[Paleopsych] Science: What Don't We Know? (125th anniversary issue)
checker at panix.com
Sun Jul 3 15:02:18 UTC 2005
What Don't We Know? -- Kennedy and Norman 309 (5731): 75 -- Science
http://www.sciencemag.org/cgi/content/summary/sci;309/5731/75 et seq.
[All articles included. Read carefully. I'd like to know if there will be
a different answer to the question, "How much can be boost i.q. and
scholastic achievement." Actually, there was very little here touching
upon the social sciences or social issues.]
Introduction to special issue
What Don't We Know?
Donald Kennedy and Colin Norman
At Science, we tend to get excited about new discoveries that lift the
veil a little on how things work, from cells to the universe. That
puts our focus firmly on what has been added to our stock of
knowledge. For this anniversary issue, we decided to shift our frame
of reference, to look instead at what we don't know: the scientific
puzzles that are driving basic scientific research.
We began by asking Science's Senior Editorial Board, our Board of
Reviewing Editors, and our own editors and writers to suggest
questions that point to critical knowledge gaps. The ground rules:
Scientists should have a good shot at answering the questions over the
next 25 years, or they should at least know how to go about answering
them. We intended simply to choose 25 of these suggestions and turn
them into a survey of the big questions facing science. But when a
group of editors and writers sat down to select those big questions,
we quickly realized that 25 simply wouldn't convey the grand sweep of
cutting-edge research that lies behind the responses we received. So
we have ended up with 125 questions, a fitting number for Science's
First, a note on what this special issue is not: It is not a survey of
the big societal challenges that science can help solve, nor is it a
forecast of what science might achieve. Think of it instead as a
survey of our scientific ignorance, a broad swath of questions that
scientists themselves are asking. As Tom Siegfried puts it in his
introductory essay, they are "opportunities to be exploited."
We selected 25 of the 125 questions to highlight based on several
criteria: how fundamental they are, how broad-ranging, and whether
their solutions will impact other scientific disciplines. Some have
few immediate practical implications--the composition of the universe,
for example. Others we chose because the answers will have enormous
societal impact--whether an effective HIV vaccine is feasible, or how
much the carbon dioxide we are pumping into the atmosphere will warm
our planet, for example. Some, such as the nature of dark energy, have
come to prominence only recently; others, such as the mechanism behind
limb regeneration in amphibians, have intrigued scientists for more
than a century. We listed the 25 highlighted questions in no special
order, but we did group the 100 additional questions roughly by
Our sister online publications are also devoting special issues to
Science's 125th anniversary. The Science of Aging Knowledge
Environment, SAGE KE (www.sageke.org), is surveying several big
questions confronting researchers on aging. The Signal Transduction
Knowledge Environment, STKE (www.stke.org), has selected classic
Science articles that have had a high impact in the field of cell
signaling and is highlighting them in an editorial guide. And
Science's Next Wave (www.nextwave.org) is looking at the careers
of scientists grappling with some of the questions Science has
We are acutely aware that even 125 unknowns encompass only a partial
answer to the question that heads this special section: What Don't We
Know? So we invite you to participate in a special forum on Science's
Web site (www.sciencemag.org/sciext/eletters/125th), in which you
can comment on our 125 questions or nominate topics we missed--and we
apologize if they are the very questions you are working on.
How Hot Will the Greenhouse World Be?
Richard A. Kerr
Scientists know that the world has warmed lately, and they believe
humankind is behind most of that warming. But how far might we push
the planet in coming decades and centuries? That depends on just how
sensitively the climate system--air, oceans, ice, land, and
life--responds to the greenhouse gases we're pumping into the
atmosphere. For a quarter-century, expert opinion was vague about
climate sensitivity. Experts allowed that climate might be quite
touchy, warming sharply when shoved by one climate driver or another,
such as the carbon dioxide from fossil fuel burning, volcanic debris,
or dimming of the sun. On the other hand, the same experts conceded
that climate might be relatively unresponsive, warming only modestly
despite a hard push toward the warm side.
The problem with climate sensitivity is that you can't just go out and
directly measure it. Sooner or later a climate model must enter the
picture. Every model has its own sensitivity, but each is subject to
all the uncertainties inherent in building a hugely simplified
facsimile of the real-world climate system. As a result, climate
scientists have long quoted the same vague range for sensitivity: A
doubling of the greenhouse gas carbon dioxide, which is expected to
occur this century, would eventually warm the world between a modest
1.5°C and a whopping 4.5°C. This range--based on just two early
climate models--first appeared in 1979 and has been quoted by every
major climate assessment since.
Figure 1 A harbinger? Coffins being lined up during the
record-breaking 2003 heat wave in Europe.
Researchers are finally beginning to tighten up the range of possible
sensitivities, at least at one end. For one, the sensitivities of the
available models (5% to 95% confidence range) are now falling within
the canonical range of 1.5°C to 4.5°C; some had gone considerably
beyond the high end. And the first try at a new approach--running a
single model while varying a number of model parameters such as cloud
behavior--has produced a sensitivity range of 2.4°C to 5.4°Cwith a
most probable value of 3.2°C.
Models are only models, however. How much better if nature ran the
experiment? Enter paleoclimatologists, who sort out how climate
drivers such as greenhouse gases have varied naturally in the distant
past and how the climate system of the time responded. Nature, of
course, has never run the perfect analog for the coming greenhouse
warming. And estimating how much carbon dioxide concentrations fell
during the depths of the last ice age or how much sunlight debris from
the eruption of Mount Pinatubo in the Philippines blocked will always
have lingering uncertainties. But paleoclimate estimates of climate
sensitivity generally fall in the canonical range, with a best
estimate in the region of 3°C.
The lower end at least of likely climate sensitivity does seem to be
firming up; it's not likely below 1.5°C, say researchers. That would
rule out the negligible warmings proposed by some greenhouse
contrarians. But climate sensitivity calculations still put a fuzzy
boundary on the high end. Studies drawing on the past century's
observed climate change plus estimates of natural and anthropogenic
climate drivers yield up to 30% probabilities of sensitivities above
4.5°C, ranging as high as 9°C. The latest study that varies model
parameters allows sensitivities up to 11°C, with the authors
contending that they can't yet say what the chances of such extremes
are. Others are pointing to times of extreme warmth in the geologic
past that climate models fail to replicate, suggesting that there's a
dangerous element to the climate system that the models do not yet
Climate researchers have their work cut out for them. They must inject
a better understanding of clouds and aerosols--the biggest sources of
uncertainty--into their modeling. Ten or 15 years ago, scientists said
that would take 10 or 15 years; there's no sign of it happening
anytime soon. They must increase the fidelity of models, a realistic
goal given the continued acceleration of affordable computing power.
And they must retrieve more and better records of past climate changes
and their drivers. Meanwhile, unless a rapid shift away from fossil
fuel use occurs worldwide, a doubling of carbon dioxide--and
more--will be inevitable.
What Can Replace Cheap Oil--and When?
Richard A. Kerr and Robert F. Service
The road from old to new energy sources can be bumpy, but the
transitions have gone pretty smoothly in the past. After millennia of
dependence on wood, society added coal and gravitydriven water to the
energy mix. Industrialization took off. Oil arrived, and
transportation by land and air soared, with hardly a worry about where
the next log or lump of coal was coming from, or what the explosive
growth in energy production might be doing to the world.
Times have changed. The price of oil has been climbing, and ice is
melting around both poles as the mercury in the global thermometer
rises. Whether the next big energy transition will be as smooth as
past ones will depend in large part on three sets of questions: When
will world oil production peak? How sensitive is Earth's climate to
the carbon dioxide we are pouring into the atmosphere by burning
fossil fuels? And will alternative energy sources be available at
reasonable costs? The answers rest on science and technology, but how
society responds will be firmly in the realm of politics.
There is little disagreement that the world will soon be running short
of oil. The debate is over how soon. Global demand for oil has been
rising at 1% or 2% each year, and we are now sucking almost 1000
barrels of oil from the ground every second. Pessimists--mostly former
oil company geologists--expect oil production to peak very soon. They
point to American geologist M. King Hubbert's successful 1956
prediction of the 1970 peak in U.S. production. Using the same method
involving records of past production and discoveries, they predict a
world oil peak by the end of the decade. Optimists--mostly resource
economists--argue that oil production depends more on economics and
politics than on how much happens to be in the ground. Technological
innovation will intervene, and production will continue to rise, they
say. Even so, midcentury is about as far as anyone is willing to push
the peak. That's still "soon" considering that the United States, for
one, will need to begin replacing oil's 40% contribution to its energy
consumption by then. And as concerns about climate change intensify,
the transition to nonfossil fuels could become even more urgent (see
If oil supplies do peak soon or climate concerns prompt a major shift
away from fossil fuels, plenty of alternative energy supplies are
waiting in the wings. The sun bathes Earth's surface with 86,000
trillion watts, or terawatts, of energy at all times, about 6600 times
the amount used by all humans on the planet each year. Wind, biomass,
and nuclear power are also plentiful. And there is no shortage of
opportunities for using energy more efficiently.
Of course, alternative energy sources have their issues. Nuclear
fission supporters have never found a noncontroversial solution for
disposing of long-lived radioactive wastes, and concerns over
liability and capital costs are scaring utility companies off.
Renewable energy sources are diffuse, making it difficult and
expensive to corral enough power from them at cheap prices. So far,
wind is leading the way with a global installed capacity of more than
40 billion watts, or gigawatts, providing electricity for about 4.5
cents per kilowatt hour.
That sounds good, but the scale of renewable energy is still very
small when compared to fossil fuel use. In the United States,
renewables account for just 6% of overall energy production. And, with
global energy demand expected to grow from approximately 13 terawatts
a year now to somewhere between 30 and 60 terawatts by the middle of
this century, use of renewables will have to expand enormously to
displace current sources and have a significant impact on the world's
future energy needs.
What needs to happen for that to take place? Using energy more
efficiently is likely to be the sine qua non of energy planning--not
least to buy time for efficiency improvements in alternative energy.
The cost of solar electric power modules has already dropped two
orders of magnitude over the last 30 years. And most experts figure
the price needs to drop 100-fold again before solar energy systems
will be widely adopted. Advances in nanotechnology may help by
providing novel semiconductor systems to boost the efficiency of solar
energy collectors and perhaps produce chemical fuels directly from
sunlight, CO, and water.
But whether these will come in time to avoid an energy crunch depends
in part on how high a priority we give energy research and
development. And it will require a global political consensus on what
the science is telling us.
Will Malthus Continue to Be Wrong?
In 1798, a 32-year-old curate at a small parish church in Albury,
England, published a sobering pamphlet entitled An Essay on the
Principle of Population. As a grim rebuttal of the utopian
philosophers of his day, Thomas Malthus argued that human populations
will always tend to grow and, eventually, they will always be
checked--either by foresight, such as birth control, or as a result of
famine, war, or disease. Those speculations have inspired many a dire
warning from environmentalists.
Since Malthus's time, world population has risen sixfold to more than
6 billion. Yet happily, apocalyptic collapses have mostly been
prevented by the advent of cheap energy, the rise of science and
technology, and the green revolution. Most demographers predict that
by 2100, global population will level off at about 10 billion.
The urgent question is whether current standards of living can be
sustained while improving the plight of those in need. Consumption of
resources--not just food but also water, fossil fuels, timber, and
other essentials--has grown enormously in the developed world. In
addition, humans have compounded the direct threats to those resources
in many ways, including by changing climate (see p. 100),
polluting land and water, and spreading invasive species.
How can humans live sustainably on the planet and do so in a way that
manages to preserve some biodiversity? Tackling that question involves
a broad range of research for natural and social scientists. It's
abundantly clear, for example, that humans are degrading many
ecosystems and hindering their ability to provide clean water and
other "goods and services" (Science, 1 April, p. 41). But exactly
how bad is the situation? Researchers need better information on the
status and trends of wetlands, forests, and other areas. To set
priorities, they'd also like a better understanding of what makes
ecosystems more resistant or vulnerable and whether stressed
ecosystems, such as marine fisheries, have a threshold at which they
Figure 1 Out of balance. Sustaining a growing world population is
threatened by inefficient consumption of resources--and by poverty.
Agronomists face the task of feeding 4 billion more mouths. Yields may
be maxing out in the developed world, but much can still be done in
the developing world, particularly sub-Saharan Africa, which
desperately needs more nitrogen. Although agricultural biotechnology
clearly has potential to boost yields and lessen the environmental
impact of farming, it has its own risks, and winning over skeptics has
There's no shortage of work for social scientists either. Perverse
subsidies that encourage overuse of resources--tax loopholes for
luxury Hummers and other inefficient vehicles, for example--remain a
chronic problem. A new area of activity is the attempt to place values
on ecosystems' services, so that the price of clear-cut lumber, for
instance, covers the loss of a forest's ability to provide clean
water. Incorporating those "externalities" into pricing is a daunting
challenge that demands much more knowledge of ecosystems. In addition,
economic decisions often consider only net present value and discount
the future value of resources--soil erosion, slash-and-burn
agriculture, and the mining of groundwater for cities and farming are
prime examples. All this complicates the process of transforming
industries so that they provide jobs, goods, and services while
damaging the environment less.
Researchers must also grapple with the changing demographics of
housing and how it will impact human well-being: In the next 35 to 50
years, the number of people living in cities will double. Much of the
growth will likely happen in the developing world in cities that
currently have 30,000 to 3 million residents. Coping with that huge
urban influx will require everything from energy efficient ways to
make concrete to simple ways to purify drinking water.
And in an age of global television and relentless advertising, what
will happen to patterns of consumption? The world clearly can't
support 10 billion people living like Americans do today. Whether
science--both the natural and social sciences--and technology can
crank up efficiency and solve the problems we've created is perhaps
the most critical question the world faces. Mustering the political
will to make hard choices is, however, likely to be an even bigger
In Praise of Hard Questions
Great cases, as U.S. Supreme Court Justice Oliver Wendell Holmes
suggested a century ago, may make bad law. But great questions often
make very good science.
Unsolved mysteries provide science with motivation and direction. Gaps
in the road to scientific knowledge are not potholes to be avoided,
but opportunities to be exploited.
"Fundamental questions are guideposts; they stimulate people," says
2004 Nobel physics laureate David Gross. "One of the most creative
qualities a research scientist can have is the ability to ask the
Science's greatest advances occur on the frontiers, at the interface
between ignorance and knowledge, where the most profound questions are
posed. There's no better way to assess the current condition of
science than listing the questions that science cannot answer.
"Science," Gross declares, "is shaped by ignorance."
There have been times, though, when some believed that science had
paved over all the gaps, ending the age of ignorance. When Science was
born, in 1880, James Clerk Maxwell had died just the year before,
after successfully explaining light, electricity, magnetism, and heat.
Along with gravity, which Newton had mastered 2 centuries earlier,
physics was, to myopic eyes, essentially finished. Darwin, meanwhile,
had established the guiding principle of biology, and Mendeleyev's
periodic table--only a decade old--allowed chemistry to publish its
foundations on a poster board. Maxwell himself mentioned that many
physicists believed the trend in their field was merely to measure the
values of physical constants "to another place of decimals."
Nevertheless, great questions raged. Savants of science debated not
only the power of natural selection, but also the origin of the solar
system, the age and internal structure of Earth, and the prospect of a
plurality of worlds populating the cosmos.
In fact, at the time of Maxwell's death, his theory of electromagnetic
fields was not yet widely accepted or even well known; experts still
argued about whether electricity and magnetism propagated their
effects via "action at a distance," as gravity (supposedly) did, or by
Michael Faraday's "lines of force" (incorporated by Maxwell into his
fields). Lurking behind that dispute was the deeper issue of whether
gravity could be unified with electromagnetism (Maxwell thought not),
a question that remains one of the greatest in science today, in a
somewhat more complicated form.
Maxwell knew full well that his accomplishments left questions
unanswered. His calculations regarding the internal motion of
molecules did not agree with measurements of specific heats, for
instance. "Something essential to the complete state of the physical
theory of molecular encounters must have hitherto escaped us," he
When Science turned 20--at the 19th century's end--Maxwell's mentor
William Thomson (Lord Kelvin) articulated the two grand gaps in
knowledge of the day. (He called them "clouds" hanging over
physicists' heads.) One was the mystery of specific heats that Maxwell
had identified; the other was the failure to detect the ether, a
medium seemingly required by Maxwell's electromagnetic waves.
Filling those two gaps in knowledge required the 20th century's
quantum and relativity revolutions. The ignorance enveloped in
Kelvin's clouds was the impetus for science's revitalization.
Throughout the last century, pursuing answers to great questions
reshaped human understanding of the physical and living world. Debates
over the plurality of worlds assumed galactic proportions,
specifically addressing whether Earth's home galaxy, the Milky Way,
was only one of many such conglomerations of stars. That issue was
soon resolved in favor of the Milky Way's nonexclusive status, in much
the same manner that Earth itself had been demoted from its central
role in the cosmos by Copernicus centuries before.
But the existence of galaxies outside our own posed another question,
about the apparent motions of those galaxies away from one another.
That issue echoed a curious report in Science's first issue about a
set of stars forming a triangular pattern, with a double star at the
apex and two others forming the base. Precise observations showed the
stars to be moving apart, making the triangle bigger but maintaining
"It seems probable that all these stars are slowly moving away from
one common point, so that many years back they were all very much
closer to one another," Science reported, as though the four stars had
all begun their journey from the same place. Understanding such motion
was a question "of the highest interest."
A half a century later, Edwin Hubble enlarged that question from one
about stellar motion to the origin and history of the universe itself.
He showed that galaxies also appeared to be receding from a common
starting point, evidence that the universe was expanding. With
Hubble's discovery, cosmology's grand questions began to morph from
the philosophical to the empirical. And with the discovery of the
cosmic microwave background in the 1960s, the big bang theory of the
universe's birth assumed the starring role on the cosmological
stage--providing cosmologists with one big answer and many new
By Science's centennial, a quarter-century ago, many gaps still
remained in knowledge of the cosmos; some of them have since been
filled, while others linger. At that time debate continued over the
existence of planets around faraway stars, a question now settled with
the discovery of dozens of planets in the solar system's galactic
neighborhood. But now a bigger question looms beyond the scope of
planets or even galaxies: the prospect of multiple universes, cousins
to the bubble of time and space that humans occupy.
And not only may the human universe not be alone (defying the old
definition of universe), humans may not be alone in their own space,
either. The possible existence of life elsewhere in the cosmos remains
as great a gap as any in present-day knowledge. And it is enmeshed
with the equally deep mystery of life's origin on Earth.
Life, of course, inspires many deep questions, from the prospects for
immortality to the prognosis for eliminating disease. Scientists
continue to wonder whether they will ever be able to create new life
forms from scratch, or at least simulate life's self-assembling
capabilities. Biologists, physicists, mathematicians, and computer
scientists have begun cooperating on a sophisticated "systems biology"
aimed at understanding how the countless molecular interactions at the
heart of life fit together in the workings of cells, organs, and whole
animals. And if successful, the systems approach should help doctors
tailor treatments to individual variations in DNA, permitting
personalized medicine that deters disease without inflicting side
effects. Before Science turns 150, revamped versions of modern
medicine may make it possible for humans to live that long, too.
As Science and science age, knowledge and ignorance have coevolved,
and the nature of the great questions sometimes changes. Old questions
about the age and structure of the Earth, for instance, have given way
to issues concerning the planet's capacity to support a growing and
Some great questions get bigger over time, encompassing an
ever-expanding universe, or become more profound, such as the quest to
understand consciousness. On the other hand, many deep questions drive
science to smaller scales, more minute than the realm of atoms and
molecules, or to a greater depth of detail underlying broad-brush
answers to past big questions. In 1880, some scientists remained
unconvinced by Maxwell's evidence for atoms. Today, the analogous
debate focuses on superstrings as the ultimate bits of matter, on a
scale a trillion trillion times smaller. Old arguments over evolution
and natural selection have descended to debates on the dynamics of
speciation, or how particular behaviors, such as altruistic
cooperation, have emerged from the laws of individual competition.
Great questions themselves evolve, of course, because their answers
spawn new and better questions in turn. The solutions to Kelvin's
clouds--relativity and quantum physics--generated many of the
mysteries on today's list, from the composition of the cosmos to the
prospect for quantum computers.
Ultimately, great questions like these both define the state of
scientific knowledge and drive the engines of scientific discovery.
Where ignorance and knowledge converge, where the known confronts the
unknown, is where scientific progress is most dramatically made.
"Thoroughly conscious ignorance," wrote Maxwell, "is the prelude to
every real advance in science."
So when science runs out of questions, it would seem, science will
come to an end. But there's no real danger of that. The highway from
ignorance to knowledge runs both ways: As knowledge accumulates,
diminishing the ignorance of the past, new questions arise, expanding
the areas of ignorance to explore.
Maxwell knew that even an era of precision measurements is not a sign
of science's end but preparation for the opening of new frontiers. In
every branch of science, Maxwell declared, "the labor of careful
measurement has been rewarded by the discovery of new fields of
research and by the development of new scientific ideas."
If science's progress seems to slow, it's because its questions get
increasingly difficult, not because there will be no new questions
left to answer.
Fortunately, hard questions also can make great science, just as
Justice Holmes noted that hard cases, like great cases, made bad law.
Bad law resulted, he said, because emotional concerns about celebrated
cases exerted pressures that distorted well-established legal
principles. And that's why the situation in science is the opposite of
that in law. The pressures of the great, hard questions bend and even
break well-established principles, which is what makes science forever
self-renewing--and which is what demolishes the nonsensical notion
that science's job will ever be done.
Tom Siegfried is the author of Strange Matters and The Bit and the
What Is the Universe Made Of?
Every once in a while, cosmologists are dragged, kicking and
screaming, into a universe much more unsettling than they had any
reason to expect. In the 1500s and 1600s, Copernicus, Kepler, and
Newton showed that Earth is just one of many planets orbiting one of
many stars, destroying the comfortable Medieval notion of a closed and
tiny cosmos. In the 1920s, Edwin Hubble showed that our universe is
constantly expanding and evolving, a finding that eventually shattered
the idea that the universe is unchanging and eternal. And in the past
few decades, cosmologists have discovered that the ordinary matter
that makes up stars and galaxies and people is less than 5% of
everything there is. Grappling with this new understanding of the
cosmos, scientists face one overriding question: What is the universe
This question arises from years of progressively stranger
observations. In the 1960s, astronomers discovered that galaxies spun
around too fast for the collective pull of the stars' gravity to keep
them from flying apart. Something unseen appears to be keeping the
stars from flinging themselves away from the center: unilluminated
matter that exerts extra gravitational force. This is dark matter.
Over the years, scientists have spotted some of this dark matter in
space; they have seen ghostly clouds of gas with x-ray telescopes,
watched the twinkle of distant stars as invisible clumps of matter
pass in front of them, and measured the distortion of space and time
caused by invisible mass in galaxies. And thanks to observations of
the abundances of elements in primordial gas clouds, physicists have
concluded that only 10% of ordinary matter is visible to telescopes.
Figure 1 In the dark. Dark matter holds galaxies together;
supernovae measurements point to a mysterious dark energy.
But even multiplying all the visible "ordinary" matter by 10 doesn't
come close to accounting for how the universe is structured. When
astronomers look up in the heavens with powerful telescopes, they see
a lumpy cosmos. Galaxies don't dot the skies uniformly; they cluster
together in thin tendrils and filaments that twine among vast voids.
Just as there isn't enough visible matter to keep galaxies spinning at
the right speed, there isn't enough ordinary matter to account for
this lumpiness. Cosmologists now conclude that the gravitational
forces exerted by another form of dark matter, made of an
as-yet-undiscovered type of particle, must be sculpting these vast
cosmic structures. They estimate that this exotic dark matter makes up
about 25% of the stuff in the universe--five times as much as ordinary
But even this mysterious entity pales by comparison to another
mystery: dark energy. In the late 1990s, scientists examining distant
supernovae discovered that the universe is expanding faster and
faster, instead of slowing down as the laws of physics would imply. Is
there some sort of antigravity force blowing the universe up?
All signs point to yes. Independent measurements of a variety of
phenomena--cosmic background radiation, element abundances, galaxy
clustering, gravitational lensing, gas cloud properties--all converge
on a consistent, but bizarre, picture of the cosmos. Ordinary matter
and exotic, unknown particles together make up only about 30% of the
stuff in the universe; the rest is this mysterious anti-gravity force
known as dark energy.
This means that figuring out what the universe is made of will require
answers to three increasingly difficult sets of questions. What is
ordinary dark matter made of, and where does it reside? Astrophysical
observations, such as those that measure the bending of light by
massive objects in space, are already yielding the answer. What is
exotic dark matter? Scientists have some ideas, and with luck, a
dark-matter trap buried deep underground or a high-energy atom smasher
will discover a new type of particle within the next decade. And
finally, what is dark energy? This question, which wouldn't even have
been asked a decade ago, seems to transcend known physics more than
any other phenomenon yet observed. Ever-better measurements of
supernovae and cosmic background radiation as well as planned
observations of gravitational lensing will yield information about
dark energy's "equation of state"--essentially a measure of how
squishy the substance is. But at the moment, the nature of dark energy
is arguably the murkiest question in physics--and the one that, when
answered, may shed the most light.
So Much More to Know ...
From the nature of the cosmos to the nature of societies, the
following 100 questions span the sciences. Some are pieces of
questions discussed above; others are big questions in their own
right. Some will drive scientific inquiry for the next century; others
may soon be answered. Many will undoubtedly spawn new questions.
Is ours the only universe?
A number of quantum theorists and cosmologists are trying to figure
out whether our universe is part of a bigger "multiverse." But others
suspect that this hard-to-test idea may be a question for
What drove cosmic inflation?
In the first moments after the big bang, the universe blew up at an
incredible rate. But what did the blowing? Measurements of the cosmic
microwave background and other astrophysical observations are
narrowing the possibilities.
When and how did the first stars and galaxies form?
The broad brush strokes are visible, but the fine details aren't. Data
from satellites and ground-based telescopes may soon help pinpoint,
among other particulars, when the first generation of stars burned off
the hydrogen "fog" that filled the universe.
Where do ultrahigh-energy cosmic rays come from?
Above a certain energy, cosmic rays don't travel very far before being
destroyed. So why are cosmic-ray hunters spotting such rays with no
obvious source within our galaxy?
What powers quasars?
The mightiest energy fountains in the universe probably get their
power from matter plunging into whirling supermassive black holes. But
the details of what drives their jets remain anybody's guess.
What is the nature of black holes?
Relativistic mass crammed into a quantum-sized object? It's a recipe
for disaster--and scientists are still trying to figure out the
Why is there more matter than antimatter?
To a particle physicist, matter and antimatter are almost the same.
Some subtle difference must explain why matter is common and
Does the proton decay?
In a theory of everything, quarks (which make up protons) should
somehow be convertible to leptons (such as electrons)--so catching a
proton decaying into something else might reveal new laws of particle
What is the nature of gravity?
It clashes with quantum theory. It doesn't fit in the Standard Model.
Nobody has spotted the particle that is responsible for it. Newton's
apple contain ned a whole can of worms.
Why is time different from other dimensions?
It took millennia for scientists to realize that time is a dimension,
like the three spatial dimensions, and that time and space are
inextricably linked. The equations make sense, but they don't satisfy
those who ask why we perceive a "now" or why time seems to flow the
way it does.
Are there smaller building blocks than quarks?
Atoms were "uncuttable." Then scientists discovered protons, neutrons,
and other subatomic particles--which were, in turn, shown to be made
up of quarks and gluons. Is there something more fundamental still?
Are neutrinos their own antiparticles?
Nobody knows this basic fact about neutrinos, although a number of
underground experiments are under way. Answering this question may be
a crucial step to understanding the origin of matter in the universe.
Is there a unified theory explaining all correlated electron systems?
High-temperature superconductors and materials with giant and colossal
magnetoresistance are all governed by the collective rather than
individual behavior of electrons. There is currently no common
framework for understanding them.
What is the most powerful laser researchers can build?
Theorists say an intense enough laser field would rip photons into
electron-positron pairs, dousing the beam. But no one knows whether
it's possible to reach that point.
Can researchers make a perfect optical lens?
They've done it with microwaves but never with visible light.
Is it possible to create magnetic semiconductors that work at room
Such devices have been demonstrated at low temperatures but not yet in
a range warm enough for spintronics applications.
What is the pairing mechanism behind high-temperature
Electrons in superconductors surf together in pairs. After 2 decades
of intense study, no one knows what holds them together in the
complex, high-temperature materials.
Can we develop a general theory of the dynamics of turbulent flows and
the motion of granular materials?
So far, such "nonequilibrium systems" defy the tool kit of statistical
mechanics, and the failure leaves a gaping hole in physics.
Are there stable high-atomic-number elements?
A superheavy element with 184 neutrons and 114 protons should be
relatively stable, if physicists can create it.
Is superfluidity possible in a solid? If so, how?
Despite hints in solid helium, nobody is sure whether a crystalline
material can flow without resistance. If new types of experiments show
that such outlandish behavior is possible, theorists would have to
What is the structure of water?
Researchers continue to tussle over how many bonds each HO molecule
makes with its nearest neighbors.
What is the nature of the glassy state?
Molecules in a glass are arranged much like those in liquids but are
more tightly packed. Where and why does liquid end and glass begin?
Are there limits to rational chemical synthesis?
The larger synthetic molecules get, the harder it is to control their
shapes and make enough copies of them to be useful. Chemists will need
new tools to keep their creations growing.
What is the ultimate efficiency of photovoltaic cells?
Conventional solar cells top out at converting 32% of the energy in
sunlight to electricity. Can researchers break through the barrier?
Will fusion always be the energy source of the future?
It's been 35 years away for about 50 years, and unless the
international community gets its act together, it'll be 35 years away
for many decades to come.
What drives the solar magnetic cycle?
Scientists believe differing rates of rotation from place to place on
the sun underlie its 22-year sunspot cycle. They just can't make it
work in their simulations. Either a detail is askew, or it's back to
the drawing board.
How do planets form?
How bits of dust and ice and gobs of gas came together to form the
planets without the sun devouring them all is still unclear. Planetary
systems around other stars should provide clues.
What causes ice ages?
Something about the way the planet tilts, wobbles, and careens around
the sun presumably brings on ice ages every 100,000 years or so, but
reams of climate records haven't explained exactly how.
What causes reversals in Earth's magnetic field?
Computer models and laboratory experiments are generating new data on
how Earth's magnetic poles might flip-flop. The trick will be matching
simulations to enough aspects of the magnetic field beyond the
inaccessible core to build a convincing case.
Are there earthquake precursors that can lead to useful predictions?
Prospects for finding signs of an imminent quake have been waning
since the 1970s. Understanding faults will progress, but routine
prediction would require an as-yet-unimagined breakthrough.
Is there--or was there--life elsewhere in the solar system?
The search for life--past or present--on other planetary bodies now
drives NASA's planetary exploration program, which focuses on Mars,
where water abounded when life might have first arisen.
What is the origin of homochirality in nature?
Most biomolecules can be synthesized in mirror-image shapes. Yet in
organisms, amino acids are always left-handed, and sugars are always
right-handed. The origins of this preference remain a mystery.
Can we predict how proteins will fold?
Out of a near infinitude of possible ways to fold, a protein picks one
in just tens of microseconds. The same task takes 30 years of computer
How many proteins are there in humans?
It has been hard enough counting genes. Proteins can be spliced in
different ways and decorated with numerous functional groups, all of
which makes counting their numbers impossible for now.
How do proteins find their partners?
Protein-protein interactions are at the heart of life. To understand
how partners come together in precise orientations in seconds,
researchers need to know more about the cell's biochemistry and
How many forms of cell death are there?
In the 1970s, apoptosis was finally recognized as distinct from
necrosis. Some biologists now argue that the cell death story is even
more complicated. Identifying new ways cells die could lead to better
treatments for cancer and degenerative diseases.
What keeps intracellular traffic running smoothly?
Membranes inside cells transport key nutrients around, and through,
various cell compartments without sticking to each other or losing
their way. Insights into how membranes stay on track could help
conquer diseases, such as cystic fibrosis.
What enables cellular components to copy themselves independent of
Centrosomes, which help pull apart paired chromosomes, and other
organelles replicate on their own time, without DNA's guidance. This
independence still defies explanation.
What roles do different forms of RNA play in genome function?
RNA is turning out to play a dizzying assortment of roles, from
potentially passing genetic information to offspring to muting gene
expression. Scientists are scrambling to decipher this versatile
What role do telomeres and centromeres play in genome function?
These chromosome features will remain mysteries until new technologies
can sequence them.
Why are some genomes really big and others quite compact?
The puffer fish genome is 400 million bases; one lungfish's is 133
billion bases long. Repetitive and duplicated DNA don't explain why
this and other size differences exist.
What is all that "junk" doing in our genomes?
DNA between genes is proving important for genome function and the
evolution of new species. Comparative sequencing, microarray studies,
and lab work are helping genomicists find a multitude of genetic gems
amid the junk.
How much will new technologies lower the cost of sequencing?
New tools and conceptual breakthroughs are driving the cost of DNA
sequencing down by orders of magnitude. The reductions are enabling
research from personalized medicine to evolutionary biology to thrive.
How do organs and whole organisms know when to stop growing?
A person's right and left legs almost always end up the same length,
and the hearts of mice and elephants each fit the proper rib cage. How
genes set limits on cell size and number continues to mystify.
How can genome changes other than mutations be inherited?
Researchers are finding ever more examples of this process, called
epigenetics, but they can't explain what causes and preserves the
How is asymmetry determined in the embryo?
Whirling cilia help an embryo tell its left from its right, but
scientists are still looking for the first factors that give a
relatively uniform ball of cells a head, tail, front, and back.
How do limbs, fins, and faces develop and evolve?
The genes that determine the length of a nose or the breadth of a wing
are subject to natural and sexual selection. Understanding how
selection works could lead to new ideas about the mechanics of
evolution with respect to development.
What triggers puberty?
Nutrition--including that received in utero--seems to help set this
mysterious biological clock, but no one knows exactly what forces
childhood to end.
Are stem cells at the heart of all cancers?
The most aggressive cancer cells look a lot like stem cells. If
cancers are caused by stem cells gone awry, studies of a cell's
"stemness" may lead to tools that could catch tumors sooner and
destroy them more effectively.
Is cancer susceptible to immune control?
Although our immune responses can suppress tumor growth, tumor cells
can combat those responses with counter-measures. This defense can
stymie researchers hoping to develop immune therapies against cancer.
Can cancers be controlled rather than cured?
Drugs that cut off a tumor's fuel supplies--say, by stopping
blood-vessel growth--can safely check or even reverse tumor growth.
But how long the drugs remain effective is still unknown.
Is inflammation a major factor in all chronic diseases?
It's a driver of arthritis, but cancer and heart disease? More and
more, the answer seems to be yes, and the question remains why and
How do prion diseases work?
Even if one accepts that prions are just misfolded proteins, many
mysteries remain. How can they go from the gut to the brain, and how
do they kill cells once there, for example.
How much do vertebrates depend on the innate immune system to fight
This system predates the vertebrate adaptive immune response. Its
relative importance is unclear, but immunologists are working to find
Does immunologic memory require chronic exposure to antigens?
Yes, say a few prominent thinkers, but experiments with mice now
challenge the theory. Putting the debate to rest would require proving
that something is not there, so the question likely will not go away.
Why doesn't a pregnant woman reject her fetus?
Recent evidence suggests that the mother's immune system doesn't
"realize" that the fetus is foreign even though it gets half its genes
from the father. Yet just as Nobelist Peter Medawar said when he first
raised this question in 1952, "the verdict has yet to be returned."
What synchronizes an organism's circadian clocks?
Circadian clock genes have popped up in all types of creatures and in
many parts of the body. Now the challenge is figuring out how all the
gears fit together and what keeps the clocks set to the same time.
How do migrating organisms find their way?
Birds, butterflies, and whales make annual journeys of thousands of
kilometers. They rely on cues such as stars and magnetic fields, but
the details remain unclear.
Why do we sleep?
A sound slumber may refresh muscles and organs or keep animals safe
from dangers lurking in the dark. But the real secret of sleep
probably resides in the brain, which is anything but still while we're
Why do we dream?
Freud thought dreaming provides an outlet for our unconscious desires.
Now, neuroscientists suspect that brain activity during REM
sleep--when dreams occur--is crucial for learning. Is the experience
of dreaming just a side effect?
Why are there critical periods for language learning?
Monitoring brain activity in young children--including infants--may
shed light on why children pick up languages with ease while adults
often struggle to learn train station basics in a foreign tongue.
Do pheromones influence human behavior?
Many animals use airborne chemicals to communicate, particularly when
mating. Controversial studies have hinted that humans too use
pheromones. Identifying them will be key to assessing their sway on
our social lives.
How do general anesthetics work?
Scientists are chipping away at the drugs' effects on individual
neurons, but understanding how they render us unconscious will be a
tougher nut to crack.
What causes schizophrenia?
Researchers are trying to track down genes involved in this disorder.
Clues may also come from research on traits schizophrenics share with
What causes autism?
Many genes probably contribute to this baffling disorder, as well as
unknown environmental factors. A biomarker for early diagnosis would
help improve existing therapy, but a cure is a distant hope.
To what extent can we stave off Alzheimer's?
A 5- to 10-year delay in this late-onset disease would improve old age
for millions. Researchers are determining whether treatments with
hormones or antioxidants, or mental and physical exercise, will help.
What is the biological basis of addiction?
Addiction involves the disruption of the brain's reward circuitry. But
personality traits such as impulsivity and sensation-seeking also play
a part in this complex behavior.
Is morality hardwired into the brain?
That question has long puzzled philosophers; now some neuroscientists
think brain imaging will reveal circuits involved in reasoning.
What are the limits of learning by machines?
Computers can already beat the world's best chess players, and they
have a wealth of information on the Web to draw on. But abstract
reasoning is still beyond any machine.
How much of personality is genetic?
Aspects of personality are influenced by genes; environment modifies
the genetic effects. The relative contributions remain under debate.
What is the biological root of sexual orientation?
Much of the "environmental" contribution to homosexuality may occur
before birth in the form of prenatal hormones, so answering this
question will require more than just the hunt for "gay genes."
Will there ever be a tree of life that systematists can agree on?
Despite better morphological, molecular, and statistical methods,
researchers' trees don't agree. Expect greater, but not complete,
How many species are there on Earth?
Count all the stars in the sky? Impossible. Count all the species on
Earth? Ditto. But the biodiversity crisis demands that we try.
What is a species?
A "simple" concept that's been muddied by evolutionary data; a clear
definition may be a long time in coming.
Why does lateral transfer occur in so many species and how?
Once considered rare, gene swapping, particularly among microbes, is
proving quite common. But why and how genes are so mobile--and the
effect on fitness--remains to be determined.
Who was LUCA (the last universal common ancestor)?
Ideas about the origin of the 1.5-billion-year-old "mother" of all
complex organisms abound. The continued discovery of primitive
microbes, along with comparative genomics, should help resolve life's
How did flowers evolve?
Darwin called this question an "abominable mystery." Flowers arose in
the cycads and conifers, but the details of their evolution remain
How do plants make cell walls?
Cellulose and pectin walls surround cells, keeping water in and
supporting tall trees. The biochemistry holds the secrets to turning
its biomass into fuel.
How is plant growth controlled?
Redwoods grow to be hundreds of meters tall, Arctic willows barely 10
centimeters. Understanding the difference could lead to
Why aren't all plants immune to all diseases?
Plants can mount a general immune response, but they also maintain
molecular snipers that take out specific pathogens. Plant pathologists
are asking why different species, even closely related ones, have
different sets of defenders. The answer could result in hardier crops.
What is the basis of variation in stress tolerance in plants?
We need crops that better withstand drought, cold, and other stresses.
But there are so many genes involved, in complex interactions, that no
one has yet figured out which ones work how.
What caused mass extinctions?
A huge impact did in the dinosaurs, but the search for other
catastrophic triggers of extinction has had no luck so far. If more
subtle or stealthy culprits are to blame, they will take considerably
longer to find.
Can we prevent extinction?
Finding cost-effective and politically feasible ways to save many
endangered species requires creative thinking.
Why were some dinosaurs so large?
Dinosaurs reached almost unimaginable sizes, some in less than 20
years. But how did the long-necked sauropods, for instance, eat enough
to pack on up to 100 tons without denuding their world?
How will ecosystems respond to global warming?
To anticipate the effects of the intensifying greenhouse, climate
modelers will have to focus on regional changes and ecologists on the
right combination of environmental changes.
How many kinds of humans coexisted in the recent past, and how did
The new dwarf human species fossil from Indonesia suggests that at
least four kinds of humans thrived in the past 100,000 years. Better
dates and additional material will help confirm or revise this
What gave rise to modern human behavior?
Did Homo sapiens acquire abstract thought, language, and art gradually
or in a cultural "big bang," which in Europe occurred about 40,000
years ago? Data from Africa, where our species arose, may hold the key
to the answer.
What are the roots of human culture?
No animal comes close to having humans' ability to build on previous
discoveries and pass the improvements on. What determines those
differences could help us understand how human culture evolved.
What are the evolutionary roots of language and music?
Neuroscientists exploring how we speak and make music are just
beginning to find clues as to how these prized abilities arose.
What are human races, and how did they develop?
Anthropologists have long argued that race lacks biological reality.
But our genetic makeup does vary with geographic origin and as such
raises political and ethical as well as scientific questions.
Why do some countries grow and others stagnate?
From Norway to Nigeria, living standards across countries vary
enormously, and they're not becoming more equal.
What impact do large government deficits have on a country's interest
rates and economic growth rate?
The United States could provide a test case.
Are political and economic freedom closely tied?
China may provide one answer.
Why has poverty increased and life expectancy declined in sub-Saharan
Almost all efforts to reduce poverty in sub-Saharan Africa have
failed. Figuring out what will work is crucial to alleviating massive
The following six mathematics questions are drawn from a list of seven
outstanding problems selected by the Clay Mathematics Institute. (The
seventh problem is discussed on p. 96.) For more details, go to
Is there a simple test for determining whether an elliptic curve has
an infinite number of rational solutions?
Equations of the form y^2 = x^3 [plus.gif] ax [plus.gif] b are
powerful mathematical tools. The Birch and Swinnerton-Dyer conjecture
tells how to determine how many solutions they have in the realm of
rational numbers--information that could solve a host of problems, if
the conjecture is true.
Can a Hodge cycle be written as a sum of algebraic cycles?
Two useful mathematical structures arose independently in geometry and
in abstract algebra. The Hodge conjecture posits a surprising link
between them, but the bridge remains to be built.
Will mathematicians unleash the power of the Navier-Stokes equations?
First written down in the 1840s, the equations hold the keys to
understanding both smooth and turbulent flow. To harness them, though,
theorists must find out exactly when they work and under what
conditions they break down.
Does Poincaré's test identify spheres in four-dimensional space?
You can tie a string around a doughnut, but it will slide right off a
sphere. The mathematical principle behind that observation can
reliably spot every spherelike object in 3D space. Henri Poincaré
conjectured that it should also work in the next dimension up, but no
one has proved it yet.
Do mathematically interesting zero-value solutions of the Riemann zeta
function all have the form a [plus.gif] bi?
Don't sweat the details. Since the mid-19th century, the "Riemann
hypothesis" has been the monster catfish in mathematicians' pond. If
true, it will give them a wealth of information about the distribution
of prime numbers and other long-standing mysteries.
Does the Standard Model of particle physics rest on solid mathematical
For almost 50 years, the model has rested on "quantum Yang-Mills
theory," which links the behavior of particles to structures found in
geometry. The theory is breathtakingly elegant and useful--but no one
has proved that it's sound.
What Is the Biological Basis of Consciousness?
For centuries, debating the nature of consciousness was the exclusive
purview of philosophers. But if the recent torrent of books on the
topic is any indication, a shift has taken place: Scientists are
getting into the game.
Has the nature of consciousness finally shifted from a philosophical
question to a scientific one that can be solved by doing experiments?
The answer, as with any related to this topic, depends on whom you
ask. But scientific interest in this slippery, age-old question seems
to be gathering momentum. So far, however, although theories abound,
hard data are sparse.
The discourse on consciousness has been hugely influenced by René
Descartes, the French philosopher who in the mid-17th century declared
that body and mind are made of different stuff entirely. It must be
so, Descartes concluded, because the body exists in both time and
space, whereas the mind has no spatial dimension.
Recent scientifically oriented accounts of consciousness generally
reject Descartes's solution; most prefer to treat body and mind as
different aspects of the same thing. In this view, consciousness
emerges from the properties and organization of neurons in the brain.
But how? And how can scientists, with their devotion to objective
observation and measurement, gain access to the inherently private and
subjective realm of consciousness?
Some insights have come from examining neurological patients whose
injuries have altered their consciousness. Damage to certain
evolutionarily ancient structures in the brainstem robs people of
consciousness entirely, leaving them in a coma or a persistent
vegetative state. Although these regions may be a master switch for
consciousness, they are unlikely to be its sole source. Different
aspects of consciousness are probably generated in different brain
regions. Damage to visual areas of the cerebral cortex, for example,
can produce strange deficits limited to visual awareness. One
extensively studied patient, known as D.F., is unable to identify
shapes or determine the orientation of a thin slot in a vertical disk.
Yet when asked to pick up a card and slide it through the slot, she
does so easily. At some level, D.F. must know the orientation of the
slot to be able to do this, but she seems not to know she knows.
Cleverly designed experiments can produce similar dissociations of
unconscious and conscious knowledge in people without neurological
damage. And researchers hope that scanning the brains of subjects
engaged in such tasks will reveal clues about the neural activity
required for conscious awareness. Work with monkeys also may elucidate
some aspects of consciousness, particularly visual awareness. One
experimental approach is to present a monkey with an optical illusion
that creates a "bistable percept," looking like one thing one moment
and another the next. (The orientation-flipping Necker cube is a
well-known example.) Monkeys can be trained to indicate which version
they perceive. At the same time, researchers hunt for neurons that
track the monkey's perception, in hopes that these neurons will lead
them to the neural systems involved in conscious visual awareness and
ultimately to an explanation of how a particular pattern of photons
hitting the retina produces the experience of seeing, say, a rose.
Experiments under way at present generally address only pieces of the
consciousness puzzle, and very few directly address the most enigmatic
aspect of the conscious human mind: the sense of self. Yet the
experimental work has begun, and if the results don't provide a
blinding insight into how consciousness arises from tangles of
neurons, they should at least refine the next round of questions.
Ultimately, scientists would like to understand not just the
biological basis of consciousness but also why it exists. What
selection pressure led to its development, and how many of our fellow
creatures share it? Some researchers suspect that consciousness is not
unique to humans, but of course much depends on how the term is
defined. Biological markers for consciousness might help settle the
matter and shed light on how consciousness develops early in life.
Such markers could also inform medical decisions about loved ones who
are in an unresponsive state.
Until fairly recently, tackling the subject of consciousness was a
dubious career move for any scientist without tenure (and perhaps a
Nobel Prize already in the bag). Fortunately, more young researchers
are now joining the fray. The unanswered questions should keep
them--and the printing presses--busy for many years to come.
Why Do Humans Have So Few Genes?
When leading biologists were unraveling the sequence of the human
genome in the late 1990s, they ran a pool on the number of genes
contained in the 3 billion base pairs that make up our DNA. Few bets
came close. The conventional wisdom a decade or so ago was that we
need about 100,000 genes to carry out the myriad cellular processes
that keep us functioning. But it turns out that we have only about
25,000 genes--about the same number as a tiny flowering plant called
Arabidopsis and barely more than the worm Caenorhabditis elegans.
That big surprise reinforced a growing realization among geneticists:
Our genomes and those of other mammals are far more flexible and
complicated than they once seemed. The old notion of one gene/one
protein has gone by the board: It is now clear that many genes can
make more than one protein. Regulatory proteins, RNA, noncoding bits
of DNA, even chemical and structural alterations of the genome itself
control how, where, and when genes are expressed. Figuring out how all
these elements work together to choreograph gene expression is one of
the central challenges facing biologists.
In the past few years, it has become clear that a phenomenon called
alternative splicing is one reason human genomes can produce such
complexity with so few genes. Human genes contain both coding
DNA--exons--and noncoding DNA. In some genes, different combinations
of exons can become active at different times, and each combination
yields a different protein. Alternative splicing was long considered a
rare hiccup during transcription, but researchers have concluded that
it may occur in half--some say close to all--of our genes. That
finding goes a long way toward explaining how so few genes can produce
hundreds of thousands of different proteins. But how the transcription
machinery decides which parts of a gene to read at any particular time
is still largely a mystery.
The same could be said for the mechanisms that determine which genes
or suites of genes are turned on or off at particular times and
places. Researchers are discovering that each gene needs a supporting
cast of hundreds to get its job done. They include proteins that shut
down or activate a gene, for example by adding acetyl or methyl groups
to the DNA. Other proteins, called transcription factors, interact
with the genes more directly: They bind to landing sites situated near
the gene under their control. As with alternative splicing, activation
of different combinations of landing sites makes possible exquisite
control of gene expression, but researchers have yet to figure out
exactly how all these regulatory elements really work or how they fit
in with alternative splicing.
Figure 1 Approximate number of genes
In the past decade or so, researchers have also come to appreciate the
key roles played by chromatin proteins and RNA in regulating gene
expression. Chromatin proteins are essentially the packaging for DNA,
holding chromosomes in well-defined spirals. By slightly changing
shape, chromatin may expose different genes to the transcription
Genes also dance to the tune of RNA. Small RNA molecules, many less
than 30 bases, now share the limelight with other gene regulators.
Many researchers who once focused on messenger RNA and other
relatively large RNA molecules have in the past 5 years turned their
attention to these smaller cousins, including microRNA and small
nuclear RNA. Surprisingly, RNAs in these various guises shut down and
otherwise alter gene expression. They also are key to cell
differentiation in developing organisms, but the mechanisms are not
Researchers have made enormous strides in pinpointing these various
mechanisms. By matching up genomes from organisms on different
branches on the evolutionary tree, genomicists are locating regulatory
regions and gaining insights into how mechanisms such as alternative
splicing evolved. These studies, in turn, should shed light on how
these regions work. Experiments in mice, such as the addition or
deletion of regulatory regions and manipulating RNA, and computer
models should also help. But the central question is likely to remain
unsolved for a long time: How do all these features meld together to
make us whole?
To What Extent Are Genetic Variation and Personal Health Linked?
Forty years ago, doctors learned why some patients who received the
anesthetic succinylcholine awoke normally but remained temporarily
paralyzed and unable to breathe: They shared an inherited quirk that
slowed their metabolism of the drug. Later, scientists traced sluggish
succinylcholine metabolism to a particular gene variant. Roughly 1 in
3500 people carry two deleterious copies, putting them at high risk of
this distressing side effect.
The solution to the succinylcholine mystery was among the first links
drawn between genetic variation and an individual's response to drugs.
Since then, a small but growing number of differences in drug
metabolism have been linked to genetics, helping explain why some
patients benefit from a particular drug, some gain nothing, and others
suffer toxic side effects.
The same sort of variation, it is now clear, plays a key role in
individual risks of coming down with a variety of diseases. Gene
variants have been linked to elevated risks for disorders from
Alzheimer's disease to breast cancer, and they may help explain why,
for example, some smokers develop lung cancer whereas many others
These developments have led to hopes--and some hype--that we are on
the verge of an era of personalized medicine, one in which genetic
tests will determine disease risks and guide prevention strategies and
therapies. But digging up the DNA responsible--if in fact DNA is
responsible--and converting that knowledge into gene tests that
doctors can use remains a formidable challenge.
Many conditions, including various cancers, heart attacks, lupus, and
depression, likely arise when a particular mix of genes collides with
something in the environment, such as nicotine or a fatty diet. These
multigene interactions are subtler and knottier than the single gene
drivers of diseases such as hemophilia and cystic fibrosis; spotting
them calls for statistical inspiration and rigorous experiments
repeated again and again to guard against introducing unproven gene
tests into the clinic. And determining treatment strategies will be no
less complex: Last summer, for example, a team of scientists linked
124 different genes to resistance to four leukemia drugs.
But identifying gene networks like these is only the beginning. One of
the toughest tasks is replicating these studies--an especially
difficult proposition in diseases that are not overwhelmingly
heritable, such as asthma, or ones that affect fairly small patient
cohorts, such as certain childhood cancers. Many clinical trials do
not routinely collect DNA from volunteers, making it sometimes
difficult for scientists to correlate disease or drug response with
genes. Gene microarrays, which measure expression of dozens of genes
at once, can be fickle and supply inconsistent results. Gene studies
can also be prohibitively costly.
Nonetheless, genetic dissection of some diseases--such as cancer,
asthma, and heart disease--is galloping ahead. Progress in other
areas, such as psychiatric disorders, is slower. Severely depressed or
schizophrenic patients could benefit enormously from tests that reveal
which drug and dose will help them the most, but unlike asthma, drug
response can be difficult to quantify biologically, making gene-drug
relations tougher to pin down.
As DNA sequence becomes more available and technologies improve, the
genetic patterns that govern health will likely come into sharper
relief. Genetic tools still under construction, such as a haplotype
map that will be used to discern genetic variation behind common
diseases, could further accelerate the search for disease genes.
The next step will be designing DNA tests to guide clinical
decision-making--and using them. If history is any guide, integrating
such tests into standard practice will take time. In emergencies--a
heart attack, an acute cancer, or an asthma attack--such tests will be
valuable only if they rapidly deliver results.
Ultimately, comprehensive personalized medicine will come only if
pharmaceutical companies want it to--and it will take enormous
investments in research and development. Many companies worry that
testing for genetic differences will narrow their market and squelch
Still, researchers continue to identify new opportunities. In May, the
Icelandic company deCODE Genetics reported that an experimental asthma
drug that pharmaceutical giant Bayer had abandoned appeared to
decrease the risk of heart attack in more than 170 patients who
carried particular gene variants. The drug targets the protein
produced by one of those genes. The finding is likely to be just a
foretaste of the many surprises in store, as the braids binding DNA,
drugs, and disease are slowly unwound.
Can the Laws of Physics Be Unified?
At its best, physics eliminates complexity by revealing underlying
simplicity. Maxwell's equations, for example, describe all the
confusing and diverse phenomena of classical electricity and magnetism
by means of four simple rules. These equations are beautiful; they
have an eerie symmetry, mirroring one another in an intricate dance of
symbols. The four together feel as elegant, as whole, and as complete
to a physicist as a Shakespearean sonnet does to a poet.
The Standard Model of particle physics is an unfinished poem. Most of
the pieces are there, and even unfinished, it is arguably the most
brilliant opus in the literature of physics. With great precision, it
describes all known matter--all the subatomic particles such as quarks
and leptons--as well as the forces by which those particles interact
with one another. These forces are electromagnetism, which describes
how charged objects feel each other's influence: the weak force, which
explains how particles can change their identities, and the strong
force, which describes how quarks stick together to form protons and
other composite particles. But as lovely as the Standard Model's
description is, it is in pieces, and some of those pieces--those that
describe gravity--are missing. It is a few shards of beauty that hint
at something greater, like a few lines of Sappho on a fragment of
The beauty of the Standard Model is in its symmetry; mathematicians
describe its symmetries with objects known as Lie groups. And a mere
glimpse at the Standard Model's Lie group betrays its fragmented
nature: SU(3) [mult.gif] SU(2) [mult.gif] U(1). Each of those pieces
represents one type of symmetry, but the symmetry of the whole is
broken. Each of the forces behaves in a slightly different way, so
each is described with a slightly different symmetry.
But those differences might be superficial. Electromagnetism and the
weak force appear very dissimilar, but in the 1960s physicists showed
that at high temperatures, the two forces "unify." It becomes apparent
that electromagnetism and the weak force are really the same thing,
just as it becomes obvious that ice and liquid water are the same
substance if you warm them up together. This connection led physicists
to hope that the strong force could also be unified with the other two
forces, yielding one large theory described by a single symmetry such
A unified theory should have observable consequences. For example, if
the strong force truly is the same as the electroweak force, then
protons might not be truly stable; once in a long while, they should
decay spontaneously. Despite many searches, nobody has spotted a
proton decay, nor has anyone sighted any particles predicted by some
symmetry-enhancing modifications to the Standard Model, such as
supersymmetry. Worse yet, even such a unified theory can't be
complete--as long as it ignores gravity.
Figure 1 Fundamental forces. A theory that ties all four forces
together is still lacking.
Gravity is a troublesome force. The theory that describes it, general
relativity, assumes that space and time are smooth and continuous,
whereas the underlying quantum physics that governs subatomic
particles and forces is inherently discontinuous and jumpy. Gravity
clashes with quantum theory so badly that nobody has come up with a
convincing way to build a single theory that includes all the
particles, the strong and electroweak forces, and gravity all in one
big bundle. But physicists do have some leads. Perhaps the most
promising is superstring theory.
Superstring theory has a large following because it provides a way to
unify everything into one large theory with a single symmetry--SO(32)
for one branch of superstring theory, for example--but it requires a
universe with 10 or 11 dimensions, scads of undetected particles, and
a lot of intellectual baggage that might never be verifiable. It may
be that there are dozens of unified theories, only one of which is
correct, but scientists may never have the means to determine which.
Or it may be that the struggle to unify all the forces and particles
is a fool's quest.
In the meantime, physicists will continue to look for proton decays,
as well as search for supersymmetric particles in underground traps
and in the Large Hadron Collider (LHC) in Geneva, Switzerland, when it
comes online in 2007. Scientists believe that LHC will also reveal the
existence of the Higgs boson, a particle intimately related to
fundamental symmetries in the model of particle physics. And
physicists hope that one day, they will be able to finish the
unfinished poem and frame its fearful symmetry.
How Much Can Human Life Span Be Extended?
When Jeanne Calment died in a nursing home in southern France in 1997,
she was 122 years old, the longest-living human ever documented. But
Calment's uncommon status will fade in subsequent decades if the
predictions of some biologists and demographers come true. Life-span
extension in species from yeast to mice and extrapolation from life
expectancy trends in humans have convinced a swath of scientists that
humans will routinely coast beyond 100 or 110 years of age. (Today, 1
in 10,000 people in industrialized countries hold centenarian status.)
Others say human life span may be far more limited. The elasticity
found in other species might not apply to us. Furthermore, testing
life-extension treatments in humans may be nearly impossible for
practical and ethical reasons.
Just 2 or 3 decades ago, research on aging was a backwater. But when
molecular biologists began hunting for ways to prolong life, they
found that life span was remarkably pliable. Reducing the activity of
an insulinlike receptor more than doubles the life span of worms to a
startling--for them--6 weeks. Put certain strains of mice on
near-starvation but nutrient-rich diets, and they live 50% longer than
Some of these effects may not occur in other species. A worm's ability
to enter a "dauer" state, which resembles hibernation, may be
critical, for example. And shorter-lived species such as worms and
fruit flies, whose aging has been delayed the most, may be more
susceptible to life-span manipulation. But successful approaches are
converging on a few key areas: calorie restriction; reducing levels of
insulinlike growth factor 1 (IGF-1), a protein; and preventing
oxidative damage to the body's tissues. All three might be
interconnected, but so far that hasn't been confirmed (although
calorie-restricted animals have low levels of IGF-1).
Can these strategies help humans live longer? And how do we determine
whether they will? Unlike drugs for cancer or heart disease, the
benefits of antiaging treatments are fuzzier, making studies difficult
to set up and to interpret. Safety is uncertain; calorie restriction
reduces fertility in animals, and lab flies bred to live long can't
compete with their wild counterparts. Furthermore, garnering
results--particularly from younger volunteers, who may be likeliest to
benefit because they've aged the least--will take so long that by the
time results are in, those who began the study will be dead.
That hasn't stopped scientists, some of whom have founded companies,
from searching for treatments to slow aging. One intriguing question
is whether calorie restriction works in humans. It's being tested in
primates, and the National Institute on Aging in Bethesda, Maryland,
is funding short-term studies in people. Volunteers in those trials
have been on a stringent diet for up to 1 year while researchers
monitor their metabolism and other factors that could hint at how
Insights could also come from genetic studies of centenarians, who may
have inherited long life from their parents. Many scientists believe
that average human life span has an inherent upper limit, although
they don't agree on whether it's 85 or 100 or 150.
One abiding question in the antiaging world is what the goal of all
this work ought to be. Overwhelmingly, scientists favor treatments
that will slow aging and stave off age-related diseases rather than
simply extending life at its most decrepit. But even so, slowing aging
could have profound social effects, upsetting actuarial tables and
Then there's the issue of fairness: If antiaging therapies become
available, who will receive them? How much will they cost? Individuals
may find they can stretch their life spans. But that may be tougher to
achieve for whole populations, although many demographers believe that
the average life span will continue to climb as it has consistently
for decades. If that happens, much of the increase may come from less
dramatic strategies, such as heart disease and cancer prevention, that
could also make the end of a long life more bearable.
What Controls Organ Regeneration?
R. John Davenport*
Unlike automobiles, humans get along pretty well for most of their
lives with their original parts. But organs do sometimes fail, and we
can't go to the mechanic for an engine rebuild or a new water pump--at
least not yet. Medicine has battled back many of the acute threats,
such as infection, that curtailed human life in past centuries. Now,
chronic illnesses and deteriorating organs pose the biggest drain on
human health in industrialized nations, and they will only increase in
importance as the population ages. Regenerative medicine--rebuilding
organs and tissues--could conceivably be the 21st century equivalent
of antibiotics in the 20th. Before that can happen, researchers must
understand the signals that control regeneration.
Researchers have puzzled for centuries over how body parts replenish
themselves. In the mid-1700s, for instance, Swiss researcher Abraham
Trembley noted that when chopped into pieces, hydra--tubelike
creatures with tentacles that live in fresh water--could grow back
into complete, new organisms. Other scientists of the era examined the
salamander's ability to replace a severed tail. And a century later,
Thomas Hunt Morgan scrutinized planaria, flatworms that can regenerate
even when whittled into 279 bits. But he decided that regeneration was
an intractable problem and forsook planaria in favor of fruit flies.
Mainstream biology has followed in Morgan's wake, focusing on animals
suitable for studying genetic and embryonic development. But some
researchers have pressed on with studies of regeneration superstars,
and they've devised innovative strategies to tackle the genetics of
these organisms. These efforts and investigations of new regeneration
models--such as zebrafish and special mouse lines--are beginning to
reveal the forces that guide regeneration and those that prevent it.
Animals exploit three principal strategies to regenerate organs.
First, working organ cells that normally don't divide can multiply and
grow to replenish lost tissue, as occurs in injured salamander hearts.
Second, specialized cells can undo their training--a process known as
dedifferentiation--and assume a more pliable form that can replicate
and later respecialize to reconstruct a missing part. Salamanders and
newts take this approach to heal and rebuild a severed limb, as do
zebrafish to mend clipped fins. Finally, pools of stem cells can step
in to perform required renovations. Planaria tap into this resource
when reconstructing themselves.
Figure 1 Self-repair. Newts reprogram their cells to reconstruct a
Humans already plug into these mechanisms to some degree. For
instance, after surgical removal of part of a liver, healing signals
tell remaining liver cells to resume growth and division to expand the
organ back to its original size. Researchers have found that when
properly enticed, some types of specialized human cells can revert to
a more nascent state (see p. 85). And stem cells help replenish
our blood, skin, and bones. So why do our hearts fill with scar
tissue, our lenses cloud, and our brain cells perish?
Animals such as salamanders and planaria regenerate tissues by
rekindling genetic mechanisms that guide the patterning of body
structures during embryonic development. We employ similar pathways to
shape our parts as embryos, but over the course of evolution, humans
may have lost the ability to tap into it as adults, perhaps because
the cell division required for regeneration elevated the likelihood of
cancer. And we may have evolved the capacity to heal wounds rapidly to
repel infection, even though speeding the pace means more scarring.
Regeneration pros such as salamanders heal wounds methodically and
produce pristine tissue. Avoiding fibrotic tissue could mean the
difference between regenerating and not: Mouse nerves grow vigorously
if experimentally severed in a way that prevents scarring, but if a
scar forms, nerves wither.
Unraveling the mysteries of regeneration will depend on understanding
what separates our wound-healing process from that of animals that are
able to regenerate. The difference might be subtle: Researchers have
identified one strain of mice that seals up ear holes in weeks,
whereas typical strains never do. A relatively modest number of
genetic differences seems to underlie the effect. Perhaps altering a
handful of genes would be enough to turn us into superhealers, too.
But if scientists succeed in initiating the process in humans, new
questions will emerge. What keeps regenerating cells from running
amok? And what ensures that regenerated parts are the right size and
shape, and in the right place and orientation? If researchers can
solve these riddles--and it's a big "if"--people might be able to
order up replacement parts for themselves, not just their '67
R. John Davenport is an editor of Science's SAGE KE.
How Can a Skin Cell Become a Nerve Cell?
Like Medieval alchemists who searched for an elixir that could turn
base metals into gold, biology's modern alchemists have learned how to
use oocytes to turn normal skin cells into valuable stem cells, and
even whole animals. Scientists, with practice, have now been able to
make nuclear transfer nearly routine to produce cattle, cats, mice,
sheep, goats, pigs, and--as a Korean team announced in May--even human
embryonic stem (ES) cells. They hope to go still further and turn the
stem cells into treatments for previously untreatable diseases. But
like the medieval alchemists, today's cloning and stem cell biologists
are working largely with processes they don't fully understand: What
actually happens inside the oocyte to reprogram the nucleus is still a
mystery, and scientists have a lot to learn before they can direct a
cell's differentiation as smoothly as nature's program of development
does every time fertilized egg gives rise to the multiple cell types
that make up a live baby.
Scientists have been investigating the reprogramming powers of the
oocyte for half a century. In 1957, developmental biologists first
discovered that they could insert the nucleus of adult frog cells into
frog eggs and create dozens of genetically identical tadpoles. But in
50 years, the oocyte has yet to give up its secrets.
The answers lie deep in cell biology. Somehow, scientists know, the
genes that control development--generally turned off in adult
cells--get turned back on again by the oocyte, enabling the cell to
take on the youthful potential of a newly fertilized egg. Scientists
understand relatively little about these on-and-off switches in normal
cells, however, let alone the unusual reversal that takes place during
Figure 1 Cellular alchemist. A human oocyte.
As cells differentiate, their DNA becomes more tightly packed, and
genes that are no longer needed--or those which should not be
expressed--are blocked. The DNA wraps tightly around proteins called
histones, and genes are then tagged with methyl groups that prevent
the proteinmaking machinery in the cell from reaching them. Several
studies have shown that enzymes that remove those methyl groups are
crucial for nuclear transfer to work. But they are far from the only
things that are needed.
If scientists could uncover the oocyte's secrets, it might be possible
to replicate its tricks without using oocytes themselves, a resource
that is fairly difficult to obtain and the use of which raises
numerous ethical questions. If scientists could come up with a
cell-free bath that turned the clock back on already-differentiated
cells, the implications could be enormous. Labs could rejuvenate cells
from patients and perhaps then grow them into new tissue that could
repair parts worn out by old age or disease.
But scientists are far from sure if such cell-free alchemy is
possible. The egg's very structure, its scaffolding of proteins that
guide the chromosomes during cell division, may also play a key role
in turning on the necessary genes. If so, developing an elixir of
proteins that can turn back a cell's clock may remain elusive.
To really make use of the oocyte's power, scientists still need to
learn how to direct the development of the rejuvenated stem cells and
guide them into forming specific tissues. Stem cells, especially those
from embryos, spontaneously form dozens of cell types, but controlling
that development to produce a single type of cell has proved more
difficult. Although some teams have managed to produce nearly pure
colonies of certain kinds of neural cells from ES cells, no one has
managed to concoct a recipe that will direct the cells to become, say,
a pure population of dopamine-producing neurons that could replace
those missing in Parkinson's disease.
Scientists are just beginning to understand how cues interact to guide
a cell toward its final destiny. Decades of work in developmental
biology have provided a start: Biologists have used mutant frogs,
flies, mice, chicks, and fish to identify some of the main genes that
control a developing cell's decision to become a bone cell or a muscle
cell. But observing what goes wrong when a gene is missing is easier
than learning to orchestrate differentiation in a culture dish.
Understanding how the roughly 25,000 human genes work together to form
tissues--and tweaking the right ones to guide an immature cell's
development--will keep researchers occupied for decades. If they
succeed, however, the result will be worth far more than its weight in
How Does a Single Somatic Cell Become a Whole Plant?
It takes a certain amount of flexibility for a plant to survive and
reproduce. It can stretch its roots toward water and its leaves toward
sunlight, but it has few options for escaping predators or finding
mates. To compensate, many plants have evolved repair mechanisms and
reproductive strategies that allow them to produce offspring even
without the meeting of sperm and egg. Some can reproduce from
outgrowths of stems, roots, and bulbs, but others are even more
radical, able to create new embryos from single somatic cells. Most
citrus trees, for example, can form embryos from the tissues
surrounding the unfertilized gametes--a feat no animal can manage. The
house-plant Bryophyllum can sprout embryos from the edges of its
leaves, a bit like Athena springing from Zeus's head.
Nearly 50 years ago, scientists learned that they could coax carrot
cells to undergo such embryogenesis in the lab. Since then, people
have used so-called somatic embryogenesis to propagate dozens of
species, including coffee, magnolias, mangos, and roses. A Canadian
company has planted entire forests of fir trees that started life in
tissue culture. But like researchers who clone animals (see p.
85), plant scientists understand little about what actually
controls the process. The search for answers might shed light on how
cells' fates become fixed during development, and how plants manage to
retain such flexibility.
Scientists aren't even sure which cells are capable of embryogenesis.
Although earlier work assumed that all plant cells were equally
labile, recent evidence suggests that only a subset of cells can
transform into embryos. But what those cells look like before their
transformation is a mystery. Researchers have videotaped cultures in
which embryos develop but found no visual pattern that hints at which
cells are about to sprout, and staining for certain patterns of gene
expression has been inconclusive.
Figure 1 Power of one. Orange tree embryos can sprout from a
single somatic cell.
Researchers do have a few clues about the molecules that might be
involved. In the lab, the herbicide 2,4-dichlorophenoxyacetic acid
(sold as weed killer and called 2,4-D) can prompt cells in culture to
elongate, build a new cell wall, and start dividing to form embryos.
The herbicide is a synthetic analog of the plant hormones called
auxins, which control everything from the plant's response to light
and gravity to the ripening of fruit. Auxins might also be important
in natural somatic embryogenesis: Embryos that sprout on top of veins
near the leaf edge are exposed to relatively high levels of auxins.
Recent work has also shown that over- or underexpression of certain
genes in Arabidopsis plants can prompt embryogenesis in otherwise
normal-looking leaf cells.
Sorting out sex-free embryogenesis might help scientists understand
the cellular switches that plants use to stay flexible while still
keeping growth under control. Developmental biologists are keen to
learn how those mechanisms compare in plants and animals. Indeed, some
of the processes that control somatic embryogenesis may be similar to
those that occur during animal cloning or limb regeneration (see p.
On a practical level, scientists would like to be able to use
lab-propagation techniques on crop plants such as maize that still
require normal pollination. That would speed up both breeding of new
varieties and the production of hybrid seedlings--a flexibility that
farmers and consumers could both appreciate.
How Does Earth's Interior Work?
Richard A. Kerr
The plate tectonics revolution went only so deep. True, it made
wonderful sense of most of the planet's geology. But that's something
like understanding the face of Big Ben; there must be a lot more
inside to understand about how and why it all works. In the case of
Earth, there's another 6300 kilometers of rock and iron beneath the
tectonic plates whose churnings constitute the inner workings of a
planetary heat engine. Tectonic plates jostling about the surface are
like the hands sweeping across the clock face: informative in many
ways but largely mute as to what drives them.
Figure 1 A long way to go. Grasping the workings of plate
tectonics will require deeper probing.
Earth scientists inherited a rather simple picture of Earth's interior
from their pre-plate tectonics colleagues. Earth was like an onion.
Seismic waves passing through the deep Earth suggested that beneath
the broken skin of plates lies a 2800-kilometer layer of rocky mantle
overlying 3470 kilometers of molten and--at the center--solid iron.
The mantle was further subdivided at a depth of 670 kilometers into
upper and lower layers, with a hint of a layer a couple of hundred
kilometers thick at the bottom of the lower mantle.
In the postrevolution era, the onion model continued to loom large.
The dominant picture of Earth's inner workings divided the planet at
the 670-kilometer depth, forming with the core a three-layer machine.
Above the 670, the mantle churned slowly like a very shallow pot of
boiling water, delivering heat and rock at mid-ocean ridges to make
new crust and cool the interior and accepting cold sinking slabs of
old plate at deep-sea trenches. A plume of hot rock might rise from
just above the 670 to form a volcanic hot spot like Hawaii. But no hot
rock rose up through the 670 barrier, and no cold rock sank down
through it. Alternatively, argued a smaller contingent, the mantle
churned from bottom to top like a deep stockpot, with plumes rising
all the way from the core-mantle boundary.
Forty years of probing inner Earth with ever more sophisticated
seismic imaging has boosted the view of the engine's complexity
without much calming the debate about how it works. Imaging now
clearly shows that the 670 is no absolute barrier. Slabs penetrate the
boundary, although with difficulty. Layered-earth advocates have duly
dropped their impenetrable boundary to 1000 kilometers or deeper. Or
maybe there's a flexible, semipermeable boundary somewhere that limits
mixing to only the most insistent slabs or plumes.
Now seismic imaging is also outlining two great globs of mantle rock
standing beneath Africa and the Pacific like pistons. Researchers
disagree whether they are hotter than average and rising under their
own buoyancy, denser and sinking, or merely passively being carried
upward by adjacent currents. Thin lenses of partially melted rock dot
the mantle bottom, perhaps marking the bottom of plumes, or perhaps
not. Geochemists reading the entrails of elements and isotopes in
mantle-derived rocks find signs of five long-lived "reservoirs" that
must have resisted mixing in the mantle for billions of years. But
they haven't a clue where in the depths of the mantle those reservoirs
might be hiding.
How can we disassemble the increasingly complex planetary machine and
find what makes it tick? With more of the same, plus a large dose of
patience. After all, plate tectonics was more than a half-century in
the making, and those revolutionaries had to look little deeper than
the sea floor.
Seismic imaging will continue to improve as better seismometers are
spread more evenly about the globe. Seismic data are already
distinguishing between temperature and compositional effects, painting
an even more complex picture of mantle structure. Mineral physicists
working in the lab will tease out more properties of rock under deep
mantle conditions to inform interpretation of the seismic data,
although still handicapped by the uncertain details of mantle
composition. And modelers will more faithfully simulate the whole
machine, drawing on seismics, mineral physics, and subtle geophysical
observations such as gravity variations. Another 40 years should do
Are We Alone in the Universe?
Richard A. Kerr
Alone, in all that space? Not likely. Just do the numbers: Several
hundred billion stars in our galaxy, hundreds of billions of galaxies
in the observable universe, and 150 planets spied already in the
immediate neighborhood of the sun. That should make for plenty of
warm, scummy little ponds where life could come together to begin
billions of years of evolution toward technology-wielding creatures
like ourselves. No, the really big question is when, if ever, we'll
have the technological wherewithal to reach out and touch such
intelligence. With a bit of luck, it could be in the next 25 years.
Workers in the search for extraterrestrial intelligence (SETI) would
have needed more than a little luck in the first 45 years of the
modern hunt for like-minded colleagues out there. Radio astronomer
Frank Drake's landmark Project Ozma was certainly a triumph of hope
over daunting odds. In 1960, Drake pointed a 26-meter radio telescope
dish in Green Bank, West Virginia, at two stars for a few days each.
Given the vacuum-tube technology of the time, he could scan across 0.4
megahertz of the microwave spectrum one channel at a time.
Almost 45 years later, the SETI Institute in Mountain View,
California, completed its 10-year-long Project Phoenix. Often using
the 350-meter antenna at Arecibo, Puerto Rico, Phoenix researchers
searched 710 star systems at 28 million channels simultaneously across
an 1800-megahertz range. All in all, the Phoenix search was 100
trillion times more effective than Ozma was.
Besides stunning advances in search power, the first 45 years of
modern SETI have also seen a diversification of search strategies. The
Search for Extraterrestrial Radio Emissions from Nearby Developed
Intelligent Populations (SERENDIP) has scanned billions of radio
sources in the Milky Way by piggybacking receivers on antennas in use
by observational astronomers, including Arecibo. And other groups are
turning modest-sized optical telescopes to searching for nanosecond
flashes from alien lasers.
Figure 1 Listening for E.T. The SETI Institute is deploying an
array of antennas and tying them into a giant "virtual telescope."
Still, nothing has been heard. But then, Phoenix, for example, scanned
just one or two nearby sunlike stars out of each 100 million stars out
there. For such sparse sampling to work, advanced, broadcasting
civilizations would have to be abundant, or searchers would have to
get very lucky.
To find the needle in a galaxy-size haystack, SETI workers are
counting on the consistently exponential growth of computing power to
continue for another couple of decades. In northern California, the
SETI Institute has already begun constructing an array composed of
individual 6-meter antennas. Ever-cheaper computer power will
eventually tie 350 such antennas into "virtual telescopes," allowing
scientists to search many targets at once. If Moore's law--that the
cost of computation halves every 18 months--holds for another 15 years
or so, SETI workers plan to use this antenna array approach to check
out not a few thousand but perhaps a few million or even tens of
millions of stars for alien signals. If there were just 10,000
advanced civilizations in the galaxy, they could well strike pay dirt
before Science turns 150.
The technology may well be available in coming decades, but SETI will
also need money. That's no easy task in a field with as high a "giggle
factor" as SETI has. The U.S. Congress forced NASA to wash its hands
of SETI in 1993 after some congressmen mocked the whole idea of
spending federal money to look for "little green men with misshapen
heads," as one of them put it. Searching for another tippy-top branch
of the evolutionary tree still isn't part of the NASA vision. For more
than a decade, private funding alone has driven SETI. But the SETI
Institute's planned $35 million array is only a prototype of the
Square Kilometer Array that would put those tens of millions of stars
within reach of SETI workers. For that, mainstream radio astronomers
will have to be onboard--or we'll be feeling alone in the universe a
long time indeed.
How and Where Did Life on Earth Arise?
For the past 50 years, scientists have attacked the question of how
life began in a pincer movement. Some approach it from the present,
moving backward in time from life today to its simpler ancestors.
Others march forward from the formation of Earth 4.55 billion years
ago, exploring how lifeless chemicals might have become organized into
Working backward, paleontologists have found fossils of microbes
dating back at least 3.4 billion years. Chemical analysis of even
older rocks suggests that photosynthetic organisms were already well
established on Earth by 3.7 billion years ago. Researchers suspect
that the organisms that left these traces shared the same basic traits
found in all life today. All free-living organisms encode genetic
information in DNA and catalyze chemical reactions using proteins.
Because DNA and proteins depend so intimately on each other for their
survival, it's hard to imagine one of them having evolved first. But
it's just as implausible for them to have emerged simultaneously out
of a prebiotic soup.
Experiments now suggest that earlier forms of life could have been
based on a third kind of molecule found in today's organisms: RNA.
Once considered nothing more than a cellular courier, RNA turns out to
be astonishingly versatile, not only encoding genetic information but
also acting like a protein. Some RNA molecules switch genes on and
off, for example, whereas others bind to proteins and other molecules.
Laboratory experiments suggest that RNA could have replicated itself
and carried out the other functions required to keep a primitive cell
Only after life passed through this "RNA world," many scientists now
agree, did it take on a more familiar cast. Proteins are thousands of
times more efficient as a catalyst than RNA is, and so once they
emerged they would have been favored by natural selection. Likewise,
genetic information can be replicated from DNA with far fewer errors
than it can from RNA.
Other scientists have focused their efforts on figuring out how the
lifeless chemistry of a prebiotic Earth could have given rise to an
RNA world. In 1953, working at the University of Chicago, Stanley
Miller and Harold Urey demonstrated that experiments could shed light
on this question. They ran an electric current through a mix of
ammonia, methane, and other gases believed at the time to have been
present on early Earth. They found that they could produce amino acids
and other important building blocks of life.
Figure 1 Cauldron of life? Deep-sea vents are one proposed site
for life's start.
Today, many scientists argue that the early atmosphere was dominated
by other gases, such as carbon dioxide. But experiments in recent
years have shown that under these conditions, many building blocks of
life can be formed. In addition, comets and meteorites may have
delivered organic compounds from space.
Just where on Earth these building blocks came together as primitive
life forms is a subject of debate. Starting in the 1980s, many
scientists argued that life got its start in the scalding,
mineral-rich waters streaming out of deep-sea hydrothermal vents.
Evidence for a hot start included studies on the tree of life, which
suggested that the most primitive species of microbes alive today
thrive in hot water. But the hot-start hypothesis has cooled off a
bit. Recent studies suggest that heat-loving microbes are not living
fossils. Instead, they may have descended from less hardy species and
evolved new defenses against heat. Some skeptics also wonder how
delicate RNA molecules could have survived in boiling water. No single
strong hypothesis has taken the hot start's place, however, although
suggestions include tidal pools or oceans covered by glaciers.
Research projects now under way may shed more light on how life began.
Scientists are running experiments in which RNA-based cells may be
able to reproduce and evolve. NASA and the European Space Agency have
launched probes that will visit comets, narrowing down the possible
ingredients that might have been showered on early Earth.
Most exciting of all is the possibility of finding signs of life on
Mars. Recent missions to Mars have provided strong evidence that
shallow seas of liquid water once existed on the Red
Planet--suggesting that Mars might once have been hospitable to life.
Future Mars missions will look for signs of life hiding in
under-ground refuges, or fossils of extinct creatures. If life does
turn up, the discovery could mean that life arose independently on
both planets--suggesting that it is common in the universe--or that it
arose on one planet and spread to the other. Perhaps martian microbes
were carried to Earth on a meteorite 4 billion years ago, infecting
our sterile planet.
Carl Zimmer is the author of Soul Made Flesh: The Discovery of the
Brain--and How it Changed the World.
What Determines Species Diversity?
Countless species of plants, animals, and microbes fill every crack
and crevice on land and in the sea. They make the world go 'round,
converting sunlight to energy that fuels the rest of life, cycling
carbon and nitrogen between inorganic and organic forms, and modifying
In some places and some groups, hundreds of species exist, whereas in
others, very few have evolved; the tropics, for example, are a complex
paradise compared to higher latitudes. Biologists are striving to
understand why. The interplay between environment and living organisms
and between the organisms themselves play key roles in encouraging or
discouraging diversity, as do human disturbances, predator-prey
relationships, and other food web connections. But exactly how these
and other forces work together to shape diversity is largely a
The challenge is daunting. Baseline data are poor, for example: We
don't yet know how many plant and animal species there are on Earth,
and researchers can't even begin to predict the numbers and kinds of
organisms that make up the microbial world. Researchers probing the
evolution of, and limits to, diversity also lack a standardized time
scale because evolution takes place over periods lasting from days to
millions of years. Moreover, there can be almost as much variation
within a species as between two closely related ones. Nor is it clear
what genetic changes will result in a new species and what their true
influence on speciation is.
Understanding what shapes diversity will require a major
interdisciplinary effort, involving paleontological interpretation,
field studies, laboratory experimentation, genomic comparisons, and
effective statistical analyses. A few exhaustive inventories, such as
the United Nations' Millennium Project and an around-the-world
assessment of genes from marine microbes, should improve baseline
data, but they will barely scratch the surface. Models that predict
when one species will split into two will help. And an emerging
discipline called evo-devo is probing how genes involved in
development contribute to evolution. Together, these efforts will go a
long way toward clarifying the history of life.
Paleontologists have already made headway in tracking the expansion
and contraction of the ranges of various organisms over the millennia.
They are finding that geographic distribution plays a key role in
speciation. Future studies should continue to reveal large-scale
patterns of distribution and perhaps shed more light on the origins of
mass extinctions and the effects of these catastrophes on the
evolution of new species.
From field studies of plants and animals, researchers have learned
that habitat can influence morphology and behavior--particularly
sexual selection--in ways that hasten or slow down speciation.
Evolutionary biologists have also discovered that speciation can stall
out, for example, as separated populations become reconnected,
homogenizing genomes that would otherwise diverge. Molecular forces,
such as low mutation rates or meiotic drive--in which certain alleles
have an increased likelihood of being passed from one generation to
the next--influence the rate of speciation.
And in some cases, differences in diversity can vary within an
ecosystem: Edges of ecosystems sometimes support fewer species than
Evolutionary biologists are just beginning to sort out how all these
factors are intertwined in different ways for different groups of
organisms. The task is urgent: Figuring out what shapes diversity
could be important for understanding the nature of the wave of
extinctions the world is experiencing and for determining strategies
to mitigate it.
What Genetic Changes Made Us Uniquely Human?
Every generation of anthropologists sets out to explore what it is
that makes us human. Famed paleoanthropologist Louis Leakey thought
tools made the man, and so when he uncovered hominid bones near stone
tools in Tanzania in the 1960s, he labeled the putative toolmaker Homo
habilis, the earliest member of the human genus. But then
primatologist Jane Goodall demonstrated that chimps also use tools of
a sort, and today researchers debate whether H. habilis truly belongs
in Homo. Later studies have honed in on traits such as bipedality,
culture, language, humor, and, of course, a big brain as the unique
birthright of our species. Yet many of these traits can also be found,
at least to some degree, in other creatures: Chimps have rudimentary
culture, parrots speak, and some rats seem to giggle when tickled.
What is beyond doubt is that humans, like every other species, have a
unique genome shaped by our evolutionary history. Now, for the first
time, scientists can address anthropology's fundamental question at a
new level: What are the genetic changes that make us human?
With the human genome in hand and primate genome data beginning to
pour in, we are entering an era in which it may become possible to
pinpoint the genetic changes that help separate us from our closest
relatives. A rough draft of the chimp sequence has already been
released, and a more detailed version is expected soon. The genome of
the macaque is nearly complete, the orangutan is under way, and the
marmoset was recently approved. All these will help reveal the
ancestral genotype at key places on the primate tree.
The genetic differences revealed between humans and chimps are likely
to be profound, despite the oft-repeated statistic that only about
1.2% of our DNA differs from that of chimps. A change in every 100th
base could affect thousands of genes, and the percentage difference
becomes much larger if you count insertions and deletions. Even if we
document all of the perhaps 40 million sequence differences between
humans and chimps, what do they mean? Many are probably simply the
consequence of 6 million years of genetic drift, with little effect on
body or behavior, whereas other small changes--perhaps in regulatory,
noncoding sequences--may have dramatic consequences.
Half of the differences might define a chimp rather than a human. How
can we sort them all out?
One way is to zero in on the genes that have been favored by natural
selection in humans. Studies seeking subtle signs of selection in the
DNA of humans and other primates have identified dozens of genes, in
particular those involved in host-pathogen interactions, reproduction,
sensory systems such as olfaction and taste, and more.
But not all of these genes helped set us apart from our ape cousins
originally. Our genomes reveal that we have evolved in response to
malaria, but malaria defense didn't make us human. So some researchers
have started with clinical mutations that impair key traits, then
traced the genes' evolution, an approach that has identified a handful
of tantalizing genes. For example, MCPH1 and ASPM cause microcephaly
when mutated, FOXP2 causes speech defects, and all three show signs of
selection pressure during human, but not chimp, evolution. Thus they
may have played roles in the evolution of humans' large brains and
But even with genes like these, it is often difficult to be completely
sure of what they do. Knockout experiments, the classic way to reveal
function, can't be done in humans and apes for ethical reasons. Much
of the work will therefore demand comparative analyses of the genomes
and phenotypes of large numbers of humans and apes. Already, some
researchers are pushing for a "great ape 'phenome' project" to match
the incoming tide of genomic data with more phenotypic information on
apes. Other researchers argue that clues to function can best be
gleaned by mining natural human variability, matching mutations in
living people to subtle differences in biology and behavior. Both
strategies face logistical and ethical problems, but some progress
A complete understanding of uniquely human traits will, however,
include more than DNA. Scientists may eventually circle back to those
long-debated traits of sophisticated language, culture, and
technology, in which nurture as well as nature plays a leading role.
We're in the age of the genome, but we can still recognize that it
takes much more than genes to make the human.
How Are Memories Stored and Retrieved?
Packed into the kilogram or so of neural wetware between the ears is
everything we know: a compendium of useful and trivial facts about the
world, the history of our lives, plus every skill we've ever learned,
from riding a bike to persuading a loved one to take out the trash.
Memories make each of us unique, and they give continuity to our
lives. Understanding how memories are stored in the brain is an
essential step toward understanding ourselves.
Neuroscientists have already made great strides, identifying key brain
regions and potential molecular mechanisms. Still, many important
questions remain unanswered, and a chasm gapes between the molecular
and whole-brain research.
The birth of the modern era of memory research is often pegged to the
publication, in 1957, of an account of the neurological patient H.M.
At age 27, H.M. had large chunks of the temporal lobes of his brain
surgically removed in a last-ditch effort to relieve chronic epilepsy.
The surgery worked, but it left H.M. unable to remember anything that
happened--or anyone he met--after his surgery. The case showed that
the medial temporal lobes (MTL), which include the hippocampus, are
crucial for making new memories. H.M.'s case also revealed, on closer
examination, that memory is not a monolith: Given a tricky mirror
drawing task, H.M.'s performance improved steadily over 3 days even
though he had no memory of his previous practice. Remembering how is
not the same as remembering what, as far as the brain is concerned.
Thanks to experiments on animals and the advent of human brain
imaging, scientists now have a working knowledge of the various kinds
of memory as well as which parts of the brain are involved in each.
But persistent gaps remain. Although the MTL has indeed proved
critical for declarative memory--the recollection of facts and
events--the region remains something of a black box. How its various
components interact during memory encoding and retrieval is
unresolved. Moreover, the MTL is not the final repository of
declarative memories. Such memories are apparently filed to the
cerebral cortex for long-term storage, but how this happens, and how
memories are represented in the cortex, remains unclear.
More than a century ago, the great Spanish neuro-anatomist Santiago
Ramòn y Cajal proposed that making memories must require neurons to
strengthen their connections with one another. Dogma at the time held
that no new neurons are born in the adult brain, so Ramòn y Cajal made
the reasonable assumption that the key changes must occur between
existing neurons. Until recently, scientists had few clues about how
this might happen.
Figure 1 Memorable diagram. Santiago Ramòn y Cajal's drawing of
the hippocampus. He proposed that memories involve strengthened neural
Since the 1970s, however, work on isolated chunks of nervous-system
tissue has identified a host of molecular players in memory formation.
Many of the same molecules have been implicated in both declarative
and nondeclarative memory and in species as varied as sea slugs, fruit
flies, and rodents, suggesting that the molecular machinery for memory
has been widely conserved. A key insight from this work has been that
short-term memory (lasting minutes) involves chemical modifications
that strengthen existing connections, called synapses, between
neurons, whereas long-term memory (lasting days or weeks) requires
protein synthesis and probably the construction of new synapses.
Tying this work to the whole-brain research is a major challenge. A
potential bridge is a process called long-term potentiation (LTP), a
type of synaptic strengthening that has been scrutinized in slices of
rodent hippocampus and is widely considered a likely physiological
basis for memory. A conclusive demonstration that LTP really does
underlie memory formation in vivo would be a big breakthrough.
Meanwhile, more questions keep popping up. Recent studies have found
that patterns of neural activity seen when an animal is learning a new
task are replayed later during sleep. Could this play a role in
solidifying memories? Other work shows that our memories are not as
trustworthy as we generally assume. Why is memory so labile? A hint
may come from recent studies that revive the controversial notion that
memories are briefly vulnerable to manipulation each time they're
recalled. Finally, the no-new-neurons dogma went down in flames in the
1990s, with the demonstration that the hippocampus, of all places, is
a virtual neuron nursery throughout life. The extent to which these
newborn cells support learning and memory remains to be seen.
How Did Cooperative Behavior Evolve?
When Charles Darwin was working out his grand theory on the origin of
species, he was perplexed by the fact that animals from ants to people
form social groups in which most individuals work for the common good.
This seemed to run counter to his proposal that individual fitness was
key to surviving over the long term.
By the time he wrote The Descent of Man, however, he had come up with
a few explanations. He suggested that natural selection could
encourage altruistic behavior among kin so as to improve the
reproductive potential of the "family." He also introduced the idea of
reciprocity: that unrelated but familiar individuals would help each
other out if both were altruistic. A century of work with dozens of
social species has borne out his ideas to some degree, but the details
of how and why cooperation evolved remain to be worked out. The
answers could help explain human behaviors that seem to make little
sense from a strict evolutionary perspective, such as risking one's
life to save a drowning stranger.
Animals help each other out in many ways. In social species from
honeybees to naked mole rats, kinship fosters cooperation: Females
forgo reproduction and instead help the dominant female with her
young. And common agendas help unrelated individuals work together.
Male chimpanzees, for example, gang up against predators, protecting
each other at a potential cost to themselves.
Generosity is pervasive among humans. Indeed, some anthropologists
argue that the evolution of the tendency to trust one's relatives and
neighbors helped humans become Earth's dominant vertebrate: The
ability to work together provided our early ancestors more food,
better protection, and better childcare, which in turn improved
However, the degree of cooperation varies. "Cheaters" can gain a leg
up on the rest of humankind, at least in the short term. But
cooperation prevails among many species, suggesting that this behavior
is a better survival strategy, over the long run, despite all the
strife among ethnic, political, religious, even family groups now
rampant within our species.
Evolutionary biologists and animal behavior researchers are searching
out the genetic basis and molecular drivers of cooperative behaviors,
as well as the physiological, environmental, and behavioral impetus
for sociality. Neuroscientists studying mammals from voles to hyenas
are discovering key correlations between brain chemicals and social
Others with a more mathematical bent are applying evolutionary game
theory, a modeling approach developed for economics, to quantify
cooperation and predict behavioral outcomes under different
circumstances. Game theory has helped reveal a seemingly innate desire
for fairness: Game players will spend time and energy to punish unfair
actions, even though there's nothing to be gained by these actions for
themselves. Similar studies have shown that even when two people meet
just once, they tend to be fair to each other. Those actions are hard
to explain, as they don't seem to follow the basic tenet that
cooperation is really based on self-interest.
The models developed through these games are still imperfect. They do
not adequately consider, for example, the effect of emotions on
cooperation. Nonetheless, with game theory's increasing
sophistication, researchers hope to gain a clearer sense of the rules
that govern complex societies.
Together, these efforts are helping social scientists and others build
on Darwin's observations about cooperation. As Darwin predicted,
reciprocity is a powerful fitness tactic. But it is not a pervasive
Modern researchers have discovered that a good memory is a
prerequisite: It seems reciprocity is practiced only by organisms that
can keep track of those who are helpful and those who are not. Humans
have a great memory for faces and thus can maintain lifelong good--or
hard--feelings toward people they don't see for years. Most other
species exhibit reciprocity only over very short time scales, if at
Limited to his personal observations, Darwin was able to come up with
only general rationales for cooperative behavior. Now, with new
insights from game theory and other promising experimental approaches,
biologists are refining Darwin's ideas and, bit by bit, hope that one
day they will understand just what it takes to bring out our
How Will Big Pictures Emerge From a Sea of Biological Data?
Biology is rich in descriptive data--and getting richer all the time.
Large-scale methods of probing samples, such as DNA sequencing,
microarrays, and automated gene-function studies, are filling new
databases to the brim. Many subfields from biomechanics to ecology
have gone digital, and as a result, observations are more precise and
more plentiful. A central question now confronting virtually all
fields of biology is whether scientists can deduce from this torrent
of molecular data how systems and whole organisms work. All this
information needs to be sifted, organized, compiled, and--most
importantly--connected in a way that enables researchers to make
predictions based on general principles.
Enter systems biology. Loosely defined and still struggling to find
its way, this newly emerging approach aims to connect the dots that
have emerged from decades of molecular, cellular, organismal, and even
environmental observations. Its proponents seek to make biology more
quantitative by relying on mathematics, engineering, and computer
science to build a more rigid framework for linking disparate
findings. They argue that it is the only way the field can move
forward. And they suggest that biomedicine, particularly deciphering
risk factors for disease, will benefit greatly.
The field got a big boost from the completion of the human genome
sequence. The product of a massive, trip-to-the-moon logistical
effort, the sequence is now a hard and fast fact. The biochemistry of
human inheritance has been defined and measured. And that has inspired
researchers to try to make other aspects of life equally knowable.
Molecular geneticists dream of having a similarly comprehensive view
of networks that control genes: For example, they would like to
identify rules explaining how a single DNA sequence can express
different proteins, or varying amounts of protein, in different
circumstances (see p. 80). Cell biologists would like to reduce
the complex communication patterns traced by molecules that regulate
the health of the cell to a set of signaling rules. Developmental
biologists would like a comprehensive picture of how the embryo
manages to direct a handful of cells into a myriad of specialized
functions in bone, blood, and skin tissue. These hard puzzles can only
be solved by systems biology, proponents say. The same can be said for
neuroscientists trying to work out the emergent properties--higher
thought, for example--hidden in complex brain circuits. To understand
ecosystem changes, including global warming, ecologists need ways to
incorporate physical as well as biological data into their thinking.
Figure 1 Systems approach. Circuit diagrams help clarify nerve
Today, systems biologists have only begun to tackle relatively simple
networks. They have worked out the metabolic pathway in yeast for
breaking down galactose, a carbohydrate. Others have tracked the first
few hours of the embryonic development of sea urchins and other
organisms with the goal of seeing how various transcription factors
alter gene expression over time. Researchers are also developing
rudimentary models of signaling networks in cells and simple brain
Progress is limited by the difficulty of translating biological
patterns into computer models. Network computer programs themselves
are relatively simple, and the methods of portraying the results in
ways that researchers can understand and interpret need improving. New
institutions around the world are gathering interdisciplinary teams of
biologists, mathematicians, and computer specialists to help promote
systems biology approaches. But it is still in its early days.
No one yet knows whether intensive interdisciplinary work and improved
computational power will enable researchers to create a comprehensive,
highly structured picture of how life works.
How Far Can We Push Chemical Self-Assembly?
Robert F. Service
Most physical scientists nowadays focus on uncovering nature's
mysteries; chemists build things. There is no synthetic astronomy or
synthetic physics, at least for now. But chemists thrive on finding
creative new ways to assemble molecules. For the last 100 years, they
have done that mostly by making and breaking the strong covalent bonds
that form when atoms share electrons. Using that trick, they have
learned to combine as many as 1000 atoms into essentially any
molecular configuration they please.
Impressive as it is, this level of complexity pales in comparison to
what nature flaunts all around us. Everything from cells to cedar
trees is knit together using a myriad of weaker links between small
molecules. These weak interactions, such as hydrogen bonds, van der
Waals forces, and [pi.gif] - [pi.gif] interactions, govern the
assembly of everything from DNA in its famous double helix to the
bonding of HO molecules in liquid water. More than just riding herd
on molecules, such subtle forces make it possible for structures to
assemble themselves into an ever more complex hierarchy. Lipids
coalesce to form cell membranes. Cells organize to form tissues.
Tissues combine to create organisms. Today, chemists can't approach
the complexity of what nature makes look routine. Will they ever learn
to make complex structures that self-assemble?
Well, they've made a start. Over the past 3 decades, chemists have
made key strides in learning the fundamental rules of noncovalent
bonding. Among these rules: Like prefers like. We see this in
hydrophobic and hydrophilic interactions that propel lipid molecules
in water to corral together to form the two-layer membranes that serve
as the coatings surrounding cells. They bunch their oily tails
together to avoid any interaction with water and leave their more
polar head groups facing out into the liquid. Another rule:
Self-assembly is governed by energetically favorable reactions. Leave
the right component molecules alone, and they will assemble themselves
into complex ordered structures.
Chemists have learned to take advantage of these and other rules to
design selfassembling systems with a modest degree of complexity.
Drug-carrying liposomes, made with lipid bilayers resembling those in
cells, are used commercially to ferry drugs to cancerous tissues in
patients. And selfassembled molecules called rotaxanes, which can act
as molecular switches that oscillate back and forth between two stable
states, hold promise as switches in future molecular-based computers.
But the need for increased complexity is growing, driven by the
miniaturization of computer circuitry and the rise of nanotechnology.
As features on computer chips continue to shrink, the cost of
manufacturing these ever-smaller components is skyrocketing. Right
now, companies make them by whittling materials down to the desired
size. At some point, however, it will become cheaper to design and
build them chemically from the bottom up.
Self-assembly is also the only practical approach for building a wide
variety of nanostructures. Making sure the components assemble
themselves correctly, however, is not an easy task. Because the forces
at work are so small, self-assembling molecules can get trapped in
undesirable conformations, making defects all but impossible to avoid.
Any new system that relies on self-assembly must be able either to
tolerate those defects or repair them. Again, biology offers an
example in DNA. When enzymes copy DNA strands during cell division,
they invariably make mistakes--occasionally inserting an A when they
should have inserted a T, for example. Some of those mistakes get by,
but most are caught by DNA-repair enzymes that scan the newly
synthesized strands and correct copying errors.
Strategies like that won't be easy for chemists to emulate. But if
they want to make complex, ordered structures from the ground up,
they'll have to get used to thinking a bit more like nature.
What Are the Limits of Conventional Computing?
At first glance, the ultimate limit of computation seems to be an
engineering issue. How much energy can you put in a chip without
melting it? How fast can you flip a bit in your silicon memory? How
big can you make your computer and still fit it in a room? These
questions don't seem terribly profound.
In fact, computation is more abstract and fundamental than figuring
out the best way to build a computer. This realization came in the
mid-1930s, when Princeton mathematicians Alonzo Church and Alan Turing
showed--roughly speaking--that any calculation involving bits and
bytes can be done on an idealized computer known as a Turing machine.
By showing that all classical computers are essentially alike, this
discovery enabled scientists and mathematicians to ask fundamental
questions about computation without getting bogged down in the
minutiae of computer architecture.
For example, theorists can now classify computational problems into
broad categories. P problems are those, broadly speaking, that can be
solved quickly, such as alphabetizing a list of names. NP problems are
much tougher to solve but relatively easy to check once you've reached
an answer. An example is the traveling salesman problem, finding the
shortest possible route through a series of locations. All known
algorithms for getting an answer take lots of computing power, and
even relatively small versions might be out of reach of any classical
Mathematicians have shown that if you could come up with a quick and
easy shortcut to solving any one of the hardest type of NP problems,
you'd be able to crack them all. In effect, the NP problems would turn
into P problems. But it's uncertain whether such a shortcut
exists--whether P = NP. Scientists think not, but proving this is one
of the great unanswered questions in mathematics.
In the 1940s, Bell Labs scientist Claude Shannon showed that bits are
not just for computers; they are the fundamental units of describing
the information that flows from one object to another. There are
physical laws that govern how fast a bit can move from place to place,
how much information can be transferred back and forth over a given
communications channel, and how much energy it takes to erase a bit
from memory. All classical information-processing machines are subject
to these laws--and because information seems to be rattling back and
forth in our brains, do the laws of information mean that our thoughts
are reducible to bits and bytes? Are we merely computers? It's an
But there is a realm beyond the classical computer: the quantum. The
probabilistic nature of quantum theory allows atoms and other quantum
objects to store information that's not restricted to only the binary
0 or 1 of information theory, but can also be 0 and 1 at the same
time. Physicists around the world are building rudimentary quantum
computers that exploit this and other quantum effects to do things
that are provably impossible for ordinary computers, such as finding a
target record in a database with too few queries. But scientists are
still trying to figure out what quantum-mechanical properties make
quantum computers so powerful and to engineer quantum computers big
enough to do something useful.
By learning the strange logic of the quantum world and using it to do
computing, scientists are delving deep into the laws of the subatomic
world. Perhaps something as seemingly mundane as the quest for
computing power might lead to a newfound understanding of the quantum
Can We Selectively Shut Off Immune Responses?
In the past few decades, organ transplantation has gone from
experimental to routine. In the United States alone, more than 20,000
heart, liver, and kidney transplants are performed every year. But for
transplant recipients, one prospect has remained unchanged: a lifetime
of taking powerful drugs to suppress the immune system, a treatment
that can have serious side effects. Researchers have long sought ways
to induce the immune system to tolerate a transplant without blunting
the body's entire defenses, but so far, they have had limited success.
They face formidable challenges. Although immune tolerance can
occur--in rare cases, transplant recipients who stop taking
immunosuppressants have not rejected their foreign organs--researchers
don't have a clear picture of what is happening at the molecular and
cellular levels to allow this to happen. Tinkering with the immune
system is also a bit like tinkering with a mechanical watch: Fiddle
with one part, and you may disrupt the whole mechanism. And there is a
big roadblock to testing drugs designed to induce tolerance: It is
hard to know if they work unless immunosuppressant drugs are
withdrawn, and that would risk rejection of the transplant. But if
researchers can figure out how to train the immune system to tolerate
transplants, the knowledge could have implications for the treatment
of autoimmune diseases, which also result from unwanted immune
attack--in these cases on some of the body's own tissues.
A report in Science 60 years ago fired the starting gun in the race to
induce transplant tolerance--a race that has turned into a marathon.
Ray Owen of the University of Wisconsin, Madison, reported that
fraternal twin cattle sometimes share a placenta and are born with
each other's red blood cells, a state referred to as mixed chimerism.
The cattle tolerated the foreign cells with no apparent problems.
A few years later, Peter Medawar and his team at the University of
Birmingham, U.K., showed that fraternal twin cattle with mixed
chimerism readily accept skin grafts from each other. Medawar did not
immediately appreciate the link to Owen's work, but when he saw the
connection, he decided to inject fetal mice in utero with tissue from
mice of a different strain. In a publication in Nature in 1953, the
researchers showed that, after birth, some of these mice tolerated
skin grafts from different strains. This influential experiment led
many to devote their careers to transplantation and also raised hopes
that the work would lead to cures for autoimmune diseases.
Immunologists, many of them working with mice, have since spelled out
several detailed mechanisms behind tolerance. The immune system can,
for example, dispatch "regulatory" cells that suppress immune attacks
against self. Or the system can force harmful immune cells to commit
suicide or to go into a dysfunctional stupor called anergy.
Researchers indeed now know fine details about the genes, receptors,
and cell-to-cell communications that drive these processes.
Yet it's one matter to unravel how the immune system works and another
to figure out safe ways to manipulate it. Transplant researchers are
pursuing three main strategies to induce tolerance. One builds on
Medawar's experiments by trying to exploit chimerism. Researchers
infuse the patient with the organ donor's bone marrow in hopes that
the donor's immune cells will teach the host to tolerate the
transplant; donor immune cells that come along with the transplanted
organ also, some contend, can teach tolerance. A second strategy uses
drugs to train T cells to become anergic or commit suicide when they
see the foreign antigens on the transplanted tissue. The third
approach turns up production of T regulatory cells, which prevent
specific immune cells from copying themselves and can also suppress
rejection by secreting biochemicals called cytokines that direct the
immune orchestra to change its tune.
All these strategies face a common problem: It is maddeningly diff
icult to judge whether the approach has failed or succeeded because
there are no reliable "biomarkers" that indicate whether a person has
become tolerant to a transplant. So the only way to assess tolerance
is to stop drug treatment, which puts the patient at risk of rejecting
the organ. Similarly, ethical concerns often require researchers to
test drugs aimed at inducing tolerance in concert with
immunosuppressive therapy. This, in turn, can undermine the drugs'
effectiveness because they need a fully functioning immune system to
do their job.
If researchers can complete their 50-year quest to induce immune
tolerance safely and selectively, the prospects for hundreds of
thousands of transplant recipients would be greatly improved, and so,
too, might the prospects for controlling autoimmune diseases.
Do Deeper Principles Underlie Quantum Uncertainty and Nonlocality?
"Quantum mechanics is very impressive," Albert Einstein wrote in 1926.
"But an inner voice tells me that it is not yet the real thing." As
quantum theory matured over the years, that voice has gotten
quieter--but it has not been silenced. There is a relentless murmur of
confusion underneath the chorus of praise for quantum theory.
Quantum theory was born at the very end of the 19th century and soon
became one of the pillars of modern physics. It describes, with
incredible precision, the bizarre and counterintuitive behavior of the
very small: atoms and electrons and other wee beasties of the
submicroscopic world. But that success came with the price of
discomfort. The equations of quantum mechanics work very well; they
just don't seem to make sense.
No matter how you look at the equations of quantum theory, they allow
a tiny object to behave in ways that defy intuition. For example, such
an object can be in "superposition": It can have two mutually
exclusive properties at the same time. The mathematics of quantum
theory says that an atom, for example, can be on the left side of a
box and the right side of the box at the very same instant, as long as
the atom is undisturbed and unobserved. But as soon as an observer
opens the box and tries to spot where the atom is, the superposition
collapses and the atom instantly "chooses" whether to be on the right
or the left.
This idea is almost as unsettling today as it was 80 years ago, when
Erwin Schrödinger ridiculed superposition by describing a half living,
half-dead cat. That is because quantum theory changes what the meaning
of "is" is. In the classical world, an object has a solid reality:
Even a cloud of gas is well described by hard little billiard
ball-like pieces, each of which has a well-defined position and
velocity. Quantum theory seems to undermine that solid reality.
Indeed, the famous Uncertainty Principle, which arises directly from
the mathematics of quantum theory, says that objects' positions and
moment a are smeary and ill defined, and gaining knowledge about one
implies losing knowledge about the other.
The early quantum physicists dealt with this unreality by saying that
the "is"--the fundamental objects handled by the equations of quantum
theory--were not actually particles that had an extrinsic reality but
"probability waves" that merely had the capability of becoming "real"
when an observer makes a measurement. This so-called Copenhagen
Interpretation makes sense, if you're willing to accept that reality
is probability waves and not solid objects. Even so, it still doesn't
sufficiently explain another weirdness of quantum theory: nonlocality.
In 1935, Einstein came up with a scenario that still defies common
sense. In his thought experiment, two particles fly away from each
other and wind up at opposite ends of the galaxy. But the two
particles happen to be "entangled"--linked in a quantum-mechanical
sense--so that one particle instantly "feels" what happens to its
twin. Measure one, and the other is instantly transformed by that
measurement as well; it's as if the twins mystically communicate,
instantly, over vast regions of space. This "nonlocality" is a
mathematical consequence of quantum theory and has been measured in
the lab. The spooky action apparently ignores distance and the flow of
time; in theory, particles can be entangled after their entanglement
has already been measured.
On one level, the weirdness of quantum theory isn't a problem at all.
The mathematical framework is sound and describes all these bizarre
phenomena well. If we humans can't imagine a physical reality that
corresponds to our equations, so what? That attitude has been called
the "shut up and calculate" interpretation of quantum mechanics. But
to others, our difficulties in wrapping our heads around quantum
theory hint at greater truths yet to be understood.
Some physicists in the second group are busy trying to design
experiments that can get to the heart of the weirdness of quantum
theory. They are slowly testing what causes quantum superpositions to
"collapse"--research that may gain insight into the role of
measurement in quantum theory as well as into why big objects behave
so differently from small ones. Others are looking for ways to test
various explanations for the weirdnesses of quantum theory, such as
the "many worlds" interpretation, which explains superposition,
entanglement, and other quantum phenomena by positing the existence of
parallel universes. Through such efforts, scientists might hope to get
beyond the discomfort that led Einstein to declare that "[God] does
not play dice."
Is an Effective HIV Vaccine Feasible?
In the 2 decades since researchers identified HIV as the cause of
AIDS, more money has been spent on the search for a vaccine against
the virus than on any vaccine effort in history. The U.S. National
Institutes of Health alone invests nearly $500 million each year, and
more than 50 different preparations have entered clinical trials. Yet
an effective AIDS vaccine, which potentially could thwart millions of
new HIV infections each year, remains a distant dream.
Although AIDS researchers have turned the virus inside-out and
carefully detailed how it destroys the immune system, they have yet to
unravel which immune responses can fend off an infection. That means,
as one AIDS vaccine researcher famously put it more than a decade ago,
the field is "flying without a compass."
Some skeptics contend that no vaccine will ever stop HIV. They argue
that the virus replicates so quickly and makes so many mistakes during
the process that vaccines can't possibly fend off all the types of HIV
that exist. HIV also has developed sophisticated mechanisms to dodge
immune attack, shrouding its surface protein in sugars to hide
vulnerable sites from antibodies and producing proteins that thwart
production of other immune warriors. And the skeptics point out that
vaccine developers have had little success against pathogens like HIV
that routinely outwit the immune system--the malaria parasite,
hepatitis C virus, and the tuberculosis bacillus are prime examples.
Yet AIDS vaccine researchers have solid reasons to believe they can
succeed. Monkey experiments have shown that vaccines can protect
animals from SIV, a simian relative of HIV. Several studies have
identified people who repeatedly expose themselves to HIV but remain
uninfected, suggesting that something is stopping the virus. A small
percentage of people who do become infected never seem to suffer any
harm, and others hold the virus at bay for a decade or more before
showing damage to their immune systems. Scientists also have found
that some rare antibodies do work powerfully against the virus in test
At the start, researchers pinned their hopes on vaccines designed to
trigger production of antibodies against HIV's surface protein. The
approach seemed promising because HIV uses the surface protein to
latch onto white blood cells and establish an infection. But vaccines
that only contained HIV's surface protein looked lackluster in animal
and test tube studies, and then proved worthless in large-scale
Now, researchers are intensely investigating other approaches. When
HIV manages to thwart antibodies and establish an infection, a second
line of defense, cellular immunity, specifically targets and
eliminates HIV-infected cells. Several vaccines which are now being
tested aim to stimulate production of killer cells, the storm troopers
of the cellular immune system. But cellular immunity involves other
players--such as macrophages, the network of chemical messengers
called cytokines, and so-called natural killer cells--that have
received scant attention.
The hunt for an antibody-based vaccine also is going through something
of a renaissance, although it's requiring researchers to think
backward. Vaccine researchers typically start with antigens--in this
case, pieces of HIV--and then evaluate the antibodies they elicit. But
now researchers have isolated more than a dozen antibodies from
infected people that have blocked HIV infection in test tube
experiments. The trick will be to figure out which specific antigens
triggered their production.
It could well be that a successful AIDS vaccine will need to stimulate
both the production of antibodies and cellular immunity, a strategy
many are attempting to exploit. Perhaps the key will be stimulating
immunity at mucosal surfaces, where HIV typically enters. It's even
possible that researchers will discover an immune response that no one
knows about today. Or perhaps the answer lies in the interplay between
the immune system and human genetic variability: Studies have
highlighted genes that strongly influence who is most susceptible--and
who is most resistant--to HIV infection and disease.
Wherever the answer lies, the insights could help in the development
of vaccines against other diseases that, like HIV, don't easily
succumb to immune attack and that kill millions of people. Vaccine
developers for these diseases will probably also have to look in
unusual places for answers. The maps created by AIDS vaccine
researchers currently exploring uncharted immunologic terrain could
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