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Science Briefs
C. Elegans Clock Genes Characterized as Researchers
Investigate Aging Processes: Implications for Humans?
Research into the mysteries of ag- can result in constitutive or defective for- matic increase in lifespan ever wit-
ing has heated up dramatically in recent mation of a larval stage known as dauer, nessed in any species.
months. A report in the April 12 issue of in which the organism does not eat. What does this imply about aging
Science presented the gene responsible These larvae arise under conditions in higher organisms such as humans?
for Werner’s syndrome, an ailment that of overcrowding or insufficient food sup- Obviously, until clk homologs are found
results in an accelerated aging process. ply and represent a hibernation-like
More recently, Siegfried Hekimi and state that allows survival until environ-
Bernard Lakowski of McGill University mental factors improve.
have reported the isolation of several Lakowski and Hekimi’s genes ap-
new genes that play an important role pear to affect lifespan by a different
in the aging of the nematode Caenor- mechanism than the dauer genes.
habditis elegans (Science, May 17, p. Double mutants of the new genes and
1010). daf-16 (a dauer defective mutation)
Mutations in the new genes, termed have the same lifespan as the clk single
clock genes (clk), slow down many of mutants.
the life processes of the worms. These While the daf mutations increase
findings suggest that there may be an lifespan by extending a stage of devel-
underlying biological master clock that opment, the clk mutations slow down ev-
determines when an organism dies. erything from the rate of cell division to
As Hekimi told Science, “It shows the rate of food intake and swimming.
that there is such a thing as a central Thus, both development and adult life
biological clock which puts into take longer to complete.
synchrony everything that has a tempo- The most drastic increase in
ral component.” lifespan occurs in a daf-2 (a dauer con-
Before the isolation of the new stitutive mutation) clk-1 double mutant
genes it was already known that muta- which lives nearly five times longer than
tions in the dauer formation (daf) genes a wild type worm. This is the most dra-
Varmus Speaks at Commencement
On June 6, Nobel laureate Harold In his speech, the current Director The nematode worm C. elegans.
E. Varmus was awarded an honorary of the National Institutes of Health (NIH)
degree and delivered the Commence- said the federal government could be a
ment Address at Harvard University’s “powerful source for public good.” in humans, little can be said. However,
345th Commencement ceremony. At the same time, Varmus cau- Hekimi has reportedly discovered a
tioned that “We should not try to bal- similar gene in yeast indicating that the
ance the budget by robbing the future mechanism through which the clk genes
to pay for today’s medical services. influence aging may be conserved
Rather, we should provide enough across many species. The next step is
money for both.” to isolate these genes and perform de-
Varmus noted that significant chal- tailed biochemical analysis on the pro-
lenges were in store for the Class of teins they encode.
1996, including Alzheimer’s Disease, One hint the authors point out is
HIV and Ebola, as well as demographic that a homozygous mutant animal born
transitions and rising medical costs. by a heterozygous mother shows almost
He also offered a solution: new tal- none of the altered aging effects. This
ent, enthusiasm for science, money, and means that the genes have a maternal
strong institutions. effect and that their translated product
Furthermore, according to Varmus, is passed on by the mother in the egg.
other countries have now surpassed Thus it seems likely that the clk
America’s spending on basic research. genes somehow control the rate of me-
Nevertheless, the NIH director was still tabolism, acting much like a conductor
optimistic about the future if taxpayers, of an orchestra. Only time will tell
citizens, and scientists remain commit- whether or not this is true, but with the
ted to addressing the needs of the fu- new findings, research into this oldest
ture in the present. of mysteries will surely heat up.
NIH Director Harold E. Varmus delivered
this year's Commencement Address. —Jeffrey A. Ferrell —Maximilian Diehn
Science Briefs
Professor Profile: J. Woodland Hastings
For J. Woodland Hastings, the Paul is focusing on the regulation of the pro- ratory, Hastings and his wife Hanna
C. Mangelsdorf Professor of Natural teins involved in maintaining the circa- have served as masters of Pforzheimer
Sciences, bioluminescence is not only dian rhythm. While they have discov- House for the past 20 years. Having just
at the core of his research, but is also ered that there is a cyclic synthesis and retired this year, Hastings and his wife
part of his personal life. “Fireflies use destruction of two key proteins in the now plan to move—but only down the
light emitting reactions for courtship, and cycle, Hastings and his colleagues have street.
so did I.” said Hastings. “That’s how I also found that the levels of mRNA for “House life has been wonderful,”
met my [future] wife—I invited her to ac- each protein remains constant through-
company me catching fireflies.” out the cycle. This implies that the regu-
The Hastings Lab is devoted to the lation is at the translational level, differ-
study of the mechanisms of biolumines- entiating this system from many others
cence and the biological clock. Using which are controlled at the level of the
the model organism Gonyaulax gene.
polyedra, a single-celled algae best To carry out these extensive stud-
known for causing “red-tide” in coastal ies, Hastings maintains two rooms, each
waters, Hastings’ lab investigates the filled with flasks of the bioluminescent
biochemistry of circadian rhythms—so algae from floor to ceiling. One room is
named because they revolve around a lit from 8:00 am to 8:00 pm, while the
cycle of about one day. other is lit from 8:00 pm to 8:00 am.
Hastings and his colleagues have “When the algae are disturbed,”
cloned two genes that play key roles in Hastings said in the pitch-black culture
this process. One of these—luciferase— room, “the organisms generate an ac-
tion potential that causes lumines-
cence.”
As Hastings picked up a culture
flask, a burst of blue light filled the room,
then quickly subsided. Professor J. Woodland Hastings.
As a scientist, Hastings empha-
sizes the value of basic research. “Suc- Hastings said. “It’s been interesting and
cess in science comes from the study fun to help students work through col-
of simple organisms and the study of lege.”
simple things,” Hastings said. During their tenure at Pforzheimer,
He also encourages students to get Hastings and his wife brought comput-
involved in a laboratory. “I feel [research] ers to the house before Harvard Univer-
is very important, even at the under- sity had begun to invest in such pro-
graduate level,” said Hastings, who has grams. They also introduced sports fa-
about four students in his lab each year. cilities as well as music and art rooms.
“I’ve tried to help get students in- “House life has been very fulfilling,”
terested,” he said, “but research is not Hastings said of his twenty years at
for everybody—you shouldn’t do it as Pforzheimer.
Scanning electron microscope image of an undergraduate just because you’re Whether in the world of science or
Gonyaulax polyedra, the model organism told to.” the realm of college house life, Profes-
used in the Hastings laboratory. “You have to do what you’re good sor Hastings is enlightening all those
at, otherwise it won’t be fun,” said around him.
combines with another protein called lu- Hastings.
ciferin to give off visible light. The other Apart from his busy life in the labo- — Vivek Jain
confines the luciferin protein to little sacs
called scintillons.
The biological clock, as Hastings
has discovered, does not revolve strictly
New Primate Species Discovered
around a 24-hour cycle. “By shining dif- Researchers in the central Amazo- The marmoset’s range has not yet
ferent colors of light on the algae, we nian rain forests of Brazil have recently been clearly defined, but it does not ap-
found the length of a day can vary any- discovered a new species of marmoset, pear to be threatened, according to pri-
where from 21 to 27 hours,” Hastings the 18th such primate. matologist Russell Mittermeier, presi-
said. Known as the Satere marmoset dent of Conservation International.
Even more interestingly, Hastings (Callithrix seterei) after a Native Ama- Marmosets are among the small-
discovered that the schedule of the clock zonian group with whom it shares a part est primates and are endemic to the
can be reset by exposure to light at cer- of its range, the new addition to the Pri- tropical forests of the New World. Most
tain times. mate order brings Brazil’s primate count tend to be canopy dwellers, living on a
Current research in the laboratory to 75. There are 250 species worldwide. diet of insects and soft fruits.
Science Briefs
Internet Conference Draws Over 1,000; Gates, McNealy
Outline Competing Plans of Future Technology
From May 28-31, more than 1000 said, referring to his brief career as a the conference on the third of four days,
scientists, businessmen, lawyers and Harvard undergraduate. spoke about how the Internet has trans-
professors descended on Cambridge to Scott McNealy, whose company formed undergraduate education at
attend the Harvard Conference on the has pioneered one of the Internet’s hot- Harvard. Using statistics from Harvard’s
Internet and Society—a gathering de- test products—the computer language computer network, he described how
voted to the growing importance and Java—spoke of the potential of such lan- connectivity among undergraduates has
potential of the Internet. guages to transform both the Internet soared, as well as new ways students
The conference attendees were and the way we think and faculty are interacting
addressed by several keynote speak- about computing. via the Internet.
ers including Bill Gates, Chairman and In a speech which “The Internet has dis-
CEO of the Microsoft Corporation, Scott featured several jokes— tinctive powers to
McNealy, Chairman, CEO and President most of which were complement many of our
of Sun Microsystems, Larry Tesler of pointed directly at Bill most powerful traditional
Apple Computer and Neil Rudenstine, Gates—McNealy, too, approaches to learning,”
Harvard’s President. spoke of his days as a said Rudenstine.
Speaking to a packed Sanders Harvard undergraduate. In between the key-
Theatre, Gates explained Microsoft’s “I want you to know I note speeches, several
intent to lead the industry in developing graduated from here. I panels were held in the
software for the Internet. At the same didn’t drop out and I’m still science center lecture
time, however, Gates tried to focus his trying to make up for his halls. Topics included se-
speech on broader societal issues two and a half year head Microsoft CEO Bill Gates. curity encryption, wire-
raised by the Internet, rather than detail start,” he joked. less technologies, online
Microsoft’s specific plans. His speech McNealy spoke of commerce and banking,
even included a comic video segment Java’s potential to deconstruct and de- the transformation of the health indus-
which mocked IBM’s and AT&T’s recent centralize computing. According to try, new educational approaches using
ad campaigns. McNealy, instead of using large cumber- the Internet, censorship and govern-
“It’s good to be back [in Sanders some applications, users will have Java ment regulation.
Theatre].” said Gates, the richest man “applets” which will perform smaller sets
in the world. “One of the few classes I of functions. — Vivek Jain
actually attended was held here,” he President Rudenstine, addressing
New Primate cont'd
Cyclospora Outbreaks Concern
They are polyandrous, meaning
that females mate with more than one Health Officials in U.S., Canada
male. The males participate in raising
young and carrying offspring on their Over the past several weeks, out- linked to blue-green algae, has been
backs as they leap among the twigs of breaks of Cyclospora cayetamensis (a identified as a distinct protozoan para-
the canopy to forage for food. protozoan parasite which causes severe site and is a relative of Cryptosporidium.
C. seterei adds a curious element diarrhea, abdominal pain, nausea, fe- It passes from an infected individual in
to marmoset reproductive biology: both ver, and extreme fatigue) have been re- an unsporulated state and requires one
sexes feature fleshy appendages on the ported in Houston, Florida, and Toronto. to two weeks to become infectious.
genitalia whose function is as yet un- Health officials in Houston and Moisture and temperatures of at
known. Other distinctive features of the Toronto reported a statistical associa- least 25°C are necessary for the organ-
species include its mahogany-colored tion with strawberries, prompting Cali- ism to sporulate and become infectious.
fur and unpigmented facial skin. fornia health officials to take preventive Virtually every outbreak in the past has
Mittermeier expressed optimism testing precautions. occurred in an area near water.
about the future of the new species, The results of the initial tests were The Alliance for Food and Fiber and
saying that marmosets are generally negative, and major hospitals have re- the California Strawberry Commission
quite adaptable to the ongoing destruc- ported no cases of Cyclospora-related announced on June 21 the formation of
tion of primary rainforests. They can illness contracted in the state. a panel of experts to study the situation.
thrive in both abandoned slash-and- Cyclospora is treatable with antibi- The panel included Cyclospora ex-
burn plots and secondary forest growth. otics sold under the name Bactrim and pert Dr. Charles Sterling of the Univer-
Unfortunately, other marmosets, Septra and is generally not fatal. sity of Arizona, who is credited with iden-
including the golden lion tamarin, rank Cyclospora is an extremely difficult tifying the parasite and determining its
among the world's most endangered organism to identify which has made it maturation process.
animals. difficult to pinpoint the cause of the re-
cent outbreaks. —Jeffrey A. Ferrell
—Daniel M. Paskowitz The parasite, once thought to be
Science Briefs
SIV Orally Transmitted; Viral Dose Required is 6,000
Times Smaller: A New Risk Factor for Spread of HIV?
Ever since human immu- lower than the amount
nodeficiency virus (HIV) was needed for intravenous infec-
demonstrated to be the cause tion.
of AIDS, public heath re- The report indicates that
searchers have attempted to casual contact such as kiss-
understand the ways in which ing is unlikely to transmit HIV,
HIV is transmitted. Clinical in- but the amount of fluid ex-
terviews and laboratory stud- change associated with oral-
ies have shown the sharing of genital contact could lead to
needles by intravenous drug high enough doses to trans-
users and vaginal and anal in- mit the virus.
tercourse are the major Several factors must be
modes of HIV transmission. considered before extrapolat-
Although it is theoreti- ing the conclusions of this
cally possible that HIV can be study to HIV transmission in
transmitted through lesions in humans. This study involved
the mouth or throat, it has infecting monkeys with cell-
been difficult to assess the free virus.
risk of oral transmission. Oral transmission among
A rendition of the HIV particle.
Recently, however, re- humans would most likely in-
searchers at Tulane and volve infected cells rather
Boston Universities have pub- than free virus; in addition,
lished a report in the June 7 A rendition of the human immunodeficiency virus (HIV) particle. other research has shown
issue of Science showing that that viral particles can be at-
monkeys can be orally infected by sim- When they placed the virus on the tenuated by human saliva.
ian immunodeficiency virus (SIV), a tongues of the monkeys, six of the seven Nevertheless, this study has alerted
close relative of HIV. animals became infected. The dose of researchers and the public to the pos-
In the study, headed up by oncologist virus need to orally infect the monkeys sibility of oral transmission of HIV and
Ruth Ruprect of the Dana Farber Cancer was 6000 times lower than the amount has laid the groundwork for further re-
Institute, various concentrations of SIV needed to infect the monkeys via rectal search.
were administered to monkeys orally, rec- exposure. However, the viral dose
tally and intravenously. needed for oral infection is still 800 times — Michael P. Dybbs
Combinatorial Chemistry: A High-Speed Pathway to
Discovery of Pharmaceutical Compounds
The development of newer, safer been discovered through this process. charide building blocks, respectively.
and more effective pharmaceutical However, the random nature and Without coincidence, these same build-
agents stands at the forefront of me- intense time and effort involved in this ing blocks were used in the early de-
dicinal chemistry. This process be- operation hinders it popularity. velopment of industrial combinatorial
gins with the identification of so-called Combinatorial chemistry repre- methods.
“lead” compounds which display desir- sents an increasingly popular alterna- The industrial process, in short, in-
able biological activity. tive method to finding lead compounds. volves submitting building block mol-
Once characterized, these com- It has been defined as the systematic ecules to a series of bond forming and
pounds are thoroughly assayed for ac- and repetitive, covalent connection of “deprotection” reactions. As shown in
tivity, tested for safety, and, if neces- a set of different “building” blocks of Figure 1, many building blocks are first
sary, modified chemically to enhance varying structures to each other to yield covalently attached to a solid support.
their activity and reduce any undesir- a large array of diverse molecular enti- These molecules are then allowed to
able side-effects they might exhibit. ties. Although conceptually simple, contact a solution of a mixture of other
Traditionally, pharmaceutical com- combinatorial chemistry is profoundly building blocks, each of which contains
panies discover lead compounds by ex- important in that the evolution of all life two reaction sites. The molecules
tracting them from organisms, particu- hinges upon combinatorial synthesis. bound to the support react with the “ac-
larly plants. Numerous molecules pos- Nucleic acids, proteins, and oli- tivated” site of the molecules in solu-
sessing highly valuable medicinal prop- gosaccharides, the base components tion to form covalent bonds.
erties such as taxol, an anti-tumor of all biomass, are synthesized from No reactions occur at the “pro-
agent produced by the yew tree, have nucleotide, amino acid, and monosac- tected” sight of the solution bound
Science Briefs
Combinatorial Chemistry cont'd say for biological activity involves divid- bind leads to the immediate identifica-
ing compound libraries into smaller tion of the biologically active com-
pools, portions of which are subse- pounds.
building blocks so as to prevent build- quently exposed to fluorescently la- Although proven effective, this
ing block polymerization. Once all re- beled receptors. technique contains a large drawback
actions have finished, excess reagents The pools of compounds which in that the receptors must be able to
are washed away leaving only the demonstrate the greatest levels of bind- bind to the synthesized compounds
linked building blocks covalently bound ing to the receptor are then subdivided while still covalently attached to the sili-
to the solid support. Subsequent and the process repeated. In this way, con wafer. This condition almost cer-
“deprotection” of the support bound pools are enriched for the desired sub- tainly hinders the activity of many com-
compounds followed by exposure to stance, which can then be identified pounds which would be biologically
another solution of building blocks elon- through spectroscopy. active in solution.
gates the chain by one more unit. This It must be emphasized that identi- Since the vast majority of biologi-
process is repeated until the desired fication of compounds which demon- cal interactions between compounds
chain length of building blocks has strate biological activity represents the and receptors occur at cell surfaces,
been assembled. key step in the combinatorial process. new combinatorial techniques have
Extremely large numbers of differ- While modern spectroscopic methods been developed in which artificial pro-
ent compounds can be created quickly are excellent, they do have limitations. teins are displayed on cell membranes.
and easily through this process. Nu- Thus, other strategies for discovering Random oligonucleotide cassettes
merically, the number of different com- bioactive compounds have recently are synthesized and placed in appro-
pounds N which can be formed in an been developed. priate genetic vectors for the produc-
Figure 1. Combinatorial chemistry enables the assembly of a large number of different molecules in a short period of time
following a simple protocol: (a) initial attachment of building blocks to a solid support; (b) exposure of these building blocks to
a solution of protected molecules; (c) subsequent deprotection; (d) re-exposure to another solution of building blocks, etc. This
process is repeated until the desired chain length of building blocks has been assembled.
ideal combinatorial synthesis is deter- One such strategy relies on the tion of membrane surface proteins.
mined by the number of building blocks spatial segregation of molecules pro- Mutant cell colonies are then screened
b available for each step and the num- duced in the reactions. A very effective for bioactive surface proteins by expos-
ber of synthetic steps x in the reaction method uses solid supports of small sili- ing the colonies to appropriately labeled
scheme. If in each step in the synthe- con wafers and building blocks contain- receptors. The specific peptides which
sis the same number of building blocks ing photolabile protecting groups. Us- display activity can then be isolated and
is used, the number of possible com- ing lasers, very fine patterns of the sili- subsequently identified via well estab-
pounds which could be made is N=bx . con wafers can be illuminated, remov- lished peptide degradation processes.
Thus, if 100 different building blocks are ing only the protecting groups of mol- The number of different com-
available for each step in the synthe- ecules present in these patterns. The pounds which can be produced via
sis, 10 billion different compounds can wafers are then exposed to a solution combinatorial chemistry is astounding.
be formed after only five steps! of a known compound. Statistically, the chances of finding lead
Once chemical libraries are pro- By successively and systemati- compounds through combinatorial syn-
duced, the compounds in these librar- cally illuminating different patterns and thesis are much greater than traditional
ies are assayed for biological activity. exposing the wafers to different chemi- methods. In addition, combinatorial
The sheer number of compounds gen- cals, the wafers become coated with a chemistry is fast, efficient, and cost ef-
erated, coupled with their minute quan- chemical library of extremely high den- fective, rendering it highly suitable for
tities, makes this process a formidable sity (40,000 oligomers/cm2). The com- industrial applications.
task. pound libraries, still covalently attached Combinatorial chemistry clearly
Most often, the biological activity to the wafers, are then exposed to represents a significant advance in the
of compounds sought through combi- fluorescently labeled receptors. continuing quest to discover pharma-
natorial chemistry involves binding to Because the pattern of illumination ceutical compounds.
a specific receptor target. While many and reactions with compounds is sys-
methods exist, one popular way to as- tematic, the position(s) where receptors —Matthew B. Oak
