bridges vol. 9, April 2006 / News from the Network
by Philipp Steger
"No," says Angelika Amon, an associate professor of biology at MIT, shaking her head emphatically, "I don't spend much time on grant writing. I am lucky that way." She smiles at the thought of her good fortune and takes another sip from her can of Diet Coke before she continues.
I note, with a mixture of relief and smug satisfaction, that it's her second Diet Coke within an hour - it's comforting to see that even overachievers like Professor Amon have their little, human vices. After all, one could easily be intimidated by her, considering that one of America's most prominent medical research organizations has for years been willing to bet serious money on this woman having the potential to make significant contributions to science. The organization does this because it "believes that science is facilitated best by providing outstanding researchers with the resources and flexibility to follow their scientific instincts and to pursue new opportunities as soon as they arise." This somewhat unusual approach is not really astonishing, given the visionary power of that organization's founder, one of America's larger-than-life personalities and enduring legends.
The aviator's legacy
When the former aviator - he had set two major records in the history of flight - died on a private airplane on the way to a hospital in Houston, the news of his death caught many, who thought he had died years earlier, off guard. After all, following decades in the public limelight - alternating between the roles of movie producer, major defense contractor, founder and owner of a large airline - Howard R. Hughes spent the last years of his life as a recluse. The news of his death set in motion a frenzied search for his last will and testament, bringing together a motley crew of claimants to Hughes' considerable fortune: a woman, who claimed that, unbeknownst to anyone, Hughes had been married to her for two decades; Melvin Dummar, a gas station owner, who said that he had once picked up an almost dead Howard Hughes in the Nevada desert; the Internal Revenue Service, with whom Hughes had fought a passionate and lifelong battle; and several US states battling each other over which of them would be able to lay claim to the expected inheritance tax windfall. After years of legal wrangling and the dismissal of numerous forged or otherwise unacceptable wills, 22 cousins on both sides of Hughes' family ended up inheriting the Hughes estate worth around $2 billion.
The absence of a will was out of character for a man who, decades earlier, had accomplished the amazing feat of transforming the Hughes Aircraft Company, a major defense contractor, into a tax-exempt charity. In 1953, in what at first sight appeared to be an act of selfless generosity, Hughes transferred all of his stock in the Hughes Aircraft Company to a medical research charity he had founded in Delaware. Upon closer inspection, the generous gift looked more like an act of tax evasion, at least to the IRS. In the ensuing long legal battle, Howard Hughes maintained the upper hand. Even attempts in Congress to pass a law closing the apparent loophole Hughes had taken advantage of faltered when intense lobbying on Hughes' behalf made sure that the new law contained a clause exempting medical research organizations.
Hughes, never one to forego big projects, called upon the newly created institute to explore "the genesis of life itself." Today, the Howard Hughes Medical Institute (HHMI) is the second largest philanthropic organization in the US: In 2005, its endowment was $14.8 billion. Following the 1985 sale of its stocks in the Hughes Aircraft Company to General Motors for $5 billion, the HHMI has developed into the country's biggest private source of funding for biomedical research. To become an HHMI investigator is among the most prestigious positions a scientist can hope for. At any time, there are about 300 HHMI investigators. These scientists are chosen based on nominations put forward by universities and academic health centers across the country. The select few are appointed for either five- or seven-year terms, with the HHMI effecting a long-term research agreement with the university where the individual scientist holds a faculty position.
Angelika Amon, who had come to the US as a postdoc in 1994, was appointed a Hughes Investigator in 2000 and just recently passed the rigorous review that brought her yet another five-year term as an HHMI investigator at MIT's Center for Cancer Research where she studies chromosome segregation during mitosis and meiosis.
In the famed halls of MIT - a look at the big picture
Waiting for Angelika Amon, who has agreed to meet with me to talk about her research, I cannot help but ponder the improbability of my being here in the famed halls of MIT. By this, I am not alluding to the notoriously unreliable nature of travel, although even a brief trip to Boston from Washington, DC, can hold surprises that lend a certain degree of uncertainty to the journey. Nor am I talking about the improbability of my getting into MIT - strangely enough you can walk right in without anyone bothering to ask for your credentials. No, I am talking about the big picture, which is what basic research is supposed to be all about. I am talking about the improbability of any one of us being here.
No matter how you look at it, it certainly took a long time to get us to where we are today. About 4.5 billion years to be precise, which is how long our planet has been around. But, of course, that is taking an arbitrary starting point, and maybe it would be fairer to put the starting point at about 3.5 billion years ago, when life in the form of prokaryotic bacteria staked its first claim on planet earth. Those who are offended by the idea of bacteria as our earliest ancestors may want to choose a time about 1.5 billion years ago, when the first cells with a proper nuclear membrane made their appearance on this earth. Even so, we are talking about an awfully long time. Considering the enormous amount of time it took the planet to come up with complex multicellular organisms like ourselves, we have every reason to be proud of how little time it took us to figure out the functioning of those organisms and the cells that constitute them. Not that we really have it entirely figured out yet; there is still enough we don't understand about the way cells work to occupy cadres of scientists like Angelika Amon for decades to come.
Amon's colleague at MIT's Center for Cancer Research, Andreas Hochwagen, calls her an "outstanding scientist" and explains why: "She has a knack for pinpointing interesting questions and problems that can be addressed with the available scientific tools. Oftentimes, she very quickly identifies the killer experiments that will unambiguously answer a question. Aside from her outstanding intellect, however, she also provides a very exciting, and motivating, and above all very caring, environment for her students and colleagues, which makes an enormous difference for everybody working with her, and distinguishes her from many other top scientists. Despite her continued success, she has remained extremely approachable and supportive, keeping alive a very family-like atmosphere in her lab." Having met with Angelika Amon twice in the course of writing this article, I still may not be the most reliable judge of her qualities as a researcher, but I can attest to her unusual approachability and generosity. Being also enviably patient, she was evidently unfazed by the daunting challenge of having to explain to a layperson what her research is all about.
Cell division - mitosis, and a variation thereof, meiosis - lies at the heart of Angelika Amon's research interests. Cell division also lies at the heart of all life on this planet. To understand what exactly happens during a well-executed mitosis is to understand how cells make sure that their correct and complete genetic information passes from one generation to the next. Simply put, a successful mitosis maintains the original cell's genome by producing two daughter cells that contain exactly the same DNA molecules as the parent cell. This is accomplished by first faithfully duplicating the DNA contained in the parent cell's chromosomes, and then segregating the duplicate copies so accurately that each daughter cell ends up with the right combination of chromosomes. This chromosome segregation is accomplished through a mechanism mediated by a structure called the spindle apparatus, whose job it is to pull the copies of the chromosomes apart and arrange them at opposite ends of the cell. When the cell divides, the chromosomes are where they are supposed to be, namely, in the separate realms of the two daughter cells.
"But," says Amon, "that does not always happen. There are instances when one daughter cell ends up with too much DNA and the other with too little. The one that gets too little usually dies, while the other one can become a precursor for cancer. By understanding how a normal cell carries out accurate chromosome segregation, we can begin to learn what goes wrong in cancer cells. It should also help detect cancer earlier and - in the long run - prevent it."
This puts Amon's research squarely into the search for a cure for cancer, a search that has involved scores of researchers around the world and has been going on for decades. While headway has been made, and certain kinds of cancer are now curable, especially when discovered early on, many of the riddles regarding cancer remain unsolved. The American Cancer Society estimates that, in 2006, nearly 565,000 Americans will die from cancer and 1,399,790 Americans will be diagnosed with the disease. This makes cancer the second leading cause of death among Americans. Five times as many Americans die from cancer as from accidents, and 31 times as many as from homicide.
Still, Amon is careful to point out the basic nature of her research. "I don't really consider myself a cancer researcher; at least not primarily. At heart, I am doing basic research. The desire to understand how cells work is what drives my work. If my work ends up contributing to the fight against cancer, I am all the happier for it," says Amon. What connects Amon's research to cancer research, though, is the effect of aneuploidy - the phenomenon of daughter cells having either too many or too few chromosomes - in cells. The worst-case scenario of a cell division gone awry is the development of cancer: as in the example of a botched mitosis in the replacement of worn-out cells of the epidermis, the skin's outermost layer. In the epidermis, mitosis occurs within cells at the basal layer, i.e. the lowest level of the epidermis, where parent cells are divided into two daughter cells. If everything goes all right, one of the daughter cells stays in the basal layer maintaining its capacity for further division, while the other one moves up and loses its capacity for cell division. In some instances, however, this does not happen and both daughter cells maintain their capacity for further division, thus giving rise to the possibility of tumor growth.
In order to understand exactly what goes wrong in cell division that causes one of the daughter cells to have too many chromosomes and the other too few, Amon has been studying the part of mitosis called "exit from mitosis," which occurs after chromosomes have been segregated and which involves the disassembly of the spindle and the division of the cytoplasm (the large fluid-filled space inside the cell) into two daughter cells.
As a geneticist, Amon approaches problems like the one described by focusing on genes, sections of DNA that carry the information for creating sequences of amino acids, the building blocks of proteins. Since it is proteins that carry out a cell's work and play a crucial role in the process of cell division, looking at the consequences of changes or mistakes in a protein's structure can provide groundbreaking insights into how a normal protein works. One way to change the structure of a protein is to alter one or several units of the gene that codes for the amino acids that constitute that protein. To do that you need to work with a model organism.
"Yeast, the movie"
"I have to show this to you. It's the best, most gorgeous, the coolest movie ever," says Angelika Amon, hunched over her desk and searching through a PowerPoint presentation on her laptop. We are halfway through the interview and about to watch an old, black-and-white movie. When the movie comes on, Professor Amon can hardly contain her excitement.
"Isn't that so cool? Aren't they cute?" she calls out, although "cute" is probably not the term that would come to most people's mind when they get a close look at Saccharomyces cerevisiae during mitosis. But then again, who says baker's yeast - "the stuff you put in cakes," as Angelika Amon explains it - can't have its cheerleaders? Angelika Amon has every reason to be enthusiastic about yeast cells, since she has spent a lot of time, in fact most of her career, with them.
After doing her Ph.D. with renowned scientist Kim Nasmyth, until recently the director of the Vienna-based Institute of Molecular Pathology (IMP), Angelika Amon came to the US to do a postdoc at MIT's Whitehead Institute for Biomedical Research. "I did not want to continue working with flies. I was in love with yeast because it grows much faster and is therefore more practical, if you want to study what is happening within a cell rather than how entire organisms develop. Yeast is cheap, easy to grow, and non-toxic. You can manipulate yeast in any way you want. And the mechanisms that regulate its cellular metabolism and cell division are basically the same as in human cells. But the main reason I love yeast is that the only rate-limiting factor in your research is your brain - technically almost anything is possible in yeast," says Angelika Amon explaining the root of her long-standing love affair with yeast.
The black-and-white movie, which shows yeast cells in the process of cell division and which Amon saw in high school the first time, triggered her interest in yeast and cell biology. One of the things yeast helped her understand was the function of a particular protein involved in the late stage of chromosome segregation. This protein, named cdc14 by its discoverer, the Nobel Laureate Leland Hartwell, seems to play a major role in the checkpoint mechanism that follows chromosome segregation. In an apparent recognition of Murphy's Law, the basic design of cell division includes mechanisms within the various phases of the cell cycle that will abort the process of cell division if something goes wrong. It's the job of these checkpoint pathways or surveillance mechanisms to ensure that the next step in the cell cycle is tackled only when the current step has been satisfactorily taken care of. In the worst-case scenario, a mishap somewhere in the cell cycle will lead to apoptosis, the self-destruction or suicide of the cell - unfortunate for the cell concerned but beneficial for the overall organism.
The very occurrence of aneuploidy in a daughter cell indicates, however, that one of the checkpoints has failed to do its job correctly and the cell cycle has progressed to the next step even though things have gone wrong. Working with yeast, Amon has been able to identify the key regulatory networks that regulate the activity of cdc14.
Amon has also studied chromosome segregation during meiosis, which leads to the production of reproductive cells called gametes. Here, instead of having two daughter cells identical to the parent cell, four haploid cells are produced, each containing only half the chromosomes of their parent cell. Meiosis is the prerequisite for sexual reproduction. The fusion of two haploid cells, so-called gametes (egg and sperm), during fertilization forms a new diploid cell.
With the increased level of complexity of meiosis, the potential for things to go wrong is even greater. Apparently, human cells are particularly bad when it comes to performing a faultless meiosis. "Errors in the chromosome segregation during meosis are the main cause of mental retardation in humans and 10 percent of all human conceptions die because they have the wrong chromosome number. These embryos die so early in development that women do not even realize they are pregnant. This is not an age-specific phenomenon that concerns only older women, but occurs across the age span. Nobody knows why humans are so bad at these divisions, but humans definitely have a higher incidence of errors during meiosis than, for instance, mice."
Angelika Amon's work has met with recognition, both within her field and in science in general. Now only in her late thirties, Professor Amon is a tenured associate professor at MIT and arguably one of the most renowned microbiologists in the country. A long list of awards attests to her outstanding accomplishments. In 2003, she received the prestigious Alan M. Waterman award. This award, created by the US Congress in 1975 to celebrate the 25th anniversary of the National Science Foundation and honor its first president, is given annually to the most outstanding young scientist or engineer under 35 and comprises $500,000. The award has a good track record when it comes to picking scientists with a great future ahead of them. In 2001, Eric Cornell, the Alan T. Waterman awardee of 1997, was one of recipients of the Nobel Prize in Physics for his work on the Bose-Einstein condensate.
Asked which of the many awards she received meant the most for her, Amon chooses the Eli Lilly & Company Research Award: "While the Waterman award is a very prestigious award, it recognizes your accomplishments as a scientist in general, whereas the Eli Lilly award is simply the most prestigious award for microbiologists. Many of the scientists I have admired for years have received this prize in the past."
The Whitehead Institute's fellowship program
Looking back at her career so far, Amon identifies one particular experience as crucial: her fellowship at the Whitehead Institute. Following two years of postdoctoral work at the Whitehead Institute, Amon was named a Whitehead Fellow in 1996. The fellowship program at the Whitehead Institute was created to provide young researchers with a maximum of creative freedom, space, resources, and mentoring guidance during what many consider to be a scientist's most creative years. Amon calls the fellowship "the best thing that happened in my life. They gave me my salary plus the salary of a co-worker, and all the supplies and equipment I needed, and a total of five years to do the research I wanted. I was a fellow for three years and that was the best time of my life. You don't have to do administrative things, sit on committees, or write grants. You are just in the lab and do science and nobody tells you what to do."
Amon, the mother of two small daughters herself, thinks that programs like this are crucial in promoting women in science: "These fellow positions are a very good thing, particularly for women. Having children during your postdoc years is usually difficult. As a fellow it's easier, because there is someone else who helps you carry out the experiments, so that it's less crucial that you are physically in the lab all the time. It's a great way to foster women in science. If people are really serious about that, that's the way to go."
Angelika Amon herself did not use the full five years of the fellowship. In 1999, she accepted a tenure-track position as assistant professor of biology at the Center for Cancer Research. Only a year later, the HHMI chose her as one of the new HHMI investigators. I ask her, somewhat sheepishly, about the chances of her returning to Austria. "My husband and I often think about going back. We love Austria and our families are there. But, look," she shakes her head and waves a hand around the room, "I am running a large lab with about 16 researchers and bring in a lot of money in research funds every year. I work with very talented people and I live a good life here." She pauses, takes yet another sip of Diet Coke and adds: "It's a golden cage."