Cell biology and cosmology will never be the same, thanks to Andrew Fire, PhD ‘83, and George Smoot ‘66, PhD ‘70.
George Smoot’s phone rang just before 3:00 a.m. on October 3, and a voice with a Swedish accent told him he’d won the 2006 Nobel Prize in physics. But the cosmologist was skeptical.
After all, a propensity for pranking runs in his family. Oliver R. Smoot ‘62, who set the standard of measurement for the Harvard Bridge (364.4 smoots and an ear), is a distant relative. And Smoot himself can still vividly recall playing a practical joke on his graduate thesis advisor, MIT physics professor David Frisch. After working an overnight shift, Smoot and a friend pretended they had filed down a precious hunk of osmium to get it to fit inside a magnet for an experiment. When Frisch entered the lab and saw metal chips strewn about, he grabbed his heart in terror, Smoot remembers. “That was why I was worried when I got the phone call in the middle of the night,” he says. “I know students can play pranks!”
But the call from Sweden was no prank. Smoot and another MIT alumnus, Andrew Z. Fire, joined a group of 61 other distinguished alumni, professors, and MIT affiliates when each won a 2006 Nobel Prize. Both have changed the way science is done in their fields.
Andrew Z. Fire, PhD ‘83, won the medicine prize for helping uncover the details of a natural gene-silencing mechanism called RNA interference. Though the groundbreaking discovery came only eight years ago, inducing RNA interference is now a common lab technique that helps biologists pinpoint the functions of individual genes. Therapies that use RNA interference to combat human diseases such as macular degeneration are already in clinical trials.
George Smoot ‘66, PhD ‘70, won the physics prize. He co-led the research team behind NASA’s COBE satellite, which made the first quantitative measurements of the initial conditions of the universe. Smoot’s 1992 map of tiny temperature variations in cosmic radiation originating from about 14 billion years ago is the big bang theory’s smoking gun. The minute fluctuations Smoot charted are thought to indicate the local concentrations of energy–the “seeds”–around which matter coalesced into the clusters of galaxies that make up today’s universe.
The Gene Silencer: Andrew Fire
Before 1998, identifying the function of a given gene was a laborious process whose success was determined in great part by luck. Researchers found cells or organisms with mutated copies of the gene and inferred from lost functions what the normal gene did. Or they tried to induce mutations in cells in the lab, a hit-or-miss technique that, in human cells, mostly missed. Now, thanks to the discovery of RNA interference (RNAi), biologists can essentially turn off individual genes in the lab. It’s akin to flipping a switch to make a few light bulbs in an array of millions change color.
Understanding RNA interference has “radically changed how we do cell biology and understand, or probe, cells,” says Phillip Sharp, an Institute Professor at MIT’s Center for Cancer Research and a Nobel laureate himself. “We went from a position of not having a general approach to investigating the function of genes to being able to silence a gene to ask what it does. Every journal you look at, one or more or all the articles in it have utilized this technology. It really has been a fundamental advance.”
Fire, now a professor of pathology and genetics at the Stanford University School of Medicine, shares the Nobel Prize with Craig Mello, now a professor of molecular medicine at the University of Massachusetts Medical School, for their discovery of the gene-silencing mechanism.
Fire came to MIT as a 19-year-old graduate student, having majored in math at the University of California, Berkeley. While partaking of what he calls Berkeley’s “intellectual smorgasbord,” he encountered molecular biology and got excited. A decade before Sharp won his Nobel Prize, Fire worked in his lab at MIT. As a student, Fire “did some important early research on the biochemistry of the control of gene expression in human cells,” Sharp recalls. “It launched another 15 years of work in my lab and others’.”
Before Fire and Mello published their breakthrough paper, RNA was known to have multiple roles, but it was primarily thought of as DNA’s go-between, the messenger that translates genes into proteins. Researchers knew, however, that when injected into an organism, RNA could sometimes prevent the production of proteins and silence genes.
But the phenomenon could not be reliably reproduced, so it was unclear what form of RNA was responsible for it. Was it “sense” RNA, which follows the sequence of the messenger RNA that codes for a specific protein? Was it sense RNA’s complement, “antisense” RNA? Or was it a double-stranded combination of the two?
Fire and Mello collaborated on a series of rigorous experiments using a nematode worm called C. elegans to determine whether sense, antisense, or double-stranded RNA caused gene silencing. In order to elicit strong visible signals from their test subjects, they worked with a gene that helps maintain normal muscle contractions in C. elegans: if the gene was silenced, the worms would twitch. When the researchers injected the worms with pure sense or pure antisense RNA, nothing happened. But when they injected double-stranded RNA, the worms twitched. Fire and Mello concluded that RNA had to be double stranded to silence the gene.
The pair published these results along with other observations about RNAi in Nature in 1998. “The insight that double-stranded RNA was the key to the silencing is why they received the [Nobel] prize,” Sharp says. Subsequent research by Fire, Mello, Sharp, and others established the molecular workings of RNAi, which is now known to occur in most organisms.
In humans, in other animals, and even in plants, RNA is normally present as single strands. Fire and others in the field believe RNAi probably developed as a defense against viruses. “When a cell sees double-stranded RNA, its first response is to chop it up into bits, which is understandable given that double-stranded [viral] RNA is [often present] when viruses replicate,” Fire explains.
“But the cell goes one step beyond that. Not only does it want to chop the stuff up, it wants to go and find anything that looks like it, in case it’s missed some RNA. So [a molecule in] the cell takes the bits of RNA that have been chopped up, and it goes searching for things that are similar. If it finds something, it chops that up.”
That something could be the cell’s own messenger RNA. When its messenger is destroyed, a gene is silenced.
“In theory,” says Sharp, RNAi “can silence any gene”–from the genes of an invading virus to the gene that makes the protein thought to cause Parkinson’s disease. That makes it therapeutically promising. Sharp and other researchers have founded companies to commercialize RNAi drugs. “If you could get RNA to the target [tissue], you could have some really cool therapeutics,” says Fire.
Alnylam, the company Sharp cofounded in Cambridge, MA, is now conducting clinical trials of a drug for the respiratory virus RSV; Acuity Pharmaceuticals of Philadelphia and Sirna Therapeutics of San Francisco are both conducting clinical trials of drugs for macular degeneration.
Fire enjoys watching these ventures–but “only as a cheerleader,” he says. He continues to study the molecular workings of gene silencing in his lab’s favorite test subject, C. elegans.
RNAi has also proved to be a mechanism that cells normally use to control the activity of their genes. Victor Ambros ‘75, PhD ‘79, and Rosalind Lee ‘76 discovered that RNA plays a key role in controlling animal development; researchers have found many genes that code for double-stranded RNA, and it’s now believed that interference by these RNAs is responsible for regulating 30 percent of the human genome.
These days, Fire is focused on establishing ties between gene silencing and human disease. “Lots of genes are silenced in cancer,” he says. “That’s been known for quite a while.” He is currently working with pathologists at Stanford to understand how the disruption of RNA regulatory processes contributes to disease.
The Cosmic Cartographer: George Smoot
George Smoot didn’t set out to be a weather reporter or a mapmaker. But in 1992, he made cartographic history when he created the first map of the young universe by charting slight variations in the temperature of 14-billion-year-old radiation. Variations in this “cosmic microwave background,” or CMB, give astrophysicists clues about how complex structures like galaxies formed.
A physics professor at the University of California, Berkeley, Smoot shares the Nobel Prize in physics with John Mather of NASA Goddard Space Flight Center for work on the CMB, whose existence supports the big bang theory.
Angelica de Oliveira-Costa, now a research scientist at MIT’s Kavli Institute for Astrophysics and Space Research, joined Smoot’s lab at Berkeley as a graduate student the year after Smoot announced his map. She says part of what makes him a first-rate physicist is that “he has a good eye for good ideas and is not afraid of change.”
Smoot was always attracted to cosmology, but he did his graduate work in particle physics and took a job with Luis Alvarez, a Nobel laureate in that field at Berkeley. Between projects, Alvarez told his staff to take a few months off and look into fertile new areas of research. Smoot seized the opportunity to move into cosmology, adopting Alvarez’s philosophy as his own: “When you finish an experiment, don’t just automatically do the next one. You should see if there is some new discovery or technology that will enable you to make measurements in an area that’s promising.”
For Smoot, the study of the cosmic microwave background was just such an area–alluring and wide open. He says he had “the intuition that whatever you measure there is going to be a fundamental measurement,” and he was right. De Oliveira-Costa says of her three years in Smoot’s lab, “Scientifically, it was one of the best times of my life. Every tiny discovery you made was new.”
Discovered in the 1960s, the CMB had been predicted by the big bang theory. The radiation comes not from a place in the universe but from a time soon after the universe’s formation. “When we look back at the radiation, we’re looking back to a time in the universe when everything was hot and dense like the plasma in our sun,” explains Edmund Bertschinger, head of the MIT physics department’s astrophysics division. As the universe expanded, it cooled, and so did the CMB, which is now only about 2.7 degrees above absolute zero. “We’re seeing that afterglow in our radiotelescopes billions of years later,” he says.
The photons of the CMB provide something like a photograph of the universe about 370,000 years after the big bang, when it cooled to about 3,000 °C, releasing particles to form the first atoms. Until then, the universe was an opaque, high-energy plasma; photons were caught up in heated and intimate conversation with subatomic particles like electrons. When the universe cooled and atoms formed, photons–including those that make up the CMB–could for the first time move freely.
When Smoot started working on the CMB, its exact spectrum was unknown, and it appeared to have completely uniform energy. This uniformity suggested an early universe where energy and matter were distributed homogeneously–a scenario apparently incompatible with today’s varied and complex universe. How could stars grouped into galaxies grouped into clusters of galaxies surrounded by large voids emerge from an early universe where matter was spread out as smoothly as icing on a wedding cake? For the big bang theory to hold up, the early universe would have to have had lumps upon which quantum-mechanical forces and then gravity could act, eventually causing galaxies and other structures to form.
In search of this lumpiness, many groups, including Smoot’s, sent radiation detectors on balloons and even in spy planes to altitudes where the CMB is almost completely unfiltered by Earth’s atmosphere. Meanwhile, others calculated what level of fluctuation in the energy of the early universe would have allowed lumps, or seeds, to form. Smoot joined a group, led by Mather at NASA, that was working to get a sensitive, radiation-detecting satellite called COBE (“Cosmic Background Explorer”) into orbit. By the time COBE was launched on November 18, 1989, astrophysicists had established that very tiny variations in the CMB–as small as a hundred-thousandth of a degree–would indicate an early universe diverse enough to have produced the current one.
Smoot was in charge of a group of six instruments on COBE, called differential microwave radiometers, that looked for temperature variations called anisotropy in the CMB. Up above Earth, the orbiting COBE had unobstructed reception of the CMB in all directions. Smoot and his Berkeley team analyzed a year’s worth of these temperature measurements–millions–looking for anisotropy; when they seemed to find it, they worked to convince themselves that it wasn’t due to noise from the instruments on COBE.
In 1992, Smoot announced that COBE had found hundred-thousandth- of-a-degree variations in the energy of the CMB. His map of these variations, showing roughly which patches in the early universe were slightly warmer and which were slightly colder, has been called the universe’s baby picture. “The amazing thing is, the universe is almost completely uniform,” he says. “It’s more uniform than a billiard ball.” Smoot received his half of the Nobel Prize for his work on the map; Mather was honored for leading the COBE project and measuring the CMB’s spectrum.
Astrophysicists say Smoot and Mather’s announcement of COBE’s results was a turning point for cosmology, when philosophical speculation about the universe’s origins gave way to a science built on quantitative evidence. Smoot’s map was subsequently verified by further balloon experiments and has since been enhanced by more sensitive measurements from WMAP, a NASA satellite still in orbit. Bertschinger likens Smoot and the other COBE scientists to explorers finding new continents. “You first find the continents and then explore the coastlines and make your maps more and more refined,” he says.
The CMB map met with so much enthusiasm that Smoot wrote a book, Wrinkles in Time, “to show young people that being in science could be an adventure,” he says. Now that he’s won the Nobel Prize, Smoot says only half-jokingly that he feels even more pressure to be an ambassador for science. “I used to be an outlaw, always going to the fringes of physics, trying strange things, being rebellious,” he reminisces.
In a universe thought to be 96 percent mysterious dark matter and dark energy, there are plenty of new and strange territories to explore. “I have a list of eight questions I think are really important,” he says (see “Smoot’s List,” below). One day, Smoot plans to start a cosmological-physics center to address them. But for now, they’re bullet points in his lectures–and the cosmic mapmaker keeps the list tacked to his wall.
The eight cosmology questions that keep George Smoot up at night
1. Did inflation1 happen? How?
2. What is dark matter?
3. What is dark energy?
4. Why is there more matter than antimatter in the universe?
5. Are there other relics2 to be found (e.g., cosmic strings)?
6. Are there extra3 dimensions?
7. Do fundamental constants vary?
8. What other exotic forces might there be?
1 the exponential expansion of the young universe
2 of the young universe
3 i.e., more than four (three spatial dimensions and time)