Princeton Innovation Magazine Volume 8 No. 2

VOL. 8 NO. 2

SPRING 2007

INNO ATION The Princeton Journal of Science and Technology

Malaria-Resistant Mosquitos

Looking towards a future free of malaria.

Miracle Cancer Drug Princeton professor’s miracle drug is considered the most effective treatment for cancer.

Virtual Reality: The future of NASA

pg. 10

INNO ATION

6

VOL. 8 NO. 2

10

SPRING 2006

p53 for Treating Cancer

BIOLOGY

Structural analysis of the cell reveals that the mechanisms regulating p53 degradation can help in the treatment of cancer.

6

Bacteria as a Model for Evolution Controlled growth of E. coli provide breakthroughs in the study of the mechanisms governing evolution.

APCase

4

6

8

Jennifer Hsiao shares her experience studying the feedback regulation of APCase.

TECHNOLOGY

The Future of NASA

Cancer Drug

MEDICINE

10

Redesigning the Hydrogen Fuel Cell Working together: An interdisciplinary group of Princeton professors collaborate to decode fMRI brain images.

Taylor’s Miracle Dr. Edward C. Taylor of Princeton University has developed what is hailed as the most successful cancer drug in history: Alimta.

Did you think that virtual reality, vertical take-off, and landing vehicles were in the realm of science fiction? Think again. A NASA chief scientist discusses future technologies of NASA and its space program.

14 17

Crossword Challenge

20 Malaria-Resistant Mosquitos A breed of mosquitos has been genetically engineered to be immune to malaria, pointing to a possible eradication of the disease..

From Laboratory to Patient A step-by-step analysis of what really goes on in drug creation and evolution.

Halting the Onset of Alzheimer’s Screening for inhibitors of protein aggregation may halt the onset of Alzheimer’s Disease.

18

23 26

L ETTER F ROM THE E DITOR

Dear Readers, This issue of Innovation is your window into the exciting world of medical research. Highlights include glimpses into cancer research, a genetically engineered cure for malaria, chemistry’s approach to Alzheimer’s disease, and the clinical studies supporting drug development. Enriching the issue’s vast swathe of medically oriented articles are excursions into evolutionary science, chemical engineering, and NASA’s ongoing conquest of space and search for the technology of tomorrow. Innovation’s mission has always been twofold – we aim to deliver a microcosm of the momentous science research conducted here at Princeton while granting students access to the eminent professors and researchers on campus, thereby forging a rapport between the present and future generations of scientists and discoverers. In other words, dear readers, we seek to bring the sciences to your doorstep, and at the same time, send you out into the vast world of scientiÞc innovation. Our journal was made possible by the hard work and dedication of our Innovation team coupled with the generous support of the University and in particular the School for Engineering and Applied Sciences. We would also like to thank the professors and researchers who so generously offered their time for the ediÞcation of the Princeton community. And Þnally, we wish to extend our gratitude to you, dear reader, for your continued support and enthusiasm.

Ad Astra Per Scientiam, Sarah Weinstein, Editor-in-Chief

Please contact us with your advice, questions, and thoughts at slweinst@princeton. edu or [email protected]. We would love to hear from you.

Many thanks to our contributors, without whom Innovation would not have been possible: The Departments of Chemical Engineering, Computer Science, Geosciences, and Molecular Biology, the Council of Science and Technology, Pharmanet, and The School of Engineering and Applied Sciences.

Cover image courtesy of cs4n.org.

2

OUR STAFF

Editor-in-Chief Sarah Weinstein

Assistant Editor-in-Chief David Tao

Business Administration Kenton Murray

Writers Lajhem Cambridge Jill Feffer Jennifer Hsiao Kevin Kung Brian LeVee Jessica Lucas David Tao Sarah Weinstein Josephine Wolff

Editors Lajhem Cambridge Kevin Kung Megan Murray Anupama Pattabiraman Angela Wu Andrew Yang Keren Zhou

Layout Team Head Alyce Tzue Janice Chou Jill Feffer Elizabeth Szamreta

INNO ATION

THE INNOVATION SOCIETY is dedicated to bringing scientiÞc topics into the mainstream of campus discussion. We are excited to be able to bring cutting-edge science research to your doors, but we can’t do it without

your support. INNOVATION MAGAZINE BOX 1376, FRIST CAMPUS CENTER PRINCETON UNIVERSITY PRINCETON, NJ 08544 For more information contact Sarah Weinstein at [email protected] or [email protected]

Structural Analysis Reveals Interactions Regulating p53 Degradation and Offers Insights into Cancer Therapeutics // BY JESSICA LUCAS

R

ecent research discoveries made by structural biologist Yigong Shi and fellow researchers lend insight into the molecular mechanisms controlling the cell cycle. The life cycle of a cell, including growth, division, and death, is a tightly regulated process that depends upon the complex, coordinated interactions of numerous molecules. Abnormalities in cell cycle control often cause cells to experience an increase in growth,

a decrease in death, or proliferation at inappropriate times, all of which contribute to tumorigenesis and the onset of cancer. Greater knowledge of how certain molecules function to

Abnormalities in cell cycle control often cause cells to experience proliferation at inappropriate times, contributing to tumorigenesis and the onset of cancer.

regulate the cell cycle or induce cell death facilitate both an understanding of how cancer develops and how to generate targeted therapies that may help to treat the disease. One such class of regulatory proteins, known as tumor suppressors, functions to negatively regulate the cell cycle and inhibit cell growth. Thus, abnormal levels of these proThe diagram shows the progression teins, along with mutations in the of p53 mutation caused by overexgenes that encode them, are frepression of its inhibitor, the MDM2 quently implicated in cancer. In fact, oncogene.

4

the most frequently mutated gene in all cancers involves one particular tumor suppressor protein p53, which weighs 53 kDa and is 393 amino acids long. When cells experience stress or DNA damage, p53 accumulates and responds with a number of anti-cancer mechanisms. First, it may activate genes that encode for proteins that are responsible for repairing damaged DNA. Second, p53 may arrest the cell cycle by upregulating cyclin dependent kinase inhibitors that prevent the transition from G1 into S phase. Lastly, upon irreparable DNA damage, p53 can initiate apoptosis, or cell death. Though 50% of cancers characterized by p53 abnormalities involve TP53 mutations that produce dysfunctional p53 protein, the other half of the time patients have a wildtype p53 gene whose product faces accelerated degradation. In normal, unstressed cells, p53 is kept at low levels by constant degradation mediated by another protein, MDM2. MDM2 is a ubiquitin ligase that specifically tags p53 for degradation by adding ubiquitin groups and facilitating its transport from the nucleus,

enzyme that functions to deubiquitylate, or remove ubiqutin from, a target protein to prevent its degradation. Though initially discovered as a p53 directing protein, it actually was rediscovered as an essential protein for MDM2 stability, inhibiting its self-degradation activity through deubiqRibbon drawing of the p53 core domain-DNA uitylation. Although complex showing the six most frequently mutated p53 and MDM2 bind residues of p53. The side chains of these residues HAUSP in a mutuare colored yellow, the core domain is light blue, and the DNA is dark blue. The zinc atom is shown ally exclusive manner, Shi’s team discovered as a red sphere. that MDM2 binds to where it acts a transcription factor, to HAUSP with a greater proteasomes in the cytosol. Accord- affinity than p53. They suggest that ingly, higher levels of MDM2 result perhaps MDM2’s conformation afin lower levels of p53. Interactions fords more extensive opportunities between p53 and MDM2 can be in- for association with HAUSP than hibited by the activity of kinases, does p53. To obtain insights into whose phosphorylation of p53 induces a conformational change that blocks MDM2 binding and instead Thus, controlling the activates the protein to transcribe cell cycle by interfering genes involved in cell damage reat a number of places pair, arrest, or death. Thus, controlin the p53 ameliorates ling the cell cycle by interfering at the cell cycle abnora number of places in the p53 pathmalities associated way offer potential mechanisms to ameliorate the cell cycle abnorwith cancer. malities associated with cancer. One such approach would involve the down-regulation of MDM2 to function, Shi and his colleagues block p53 degradation and thus up- used crystallography to determine regulate its levels. This should help the structure of HAUSP’s catalytic to achieve normal rates of cell pro- domain. They discovered that subliferation and death in cancer cells. strates bind to a groove in a section Insights into achieving this end called the TRAF (Tumor Recepbecame possible several years ago tor Associating Factor) domain at with the discovery of HAUSP, an the N-terminus of HAUSP via a

small peptide of five to six amino acids. They were able to elucidate the oligopeptide sequence by generating mutations in amino acid residues at the substrates’ binding sites and observing the effects. The researchers reason that interfering with HAUSP function antagonizes cells’ ability to deubiquitylate MDM2. If MDM2 remains tagged for degradation, its levels will decrease. Without functional ubiquiting ligase to target p53 for degradation, the protein’s levels will rise. The therapeutic approach involves designing small inorganic or peptide-like molecules, which simulate the MDM 2 moeity that binds to the TRAF domain of HAUSP. This “peptidomimetic” molecule would thus act as a competitive inhibitor by associating with HAUSP in such a way that prevents it from interacting with MDM2. As a result, MDM2 will remain ubiquitylated and it will be degraded, boosting the amount of p53 to levels that will slow growth and induce apoptosis of tumor cells. Shi looks enthusiastically toward collaboration with venture capitalist firms to synthesize such compounds. Once a few lead molecules have been produced, pharmacokinetic analysis of their effect on restoring p53 can be tested in cells that over express MDM2.

I’m a junior in the MOL departments pursuing a WWS certificate, and I’m from Pearl River, NY, a suburb outside NYC. I’m interested in a career in oncology clinical research.

5

ba cter i a

provide model for

EVOLUTION // BY LAJHEM CAMBRIDGE

I

n order to understand the complexities of the real world, scientists often refer to models. In this same manner, a team made up of Princeton scientists, including Juan Keymer, Peter Galajda and Robert Austin – all members of the Physics Department, with strong backgrounds in Biology – have come up with a way to model evolution. In year and a half, these scientists have created a mini ecosystem played out on silicon. Escherichia coli, a bacterium commonly found in the intestines of humans and other animals, has commonly been used in laboratories and is well researched. In this model, a silicon structure which provides compartments that contain different levels of resources houses the E. coli. The bacteria must then adapt to the different environments in order to survive. The scientists track the E. coli and observe how these factors affect the population growth. They are able to monitor and tweak the different en-

6

vironments in which the E. coli live. important to consider that human Initially, Keymer and his col- cells are approximately the same leagues were unsure if their experi- size as the E. coli bacteria, and that mental bacteria would behave in the even the most complex biological systems are entirely same manner as they would By simply rewarding dependent upon the interaction between under normal bacteria with food or cells. Moreover, conditions punishing them with just as in natural given that the a laser, scientists can environments, the E. coli might interact differcreate the bacterial bacteria find nichor “pockets of ently in a concells they prefer . es, opportunity,” acfined space. cording to KeyYet using such a small scale to model real world mer, responding to abundant recomplexities can be quite useful, sources or competition. The E. especially in this case. First, it is coli bacteria interact in the same

way, finding niches and adapting for example, using and evolving to find and fill them. plasmids to alter The research being done is heav- the cell’s DNA or ily based in both theoretical and using macrophages evolutionary biology. Darwin is as a microbiologist most famous for putting forth his would, these scientheory of evolution in On the Origin tists need only to of Species. This theory states that alter the environby natural selection those organisms ment to effect the better adapted to an environment desired changes. will produce offspring that have in- With this nanotechherited the genes that enabled the nology, the scienparents to survive. This process can tists can essentially then lead to a new species. In this engineer cells. Just experiment, however, it is difficult through what is to say definitively whether or not the understood about A florescently labeled sample of E. coli bacteria. E. coli bacteria have evolved, since natural selection, they drawing the line between species is can select for bacteria that produce be replaced by inexhaustible appamore difficult for single-celled or- a certain byproduct. By simply “re- ratuses, as long as food is provided ganisms. Furthermore, the common warding” the bacteria with food or for the bacteria. According to Keydefinition of a species requires the space, or by “punishing” them with mer, another outcome is the possilight from a laser, bility of adding “bio-functionality” organisms to interscientists can choose to certain materials, such as silicon breed and produce The industrial and create the bacte- or metal alloys, so that the materifertile offspring, applications of rial cells they prefer. als gain organic function. Similarly, but bacteria such this technology are In theory, the sci- the medicinal uses may become iras E.coli asexubound only by entists can make a replaceable, as the bacteria strucally reproduce, the imagination. whole structure, on ture could be used in transplants, thus quickly rena bigger scale, with perhaps to consume an unwanted dering this definition inapplicable. The team of compartments full of bacteria cre- toxin or provided any number of scientists, however, has been able ating different products. This in- life saving substances. Although the to obtain cells that have adapted frastructure can become a cheaper realization of such applications will to and survived the environments or more efficient alternative in re- require a great deal of research and in which they have been placed, source production. What normally time, the merge of nanotechnology and thus, they have been able to would require money, many trials, and biology in this project to create observe the process of speciation and space, can be simplified and these “bacteria machines” is comand evolution from the beginning. streamlined. For example, in one pletely innovative and surely will Moreover, despite initial concerns, compartment scientists can select for lead to advances in many industries. the bacteria are successfully pro- bacteria that produce hydrogen and viding a great experimental eco- another, oxygen; alter the niche and system that is helping scientists to alter the cells. It’s as simple as that. Lajhem is a freshman who The industrial applications of understand the natural environment. plans on majoring in molecular biology with a pre-med focus. Another novel development born this technology are bound only by She is very involved in biology research and has spent the last of this research has several interest- the imagination. For instance, givtwo summers in a biology lab at Rider University. She has lived in ing implications. Instead of working en this technology, cumbersome New Jersey for most of her life. from the inside of the bacterial cells, oxygen tanks could theoretically

7

Feedback A

Regulation of T // BY JENNIFER HSIAO

A

n important metabolic pathway for organisms is de novo (i.e. synthesis from smaller molecular precursors with lower molecular weight) pyrimidine biosynthesis. Pyrimidine nucleotides include uridine, cytidine, and thymidine phosphates and they are needed for DNA replication and RNA synthesis, processes which are important for all organisms. In the first step towards pyrimidine biosynthesis, an enzyme called aspartate transcarbamylase (ATCase) catalyzes the conversion of reactants L-aspartate and carbamoyl phosphate to carbamoyl aspartate. ATCase is a model enzyme for studying allosteric regulation. Allosteric comes from the Greek words allos, meaning “other,” and stereos, meaning “shape.” Therefore, allosteric regulation refers to the control of enzyme activity through binding of an effector molecule to a site other than its active site (i.e. an allosteric site). The allosteric binding causes a conformational change in the structure of the enzyme. This can either inhibit or enhance the activity of the enzyme. Another common example of an allosterically regulated protein is hemoglobin, which carries oxygen within a red blood cell. The binding of oxygen to hemoglobin causes a

8

C

conformational change in hemoglobin such that the affinity for oxygen of its active sites is increased. ATCase is comprised of two different subunits; the larger subunit is the catalytic (c) subunit, while the smaller one is the regulatory (r) subunit. The regulatory subunit has no catalytic activity. The catalytic subunit binds the substrates (both reactants, L-aspartate and carbamyl phosphate), while the regulatory subunit can bind NTPs (N=A, C, G, or U), and is responsible for the allosteric aspects of ATCase. Wang et al. have experimentally observed ordered substrate binding, whereby carbamoyl phosphate binds first, causing an induced-fit conformational change. This transformation alters the electrostatics of ATCase’s active site, thus establishing a suitable binding site for L-aspartate. The binding of L-aspartate triggers a second induced fit conformational change, the “domain closure,” which not only causes a quaternary conformational change, but more importantly facilitates the catalytic reaction (Wang 2005). CTP and UTP are inhibitors, and ATP is an activator; these have all been shown to bind to the regulatory (r) subunits (Bethell 1968). According to Bethell et al.,

A S E

inhibition of ATCase by CTP results because such allosteric binding by CTP drastically reduced the affinity of ATCase for its substrate carbamoyl phosphate (Bethell 1968). ATCase exists in two states: the relaxed (R) and tense (T) states; in the absence of a fixed concentration of either substrate, ATCase is in equilibrium between the two states. ATCase has a lower affinity for substrate (and thus lower catalytic activity) when it is in the tense state. CTP inhibition of ATCase activity is an example of feedback regulation where the end product regulates the activity of an earlier step. The mechanism of inhibition is stabilization of the tense state. ATP, on the other hand, binds to ATCase at an allosteric site in such a way as to enhance the activity by stabilizing its R state conformation. I have been doing experiments with ATCase in Professor Josh Rabinowitz’s lab at Princeton for about a year. For my experiments, Professor Evan Kantrowitz of Boston College has generously provided me with ATCase that has been purified from E. coli cells from his lab. My first experiments consisted of trying to replicate data from the literature. There has been an enormous amount

of research done on this enzyme. For my experiments, I use a colorimetric assay modified from that of Prescott and Jones and also that of Kantrowitz. An acidic color reagent – which quenches (stops) the reaction – is added to the reactions after they have been allowed to run for about 16 minutes. After being incubated in the dark at room temperature for at least 16 hours (during which it reacts with the product carbamoyl aspartate), it is then exposed to fluorescent light at 45°C for 24 minutes (the reaction is timesensitive). A yellow color develops that is linearly proportional to the amount of carbamoyl aspartate produced during the reaction: the more intense the yellow color, the more product has formed. An instrument called a spectrophotometer is used to measure the intensity of the yellow color at an absorbance of 466 nm. The reactions are carried out in borosilicate glass tubes at pH 7. Water, buffer (with a known concentration of ATCase), and a known concentration of L-aspartate are added to each tube. Then NTPs are added. The reaction is initiated by the addition of carbamoyl phosphate and is allowed to run for 16 minutes before being quenched with the color reagent. At first, I only experimented with

a single NTP. This was mainly done to ensure that my experiments produced results that matched the literature. It was found that—in agreement with the literature—at pH 7, ATCase activity was inhibited by CTP, further inhibited when UTP was used in combination with CTP, inhibited slightly by GTP, and enhanced by ATP. These experiments have already been performed, so what is more interesting now is the effect of different concentrations of multiple NTPs on the activity of ATCase. Recently, I have been investigating—in conjunction with Professor Herschel Rabitz’s lab, which is modeling the data using random sampling-high dimensional model representation—the effect of four NTPs (CTP, ATP, GTP, and UTP) in combination, varying the concentrations of each for each reaction tube. The analyses from these experiments are still in progress. The study of the effects of NTPs on ATCase provides insight into crucial and interesting mechanisms in the cell, especially that of feedback regulation. The cell has developed its own way of synthesizing some of the components it needs to function as well as its own way of regulating how much of the product it

produces. In the case of pyrimidine biosynthesis, the end product of the pathway (e.g. CTP) can inhibit the activity of the enzyme. In doing so, it prevents the cell from wasting its resources and making too much of the product. On the other hand, if there is more end product needed, ATP, a purine nucleotide that is not part of that pathway, can enhance the activity of the enzyme and induce it to produce more pyrimidine. _____________ References: Bethell, M. R. (1968). “Carbamyl Phosphate: An Allosteric Substrate for Aspartate Trancarbamylase of E. Coli.” Proceedings of the National Academy of Sciences of the United States of America 60(4): 1442-49. Else, A. J., and Herve, G. (1989). “A Microtiter Plate Assay for Aspartate Transcarbamylase.” Analytical Biochemistry 186: 219-221. England, P., Leconte, C., Tauc, P., Herve, G. (1994). “Apparent Cooperativity for carbamylphosphate in Escheria coli aspartate transcarbamylase only reflects cooperativity for aspartate.” EJB 94: 775-80. Gerhart, J. C., and Pardee, A.B. (1961). “The Enzymology of Control by Feedback Inhibition.” The Journal of Biological Chemistry 237(3): 891-6. Prescott, L. M., Jones, M.E. (1969). “Modified Methods for Determination of Carbamyl Aspartate.” Analytical Biochemistry 32: 408-419. Tymoczko, J. L., Berg, J., and Stryer, L. Biochemistry. 5th Ed. New York: W.H. Freeman and Co., 2002. Wang, J., et al. (2005). “Structural basis for ordered substrate binding and cooperativity in aspartate transcarbamylase.” PNAS 102(25): 8881-8886.

Jennifer Hsiao ‘07 is from Windsor, CT. She is majoring in Chemistry with certificates in Latin and Music Performance. She is working in the Rabinowitz lab for her senior thesis.

9

NASA Chief Scientist Discusses

and Space Program

ertical take-off, landing vehicles, virtual reality, antimatter fuels—you may think that these belong to the realm of science fiction... ...and are not a part of the technology of the immediate future, but for researchers working in technological frontiers, the boundary between the two realms is rapidly merging. Such is the view of Dennis Bushnell of the National Aeronautics and Space Administration (NASA). Dennis Bushnell, invited by the Princeton chapter of the American

Institute for Aeronautics and Astronautics (AIAA), discussed the future of NASA’s projects and space program. Having worked at NASA for 41 years, Bushnell is now the chief scientist at the administration’s Langley Center at Hampton, Virginia. Before working for NASA, Bushnell completed his B.S. in Mechanical Engineering at the University of Connecticut and a M.S. degree in Mechanical Engineering at the Univer-

by Kevin Kung 10

sity of Virginia. He has been fascinated by flow modeling and speed range control research, which was partly why he decided to work for NASA. Throughout his career, Bushnell has received numerous awards and has been appointed by groups like the National Academy of Engineers. Presently, Bushnell considers the space program to be in crisis because of major job cuts and reduced research funding. But despite these conditions, Bushnell is confident that “things can only get better.” In order to improve, however, there is a tremendous need to reinvent. Bushnell focused on two aspects: the social application of past space research and the space pro-

“The major feature of VTOL is that it is point-to-point, safe, long-ranged, and automatic; there is no need to steer.”

gram of tomorrow. The primary social application of space-program technologies can be divided into three groups: transportation, telecommunications, and virtual reality. With regard to transportation, Bushnell concentrated on what he called the PC version of aviation, the automatic robotic vertical take-off and landing (VTOL) delivery vehicles. The major feature of VTOL is that it is point-to-point, safe, long-ranged, and automatic; there is no need to steer. Bushnell envisions the replacement of ordinary automobiles with VTOL, accompanied by the civilian use of high-resolution global positioning system (GPS) and satellite communications. VTOL’s ability to fly and drive as well as its higher energy efficiency have many implications. The population density along the Eastern Seaboard can be reduced as long-distance travel becomes more affordable, and in turn, traffic congestions will diminish. Furthermore, Bushnell mentioned that VTOL was approved for possible use in future warfare. Thus, there is potentially a twofold market for VTOL: commercial and military. Telecommunications and virtual reality are two other intricately linked areas within NASA. In the

area of virtual reality, the successful implementation of haptic touch, smell, and taste by an M.I.T. group in 2004 has been one such breakthrough. Bushnell mentioned future advances such as optical communications and direct brain feeds by virtual stimuli. In five to seven years, he predicts many business meetings and conferences will be held through virtual reality, preventing the need of extensive travel. Even ordinary routines such as shopping may also take the form of tele-control. What exactly will motivate these technological developments? According to Bushnell, lowered costs and reduced traffic congestion will serve as a strong incentive: he estimates that the combined profit for these technologies may sum up to one trillion dollars annually. The other facet of NASA is the future of the aerospace program. The path of airplane research will likely differ from that of spacecrafts because the two areas of research

are surrounded by different environmental and technical issues. In aircraft design, Bushnell emphasized that it is the emission of water vapor, instead of CO2, that will produce the most significant environmental impact. This is because high-altitude water vapor induces artificial cirrus clouds, which in turn alter the Earth’s albedo—the means through which solar energy enters and leaves the planet. Thus, while fuel cells are an important technology in reducing CO2 and nitrous oxide emissions, they are equally disastrous for NASA because the burning of hydrogen gas produces dangerous amounts of water vapor. Other environmental problems related to airplanes include ozone depletion, the generation of high-temperature regions, and sonic booms. Several proposals have been offered to effectively deal with these problems. Some of them include flying below 30,000 feet, storing electricity in airplanes, injecting water for take-off, managing waste products more appropriately, and improving aircraft design. Bushnell explored the latter three proposals at length. The main function of take-off water injection is to reduce aircraft noise.

“In aircraft design, Bushnell emphasized that it is the emission of water vapor, instead of CO2, that will produce the most significant environmental impact.“

11

“...one method of reducing radiation exposure is to bury the crew inside a hydrogen gas tank. A low-level pulsating electromagnetic field may slow down bone loss due to microgravity.”

12

Though high-altitude water vapor creates problems, it usually poses no significant issues at ground level. On the other hand, the emission of waste products can be avoided by efflux-storage technologies such as storing water as ice crystals to be brought back to the ground. Concurrently, an important area of design development is the so-called Pfenninger strut and truss-braced wings. The tail of an airplane in this design actually slants forward and joins the main wings. If the concept is optimized, then a high aspect ratio can be achieved, allowing the aircraft to travel at high speeds (Mach 2) without experiencing considerable drag and conserving fuel. Perhaps the field most easily associated with NASA is space exploration. Bushnell sums up the present paradox as “what is safe is not affordable and what is affordable is not safe.” Indeed, especially after the explosion of Columbia, the question of human and operational safety is of paramount importance to NASA. In addressing hazards to humans in space, Bushnell raised several possible solutions. For instance, one method of reducing radiation exposure is to bury the crew inside a hydrogen gas tank. A low-level pulsating electromagnetic field may slow down bone loss due to microgravity. In addition, there is the more controversial concept of “designer humans,” whereby some people are genetically modified to be fit in space. In some instances, it is advisable to reduce the number of people in space. To achieve this end, holographic astronauts, generated on

earth using virtual reality techniques discussed above, may replace actual crew. Of course, a problem with a holographic crew is that the spacecraft is confined to a limited space around the Earth: a longer distance delays transmission. Bushnell even hinted at 2001: A Space Odyssey, a Stanley Kubrick film from the late 1960’s, in which, for long-distance travel, the astronaut’s hypothalamus is suppressed, leading to suspended animation and a lower metabolic rate. In addition to crew safety in longdistance flights, the possession of an affordable and efficient power and propulsion source is indispensable. There are no less than eight current areas of research. For example, antimatter fuels and nuclear fusion exploit the enormous amount of energy released by converting mass to energy, drawing upon Einstein’s proverbial equality, E = mc2. There are also thoughts on capturing the radiation pressure from cosmic rays using “solar sails” and cultivating hydrogen-fuel-producing plants or microbes, which may be promising not only for space flight but also as a substitute for oil in cars. Bushnell also stresses the importance of inspace infrastructures, such as the International Space Station (ISS), as nodes between near-Earth and interplanetary travels. If some of these technologies can be developed successfully, then they will translate into important applications within our society, repeating a cycle of invention and application. In Bushnell’s view, the predicted era of change from automobile to

VTOL vehicle resembles the transformation from horse to automobile of the early 20th century. Both eras, he argued, are characterized by growths in economy, speed, and possibility frontiers. However, he also believes that the current transition will be easier, since, whereas a high cost was expended to build the infrastructure for automobiles, the transformation from cars to VTOL vehicles and other comparable technologies “is a matter of electrons.” We eagerly await the technological advances the future will bring. translate into important applications within our society, repeating a cycle of invention and application.

The Bell Boeing V-22 Osprey, a successful V/STOL military aircraft designed both to take off like a helicopter and fly at high altitudes as a turboprop airplane.

A physics major hailing from Taipei, Kevin Kung (‘08) has enjoyed writing for magazines such as The Innovation, besides various other exploits. He writes half what he believes, and he believes half what he writes.

The Cosmos 1 spacecraft, designed to be propelled by its solar sails (prominent in this illustration), is one of the first attempts to implement this method of energy capture.

The Moller M400 Skycar, a commercial VTOL model that its makers hopes will become an affordable household item.

13

Redesigning the Hydrogen Fuel Cell

// BY BRIAN LEVEE

An accidental discovery made by Professor Jay Benziger and Claire Woo ‘06 is redesigning fuel cells in an unforeseen niche market.

S

ome of the best discoveries are accidental. Penicillin, the x-ray, and Velcro are some examples. Although accidental discoveries are impressive because of their novelty and unpredictability, it still takes a pioneering intellect to appreciate the applicability of what has been found. In the summer of 2006, such a discovery in hydrogen fuel cells was made by Jay Benziger, Professor of Chemical Engineering, and Claire Woo ’06. In order to appreciate the ingenuity and significance of the Benziger-Woo fuel cell, it is helpful to understand the way the typical fuel cell works. First, hydrogen fuel enters the cell and is broken up into its constituents upon reaching the anode catalyst, forming a proton and an electron. The electrolytic membrane then allows the proton to filter

14

through while the electron is forced more current. In order to control to move around the membrane, pro- output, the typical fuel cell utilizes a viding a flow of electrons that pro- mechanism that modifies the amount of fuel allowed vides the current to enter the cell. that produces What differentielectric power. Not only did the ates the BenzigerThe electron cell provide a simWoo fuel cell is that and proton join ple and efficient it does not need an at the cathode water regulating external power-conwhere they react mechanism, but it suming mechanism with oxygen to also allowed the to control power form water. In the output. It regutypical fuel cell, fuel cell to maintain lates its own power. the water is then constant power When Benziger transported out output without reand Woo began their of the fuel cell quiring any outside research project, through evacumechanism. their intention was ation tubes. The to illustrate that such power output of self-regulation was the fuel cell is related to the amount of hydrogen impossible. Rather than designing fuel that enters the cell—the more the fuel cell to regulate its air inhydrogen, the more electrons, the take, which was the conventional

inside the chamber increases due approach to integrate self-regula- to additional hydrogen fuel intake, tion into fuel cells, Benziger and water is pushed downwards causWoo designed a cell that regulates ing the volume of the chamber to the volume of the reaction chamber. increase, thus decreasing the fuel By allowing the water produced in cell’s power output. A drop in presthe reaction to fall to the bottom of sure causes the water level to rise the chamber, rather than evacuat- while lowering the chamber volume ing it through complex channels, and increasing power output. DYT as was done in previous fuel cells, When their simple power they unknowregulating cell worked, Beningly created the ziger and Woo new self-reguWhereas the typical were astonlating fuel cell. Honda or Toyota veIf the figure ished. They hicle fuel cell converts soon realized of the fuel cell that their design were turned on only 30 to 40% of the was progresits side so that hydrogen fuel into sive in a numthe cathode pole power, the Benzigerthat allows waber of ways. Woo fuel cell is nearly Not only did ter and heat to the cell provide leave the system 100% efficient. a simple and is on the botefficient water tom, water collects on the bottom of the cell due regulating mechanism, but it also alto gravity. The water level is able to lowed the fuel cell to maintain conrise or fall due to the pressure inside stant power output without requirthe cell by attaching a tube to the ing any outside mechanism. This hole where the water would typi- new design increases the efficiency cally leave the cell thus allowing of the fuel cell by eliminatthe water to reach an equilibrium ing the need level that is sensitive to air pressure. When the pressure

to expend energy on power output control and water evacuation. In addition, whereas the typical Honda or Toyota vehicle fuel cell converts only 30 to 40% of the hydrogen fuel into water and power and then relies on another mechanism to retain the extra hydrogen fuel that was left over for the next cycle, the Benziger-Woo fuel cell is nearly 100% efficient. The water at the bottom of the chamber blocks all escape paths during the reaction, causing the chamber to be securely enclosed, allowing it to be perfectly efficient, bypassing the need for hydrogen clean-up. Benziger explains that their “work is leading the way for thinking about how to redesign the fuel cell as a chemical reactor.” Rather than using the fuel cells in automobilesDYT, which is the primary focus of most private hydrogen fuel cell developers, the newly designed fuel cell will function mainly in small engines, such as lawn mowers. According to Benziger, the small engine mar-

Professor Benziger in his lab at Princeton.

15

Hydrogen fuel could be bought from stores and plugged into fuel cell devices in the same way that propane is purchased to fuel barbeques.

ket is a major source of pollution in suburbia because such engines lack emission controls and therefore most are highly polluting. The BenzigerWoo design holds a significant potential for reducing such pollutants. The Benziger-Woo fuel cell also provides the most utility to small engines because in small fuel cells, a large portion of the power output is used for regulating and exporting water. In small engines, like lawn mowers, the new design

may save a significant percentage of the power output, causing the Benziger-Woo fuel cell to be more economically viable in this niche rather than in larger engines where the extra power is less significant. Unlike the serious infrastructural problems facing fuel cell-powered automobiles, the use of this technology in smaller engines would not present such a problem. Hydrogen fuel could be bought from stores and plugged into fuel cell devices in the same way that propane is purchased to fuel barbeques.

Although their innovation will probably not reshape contemporary electronics, it holds great promise for solving a myriad of technical problems making hydrogen fuel cells more efficient and useful to an environmentally conscious world.

My intended major is either EE or physics. I am a freshman from Los Angeles. I don’t surf, but I live a few blocks from the beach. I know, its a crime.

17

Genetically N Engineered

Malaria Resistant Mosquitoes // BY JOSEPHINE WOLFF

18

ew advances in the development of malaria-resistant mosquitoes suggest that when a cure for malaria is discovered it may bring about a new breed of mosquitoes rather than a vaccine. For decades, scientists have been working to create a malaria vaccination to combat the widespread mosquito- Plasmodium merozoites being released from borne infectious disease a lysed red blood cell. that kills between 700,000 and 2.7 million people every year . Some biologists, however, have been working on developing genetically engineered mosquitoes which are immune to the disease and thus can not transmit the disease to humans. Two recent breakthroughs in this line of genetic engineer- The mouse and chicken strains ing may prove to be more in- of malaria are easier to manipustrumental in eradicating ma- late for laboratory research than laria than the ongoing search the human strain, and although for a vaccine has ever been. they, represent fairly accurate Jason Rasgon, a professor of models for the human strain, the microbiology and immunology parasites are not entirely similar. Malaria is caused by Plasat Johns Hopkins University, led modium parasites that are transa research team that developed a breed of mosquitoes resistant to mitted by female Anopheles Plasmodium berghei, the strain mosquitoes. The mosquitoes of malaria that infects mice. An- consume the parasites while other study, led by molecular bi- feeding, and, once ingested, the ology professor Anthony James Plasmodium parasite’s male and from the University of California female gametes fuse and form at Irvine, genetically engineered an ookinete in the mosquito’s mosquitoes that are resistant to gut. The ookinete then develPlasmodium gallinacium, the ops into an oocyst that releases malaria parasite for chickens. sporozoites. The sporozoites Although researchers have yet move through the mosquito’s to develop a breed of mosqui- circulatory system to the salitoes resistant to human malaria, vary glands and are then inthese two studies represent ma- jected into a human host when jor progress towards that goal. the mosquito bites a person.

the challenge of how to genetically modify the Anopheles mosquito. In order to alter the genetic code, they needed to attach a new gene to a transposon (short piece of DNA) that would incorporate itself into the mosquito’s genome. This process had been successfully implemented with fruit flies using How malaria from a parasite infects its host. the P transposon. However, researchDifferent scientists have attempted ers discovered that the same transto target the Plasmodium parasites poson used in fruit flies did not sucand eliminate them in the engicessfully modify neered mosquithe genome of toes at different mosquitoes. points in the In the 1990s, The advances made parasite’s life researchers at cycle. James’ by Rasgon and the University research team of Maryland at James suggest that created a gene College Park that produces it will not be long and the Univeran antibody for sity of Califorbefore a mosquito a protein found at Riverside in the Plasmodiresistant to human nia discovered a um sporozoites. new series of malaria can be The researchtransposons ers introduced engineered. including the the gene into Hermes transthe mosquiposon, which toes by inbiologists found fecting them with a virus and the could be used to successfully modify mosquitoes effectively eliminatthe genome ofAnopheles mosquitoes. ed 99.99% of the sporozoites in The advances made by Rasthe mosquitoes’ salivary glands. gon and James suggest that it will Initially, scientists struggled with

not be long before a mosquito resistant to human malaria can be engineered. Once that task is accomplished, however, scientists will face the obstacle of replacing the existing mosquito population with the new malaria-resistant breed. Since the malaria disease affects mosquitoes as well as humans, the resistant mosquitoes would have a significant advantage over the nonengineered mosquitoes. Rasgon’s team performed a study showing that, in a population with equal numbers of the malaria-resistant mosquitoes and regular mosquitoes, after nine generations, the genetically-engineered mosquitoes comprised over 70 percent of the population. These results indicate that if enough of the engineered mosquitoes were released, they could rapidly eliminate a large majority of the malaria-carrying mosquitoes by the process of natural selection. There would be no need to resort to the use of environmentally-hazardous pesticides. Though these studies are promising indicators of a future end to malaria, Rasgon warns that “we’re not anywhere near a field release.” The continued development of well-engineered malariaresistant mosquitoes is undoubtedly bringing biologists closer and closer to ultimately finding a cure.

Josephine Wolff is a freshman from Cambridge, MA. She hopes to study math or architecture and pursue a certificate in French. She also enjoys sudoku puzzles, playing the piano, Grey’s Anatomy, the Boston Red Sox, and the New York Times Sunday Styles section.

19

Taylor’s miracle cancer drug: Alimta // BY DAVID TAO f you were a lung cancer patient, your five-year survival rate would be around 6 percent for men and 7 for women. That very statistic itself could almost obliterate your hope for life, but a new pill on the market approved by the FDA could change that. Online fan clubs and doctors worldwide are hailing the drug as the most successful cancer drug in history. Approved in over 70 countries, this drug is not your typical extensively chemotherapy-backed, side-effects-ridden drug. Its name is Alimta and it could just make battling cancer that much easier. Dr. Edward C. Taylor of Princeton University developed Alimta in collaboration with Eli Lilly and Company. Dr. Taylor is the A. Barton Hepburn Professor of Organic Chemistry, Emeritus at Princeton. He is one of the world’s foremost experts on heterocyclic compounds

I

20

and was previously a consultant for Eli Lilly. He did his undergraduate and graduate studies at Cornell. Surprisingly, chemistry was not even on his radar until late in high school. He was planning to do English, but after taking one chemistry class he became so enticed by the subject that he went on to take all of them his school had offered. The discovery of Alimta was not his expected goal. He jokes in a speech given at Princeton “No one would want to fund a project on the investigation of pigments in butterfly wings.” He points out that the lesson to be learned is the importance of original inquiry and he reminisces about “the golden days when researchers didn’t have to know the outcome before starting a project.” When Dr. Taylor sent the first sample of his new compound to Eli Lilly for tests, the company sent a letter to him saying there must have been a mistake and further trials were needed. When he received a second letter, Eli Lilly apologized to him and said there was actually no mistake. They were just extremely surprised that all types of cancer cells reacted to his new compound. In February 2004 after 12 long years of clinical trials, Dr. Taylor’s drug that goes by the brand name of Alimta also known as

Professor emeritus Edward Taylor developed Alimta at Princeton.

Pemetrexed (C20H21N5O6 ) was first approved by the FDA for treatment of non-small cell lung cancer and malignant pleural mesothelioma. Mesothelioma often surfaces approximately forty years after exposure to asbestos, and its effects are only now beginning to emerge. Luckily, however, this latency period has allowed Alimta to be devel-

“When Dr. Taylor sent the first sample of his new compound to Eli Lilly for tests, the company sent a letter to him saying there must have been a mistake. When he received a second letter, Eli Lilly apologized and said there was actually no mistake. They were just extremely surprised that all types of cancer cells reacted to his new compound. “

oped just in time to treat it. Alimta is in a chemical group similar to folic acid known as antimetabolites, and therefore, patients must be on folic acid and vitamin B12 supplements during the course of their therapy. Alimta functions by inhibiting three enzymes used in purine and pyrimidine synthesis—thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyl transferase (GARFT). This stops the precursors to nucleotide formation thereby preventing the synthesis of the DNA and RNA of cancer cells. A major advantage of

Alimta is the minimal preventive measures needed to counteract the side effects of the drug as compared to traditional chemotherapeutic procedures. Five to seven days before the first Alim-

ta injection, the patient is required to take a folic acid pill once every day. Folic acid can counteract the anemia associated with vitamin B12 deficiency over the course of the therapy. 350 to 1000 mg should continue to be taken until 21 days after the last cycle of Alimta. The

doctor will inject vitamin B12 the week the patient starts on Alimta and then every 9 weeks after that. The use of an oral steroid called dexamethasone will minimize the risk of a skin rash. What is most surprising is that this is also an outpatient treatment, almost unheard of in treatments against cancer. In addition, the side effects of this regimen amount to those characteristics of a minor flu including nausea, fever, sore throat, and loss of appetite. Compare this with those of traditional chemotherapy, usually

involving a combination of immune suppression, radiation therapy, and surgery with serious well-known side effects such as hair loss, anemia, malnutrition, cardiotoxicity, and even death. Currently, Alimta is under clinical trials for a host of other cancers. Dr. Taylor said “We have had complete cures of breast cancer, but it has not been approved yet and the treatment of colon cancer has been effective at Mayo Clinic.” Treatments of some are more effective than others, but Dr. Taylor hopes that some day Alimta can replace or supplement many of the other procedures and reduce the suffering of cancer patients. His contributions to chemistry and medicine have earned him the Heroes in Chemistry Award from the American Chemical Society and will continue to offer hope to thousands of cancer patients around the world. 1

From Lexington, KY Princeton Class of 2010 Potential molecular biology major and neuroscience minor.

Structural drawing of Alimta 1 “Cancer Survival Rates Improved During 19982001,” National Statistics Online, http://www.statistics.gov.uk/cci/nugget.asp?id=861 (accessed March 20, 2007). 2 Wikipedia.org, s.v. “Alimta”, http://en.wikipedia. org/wiki/Alimta (accessed March 20, 2007). 3 Ibid. 4 “Treatment with Alimta,” Alimta.com, http:// www.alimta.com/treatment/treatment/index. jsp?reqNavId=2.1 (accessed March 21, 2007). 5 “Alimta,” Drugs.com, September 29, 2006, http://www.drugs.com/alimta.html (accessed March 21, 2007). 6 Wikipedia.org, s.v. “Chemotherapy”, http:// en.wikipedia.org/wiki/Chemotherapy (accessed March 20, 2007).

21

The Art of Choosing Well

SM

Choosing a clinical research organization requires careful consideration of the differences among service providers. PharmaNet provides an unrivaled combination of experienced project management teams, senior management oversight, and an exclusive approach to building cooperative relationships with sponsors. For comprehensive Phase I–IV services in clinical development and consulting, choose your CRO wisely. Choose PharmaNet. Learn more about the premier global CRO serving pharmaceutical, biotechnology, generic drug, and medical device companies at:

www.pharmanet.com

© 2007 PharmaNet Development Group, Inc. All rights reserved. 0307.9989. The PharmaNet name, logo, and The Art of Choosing Well are marks of PharmaNet Development Group, Inc.

The Science and Ethics Behind Drug Testing and by Sarah Weinstein Clinical Studies S niffles, a scratchy throat, and a throbbing headache. Upon rushing off to the doctor’s office, eager to get antibiotics, one hardly stops to think of the creation and evolution of the desired medication. In fact, drugs undergo a lengthy process from lab tests to an eventual approval by the FDA before they can be sold on the pharmaceutical market. Pharmanet, for instance, is a company involved in the regulation of the clinical studies in drug development held subsequent to the drug-discovery phase in laboratories. A company like Pharmanet is employed by a pharmaceutical company looking to market a new medication and carries out and oversees all phases of the drug study. There are four such phases of testing that a drug must undergo before it gains FDA approval. Phase I is primarily focused on toxicity studies wherein patients are subjected to what is known as “dose escalation studies.” In these studies, the participants are given a certain dosage of the medicine that is gradually and incrementally increased to find the maximum tolerated dose of the drug. Given the nature of Phase I, patients par-

ticipating in the study are likely not expecting full treatment or recovery but rather are volunteering with the understanding that there is no guarantee that the drug will even produce the desired effects. Following this, Phase II involves the actual targeting of the population of patients that would be treated in a real world setting; thus the aim of these studies is efficacy, understanding how well the drug in question cures a particular illness. These studies are small in scale, involving no more than 10-20 hospitals and approximately one hundred patients. Phase III continues to focus on the patients targeted for use of a specific drug. These studies are large in scale, often global, and yield enough data for the FDA to decide whether or not to approve the drug. Phase IV, the final stage, involves thousands of patients taken from large patient registries. Participants in these studies will often buy a drug with the understanding that their results will be documented and used for these larger-scale studies. This phase tends to focus on the long-term effects of the drug and is consequently conducted after the drug has been approved by the FDA and sold on the market (i.e.

post marketing studies), and companies often use this phase to expand their label.

This entire process (Phases I-IV) can take anywhere from 7-10 years, and its duration depends heavily upon how quickly companies can recruit the patients needed for the study. Given the apparent complexity, there are several regulatory steps designed to keep the tests both ethically and scientifically sound. There are two boards in particular that monitor the studies – the Data Safety Monitoring Board and the Institutional Review Board (IRB). The Data Safety Monitoring Board is active during phases II-IV, reviewing the data (often blindly) and deciding whether or not to push the study through to the next phase. Thus, they look at the data and judge from a scientific standpoint whether or not it makes sense to move on with a study. The IRB on the other hand, is concerned less with what makes sense from a scientific or logical standpoint, and more

23

Phases of Clinical Drug Trials: Phase I: toxicity and dosage studies

Phase II: efficacy studies

Phase III: global efficacy studies

Phase IV: long term effects and post-marketing studies with whether or not the studies are ethically sound. At any point in the study, the IRB is capable of putting an end to the

tests on ethical grounds. Clinical drug studies present the companies with myriad pressing ethical issues. One of the first and most important considerations of a company conducting medicinal studies is ensuring that the participants are adequately informed about all the procedures and possible outcomes of the study. Prior to recently mandated informed consent forms, there was little regulation in this area, and in fact, these measures were developed in response to ethically repugnant experiments where the participants were not adequately informed about the study. The Tuskegee Experiment (1932-1972), for instance, was one of the most serious and notable studies gone morally awry. In this experiment, the physicians involved were aware that the participants were infected with syphilis, a serious sexually transmitted disease, and knowing this only told the patients that they were being treated for “bad blood” and in fact offered next to no treatment. Essentially, the physicians knowingly did nothing for the patients and instead followed the progress of the disease to completion. The participants of the study,

who were mostly poor, uneducated sharecroppers from Alabama were deliberately misled in order to ensure their full participation.

At one point, the patients were duped into participating in a dangerous spinal tap with a letter that was sent out entitled “Last Chance for Special Free Treatment.” The Tuskegee experiment has been referred to as “the longest nontherapeutic experiment on human beings in medical history1,” and indeed, the experiment had severe consequences. After the forty years of experimentation, 28 of the men had died of syphilis, 100 had died of related complications, 40 of their wives had been infected, and 19 of their children had been born with congenital syphilis. Thus, when the full gamut of the researchers’ ethical transgressions were revealed to the public, it became painstakingly clear that stricter regulations were necessary. A second more circumstantial ethical issue in clinical studies arises when a particular patient wants to participate in a study but for whatever reason does not qualify. For instance, oncology studies often require of their patients a certain white blood cell count; patients falling below the desired count would not be admitted to the study. In this case,

Upon rushing off to the doctor’s office, eager to get antibiotics, one hardly stops to think of the creation and evolution of the desired medication. 24

the doctors are aware that on the one hand the patient might benefit significantly from having access to this medicine, but on the other hand, they are conscious of the fact that allowing a participant who failed to meet the necessary requirements is likely to contaminate the results. Most companies are thus rather strict about not allowing unqualified participants into the study. However, some patients can acquire what is known as a single patient IND (investigational new drug) on a “compassionate use basis.” This type of exception allows one patient to get the drug apart from the study for one cycle of treatment even though the drug is not FDA-approved.

access to the experimental drug – once the study is concluded. The current system of clinical drug testing is long and painstaking, compounded by a series of ethical concerns, and yet it is only one small step in the larger process taking a drug from its inception to a shelf in your local pharmacy. Perhaps in leaving the drug store, antibiotics in hand, you might stop to consider the complexity and evolution of drug development and the years of laboratory work and clinical testing that made your purchase possible.

Finally, the most widely discussed ethical issue concerning clinical drug studies is the use of placebos for studying the treatment of serious medical conditions.

Sarah is a junior in the philosophy department pursuing certificates in French and music performance. She is from Ft. Lauderdale, Florida but secretly loves the snow.

Along the same lines as the last ethical conundrum, the use of placebos is essentially the purposeful nontreatment of a condition that is potentially terminal – one that might theoretically be cured by dispensing the actual drug to all test subjects. To avoid this problem, drug companies often will give the standard treatment to one group of patients, and to the second group they will give the standard treatment plus the experimental drug, so that each patient is at least receiving some form of treatment. When it is impossible to incorporate a standard drug into the study, then patients who are initially given only placebos later have

1

Encylopedia Brittanica.

A man being treated during the Tuskegee Experiment, which involved the deliberate withholding of treatment information from citizens suffering from syphilis.

25

Screening for inhibitors of protein aggregation to halt the onset of

Alzheimer’s Disease // BY JILL FEFFER

A

ccording to chemistry professor Michael Hecht, Alzheimer’s disease (AD) is becoming “a number one health problem” because people are living longer nowadays. AD has become prevalent because the average human lifespan has been lengthened by advances in medical technology. He elaborated that AD is a “post-evolutionary disease,” meaning it was not eradicated by natural selection because it only strikes after the reproductive age and at an age that people did not naturally live to see, so it was never an evolutionary concern. According to the Alzheimer’s Association’s web-

26

site, “one in 10 individuals over 65 and nearly half of those over 85 are affected.” The most apparent symptoms of AD are loss of memory and cognitive functions, and physiological signs of AD include the degeneration of neural cells and the growth of protein tangles in the brain. Evidence from previous scientific studies indicates that a certain threshold of protein tangle accumulation is associated with the onset Michael Hecht developed the of AD, so Dr. Hecht rationalized Professor screen in his Princeton chemistry lab. that an effective treatment would only have to slow the aggregation marker provides the basis for one process enough to keep accumula- ongoing research project in Hecht’s tion below this threshold, not stop chemistry laboratory. As a result of it entirely, which would be a more an investigation into the molecular daunting task because protein ag- causes of AD, he has developed an gregation is a naturally occurring, inexpensive method for screening constant process in the brain. In libraries of small organic molecules fact, it is estimated that there is a for inhibitors of the aggregation of mere 20% difference in the accumu- the protein A-ß-42, a known component of the amyloid lation totals between protein plaque that non-AD patients and builds up in the brains those afflicted with The screen is a of AD patients, with the disease. The promising initial the hope that their realistic research tool for selecting identification will lead goal is therefore to find a way of delay- proteins that mer- to a preventive treating the threshold it further scrutiny. ment. The screen is advantageous because level of accumulait is high-throughput, tion for a few years, meaning it can test many candidates thereby delaying the onset of at once; it is cost-effective; it is selecAD, perhaps permanently if the tive for inhibition at earlier stages of lag is long enough for people to amyloid accumulation; and its trials die of something else in old age. are relatively easily reproducible. This particular physiological

The screening process employs the bated for three hours becommon biological method of iden- fore an automated plate tifying inhibitors by monitoring the reader checked for fluoactivity level of a reporter protein. rescence. Samples were In this case, A-ß-42 is fused to green screened multiple times fluorescent protein (GFP) from jel- and consistent fluoreslyfish. GFP activity is easy to deter- cent positives, or “hits,” mine because, as the name suggest, were identified as posit fluoresces. This protein folds into sible A-ß-42 aggregaan active state at a much slower tion inhibitors. Subserate than A-ß-42 aggregates, so in quent experiments have the absence of an inhibitor, A-ß-42 proven that a comparawill aggregate quickly and interfere ble screen, although less A protein inhibitor at work. with GFP’s folding process. Conse- efficient, can be performed in vitro the Broad Institute at MIT using the quently, the fused GFP will only be rather than in E. coli cells to detect screen to test libraries there for inable to fold correctly and fluoresce the same hits so the hits are not con- hibitory capacity. Once inhibitors if the fused A-ß-42 does not aggre- tingent on the presence of bacterial are identified, the next steps would gate because an inhibitor is present. cells. Electron microscopy results be to perform specialized research such as animal studies in order to This screen have confirmed the eventually produce something that avoids the pitinhibitory capacis clinically useful such as pharmaOnce inhibitors are fall of being ity toward A-ß-42 of ceuticals that can be preventive rathidentified, the next prone to genermany proteins idener than therapeutic, as all presently ic inhibitors of steps would be to tified as hits by the available treatments for AD are. Dr. protein folding screen. Thus, the perform specialized Hecht hopes the screen’s potential to because GFP screen is a promising research such as ani“turn partial chemical effectiveness folding would initial tool for selectmal studies in order into full effectiveness at the pubbe likewise ining proteins that merlic health level” will be recognized to eventually produce hibited by them. it further scrutiny. something that is clini- Dr. Hecht said the in time to save many aging Baby In the initial Boomers and their families from the execution of the cally useful original AD-related drawn-out suffering caused by AD. screen, a library experiment involved of approximatemutating parts of ____________________ ly 1000 triazine compounds (a class A-ß-42 to see how to prevent agof organic molecules with the em- gregation. The idea for utilizing Kim W, Kim Y, Min J, Kim DJ, Chang YT, & Hecht MH (2006) A High-Throughpirical formula C3H3N3) was test- GFP as a reporter protein arose put Screen for Compounds That Inhibit ed for inhibitory capacity toward separately, from a 1999 paper about Aggregation of the Alzheimer’s Peptide. A-ß-42 aggregation in the following proteomics, specifically testing the ACS Chemical Biology 1, 461-469. manner: E. coli cells containing the solubility of proteins. Initially, his genes to express the fused protein laboratory wanted to use this techwere distributed into 96 wells. In- nique for devising solubility for dividual candidate molecules from proteins they generated de novo. Jill is a sophomore from New York majoring in molecular biology. She the library were added to each well The two strains of thought eventuplays flute and is Business Manager for the Wind Ensemble. In addiand an activator, isopropyl-ß-D- ally merged to produce the screen, tion to the biology and chemistry thiogalactopyranoside, was added which was published in 2006. involved, Jill is personally interested in research that holds promise for to induce production of the fused Currently, a graduate student treating Alzheimer’s disease. protein. The setup was then incu- from Dr. Hecht’s laboratory is at

27

Two New Courses Coming Next Fall Science Journalism

Fountain of Youth Lecture

STC 349 Professor Michael D. Lemonick Develop your science writing skills from a journalism perspective and learn how to present complex material about science and technology for non-technical readers. Through class discussion, analysis of published writing exercises, as well as interviews with Princeton scientists, participants will learn to write about science with both clarity and style.

Health and Human Rights in the World Community STC 398 Allen S. Keller

2007 E vening L ecture Genes from the Fountain of Youth From Worms to Mammals: Genes that Control the Rate of Aging

Thursday, May 3, 2007

Interested in the relationship between health and human rights? Learn about human rights violations in the world today and analyze their health consequences. In this course you will consider how individual and community health can be improved by protecting and promoting human rights. You will also explore the role of the health professional in caring for victims of human rights abuses, documenting the health consequences of human rights violations, and participating in human rights advocacy in education.

PROFESSOR CYNTHIA KENYON Herbert Boyer Distinguished Professor of Biochemistry and Biophysics, University of California, San Francisco

8:00 p.m. Reynolds Auditorium, McDonnell Hall

The Gregory T. Pope ‘80 Prize for Science Writing Awarded annually to a graduating senior for an outstanding article on a scientiÞc topic written for a broad audience. This article may be based on work previously submitted or be original work, but may not exceed 3000 words. Entry deadline: May 15, 2007 Award presented: Class Day: June 4, 2007 Prize: $500