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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
Virtual Reality:
effective treatment The future of NASA
for cancer.

pg. 10
INNO ATION
6 VOL. 8 NO. 2 SPRING 2006

10 p53 for Treating Cancer
Structural analysis of the cell reveals that the mechanisms regulat-
ing p53 degradation can help in the treatment of cancer.
4

BIOLOGY
Bacteria as a Model for Evolution
Controlled growth of E. coli provide breakthroughs in the study of 6
6 the mechanisms governing evolution.

APCase
Jennifer Hsiao shares her experience studying the feedback regu- 8
lation of APCase.

The Future of NASA
10
TECHNOLOGY

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.

Redesigning the Hydrogen Fuel Cell
Working together: An interdisciplinary group of Princeton profes- 14
Taylor’s Miracle sors collaborate to decode fMRI brain images.

Cancer Drug 17
Crossword Challenge
Dr. Edward C. Taylor of Princ-
eton University has developed
20
what is hailed as the most suc- Malaria-Resistant Mosquitos
cessful cancer drug in history: A breed of mosquitos has been genetically engineered to be im-
18
Alimta.
MEDICINE

mune 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.
23
Halting the Onset of Alzheimer’s
Screening for inhibitors of protein aggregation may halt the
onset of Alzheimer’s Disease. 26
L ETTER F ROM THE E DITOR OUR STAFF

Dear Readers, Editor-in-Chief
Sarah Weinstein
This issue of Innovation is your window into the exciting
world of medical research. Highlights include glimpses into can-
cer research, a genetically engineered cure for malaria, chem- Assistant Editor-in-Chief
istry’s approach to Alzheimer’s disease, and the clinical stud- David Tao
ies supporting drug development. Enriching the issue’s vast
swathe of medically oriented articles are excursions into evo-
lutionary science, chemical engineering, and NASA’s ongoing Business Administration
conquest of space and search for the technology of tomorrow. Kenton Murray

Innovation’s mission has always been twofold – we aim to
deliver a microcosm of the momentous science research con- Writers
ducted here at Princeton while granting students access to the Lajhem Cambridge
eminent professors and researchers on campus, thereby forg- Jill Feffer
ing a rapport between the present and future generations of Jennifer Hsiao
scientists and discoverers. In other words, dear readers, we Kevin Kung
seek to bring the sciences to your doorstep, and at the same Brian LeVee
time, send you out into the vast world of scientiÞc innovation. Jessica Lucas
David Tao
Our journal was made possible by the hard work and dedication Sarah Weinstein
of our Innovation team coupled with the generous support of the Josephine Wolff
University and in particular the School for Engineering and Applied
Sciences. We would also like to thank the professors and research-
ers who so generously offered their time for the ediÞcation of the Editors
Princeton community. And Þnally, we wish to extend our gratitude Lajhem Cambridge
to you, dear reader, for your continued support and enthusiasm. Kevin Kung
Megan Murray
Anupama Pattabiraman
Ad Astra Per Scientiam, Angela Wu
Sarah Weinstein, Editor-in-Chief Andrew Yang
Keren Zhou

Please contact us with your advice, questions, and thoughts at slweinst@princeton. Layout Team
edu or innov@princeton.edu. We would love to hear from you. Head Alyce Tzue
Janice Chou
Jill Feffer
Many thanks to our contributors, without whom Innovation would not have been
possible:
Elizabeth Szamreta

The Departments of Chemical Engineering, Computer Science, Geosciences, and Mo-
lecular Biology, the Council of Science and Technology, Pharmanet, and The School of
Engineering and Applied Sciences.

Cover image courtesy of cs4n.org.

2
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 slweinst@princeton.edu or innov@princeton.edu
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 research-
a decrease in death, or proliferation
at inappropriate times, all of which
contribute to tumorigenesis and the
the most frequently mutated gene in
all cancers involves one particular
tumor suppressor protein p53, which
ers lend insight into the molecular onset of cancer. Greater knowledge weighs 53 kDa and is 393 amino
mechanisms controlling the cell cy- of how certain molecules function to acids long. When cells experience
cle. The life cycle of a cell, includ- stress or DNA damage, p53 accu-
ing growth, division, and death, mulates and responds with a number
is a tightly regulated process that of anti-cancer mechanisms. First, it
depends upon the complex, coor-
Abnormalities in cell cy- may activate genes that encode for
dinated interactions of numerous cle control often cause proteins that are responsible for
molecules. Abnormalities in cell cells to experience pro- repairing damaged DNA. Second,
cycle control often cause cells to liferation at inappropri- p53 may arrest the cell cycle by up-
experience an increase in growth, ate times, contributing regulating cyclin dependent kinase
to tumorigenesis and inhibitors that prevent the transi-
tion from G1 into S phase. Lastly,
the onset of cancer. upon irreparable DNA damage, p53
can initiate apoptosis, or cell death.
Though 50% of cancers char-
regulate the cell cycle or induce cell acterized by p53 abnormalities in-
death facilitate both an understand- volve TP53 mutations that produce
ing of how cancer develops and dysfunctional p53 protein, the other
how to generate targeted therapies half of the time patients have a wild-
that may help to treat the disease. type p53 gene whose product faces
One such class of regulatory pro- accelerated degradation. In normal,
teins, known as tumor suppressors, unstressed cells, p53 is kept at low
functions to negatively regulate the levels by constant degradation me-
cell cycle and inhibit cell growth. diated by another protein, MDM2.
Thus, abnormal levels of these pro- MDM2 is a ubiquitin ligase that spe-
The diagram shows the progression teins, along with mutations in the cifically tags p53 for degradation by
of p53 mutation caused by overex-
genes that encode them, are fre- adding ubiquitin groups and facili-
pression of its inhibitor, the MDM2
oncogene. quently implicated in cancer. In fact, tating its transport from the nucleus,

4
enzyme that functions small peptide of five to six amino
to deubiquitylate, acids. They were able to elucidate
or remove ubiqutin the oligopeptide sequence by gen-
from, a target protein erating mutations in amino acid
to prevent its degra- residues at the substrates’ bind-
dation. Though ini- ing sites and observing the effects.
tially discovered as a The researchers reason that inter-
p53 directing protein, fering with HAUSP function antago-
it actually was redis- nizes cells’ ability to deubiquitylate
covered as an essen- MDM2. If MDM2 remains tagged
tial protein for MDM2 for degradation, its levels will de-
stability, inhibiting its crease. Without functional ubiquit-
self-degradation ac- ing ligase to target p53 for degrada-
tivity through deubiq- tion, the protein’s levels will rise.
Ribbon drawing of the p53 core domain-DNA uitylation. Although The therapeutic approach involves
complex showing the six most frequently mutated p53 and MDM2 bind designing small inorganic or pep-
residues of p53. The side chains of these residues
HAUSP in a mutu- tide-like molecules, which simulate
are colored yellow, the core domain is light blue,
and the DNA is dark blue. The zinc atom is shown ally exclusive manner, the MDM 2 moeity that binds to
as a red sphere. Shi’s team discovered the TRAF domain of HAUSP. This
that MDM2 binds to “peptidomimetic” molecule would
where it acts a transcription factor, to HAUSP with a greater thus act as a competitive inhibitor
proteasomes in the cytosol. Accord- affinity than p53. They suggest that by associating with HAUSP in such
ingly, higher levels of MDM2 result perhaps MDM2’s conformation af- a way that prevents it from interact-
in lower levels of p53. Interactions fords more extensive opportunities ing with MDM2. As a result, MDM2
between p53 and MDM2 can be in- for association with HAUSP than will remain ubiquitylated and it will
hibited by the activity of kinases, does p53. To obtain insights into be degraded, boosting the amount of
whose phosphorylation of p53 in- p53 to levels that will slow growth
duces a conformational change that and induce apoptosis of tumor
blocks MDM2 binding and instead Thus, controlling the cells. Shi looks enthusiastically
activates the protein to transcribe cell cycle by interfering toward collaboration with venture
genes involved in cell damage re- capitalist firms to synthesize such
at a number of places
pair, arrest, or death. Thus, control- compounds. Once a few lead mol-
ling the cell cycle by interfering at in the p53 ameliorates
ecules have been produced, phar-
a number of places in the p53 path- the cell cycle abnor- macokinetic analysis of their ef-
way offer potential mechanisms malities associated fect on restoring p53 can be tested
to ameliorate the cell cycle abnor- with cancer. in cells that over express MDM2.
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
I’m a junior in the MOL de-
to achieve normal rates of cell pro- domain. They discovered that sub- partments pursuing a WWS
liferation and death in cancer cells. strates bind to a groove in a section certificate, and I’m from
Pearl River, NY, a suburb
Insights into achieving this end called the TRAF (Tumor Recep- outside NYC. I’m interested in
became possible several years ago tor Associating Factor) domain at a career in oncology clinical
research.
with the discovery of HAUSP, an the N-terminus of HAUSP via a

5
ba cter i a
provide model
for
EVOLUTION
// BY LAJHEM CAMBRIDGE

I n order to understand the com-
plexities of the real world, sci-
entists 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 scien- vironments in which the E. coli live. important to consider that human
tists have created a mini ecosystem Initially, Keymer and his col- cells are approximately the same
played out on silicon. Escherichia leagues were unsure if their experi- size as the E. coli bacteria, and that
coli, a bacterium commonly found mental bacteria would behave in the even the most complex biological
in the intestines of humans and other same manner systems are entirely
animals, has commonly been used in as they would By simply rewarding dependent upon the
laboratories and is well researched. under normal interaction between
In this model, a silicon structure conditions
bacteria with food or cells. Moreover,
which provides compartments that given that the punishing them with just as in natural
contain different levels of resourc- E. coli might a laser, scientists can environments, the
es houses the E. coli. The bacteria interact differ- create the bacterial bacteria find nich-
must then adapt to the different en- ently in a con-
vironments in order to survive. The fined space.
cells they prefer . es, or “pockets of
opportunity,” ac-
scientists track the E. coli and ob- Yet using such cording to Key-
serve how these factors affect the a small scale to model real world mer, responding to abundant re-
population growth. They are able to complexities can be quite useful, sources or competition. The E.
monitor and tweak the different en- especially in this case. First, it is coli bacteria interact in the same

6
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 scien-
theory of evolution in On the Origin tists need only to
of Species. This theory states that alter the environ-
by natural selection those organisms ment to effect the
better adapted to an environment desired changes.
will produce offspring that have in- With this nanotech-
herited the genes that enabled the nology, the scien-
parents 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 appa-
more 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 Key-
definition of a species requires the space, or by “punishing” them with mer, another outcome is the possi-
organisms to inter- light from a laser, bility of adding “bio-functionality”
breed and produce The industrial scientists can choose to certain materials, such as silicon
fertile offspring, and create the bacte- or metal alloys, so that the materi-
but bacteria such
applications of rial cells they prefer. als gain organic function. Similarly,
as E.coli asexu-
this technology are In theory, the sci- the medicinal uses may become ir-
ally reproduce, bound only by entists can make a replaceable, as the bacteria struc-
thus quickly ren- the imagination. whole structure, on ture could be used in transplants,
dering this defi- a bigger scale, with perhaps to consume an unwanted
nition 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 com-
and 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
understand the natural environment. The industrial applications of 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, giv- two summers in a biology lab at
ing implications. Instead of working en this technology, cumbersome Rider University. She has lived in
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
C A S E
A n important metabolic path-
way for organisms is de novo
(i.e. synthesis from smaller molecu-
conformational change in hemoglo-
bin such that the affinity for oxy-
gen of its active sites is increased.
inhibition of ATCase by CTP results
because such allosteric binding by
CTP drastically reduced the affin-
lar precursors with lower molecular ATCase is comprised of two dif- ity of ATCase for its substrate car-
weight) pyrimidine biosynthesis. ferent subunits; the larger subunit bamoyl phosphate (Bethell 1968).
Pyrimidine nucleotides include uri- is the catalytic (c) subunit, while ATCase exists in two states: the
dine, cytidine, and thymidine phos- the smaller one is the regulatory (r) relaxed (R) and tense (T) states; in
phates and they are needed for DNA subunit. The regulatory subunit has the absence of a fixed concentra-
replication and RNA synthesis, pro- no catalytic activity. The catalytic tion of either substrate, ATCase is in
cesses which are important for all subunit binds the substrates (both equilibrium between the two states.
organisms. In the first step towards reactants, L-aspartate and carbamyl ATCase has a lower affinity for sub-
pyrimidine biosynthesis, an enzyme phosphate), while the regulatory strate (and thus lower catalytic ac-
called aspartate transcarbamylase subunit can bind NTPs (N=A, C, tivity) when it is in the tense state.
(ATCase) catalyzes the conversion of G, or U), and is responsible for the CTP inhibition of ATCase activity
reactants L-aspartate and carbamoyl allosteric aspects of ATCase. Wang is an example of feedback regula-
phosphate to carbamoyl aspartate. et al. have experimentally observed tion where the end product regu-
ATCase is a model enzyme for ordered substrate binding, whereby lates the activity of an earlier step.
studying allosteric regulation. Allo- carbamoyl phosphate binds first, The mechanism of inhibition is sta-
steric comes from the Greek words causing an induced-fit conforma- bilization of the tense state. ATP,
allos, meaning “other,” and stereos, tional change. This transformation on the other hand, binds to ATCase
meaning “shape.” Therefore, allo- alters the electrostatics of ATCase’s at an allosteric site in such a way
steric regulation refers to the control active site, thus establishing a suit- as to enhance the activity by sta-
of enzyme activity through binding able binding site for L-aspartate. bilizing its R state conformation.
of an effector molecule to a site other The binding of L-aspartate triggers I have been doing experiments
than its active site (i.e. an allosteric a second induced fit conformational with ATCase in Professor Josh Rabi-
site). The allosteric binding causes a change, the “domain closure,” which nowitz’s lab at Princeton for about a
conformational change in the struc- not only causes a quaternary confor- year. For my experiments, Profes-
ture of the enzyme. This can either mational change, but more impor- sor Evan Kantrowitz of Boston Col-
inhibit or enhance the activity of the tantly facilitates the catalytic reac- lege has generously provided me
enzyme. Another common example tion (Wang 2005). CTP and UTP are with ATCase that has been purified
of an allosterically regulated protein inhibitors, and ATP is an activator; from E. coli cells from his lab. My
is hemoglobin, which carries oxygen these have all been shown to bind to first experiments consisted of trying
within a red blood cell. The binding the regulatory (r) subunits (Bethell to replicate data from the literature.
of oxygen to hemoglobin causes a 1968). According to Bethell et al., There has been an enormous amount

8
of research done on this enzyme. a single NTP. This was mainly produces. In the case of pyrimidine
For my experiments, I use a colo- done to ensure that my experiments biosynthesis, the end product of the
rimetric assay modified from that produced results that matched the pathway (e.g. CTP) can inhibit the
of Prescott and Jones and also that literature. It was found that—in activity of the enzyme. In doing so,
of Kantrowitz. An acidic color re- agreement with the literature—at it prevents the cell from wasting its
agent – which quenches (stops) the pH 7, ATCase activity was in- resources and making too much of
reaction – is added to the reactions hibited by CTP, further inhibited the product. On the other hand, if
after they have been allowed to run when UTP was used in combina- there is more end product needed,
for about 16 minutes. After being tion with CTP, inhibited slightly ATP, a purine nucleotide that is not
incubated in the dark at room tem- by GTP, and enhanced by ATP. part of that pathway, can enhance
perature for at least 16 hours (dur- These experiments have already the activity of the enzyme and in-
ing which it reacts with the product been performed, so what is more duce it to produce more pyrimidine.
carbamoyl aspartate), it is then ex- interesting now is the effect of dif- _____________
posed to fluorescent light at 45°C ferent concentrations of multiple
References:
for 24 minutes (the reaction is time- NTPs on the activity of ATCase.
Bethell, M. R. (1968). “Carbamyl Phosphate: An Allosteric Substrate
sensitive). A yellow color develops Recently, I have been investigat- for Aspartate Trancarbamylase of E. Coli.” Proceedings of the
that is linearly proportional to the ing—in conjunction with Profes- National Academy of Sciences of the United States of America 60(4):
1442-49.
amount of carbamoyl aspartate pro- sor Herschel Rabitz’s lab, which Else, A. J., and Herve, G. (1989). “A Microtiter Plate Assay for Aspar-
duced during the reaction: the more is modeling the data using random tate Transcarbamylase.” Analytical Biochemistry 186: 219-221.

intense the yellow color, the more sampling-high dimensional model England, P., Leconte, C., Tauc, P., Herve, G. (1994). “Apparent Coop-
erativity for carbamylphosphate in Escheria coli aspartate transcarba-
product has formed. An instrument representation—the effect of four mylase only reflects cooperativity for aspartate.” EJB 94: 775-80.

called a spectrophotometer is used to NTPs (CTP, ATP, GTP, and UTP) in Gerhart, J. C., and Pardee, A.B. (1961). “The Enzymology of Control
by Feedback Inhibition.” The Journal of Biological Chemistry 237(3):
measure the intensity of the yellow combination, varying the concentra- 891-6.

color at an absorbance of 466 nm. tions of each for each reaction tube. Prescott, L. M., Jones, M.E. (1969). “Modified Methods for Determi-
nation of Carbamyl Aspartate.” Analytical Biochemistry 32: 408-419.
The reactions are carried out in bo- The analyses from these experi- Tymoczko, J. L., Berg, J., and Stryer, L. Biochemis-
try. 5th Ed. New York: W.H. Freeman and Co., 2002.
rosilicate glass tubes at pH 7. Water, ments are still in progress. Wang, J., et al. (2005). “Structural basis for ordered substrate binding and
cooperativity in aspartate transcarbamylase.” PNAS 102(25): 8881-8886.
buffer (with a known concentration The study of the effects of NTPs
of ATCase), and a known concentra- on ATCase provides insight into cru-
tion of L-aspartate are added to each cial and interesting mechanisms in
tube. Then NTPs are added. The re- the cell, especially that of feedback Jennifer Hsiao ‘07 is from
action is initiated by the addition of regulation. The cell has developed Windsor, CT. She is major-
ing in Chemistry with
carbamoyl phosphate and is allowed its own way of synthesizing some certificates in Latin and
to run for 16 minutes before being of the components it needs to func- Music Performance. She is
working in the Rabinowitz
quenched with the color reagent. tion as well as its own way of regu- lab for her senior thesis.
At first, I only experimented with lating how much of the product it

9
NASA Chief Scientist Discusses

and Space Program

ertical take-off, sity of Virginia.
He has been
landing vehicles, fascinated by
flow modeling
virtual reality, antimatter and speed range
control research,
fuels—you may think which was partly why
that these belong to the he decided to work for
NASA. Throughout his
realm of science fiction... career, Bushnell has
received numerous
awards and has been
appointed by groups
...and are not a part of the technol- Institute for Aeronautics and Astro- like the National Acad-
ogy of the immediate future, but for nautics (AIAA), discussed the fu- emy of Engineers.
researchers working in technologi- ture of NASA’s projects and space Presently, Bushnell considers
cal frontiers, the boundary between program. Having worked at NASA the space program to be in crisis
the two realms is rapidly merging. for 41 years, Bushnell is now the because of major job cuts and re-
Such is the view of Dennis Bush- chief scientist at the administration’s duced research funding. But despite
nell of the National Aeronautics and Langley Center at Hampton, Vir- these conditions, Bushnell is confi-
Space Administration (NASA). ginia. Before working for NASA, dent that “things can only get bet-
Dennis Bushnell, invited by the Bushnell completed his B.S. in Me- ter.” In order to improve, however,
Princeton chapter of the American chanical Engineering at the Univer- there is a tremendous need to rein-
sity of Connecticut and a vent. Bushnell focused on two as-

by Kevin Kung M.S. degree in Mechanical
Engineering at the Univer-
pects: the social application of past
space research and the space pro-

10
are surrounded by different envi-
“The major feature of VTOL is that it is ronmental and technical issues. In
aircraft design, Bushnell empha-
point-to-point, safe, long-ranged, and sized that it is the emission of wa-
automatic; there is no need to steer.” ter vapor, instead of CO2, that will
produce the most significant envi-
area of virtual reality, the success- ronmental impact. This is because
ful implementation of haptic touch, high-altitude water vapor induces
smell, and taste by an M.I.T. group artificial cirrus clouds, which in turn
gram of tomorrow. in 2004 has been one such break- alter the Earth’s albedo—the means
The primary social application through. Bushnell mentioned future through which solar energy enters
of space-program technologies can advances such as optical communi- and leaves the planet. Thus, while
be divided into three groups: trans- cations and direct brain feeds by vir- fuel cells are an important technol-
portation, telecommunications, and tual stimuli. In five to seven years, ogy in reducing CO2 and nitrous
virtual reality. With regard to trans- he predicts many business meetings oxide emissions, they are equally
portation, Bushnell concentrated on and conferences will be held through disastrous for NASA because the
what he called the PC version of virtual reality, preventing the need burning of hydrogen gas produces
aviation, the automatic robotic ver- of extensive travel. Even ordinary dangerous amounts of water vapor.
tical take-off and landing (VTOL) routines such as shopping may also Other environmental problems re-
delivery vehicles. The major feature take the form of tele-control. lated to airplanes include ozone de-
of VTOL is that it is point-to-point, What exactly will motivate these pletion, the generation of high-tem-
safe, long-ranged, and automatic; technological developments? Ac- perature regions, and sonic booms.
there is no need to steer. Bushnell cording to Bushnell, lowered costs Several proposals have been offered
envisions the replacement of ordi- and reduced traffic congestion will to effectively deal with these prob-
nary automobiles with VTOL, ac- serve as a strong incentive: he es- lems. Some of them include flying
companied by the civilian use of timates that the combined profit for below 30,000 feet, storing electric-
high-resolution global positioning these technologies may sum up to ity in airplanes, injecting water for
system (GPS) and satellite commu- one trillion dollars annually. take-off, managing waste products
nications. VTOL’s ability to fly and The other facet of NASA is the more appropriately, and improving
drive as well as its higher energy future of the aerospace program. aircraft design. Bushnell explored
efficiency have many implications. The path of airplane research will the latter three proposals at length.
The population density along the likely differ from that of spacecrafts The main function of take-off water
Eastern Seaboard can be reduced as because the two areas of research injection is to reduce aircraft noise.
long-distance travel becomes more
affordable, and in turn, traffic con-
gestions will diminish. Furthermore,
Bushnell mentioned that VTOL was
“In aircraft design, Bushnell em-
approved for possible use in future phasized that it is the emission
warfare. Thus, there is potentially
a twofold market for VTOL: com- of water vapor, instead of CO2,
mercial and military.
Telecommunications and vir-
that will produce the most sig-
tual reality are two other intricately nificant environmental impact.“
linked areas within NASA. In the

11
Though high-altitude water vapor earth using virtual reality techniques
creates problems, it usually poses discussed above, may replace actual
no significant issues at ground level. crew. Of course, a problem with a
On the other hand, the emission of holographic crew is that the space-
waste products can be avoided by craft is confined to a limited space
efflux-storage technologies such as around the Earth: a longer distance
storing water as ice crystals to be delays transmission. Bushnell even
brought back to the ground. Concur- hinted at 2001: A Space Odyssey, a
rently, an important area of design Stanley Kubrick film from the late
development is the so-called Pfen- 1960’s, in which, for long-distance
ninger strut and truss-braced wings. travel, the astronaut’s hypothalamus
The tail of an airplane in this design is suppressed, leading to suspended
“...one method of actually slants forward and joins the animation and a lower metabolic
main wings. If the concept is opti- rate.
reducing radia- mized, then a high aspect ratio can In addition to crew safety in long-
tion exposure is be achieved, allowing the aircraft to distance flights, the possession of an
travel at high speeds (Mach 2) with- affordable and efficient power and
to bury the crew out experiencing considerable drag propulsion source is indispensable.
and conserving fuel. There are no less than eight cur-
inside a hydro- Perhaps the field most easily as- rent areas of research. For example,
gen gas tank. A sociated with NASA is space explo- antimatter fuels and nuclear fusion
ration. Bushnell sums up the pres- exploit the enormous amount of en-
low-level pulsat- ent paradox as “what is safe is not ergy released by converting mass
affordable and what is affordable to energy, drawing upon Einstein’s
ing electromag- is not safe.” Indeed, especially af- proverbial equality, E = mc2. There
netic field may ter the explosion of Columbia, the are also thoughts on capturing the
question of human and operational radiation pressure from cosmic rays
slow down bone safety is of paramount importance using “solar sails” and cultivating
to NASA. In addressing hazards to hydrogen-fuel-producing plants or
loss due to mi- humans in space, Bushnell raised microbes, which may be promising
crogravity.” several possible solutions. For in- not only for space flight but also as
stance, one method of reducing a substitute for oil in cars. Bushnell
radiation exposure is to bury the also stresses the importance of in-
crew inside a hydrogen gas tank. A space infrastructures, such as the
low-level pulsating electromagnetic International Space Station (ISS), as
field may slow down bone loss due nodes between near-Earth and inter-
to microgravity. In addition, there is planetary travels. If some of these
the more controversial concept of technologies can be developed suc-
“designer humans,” whereby some cessfully, then they will translate
people are genetically modified to into important applications within
be fit in space. In some instances, it our society, repeating a cycle of in-
is advisable to reduce the number of vention and application.
people in space. To achieve this end, In Bushnell’s view, the predicted
holographic astronauts, generated on era of change from automobile to

12
VTOL vehicle resembles the trans-
formation from horse to automo-
bile 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 transi-
tion 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 tech-
nologies “is a matter of electrons.” 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.
We eagerly await the technological
advances the future will bring.
translate into important applications
within our society, repeating a cycle
of invention and application.

A physics major hailing
from Taipei, Kevin Kung
(‘08) has enjoyed writing The Cosmos 1 spacecraft, designed to be
for magazines such as The
Innovation, besides various propelled by its solar sails (prominent in this
other exploits. He writes illustration), is one of the first attempts to im-
half what he believes, and plement this method of energy capture.
he believes half what he
writes.

The Moller M400
Skycar, a com-
mercial VTOL
model that its
makers hopes will
become an af-
fordable house-
hold item.

13
Redesigning the
Hydrogen Fuel
// BY BRIAN LEVEE Cell

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. Al-
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
though accidental discoveries are vides the current of fuel allowed
impressive because of their nov- that produces to enter the cell.
elty and unpredictability, it still electric power. Not only did the What differenti-
takes a pioneering intellect to ap- The electron cell provide a sim- ates the Benziger-
preciate the applicability of what and proton join Woo fuel cell is that
ple and efficient
has been found. In the summer of at the cathode it does not need an
2006, such a discovery in hydro- where they react water regulating external power-con-
gen fuel cells was made by Jay with oxygen to mechanism, but it suming mechanism
Benziger, Professor of Chemical form water. In the also allowed the to control power
Engineering, and Claire Woo ’06. typical fuel cell, fuel cell to maintain output. It regu-
In order to appreciate the inge- the water is then constant power lates its own power.
nuity and significance of the Ben- transported out When Benziger
output without re-
ziger-Woo fuel cell, it is helpful to of the fuel cell and Woo began their
understand the way the typical fuel through evacu- quiring any outside research project,
cell works. First, hydrogen fuel en- ation tubes. The mechanism. their intention was
ters the cell and is broken up into its power output of to illustrate that such
constituents upon reaching the an- the fuel cell is self-regulation was
ode catalyst, forming a proton and related to the amount of hydrogen impossible. Rather than designing
an electron. The electrolytic mem- fuel that enters the cell—the more the fuel cell to regulate its air in-
brane then allows the proton to filter hydrogen, the more electrons, the take, which was the conventional

14
inside the chamber increases due to expend energy on power out-
approach to integrate self-regula- to additional hydrogen fuel intake, put control and water evacuation.
tion into fuel cells, Benziger and water is pushed downwards caus- In addition, whereas the typi-
Woo designed a cell that regulates ing the volume of the chamber to cal Honda or Toyota vehicle fuel
the volume of the reaction chamber. increase, thus decreasing the fuel cell converts only 30 to 40% of the
By allowing the water produced in cell’s power output. A drop in pres- hydrogen fuel into water and power
the reaction to fall to the bottom of sure causes the water level to rise and then relies on another mecha-
the chamber, rather than evacuat- while lowering the chamber volume nism to retain the extra hydrogen
ing it through complex channels, and increasing power output. DYT fuel that was left over for the next
as was done in previous fuel cells, When their simple power cycle, the Benziger-Woo fuel cell
they unknow- regulating cell is nearly 100% efficient. The wa-
ingly created the worked, Ben- ter at the bottom of the chamber
new self-regu- Whereas the typical ziger and Woo blocks all escape paths during the
lating fuel cell. were aston- reaction, causing the chamber to
If the figure
Honda or Toyota ve- ished. They be securely enclosed, allowing it
of the fuel cell hicle fuel cell converts soon realized to be perfectly efficient, bypassing
were turned on only 30 to 40% of the that their design the need for hydrogen clean-up.
its side so that hydrogen fuel into was progres- Benziger explains that their
the cathode pole sive in a num- “work is leading the way for think-
that allows wa-
power, the Benziger- ber of ways. ing about how to redesign the
ter and heat to Woo fuel cell is nearly Not only did fuel cell as a chemical reactor.”
leave the system 100% efficient. the cell provide Rather than using the fuel cells in au-
is on the bot- a simple and tomobilesDYT, which is the primary
tom, water col- efficient water focus of most private hydrogen fuel
lects on the bottom of the cell due regulating mechanism, but it also al- cell developers, the newly designed
to gravity. The water level is able to lowed the fuel cell to maintain con- fuel cell will function mainly in
rise or fall due to the pressure inside stant power output without requir- small engines, such as lawn mowers.
the cell by attaching a tube to the ing any outside mechanism. This According to Benziger, the small en-
hole where the water would typi- new design increases the efficiency gine mar-
cally leave the cell thus allowing of the fuel cell by eliminat-
the water to reach an equilibrium ing the need
level that is sensitive to air pressure.
When the pressure

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.
Although their innovation will
probably not reshape contemporary
may save a significant percentage electronics, it holds great promise
of the power output, causing the for solving a myriad of technical
ket is a major source of pollution in Benziger-Woo fuel cell to be more problems making hydrogen fuel
suburbia because such engines lack economically viable in this niche cells more efficient and useful to an
emission controls and therefore most rather than in larger engines where environmentally conscious world.
are highly polluting. The Benziger- the extra power is less significant.
Woo design holds a significant po- Unlike the serious infrastructural
tential for reducing such pollutants. problems facing fuel cell-powered
The Benziger-Woo fuel cell also automobiles, the use of this tech-
provides the most utility to small nology in smaller engines would My intended major is either
not present such a problem. Hy- EE or physics. I am a fresh-
engines because in small fuel cells, man from Los Angeles. I
a large portion of the power out- drogen fuel could be bought from don’t surf, but I live a few
stores and plugged into fuel cell blocks from the beach. I
put is used for regulating and ex- know, its a crime.
porting water. In small engines, devices in the same way that pro-
like lawn mowers, the new design pane is purchased to fuel barbeques.
17
Genetically N
ew advances in the
development of ma-
laria-resistant mosquitoes
suggest that when a cure
Engineered for malaria is discovered
it may bring about a new
breed of mosquitoes rather

Malaria than a vaccine. For de-
cades, scientists have been
working to create a ma-
Resistant laria vaccination to combat
the widespread mosquito- Plasmodium merozoites being released from
borne infectious disease a lysed red blood cell.

Mosquitoes that kills between 700,000 and
2.7 million people every year
. Some biologists, however,
have been working on devel-
oping genetically engineered
mosquitoes which are immune
// BY JOSEPHINE WOLFF 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 manipu-
strumental 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.
at Johns Hopkins University, led Malaria is caused by Plas-
a research team that developed a modium parasites that are trans-
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 devel-
Plasmodium 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 sali-
toes resistant to human malaria, vary glands and are then in-
these two studies represent ma- jected into a human host when
jor progress towards that goal. the mosquito bites a person.

18
the challenge of not be long before a mosquito re-
how to geneti- sistant to human malaria can be en-
cally modify the gineered. Once that task is accom-
Anopheles mos- plished, however, scientists will
quito. In order face the obstacle of replacing the
to alter the ge- existing mosquito population with
netic code, they the new malaria-resistant breed.
needed to attach Since the malaria disease affects
a new gene to a mosquitoes as well as humans, the
transposon (short resistant mosquitoes would have a
piece of DNA) significant advantage over the non-
that would incor- engineered mosquitoes. Rasgon’s
porate itself into team performed a study showing
the mosquito’s that, in a population with equal
genome. This numbers of the malaria-resistant
process had been mosquitoes and regular mosquitoes,
successfully im- after nine generations, the geneti-
plemented with cally-engineered mosquitoes com-
fruit flies using prised over 70 percent of the popu-
How malaria from a parasite infects its host.
the P transposon. lation. These results indicate that
However, research- if enough of the engineered mos-
Different scientists have attempted
ers discovered that the same trans- quitoes were released, they could
to target the Plasmodium parasites
poson used in fruit flies did not suc- rapidly eliminate a large majority
and eliminate them in the engi-
cessfully modify of the malaria-carrying mosquitoes
neered mosqui-
the genome of by the process of natural selection.
toes at different
mosquitoes. There would be no need to resort to
points in the
parasite’s life The advances made In the 1990s, the use of environmentally-hazard-
researchers at ous pesticides. Though these stud-
cycle. James’ by Rasgon and the University ies are promising indicators of a fu-
research team
created a gene James suggest that of Maryland at ture end to malaria, Rasgon warns
College Park that “we’re not anywhere near a
that produces it will not be long and the Univer- field release.” The continued devel-
an antibody for
a protein found before a mosquito sity of Califor- opment of well-engineered malaria-
in the Plasmodi- resistant to human nia at Riverside
discovered a
resistant mosquitoes is undoubt-
edly bringing biologists closer and
um sporozoites.
The research- malaria can be new series of closer to ultimately finding a cure.
transposons
ers introduced engineered. including the
the gene into
Hermes trans-
the mosqui-
poson, which
toes by in- Josephine Wolff is a freshman
from Cambridge, MA. She
biologists found
fecting them with a virus and the hopes to study math or archi-
tecture and pursue a certifi-
could be used to successfully modify
mosquitoes effectively eliminat- cate in French. She also enjoys
sudoku puzzles, playing the pi-
the genome ofAnopheles mosquitoes.
ed 99.99% of the sporozoites in ano, Grey’s Anatomy, the Bos-
ton Red Sox, and the New York
The advances made by Ras-
the mosquitoes’ salivary glands. Times Sunday Styles section.

gon and James suggest that it will
Initially, scientists struggled with

19
Taylor’s miracle cancer drug: Alimta
// BY DAVID TAO

I f you were a lung cancer pa-
tient, your five-year survival rate
would be around 6 percent for men
and was previously a consultant for
Eli Lilly. He did his undergraduate
and graduate studies at Cornell. Sur-
and 7 for women. That very sta- prisingly, chemistry was not even
tistic itself could almost obliterate on his radar until late in high school.
your hope for life, but a new pill He was planning to do English, but
on the market approved by the after taking one chemistry class he
FDA could change that. Online became so enticed by the subject
fan clubs and doctors worldwide that he went on to take all of them
are hailing the drug as the most his school had offered. The discov-
successful cancer drug in history. ery of Alimta was not his expected
Approved in over 70 countries, goal. He jokes in a speech given Professor emeritus Edward Taylor de-
veloped Alimta at Princeton.
this drug is not your typical ex- at Princeton “No one would want
tensively chemotherapy-backed, to fund a project on the investiga- Pemetrexed (C20H21N5O6 ) was
side-effects-ridden drug. Its name tion of pigments in butterfly wings.” first approved by the FDA for treat-
is Alimta and it could just make He points out that the lesson to be ment of non-small cell lung cancer
battling cancer that much easier. learned is the importance of origi- and malignant pleural mesothelio-
Dr. Edward C. Taylor of Princ- nal inquiry and he reminisces about ma. Mesothelioma often surfaces
eton University developed Alimta “the golden days when researchers approximately forty years after ex-
in collaboration with Eli Lilly and didn’t have to know the outcome posure to asbestos, and its effects
Company. Dr. Taylor is the A. Bar- before starting a project.” When are only now beginning to emerge.
ton Hepburn Professor of Organic Dr. Taylor sent the first sample of Luckily, however, this latency peri-
Chemistry, Emeritus at Princeton. his new compound to Eli Lilly for od has allowed Alimta to be devel-
He is one of the world’s foremost tests, the company sent a letter to
experts on heterocyclic compounds him saying there must have been
a mistake and further “When Dr. Taylor sent the
trials were needed. first sample of his new
When he received a compound to Eli Lilly for
second letter, Eli Lilly
apologized to him and
tests, the company sent a
said there was actu- letter to him saying there
ally no mistake. They must have been a mistake.
were just extremely When he received a second
surprised that all types letter, Eli Lilly apologized
of cancer cells reacted and said there was actually
to his new compound.
In February 2004
no mistake. They were just
after 12 long years of extremely surprised that
clinical trials, Dr. Tay- all types of cancer
lor’s drug that goes cells reacted to his
by the brand name of new compound. “
Alimta also known as

20
oped just in time to treat it. Alimta ta injection, the patient is required involving a combination of immune
is in a chemical group similar to fo- to take a folic acid pill once every suppression, radiation therapy, and
lic acid known as antimetabolites, day. Folic acid can counteract the surgery with serious well-known
and therefore, patients must be on anemia associated with vitamin B12 side effects such as hair loss, ane-
folic acid and vitamin B12 supple- deficiency over the course of the mia, malnutrition, cardiotoxicity,
ments during the course of their therapy. 350 to 1000 mg and even death. Currently, Alim-
therapy. Alimta functions by inhib- should continue to be ta is under clinical trials for a host
iting three enzymes used in purine taken until of other cancers. Dr. Taylor said
and pyrimidine synthesis—thymi- 21 days after “We have had complete cures of
dylate synthase (TS), dihydrofolate the last cycle breast cancer, but it has not been
reductase (DHFR), and glycinamide of Alimta. The approved yet and the treatment of
ribonucleotide formyl transferase colon cancer has been effective at
(GARFT). This stops the precur- Mayo Clinic.” Treatments of some
sors to nucleotide formation are more effective than others, but
thereby preventing the syn- Dr. Taylor hopes that some day Al-
thesis of the DNA and doctor imta can replace or supplement many
RNA of cancer cells. will inject of the other procedures and reduce
A major ad- vitamin B12 the suffering of cancer patients. His
vantage of the week the patient contributions to chemistry and med-
starts on Alimta and icine have earned him the Heroes in
then every 9 weeks after that. Chemistry Award from the Ameri-
The use of an oral steroid called can Chemical Society and will con-
dexamethasone will minimize the tinue to offer hope to thousands of
risk of a skin rash. What is most cancer patients around the world. 1
surprising is that this is also an out-
patient treatment, almost unheard
Alimta is the of in treatments against cancer.
minimal pre- In addition, the side effects of this From Lexington, KY
ventive measures regimen amount to those character-
Princeton Class of 2010
needed to counteract the side effects istics of a minor flu including nau-
of the drug as compared to traditional sea, fever, sore throat, and loss of Potential molecular biol-
ogy major and neurosci-
chemotherapeutic procedures. Five appetite. Compare this with those ence minor.
to seven days before the first Alim- of traditional chemotherapy, usually

Structural drawing of Alimta
1 “Cancer Survival Rates Improved During 1998-
2001,” National Statistics Online, http://www.statis-
tics.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
Clinical Studies by Sarah Weinstein
S niffles, a scratchy throat, and
a throbbing headache. Upon
rushing off to the doctor’s office,
ticipating in the study are likely not
expecting full treatment or recovery
but rather are volunteering with the
post marketing studies), and compa-
nies often use this phase to expand
their label.
eager to get antibiotics, one hardly understanding that there is no guar-
stops to think of the creation and antee that the drug will even pro- This entire process (Phases
evolution of the desired medication. duce the desired effects. Following
I-IV) can take anywhere
In fact, drugs undergo a lengthy this, Phase II involves the actual tar-
process from lab tests to an eventual geting of the population of patients from 7-10 years, and its du-
approval by the FDA before they that would be treated in a real world ration depends heavily upon
can be sold on the pharmaceutical setting; thus the aim of these stud- how quickly companies can
market. Pharmanet, for instance, is ies is efficacy, understanding how recruit the patients needed
a company involved in the regula- well the drug in question cures a for the study.
tion of the clinical studies in drug particular illness. These studies are
development held subsequent to the small in scale, involving no more Given the apparent complexity,
drug-discovery phase in laborato- than 10-20 hospitals and approxi- there are several regulatory steps
ries. mately one hundred patients. Phase designed to keep the tests both ethi-
A company like Pharmanet is em- III continues to focus on the patients cally and scientifically sound. There
ployed by a pharmaceutical compa- targeted for use of a specific drug. are two boards in particular that
ny looking to market a new medi- These studies are large in scale, of- monitor the studies – the Data Safe-
cation and carries out and oversees ten global, and yield enough data for ty Monitoring Board and the Insti-
all phases of the drug study. There the FDA to decide whether or not to tutional Review Board (IRB). The
are four such phases of testing that approve the drug. Phase IV, the fi- Data Safety Monitoring Board is ac-
a drug must undergo before it gains nal stage, involves thousands of pa- tive during phases II-IV, reviewing
FDA approval. Phase I is primarily tients taken from large patient reg- the data (often blindly) and decid-
focused on toxicity studies wherein istries. Participants in these studies ing whether or not to push the study
patients are subjected to what is will often buy a drug with the un- through to the next phase. Thus,
known as “dose escalation studies.” derstanding that their results will be they look at the data and judge from
In these studies, the participants are documented and used for these larg- a scientific standpoint whether or
given a certain dosage of the medi- er-scale studies. This phase tends to not it makes sense to move on with
cine that is gradually and incremen- focus on the long-term effects of the a study. The IRB on the other hand,
tally increased to find the maximum drug and is consequently conducted is concerned less with what makes
tolerated dose of the drug. Given after the drug has been approved by sense from a scientific or logical
the nature of Phase I, patients par- the FDA and sold on the market (i.e. standpoint, and more

23
tests on ethical grounds. who were mostly poor, uneducated
Clinical drug studies present sharecroppers from Alabama were
Phases of Clinical Drug Trials:
the companies with myriad press- deliberately misled in order to en-
Phase I: toxicity and dosage studies ing ethical issues. One of the first sure their full participation.
and most important considerations
of a company conducting medici- At one point, the patients
nal studies is ensuring that the par- were duped into participat-
ticipants are adequately informed
ing in a dangerous spinal tap
about all the procedures and pos-
Phase II: efficacy studies sible outcomes of the study. Prior with a letter that was sent
to recently mandated informed out entitled “Last Chance
consent forms, there was little for Special Free Treatment.”
regulation in this area, and in fact,
these measures were developed in The Tuskegee experiment has been
response to ethically repugnant ex- referred to as “the longest nonthera-
Phase III: global efficacy studies
periments where the participants peutic experiment on human beings
were not adequately informed in medical history1,” and indeed, the
about the study. The Tuskegee experiment had severe consequenc-
Experiment (1932-1972), for in- es. After the forty years of experi-
stance, was one of the most serious mentation, 28 of the men had died
Phase IV: long term effects and notable studies gone morally of syphilis, 100 had died of related
and post-marketing studies awry. In this experiment, the phy- complications, 40 of their wives had
sicians involved were aware that been infected, and 19 of their chil-
the participants were infected with dren had been born with congenital
with whether or not the studies are syphilis, a serious sexually trans- syphilis. Thus, when the full gamut
ethically sound. At any point in the mitted disease, and knowing this of the researchers’ ethical transgres-
study, the IRB is capable of putting only told the patients that sions were revealed to the public,
an end to the they were being treated it became painstakingly clear that
for “bad blood” and in stricter regulations were necessary.
fact offered next to no A second more circumstantial
treatment. Essentially, ethical issue in clinical studies aris-
the physicians know- es when a particular patient wants to
ingly did nothing for the participate in a study but for what-
patients and instead ever reason does not qualify. For
followed the prog- instance, oncology studies often re-
ress of the disease quire of their patients a certain white
to completion. blood cell count; patients falling be-
The partici- low the desired count would not be
pants of the study, admitted to the study. In this case,

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

24
the doctors are aware that on the access to the experimental drug
one hand the patient might benefit – once the study is concluded.
significantly from having access to The current system of clinical
this medicine, but on the other hand, drug testing is long and painstaking,
they are conscious of the fact that compounded by a series of ethical
allowing a participant who failed concerns, and yet it is only one small
to meet the necessary requirements step in the larger process taking a
is likely to contaminate the results. drug from its inception to a shelf
Most companies are thus rather strict in your local pharmacy. Perhaps in
about not allowing unqualified par- leaving the drug store, antibiotics in
ticipants into the study. However, hand, you might stop to consider the
some patients can acquire what is complexity and evolution of drug
known as a single patient IND (in- development and the years of labo-
vestigational new drug) on a “com- ratory work and clinical testing that
passionate use basis.” This type of made your purchase possible.
exception allows one patient to get
the drug apart from the study for 1
Encylopedia Brittanica.
one cycle of treatment even though
the drug is not FDA-approved.

Finally, the most widely dis- Sarah is a junior in the
philosophy department
cussed ethical issue con- pursuing certificates in
French and music per-
cerning clinical drug studies formance. She is from Ft.
Lauderdale, Florida but
is the use of placebos for secretly loves the snow.
studying the treatment of
serious medical conditions.

Along the same lines as the last eth-
ical conundrum, the use of placebos
is essentially the purposeful non-
treatment of a condition that is po-
tentially terminal – one that might A man being treated during
the Tuskegee Experiment,
theoretically be cured by dispensing
which involved the delib-
the actual drug to all test subjects. erate withholding of treat-
To avoid this problem, drug com- ment information from citi-
panies often will give the standard zens suffering from syphilis.
treatment to one group of patients,
and to the second group they will
give the standard treatment plus the
experimental drug, so that each pa-
tient is at least receiving some form
of treatment. When it is impossible
to incorporate a standard drug into
the study, then patients who are ini-
tially given only placebos later have

25
Screening for inhibitors of protein
aggregation to halt the onset of
Alzheimer’s Disease
// BY JILL FEFFER site, “one in 10 individuals over 65
and nearly half of those over 85 are
A ccording to chemistry profes-
sor Michael Hecht, Alzheim-
er’s disease (AD) is becoming “a
affected.” The most apparent symp-
toms of AD are loss of memory and
cognitive functions, and physiologi-
number one health problem” be-
cal signs of AD include the degener-
cause people are living longer now-
ation of neural cells and the growth
adays. AD has become prevalent
of protein tangles in the brain.
because the average human lifespan
Evidence from previous scien-
has been lengthened by advances in
tific studies indicates that a certain
medical technology. He elaborated
threshold of protein tangle accumu-
that AD is a “post-evolutionary dis-
lation is associated with the onset
ease,” meaning it was not eradicated
of AD, so Dr. Hecht rationalized Professor Michael Hecht developed the
by natural selection because it only screen in his Princeton chemistry lab.
that an effective treatment would
strikes after the reproductive age and
only have to slow the aggregation marker provides the basis for one
at an age that people did not natu-
process enough to keep accumula- ongoing research project in Hecht’s
rally live to see, so it was never an
tion below this threshold, not stop chemistry laboratory. As a result of
evolutionary concern. According to
it entirely, which would be a more an investigation into the molecular
the Alzheimer’s Association’s web-
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 com-
lation totals between ponent of the amyloid
non-AD patients and protein plaque that
those afflicted with The screen is a builds up in the brains
the disease. The of AD patients, with
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 treat-
ing the threshold it further scrutiny. ment. The screen is
level of accumula- advantageous because
tion for a few years, it is high-throughput,
thereby delaying the onset of meaning it can test many candidates
AD, perhaps permanently if the at once; it is cost-effective; it is selec-
lag is long enough for people to tive for inhibition at earlier stages of
die of something else in old age. amyloid accumulation; and its trials
This particular physiological are relatively easily reproducible.

26
The screening process employs the bated for three hours be-
common biological method of iden- fore an automated plate
tifying inhibitors by monitoring the reader checked for fluo-
activity 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 fluores-
lyfish. GFP activity is easy to deter- cent positives, or “hits,”
mine because, as the name suggest, were identified as pos-
it fluoresces. This protein folds into sible A-ß-42 aggrega-
an active state at a much slower tion inhibitors. Subse-
rate than A-ß-42 aggregates, so in quent experiments have
the absence of an inhibitor, A-ß-42 proven that a compara-
will 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 in-
able 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
This screen such as animal studies in order to
have confirmed the
avoids the pit- eventually produce something that
inhibitory capac-
fall of being Once inhibitors are ity toward A-ß-42 of
is clinically useful such as pharma-
prone to gener- identified, the next ceuticals that can be preventive rath-
many proteins iden-
ic inhibitors of steps would be to er than therapeutic, as all presently
tified as hits by the
protein folding available treatments for AD are. Dr.
perform specialized screen. Thus, the
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 select-
be likewise in- mal studies in order into full effectiveness at the pub-
ing proteins that mer-
hibited by them. to eventually produce it further scrutiny.
lic health level” will be recognized
In the initial something that is clini- Dr. Hecht said the in time to save many aging Baby
execution of the cally useful Boomers and their families from the
original AD-related
screen, a library drawn-out suffering caused by AD.
experiment involved
of approximate- mutating parts of ____________________
ly 1000 triazine compounds (a class A-ß-42 to see how to prevent ag-
of 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-Through-
pirical 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 tech-
were 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
the library were added to each well The two strains of thought eventu- majoring in molecular biology. She
plays flute and is Business Manager
and an activator, isopropyl-ß-D- ally merged to produce the screen, for the Wind Ensemble. In addi-
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 Fountain
Science Journalism of Youth
STC 349
Professor Michael D. Lemonick
Lecture
Develop your science writing skills from a jour-
nalism perspective and learn how to present
complex material about science and technology
for non-technical readers. Through class discus- 2007 E vening L ecture
sion, analysis of published writing exercises,
as well as interviews with Princeton scientists, Genes from the
participants will learn to write about science with Fountain of Youth
both clarity and style.
From Worms to Mammals:
Health and Human Rights in the Genes that Control the
World Community Rate of Aging
STC 398
Allen S. Keller
Thursday, May 3, 2007

Interested in the relationship between health and PROFESSOR CYNTHIA KENYON
human rights? Learn about human rights viola- Herbert Boyer Distinguished Professor
tions in the world today and analyze their health of Biochemistry and Biophysics,
consequences. In this course you will consider University of California,
how individual and community health can be San Francisco
improved by protecting and promoting human
rights. You will also explore the role of the health 8:00 p.m. Reynolds Auditorium,
professional in caring for victims of human rights McDonnell Hall
abuses, documenting the health consequences of
human rights violations, and participating in hu-
man rights advocacy in education.

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