The Best American Science and Nature Writing 2011 (30 page)

 

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 that I would be so romantic that I become deluded enough to keep hoping."

FROM
Discover

I
N 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 for 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.

Now that Greenberg knew interstellar space harbored frozen molecules as well as gaseous ones, he wanted to know how these chemicals interact under such extraordinary conditions. Theory alone could not provide the answer; this question called for some hands-on experiments. So in 1976 Greenberg hired Louis Allamandola, a recent Berkeley PhD graduate in low-temperature chemistry, to re-create the kinds of reactions that might take place on microscopic icy grains thousands of light-years away.

 

Allamandola's solution was to create an apparatus that could replicate the exotic cold depths of space—in essence, an extraterrestrial version of the Miller-Urey experiment. With his colleague Fred Baas, he installed equipment to chill a shoebox-size chamber to within several degrees of absolute zero and depressurize it to a near vacuum. Then he set up a plasma lamp to fire beams of ultraviolet light at the chamber, much like the radiation present in planet- and star-forming regions of dust clouds. Finally, in true Miller-Urey fashion, he threw in a gaseous mixture of simple molecules, mimicking what was then known about the composition of interstellar clouds, and watched the results.

Allamandola's simulations, carried out first at Leiden and now at NASA's Ames Research Center, revealed not only that some chemical reactions really do occur at extremely low temperatures, but also that these reactions produce other reactive chemicals, thereby providing the spark for more molecular hookups. Ultraviolet radiation spices things up as well: it heats the grains and breaks up some of the molecules into reactive fragments, which in turn bond with other fragments to form new kinds of molecules.

Once again, nature proved extremely adept at brewing complex molecules. In current versions of Allamandola's experiment, the resulting icy mixtures contain dozens of prebiotic molecules, among them the same amino acids that Miller and Urey found. In fact, Allamandola's nebula-in-a-box has yielded an even richer chemical palette. He has manufactured intricate molecular rings containing carbon, nitrogen, and hydrogen; fatty-acid-like molecules that look and behave like the membranes protecting living cells; and nucleic acids or nucleotides, the primary components of RNA and DNA.