and Indian scientists, nearly all of whom have relationships with the IOB facility 12 time zones away. Several are IOB staffers pursuing their doctorates here. A few are full-time Hopkins lab scientists investigating questions about the proteomic bases for breast cancer and pancreatic diseases—the data from which also funnels back into the IOB’s database.

Today’s presentation centers on Pandey’s latest toy for probing the human proteome—a half-million-dollar mass spectrometer just installed in Bangalore that outclasses even the best equipment that Pandey’s lab has at Hopkins. Mass spectrometers have emerged as Pandey’s preferred technology, allowing him and his teammates to atomize proteins into their finest particles and display their compositions on charts for analysis. The new unit in Bangalore was a glorious acquisition, but its debut was inauspicious: While its on-site engineering consultant was distracted, the device exploded. A heavy metal tube shot into the roof.

“He made a rookie mistake,” Pandey tells his gathered lab group. While the engineer was chatting with an IOB staffer, says Pandey, “compressed nitrogen gas continued to be injected until it became a projectile.”

But all was not lost. With smartly applied glue, the system was restored to functionality. And in the hands of Pandey’s team, it tapped into a rich new level of proteomic data that the gathered scientists had never seen before. With the spectrometer’s delicate settings manually adjusted to explore low-level tracings previously deemed “noise,” illuminating new patterns emerged. Captured in Bangalore and now rendered in slides displayed on a conference room screen in East Baltimore, the once-buried treasure elicits oohs and ahs around the table. “Yes,” coos Pandey, “this is two times higher resolution. The peptide was always there. All the excitement is at the level of the software, really,” he explains. “It allows you to do new tricks.”

Pandey breaks into a broad smile and chuckles at the irony that increasingly surrounds him. With one foot in his old country and another in the new, he’s getting the best of both worlds. Here in East Baltimore, he and his teammates are surrounded by the ultimate in scientific research collaborators, armed with state-of-the-art wet labs that pursue proteomics’ most basic questions: Which proteins herald the coming of heart failure? Which the risks of breast cancer? While in Bangalore, they’ve got the ultimate mass spectrometer for refining their view into the human proteome’s deeper secrets, and it’s all enhanced by 40 biochemical specialists there whose modest salaries allow him to contain his costs below those of his Western-based rivals.

But even as he smiles, Pandey knows he must further harness this high-stakes balancing act beyond mere irony. His hungry IOB project needs its own sources of revenue to stay alive. The group’s regular consulting contracts are shrinking, and the baby is lately looking thin. As the pressures close in on all fronts, Pandey has been courting suitors east and west.

In his hunt for angels, Pandey doesn’t bank exclusively on government funders. Though his IOB refuses to charge a fee to everyday scientific users of his protein database, his need for survival has introduced a threshold when it comes to commercial users. In a prominent note on the Human Protein Reference Database’s home page, Pandey requests that its commercial users contact him.

That new gambit has already begun to work. The national Breast Cancer Research Program, for instance, knows proteomics holds answers to the tumors that plague millions worldwide. Through the aid of breast cancer researcher Nancy Davidson here, a deal was struck with Pandey’s team of scientists to focus on their targeted constellation of proteins, along with an authoritative interpretation of what makes those proteins behave the way they do, and how to make them behave otherwise. The results of that collaboration, says Pandey, are being finalized for submission to Nature Genetics. “The breast cancer database is almost wrapped up,” he smiles, “and the world doesn’t even know about it yet.”

The IOB’s consulting fee was $100,000, says Pandey. Given what the cause wins in return, that seems like a small contribution to the IOB’s team of scientists, whose salary needs are only about a third of those in the U.S. But Pandey says Davidson’s group was also happy to accommodate the IOB’s additional request. After the study is published, the breast cancer group—as with any other private interest enjoined in a partnership with the IOB—agrees that all of its relevant proteomic data will be entered into the worldwide database for all the world to share.

The breast cancer findings, he explains, provide insights into mechanisms that researchers can soon use to advance their fight. They will have a new set of proteomic biomarkers to identify the presence of the disease in advance of traditional imaging and biopsies. And further, asserts Pandey, they will be able to identify particular expressions of the disease that will allow future oncologists to sharpen their therapeutic targeting.

The deeper knowledge is expected to arm scientists with new approaches for individualized medicine, enabling them to learn more precisely why some patients respond perfectly to one medicine while it does little or nothing for others. It comes down to the character of their inherited proteins.

In Pandey’s lab here, research associate Harsha Gowda also heralds the team’s growing insights into one of mankind’s most unforgiving cancers, those that afflict the pancreas. He and his colleagues have introduced pancreatic cancer into mice. When they inject all of the mice with one cancer-fighting agent, they can see that 90 percent of them have no response, but 10 percent show a dramatic remission. The group is convinced the difference lies in the mechanics of a particular molecule, a protein. “So who responds to what and how do we separate them?” asks Gowda. The process of dividing and conquering could also prompt the development of a new agent against pancreatic cancer, an agent that precisely targets the mystery proteins at the source of a chronically elusive monster.

Similar advances are unfolding in other proteomics labs around the world, including one remarkable discovery just published by the lab of Jennifer Van Eyk, who directs the Johns Hopkins NHLBI Proteomics Center [see below]. From her lab on the Bayview campus, Van Eyk and her team hope to identify key proteomic biomarkers that signal the likelihood of a coming heart attack, long before it strikes. The biomarkers could be identified in a simple blood test.

 

*****

 

 

IT'S ALL QUITE EXCITING, OF COURSE, but Akhilesh Pandey remains deeply in touch with his risk. “I always tell people that the IOB is headed for a wall,” he says. “I tell them ‘we’re going to crash.’” Yet he never seems to stop smiling. “Sometimes the wall just moves,” he says. “Money comes in.”

1 1 1
Heart
Ensconced in his wet lab at Hopkins, Pandey also presides over trench-level discoveries that will add to his global database. At left is postdoctoral fellow Yi Yang; at right is mass spectrometer specialist Raghothama Chaerkady.
Pandey’s wall saw a seismic shift in late November, when he received word that an up-and-coming group of institutes in India was warming to his frequent advances. They had some money looking for a place to go. Could he catch a quick flight to Bangalore by the end of the week?

Within hours of his setting foot on the tarmac at an airport in his resurgent ancestral country—whose tribal elders once scolded him for abandoning his Indian military career for a life in Western research—Akhilesh Pandey was suddenly on the receiving end of a series of overtures for which he had been almost afraid to dream about. The most precious: a $2 million government grant to be sprinkled over five years to identify biomarkers for diseases that disproportionately afflict the Indian population—tuberculosis and stroke. It will fund their acquisition of the world’s most powerful mass spectrometer, the development of a high end computational infrastructure, and another 10 positions at the IOB.

The package appears to support Pandey’s expressed wish to maintain the East-West balancing act that he considers so central to the strength of his grander quest. “It will be hard for us to say who’s benefiting from whom,” he says.

But amid the hurried discussions, the overtures at one point seemed to threaten the balance. One senior official asked Pandey to consider the top job at a prestigious Indian scientific institute, to become a larger figure who could draw even more scientific capital to the Indian portfolio. Pandey demurred. He explained that he has no appetite for scaling the administrative heights. The IOB’s global presence is his baby, he said. He can’t abandon it now.

Pandey pauses in sharing the story, almost self-consciously. “This thing is so near and dear to me,” he says. “It has meant everything to me.” *

 

 

Heart
When he’s not steeped in proteomics or tending to his wife and two baby daughters, Pandey indulges a passion for aerobatics.

 

 


Proteins and the Telltale Heart
How a brave new field is delivering for cardiac care

 

Proteomics is so rich with new discoveries that it’s setting off alarms in

1 1 1
Heart
 
Jennifer Van Eyk’s lab. About once every month in her Hopkins shop of 23 scientists, a ship’s bell sounds, signaling an exciting new find worthy of sharing with colleagues.

“That bell goes off a lot,” says Van Eyk, who directs the 40-plus proteomics projects—most of them heart-related—now under way at Hopkins’ Bayview campus. “It’s a way to tell the lab to gather round,” she explains, to recognize any proteomics advance. “It could be the first time you discover a new protein, the first time you figure out that your protein is modified, it doesn’t matter. We all just come running to celebrate the discoveries that we’ve made.”

In November, Van Eyk’s bell marked the promise of new early warning signs for heart attacks. If the early findings, described at a conference in New Orleans, play out in ongoing trials, she hopes, future ER physicians will use a simple blood test to learn more precisely which chest pains warrant intervention.

Most emergency workers responding to a patient with cardiac symptoms know to test for a telltale protein, an element of triponin. But the presence of that complex protein only confirms that cardiac damage has already occurred.

Van Eyk’s team believes the science of proteomics can detect impending damage and intercept it before it can harm the patient. Her group has identified a cluster of five proteins that, when found at certain levels, indicate the advanced stage of ischemia that can graduate to a deadly stage if left unchecked. The team, which collaborates with clinical partners around the world, has even assigned names to their new biomarkers, all of which were found to spike in patients with dangerously narrowed blood vessels: lumican, semenogelin, angiogenin, extracellular matrix protein, and so-called long palate—lung and nasal epithelium carcinoma-associated protein 1.

A positive reading on the blood test could tell physicians to urgently deploy blood thinners or cardiac catheterization before the distressed vessels close off completely. Such an early-warning system could save tens of thousands annually in the U.S. alone, she says.

Van Eyk’s group sometimes collaborates with Akhilesh Pandey’s lab, she says, and it also contributes to the growing proteomic archives at Pandey’s Institute of Bioinformatics. The chief difference between the two groups, she explains, is that hers is more exclusively focused on the study of protein properties themselves. “Our expertise is on the front end,” she says. “We’re driven by clinical questions.” —RF

 
 
 
 
Features
 Thinking Large
 A Place to Come Back to
 Sweet Relief
 
Departments
 Circling the Dome
 Medical Rounds
 Annals of Hopkins
 
Class Notes
 Where Are They Now?
 
Opinions
 Learning Curve
 Post-Op
 
Johns Hopkins Medicine

© The Johns Hopkins University 2009