It wasn't Folkman's triumph that Bahcall kept coming back to, however. It was his struggle. Folkman's great insight at the Naval Medical Center occurred in 1960. O'Reilly's breakthrough experiment occurred in 1994. In the intervening years, Folkman's work was dismissed and attacked and confronted with every obstacle.
At times Bahcall tried to convince himself that elesclomol's path might be different. Synta had those exciting Phase 2 results and the endorsement of the Glaxo deal. "For the results not to be real, you'd have to believe that it was just a statistical fluke that the patients who got drugs are getting better," Bahcall said, in one of those dining-room-table moments. "You'd have to believe that the fact that there were more responses in the treatment group was also a statistical fluke, along with the fact that we've seen these signs of activity in Phase 1, and the fact that the underlying biology strongly says that we have an extremely active anticancer agent."
But then he would remember Folkman. Angiostatin and a companion agent also identified by Folkman's laboratory, endostatin, were licensed by a biotech company called EntreMed. And EntreMed never made a dime off either drug. The two drugs failed to show any clinical effects in both Phase 1 and Phase 2. Avastin was a completely different anti-angiogenesis agent, discovered and developed by another team entirely and brought to market a decade after O'Reilly's experiment. What's more, Avastin's colorectal-cancer trial—the one that received a standing ovation at ASCO—was the drug's second round. A previous Phase 3 trial for breast cancer had been a crushing failure. Even Folkman's beautifully elaborated theory about angiogenesis may not fully explain the way Avastin works. In addition to cutting off the flow of blood vessels to the tumor, Avastin seems also to work by repairing some of the blood vessels feeding the tumor, so that the drugs administered in combination with Avastin can get to the tumor more efficiently.
Bahcall followed the fortunes of other biotech companies the way a teenage boy follows baseball statistics, and he knew that nothing ever went smoothly. He could list, one by one, all the breakthrough drugs that had failed their first Phase 3 or had failed multiple Phase 2s or that turned out not to work the way they were supposed to work. In the world of serendipity and of trial and error, failure was a condition of discovery, because, when something was new and worked in ways that no one quite understood, every bit of knowledge had to be learned, one experiment at a time. You ended up with VAMP, which worked, but only after you compared daily 6-MP and daily methotrexate with daily 6-MP and methotrexate every four days, and so on, through a great many iterations, none of which worked very well at all. You had results that looked "boinking good," but only after a trial with a hundred compromises.
Chen had the same combination of realism and idealism that Bahcall did. He was the in-house skeptic at Synta. He was the one who worried the most about the hand shaking of the drugs in the SYMMETRY trial. He had never been comfortable with the big push behind melanoma. "Everyone at Dana-Farber"—the cancer hospital at Harvard—"told me, 'Don't touch melanoma,'" Chen said. "'It is so hard. Maybe you save it as the last, after you have already treated and tried everything else.'" The scientists at Synta were getting better and better at understanding just what it was that elesclomol did when it confronted a cancer cell. But he knew that there was always a gap between what could be learned in the laboratory and what happened in the clinic. "We just don't know what happens in vivo," he said. "That's why drug development is still so hard and so expensive, because the human body is such a black box. We are totally shooting in the dark." He shrugged. "You have to have good science, sure. But once you shoot the drug in humans you go home and pray."
Chen was sitting in the room at Synta where Eric Jacobson had revealed the "boinking good" news about elesclomol's Phase 2 melanoma study. Down the hall was a huge walk-in freezer, filled with thousands of chemicals from the Russian haul. In another room was the Rube Goldberg drug-screening machine, bought with Milken's money. Chen began to talk about elesclomol's earliest days, when he was still scavenging through the libraries of chemical companies for leads and Bahcall was still an ex-physicist looking to start a biotech company. "I could not convince anyone that elesclomol had potential," Chen went on. "Everyone around me tried to stop it, including my research partner, who is a Nobel laureate. He just hated it." At one point Chen was working with Fujifilm. The people there hated elesclomol. He worked for a while for the Japanese chemical company Shionogi. The Japanese hated it. "But you know who I found who believed in it?" Chen's eyes lit up: "Safi!"
Last year, on February 25, Bahcall and Chen were at a Synta board meeting in midtown Manhattan. It was five-thirty in the afternoon. As the meeting was breaking up, Bahcall got a call on his cell phone. "I have to take this," he said to Chen. He ducked into a nearby conference room, and Chen waited for him with the company's chairman, Keith Gollust. Fifteen minutes passed, then twenty. "I tell Keith it must be the data-monitoring committee," Chen recalls. "He says, 'No way. Too soon. How could the DMC have any news just yet?' I said, 'It has to be.' So he stays with me and we wait. Another twenty minutes. Finally Safi comes out, and I looked at him and I knew. He didn't have to say anything. It was the color of his face."
The call had been from Eric Jacobson. He had just come back from Florida, where he had met with the DMC on the SYMMETRY trial. The results of the trial had been unblinded. Jacobson had spent the last several days going over the data, trying to answer every question and double-check every conclusion. "I have some really bad news," he told Bahcall. The trial would have to be halted: more people were dying in the treatment arm than in the control arm. "It took me about a half hour to come out of primary shock," Bahcall said. "I didn't go home. I just grabbed my bag, got into a cab, went straight to LaGuardia, took the next flight to Logan, drove straight to the office. The chief medical officer, the clinical guys, statistical guys, operational team were all there, and we essentially spent the rest of the night, until about one or two in the morning, reviewing the data." It looked as if patients with high-LDH tumors were the problem: elesclomol seemed to fail them completely. It was heartbreaking. Glaxo, Bahcall knew, was certain to pull out of the deal. There would have to be many layoffs.
The next day Bahcall called a meeting of the management team. They met in the Synta conference room. "Eric has some news," Bahcall said. Jacobson stood up and began. But before he got very far he had to stop, because he was overcome with emotion, and soon everyone else in the room was, too.
On December 7, 2009, Synta released the following statement:
Synta Pharmaceuticals Corp. (NASDAQ: SNTA), a biopharmaceutical company focused on discovering, developing, and commercializing small molecule drugs to treat severe medical conditions, today announced the results of a study evaluating the activity of elesclomol against acute myeloid leukemia (AML) cell lines and primary leukemic blast cells from AML patients, presented at the Annual Meeting of the American Society of Hematology (ASH) in New Orleans...
"The experiments conducted at the University of Toronto showed elesclomol was highly active against AML cell lines and primary blast cells from AML patients at concentrations substantially lower than those already achieved in cancer patients in clinical trials," said Vojo Vukovic, M.D., Ph.D., Senior Vice President and Chief Medical Officer, Synta. "Of particular interest were the ex vivo studies of primary AML blast cells from patients recently treated at Toronto, where all 10 samples of leukemic cells responded to exposure to elesclomol. These results provide a strong rationale for further exploring the potential of elesclomol in AML, a disease with high medical need and limited options for patients."
"I will bet anything I have, with anybody, that this will be a drug one day," Chen said. It was January. The early AML results had just come in. Glaxo was a memory. "Now, maybe we are crazy, we are romantic. But this kind of characteristic you have to have if you want to be a drug hunter. You have to be optimistic, you have to have supreme confidence, because the odds are so incredibly against you. I am a scientist. I just hope tha
t I would be so romantic that I become deluded enough to keep hoping."
Cosmic Blueprint of Life
Andrew Grant
FROM Discover
IN THE LATEST scientific version of Genesis, life begins, paradoxically, with an act of destruction. After 10 billion years of guzzling the hydrogen in its core, a sun-size star runs out of nuclear fuel and becomes unstable. It goes through a series of convulsions and expels a shell of searing-hot atoms—including hydrogen, carbon, and oxygen. The star fizzles into an inert cinder, and its atoms drift off, seemingly lost in the interstellar gloom.
But next the story takes a surprise turn, from destruction to construction. Some of those rogue atoms float into a nearby gas cloud and stick to fine grains of dust there. Even at a frigid—440 degrees Fahrenheit, the atoms bump and crash into each other, merging to form simple molecules. Over millions of years, one relatively dense region of the cloud begins to collapse in on itself. An infant star takes shape at the center. In the surrounding areas, temperatures rise, molecules evaporate from their icy dust grains, and a new round of more intricate chemical reactions begins.
Then comes the most wondrous part of the whole tale. Those reactions weave the simple atoms of hydrogen, carbon, and oxygen into complex organic molecules. Such carbon-bearing compounds are the raw material for life—and they seem to emerge spontaneously, inexorably, in the enormous stretches between the stars. "The abundance of organics and their role in getting life started may make a big, big difference between a giant universe with a lot of life and one with very little," says Scott Sandford of NASA's Ames Research Center in Moffett Field, California, who studies organic molecules from space.
The notion that the underlying chemistry of life could have begun in the far reaches of space, long before our planet even existed, used to be controversial, even comical. No longer. Recent observations show that nebulas throughout our galaxy are bursting with prebiotic molecules. Laboratory simulations demonstrate how intricate molecular reactions can occur efficiently even under exceedingly cold, dry, near-vacuum conditions. Most persuasively, we know for sure that organic chemicals from space could have landed on Earth in the past—because they are doing so right now. Detailed analysis of a meteorite that landed in Australia reveals that it is chock-full of prebiotic molecules.
Similar meteorites and comets would have blanketed Earth with organic chemicals from the time it was born about 4.5 billion years ago until the era when life appeared, a few hundred million years later. Maybe this is how Earth became a living world. Maybe the same thing has happened in many other places as well. "The processes that made these materials and dumped them on our planet are universal. They should happen anywhere you make stars and planets," Sandford says.
The first persuasive hints of life's possible cosmic ancestry came in 1953, courtesy of a renowned experiment devised by chemists Stanley Miller and Harold Urey. From studies of ancient rocks, geologists had a rough sense of our planet's original chemical composition. Biologists, meanwhile, had uncovered the amazingly complex organic molecules that allow living cells to survive. Miller and Urey wanted to see if pure chemistry could help explain how the former transformed into the latter.
The two researchers prepared a closed system of glass flasks and tubes and injected a gaseous mixture of methane, ammonia, hydrogen, and water—four basic compounds thought to be abundant in Earth's primitive atmosphere. Then Miller and Urey applied an electric current to simulate the energy unleashed by lightning strikes. Within a week their concoction had produced several intriguing prebiotic compounds. Many scientists interpreted this as hard experimental evidence that the building blocks of life could have emerged on Earth from nonbiological reactions.
In many ways, though, the experiment supported the opposite view. Even the simplest life forms incorporate two amazingly complex types of organic molecules: proteins and nucleic acids. Proteins perform the basic tasks of metabolism. Nucleic acids (specifically RNA and DNA) encode genetic information and pass it along from one generation to the next. Although the Miller-Urey experiment produced amino acids, the fundamental units of proteins, it never came close to manufacturing nucleobases, the molecular building blocks of DNA and RNA. Furthermore, it is likely that Miller and Urey erred by simulating Earth's early atmosphere with gases containing hydrogen, which reacts easily, as opposed to carbon dioxide, a gas that is far less reactive but was probably far more plentiful at the time. "Interesting chemicals could not have been made as easily as the experiment made it seem," says the astrobiologist Douglas Whittet of Rensselaer Polytechnic Institute in upstate New York.
If life could not so easily have begun on Earth, a few voices argued, perhaps it originated from beyond. The most notable advocate of that hypothesis was the influential British cosmologist Fred Hoyle, who coined the term Big Bang. His 1957 science-fiction novel, The Black Cloud, envisioned a living, intelligent dust cloud in space; it foreshadowed his later support of panspermia, the theory that life evolves in space and spreads throughout the universe. Starting in the 1960s, Hoyle wrote a series of academic papers describing how bacterial cells could make their way from interstellar dust grains to comets and eventually down to planets like Earth.
Most of Hoyle's peers considered his ideas borderline delusional. Back then almost nobody thought prebiotic molecules, let alone entire microbes, could survive the harsh vacuum of space. "Everyone assumed space was too cold and too low-density to form molecules," says the National Radio Astronomy Observatory (NRAO) astrochemist Anthony Remijan, a leading expert in interstellar chemistry. "That assumption became 'fact' without any evidence behind it at all."
One of Remijan's mentors, the astronomer Lew Snyder, then at NRAO, dared to disagree. He did not share Hoyle's vision of bacteria hitching rides across the galaxy, but he thought that interesting molecules might subsist in the alleged desert of interstellar space. Snyder had a strategy for finding them, too. He knew that many chemical compounds are dipolar—they have a positively charged side and a negatively charged one—and that charged particles in motion release energy. If molecules were freely floating as gases, Snyder realized, some of them should spin like batons and create a faint radio-wave signal. Even better, each type of molecule should have its own unique energy signature: it should broadcast at a specific set of frequencies that could be detected and identified by astronomers using radio telescopes on Earth.
Starting in the mid-1960s, Snyder applied for observing time on the main radio telescopes, to no avail. The scientists in charge of the observatories agreed with the consensus view that space could not support complex chemistry. In December 1968 Snyder traveled to Austin, Texas, for a meeting of the American Astronomical Society, where he and a colleague, David Buhl, hoped to change some minds. At the end of their talk, the famed physicist Charles Townes (who won a Nobel Prize for his work in the development of the laser) stood up and announced that he had found ammonia molecules near the center of the Milky Way using the radio telescope at the University of California, Berkeley. "Suddenly the people at NRAO decided we weren't crazy anymore," Snyder says, "and asked us for a list of molecules we wanted to look for."
Early in 1969 Snyder and Buhl set up shop at NRAO's Green Bank Telescope in West Virginia and chose their first target: formaldehyde, an organic molecule made up of two hydrogen atoms and an oxygen atom tethered to an atom of carbon. Sure enough, when they pointed the 140-foot radio dish at a massive cloud of gas and dust near the center of the Milky Way, there was a distinctive dip in the radio signal at 4.8 gigahertz—the music of formaldehyde. The same signal appeared in cloud after cloud. After waiting for more than a year to get observing time, Snyder needed just a few nights at the telescope to demonstrate that complex organic molecules, formaldehyde in particular, permeate the galaxy. He soon found hydrogen cyanide (88.6 gigahertz) in the Orion nebula and isocyanic acid (87.9 gigahertz) in a cloud called Sagittarius B2. "After that, we could have gotten telescope time to do anything," Snyder says. "We could have looked f
or interstellar flu germs."
Within a few years, Snyder and other radio astronomers had identified dozens of organic molecules, including formic acid (which causes the sting in ant bites) and methanol (a simple alcohol). Although none of these molecules reached the complexity of Miller and Urey's amino acids, some of them can form proteins and other biologically important compounds when mixed together in water on Earth. Contrary to all expectation, interstellar clouds proved to be very friendly environments for breeding complex chemistry. Now a whole new discipline—astrochemistry—began to emerge, and its emboldened practitioners set out to learn more about what is cooking in those colorful nebulas.
Despite the large and growing catalog of space chemicals coming from the radio observatories, the astronomer J. Mayo Greenberg of the University of Leiden in the Netherlands suspected that his colleagues were missing a vital piece of the puzzle. The radio astronomers were searching for free-floating gas molecules in space, but nebulas also contain dust, microscopic grains of carbon and silicon. What would happen, Greenberg wondered, if interstellar gas molecules like formaldehyde collided with frigid grains of dust? They would freeze there instantly, he surmised, creating another kind of environment in which chemical reactions, driven by starlight, could take place. At temperatures just a few degrees above absolute zero, the molecules would still vibrate. These vibrating molecules—just like the rotating dipolar ones Snyder observed—could absorb and emit radiation. The frozen chemicals Greenberg was postulating would show up not in radio, however, but at infrared wavelengths. Starting in the 1970s, Greenberg was vindicated by a team of astronomers at the University of California, San Diego. They pointed a variety of infrared telescopes at interstellar dust clouds and discovered dips at specific frequencies corresponding to molecules including methanol, ammonia, and water ice.