## Future of Chemistry

## Assumptions: Taking Chemistry in New Directions**

George M. Whitesides*

## Keywords:

ftioorganic chemistry • genomics • medicinal chemistry philosophy of chemistry

it

scien-tist When states a distinguishedbut that something is elderly possible, he is almost certainly right. When he states that something is impossible, he is very probably wrong."

Arthur C. Clarke

## The Temptations and Hazards of
Predicting the Future

sci-ence Speculating seems to be about genetically the future encoded of in scientists. We all do it. We also take it as think-ing predic-tions an to article do. about are or almost the of just faith future a always diversion—like that an wrong. important serious Is thing day-dreaming, lottery? Why or gardening, do we spend or playing our time the guessing about matters we believe we cannot predict?

There are at least five reasons. The first is utilitarian: to plan our work. Thinking about the future is a part of choosing research problems. We who make our living in science tell ourselves that we work for the satisfaction of solving problems and for the thrill of discovery; sociologists, less charitably, suggest that we do so to make a living and to get ahead professionally. The truth is probably a mixture of the two. Finding good problems-problems that

mixture pre-dictable quite unpredictable of "ordinary", a lot of the and "extraordinary". relatively a little of the

(al I thank Michael Mayer, Mila Boncheva.
sugges-tions and Barbara and editorial Whitesides help with for their this paper.

polish a new facet of reality and that change the way some part of the world works—is both satisfying intellectually and rewarding professionally.

The second reason is to feed our curiosity. We wonder about the world of the future. What neat widgets will make that world run? Which of our fantasies will grow into our grandchildren's realities?

The third is philosophical. Science and technology are major elements of the culture of our times. They, probably more than other elements (materialism, religious fundamentalism, capitalism, ...), will change the nature of individuals and of society. We wonder: What will the big changes be? How will science be involved?

The fourth is that society expects us to speculate. We are part of its early warning system for change.

The fifth is to answer an uncomfortable question: "Is there research that we should not do?" We scientists generally cohabit quite comfortably with an amor-

al curiosity. We should ask if there is research we can do now—research that is technically feasible and scientifically interesting—that we should forgo because it is ethically

problematic. Are there questions we don't want to ask, because there are no circumstances in which we might want to know the answers?

## The objective of science is to make a difference.

Surprises: Is the future of science really so unpredictable? The answer is both "no" and "yes". Science is a

## Science is a Mixture of the Ordinary and the Extraordinary

lighted—in fact, ecstatic—to learn that XeF₂ is a stable compound; because I knew less about biology, it took me years to assimilate the discovery of apoptosis, and to begin to appreciate how the cell chooses between life and death. Not all surprises are equal: xenon tetrafluoride clarified the chemical bond for chemists; apoptosis changed the understanding of “life” for all of science.

The pan of science that is ordinary and business-as-usual—useful, important. familiar science—can often be extrapo• lated into the future with fair accuracy. sur-prises—that It this is science the extraordinary that we cannot gives speculation science—the predict. and about it is reputa-tion. the future It is its also well-deserved the surprises bad that make science so intensely interesting, and that have the power, for better or worse, to up-side turn down. the lives of our grandchildren

One of the many charms of science is that it provides an endless string of surprises. Some surprises grow slowly and incrementally, while some come, apparently, out of the blue. Each of us can make two lists of surprises: one of personal favorites, and one of surprises that have remade the world. These two lists are usually rather different. We have a particular affection for what we

know, and find small quirks in familiar science endearing. Appreciation for big discoveries in unfamiliar fields requires more effort.

Since I am a chemist,

I was immediately de-

One unstated objective of science is to make a difference: to learn something,

## Science is a Mixture of the Ordinary and the Extraordinary (cont.)

or make something, that changes the way people think or behave. Many of the biggest discoveries—the most important scientifically, and the most consequential conse-quences socially—are are surprises, unimaginable and at their the time pre-dicted they are the made. changes Who in would society have that have come from classification of the elements into the periodic table, or from quantum mechanics, or the world wide web? Who could have guessed that the first NMR spectrum of ethanol would grow into the ability to watch the brain think?

The unpredictability of these big surprises makes us timid in our speculations: it is embarrassing to be publicly wrong, and big surprises make dunces of us all. But, avoiding speculation makes science dreary, and neglects our responsibility to society to warn of change, even as we cause it.

## Picking Assumptions, Not Making Predictions

In speculating about the future, we—scientists and nonscientists—are really interested in knowing what the science and technology will be that will make a big difference, and in knowing whether that difference will be good, or bad, or both, or a matter of context, or circumstance, or personal opinion.

The process of starting with current science, extrapolating it into the future. and then guessing how society will use un-certain or abuse it this will future probably science fail. I is suggest so that a different and perhaps more direct approach to identifying where science might reshape society is to start by identifying areas where change would sci-ence matter, might and cause then ask this if change. imaginable

How are we to identify areas where society is vulnerable to change? Or where the push of a new idea or a new in-stitutions? identifying technology I might the propose assumptions topple that established we begin that our by society makes, and then ask about the vulnerability of these assumptions in the face of plausible science.

An assumption is an idea that is taken for granted: it tacitly separates the imaginable from the unimaginable. If an assumption is vulnerable, then the prob-

ability that it will eventually fracture—for better or worse—under the blows of science is very high. Let me give an example. We assume, as an article of faith—a deeply held assumption—that we are the most intelligent entities on the planet. We would certainly be disconcerted to discover that science and technology had generated an entity more intelligent than we: a peer competitor (or perhaps a peer partner, although, as a species, we have never been good at “sharing”). How probable,

technically, is it that science will do so? The answer to this question depends on whether you believe that intelligence is an oddity characteristic of highly

## Society changes when
it discards a major
<u>assumption.</u> 

evolved living organisms (humans, porpoises, whales, chimpanzees), or whether it is inevitable in (or perhaps can be engineered into) any information-processing system of sufficient complexity. So, will information science produce intelligent machines? (... and what is "intelligence" in a machine, anyway?) I don't know, but I (and others more knowledgeable than I) also don't know that it is impossible. Hence it is an area that we, and society, should watch carefully.

Where, in the past, has science dissolved important assumptions with profound consequences for society? Failed assumptions are easy to identify in hindsight: they are the facts of daily life that we now accept as routine, but that would, at some earlier time, have provoked a reaction of "impossible!" If one had asked Frederick the Great or Sun Tsu if it would ever be possible utterly to destroy a city on the other side of the globe in a single stroke, their answer would have been "No!" They, and their societies, assumed this limitation to the art of war. We now accept as unremarkable a world in which science and technology-born as quantum mechanics and grown to be nuclear-tipped intercontinental ballistic missiles (ICBMs; or perhaps just a rental truck containing an amateur's fully functional fission bomb)-make this single stroke distressingly possible. The failure of this assumption has changed society.

We have discarded many other as-
sumptions, with consequences both

good and bad. At one time, knowledge could be passed on only through speech: the written word and moveable type gave our society a long-term memory. At one time it was impossible to talk to or to see others over long distances; the telephone. radio. TV, and the web are now among the threads that hold society together. Controlling human fertility fundamentally changed the relation of women to society. Society changes when it discards a major assumption.

Thinking

about assumptions and
working backward is
falli-ble not necessarily than thinking less about

for-wards, science and working it
but tends to focus more on big soci-etal problems and less it
problems and less

evolutions. on small technological Con-centrating on assumptions might. there-fore, provide better advance warning about issues that the scientific evolutions. commun-ity science. about care-fully (and provide than issues It society) extrapolating would that better the should also scientific advance accomplish consider from warning existing four other ends It would: 1) show that the dreary intellectual senescence suggested by John Horgan'sstimulating book "The End of Science" is wrong-headed: 2) identify directions where science im-pact; would 3) unquestionably indicate especially have interesting large problems on which scientists might work; and 4) suggest new ways of doing business: big problems do not have disciplinary boundaries—academic departments do.

assump-tions In that. what I believe, follows, are I list fundamental nine to western society, and that, I believe, are vulnerable to disproof by science. This list is entirely personal: others would make other lists. These assumptions are conceptu-al, different some in are nature: practical, some and are some are sociological.

## Where Does Chemistry Fit In?

peri-od manip-ulation revolu-tionized of Chemistry two of the the centuries understanding physical has had in world: a which wonderful and it it revealed the atomic and molecular structure of matter, and provided physical things— drugs, clothing, fuels, weapons. materi-

## Where Does Chemistry Fit In? (cont.)

als—that changed society. There is still much to be learned about molecules, bonds. and reactivity, but these subjects seem of a different character than aging. machine intelligence, and privacy— more evolutionary than revolutionary. Are the revolutionary discoveries now elsewhere, or are there still chemical discoveries as profound as the laws of thermodynamics. the nature of the chemical bond, and the molecular basis of inheritance waiting to be made?

Any answers to this question hinge defini-tion on personal of "chemistry". opinion, and Is it on profound the to understand the origin of life, or the nature of sentience? It is, to me. Are these subjects "chemistry"? They are, to com-plexity me. or to Is it develop (whatever profound nonliving "complexity" to understand intelligence? means), Yes, and both have important chemical components. Is it profound to hybridize living and nonliving systems? Of course, and chemistry offers much to the effort.

This Essay is about the assumptions poten-tial that our of science society accepts to sweep and aside the these assumptions. It is not specifically about chemistry. However.I am a chemist, and I every-where, believe if chemists that chemistry so choose, can be or that it can contract into an invisible part of the infrastructure of technology, if they don't. Chemistry, by its culture, has been repeat-edly almost reminded blindly reductionist. that "Chemists I am work on molecules", as if to do anything else were suspect. Chemists do and should work on molecules, but also on the uses of molecules, and on problems of which molecules may be only a pan of the mol-ecules solution. to If learn chemists the entire move problem—from beyond design of surfactants, to synthesis of colloids. to MRI contrast agents. to the trajectories of cells in the embryo, to the applications of regenerative medicine— then the flow of ideas problems. and solutions between chemistry and society will animate both.

As a technology, chemistry has built the foundation from which many of the "microelec-tronics", "plane-tary discoveries grown. exploration", There or of "brain "biology", would for science" that be or matter) no (or genomics have separat-ing without fragments chemical of DNA, methods and for for synthe-

sizing primers and probes, and for separating restriction endonucleases into pure activities. There would be no nuclear ICBMs without methods of refining plutonium and uranium, and making explosive lenses. There would be no drugs without synthesis and mass spectrometry. There would be no interplanetary probes without fuels, and carbon/carbon rocket throat nozzles, and silicon single crystals.

Those are the past. What about the future? Chemistry is, still, everywhere: It must be! It is the science of the real world. But, to remain a star in the play rather than a stagehand, it must open its eyes to new problems. It is impossible that the human life span will increase dramatically without manipulation of the molecules of the human organism, but understanding this problem will require more than manipulating molecules. Communication between the living and nonliving will also require engineering a molecular interface between them, but designing this interface will require understanding the nature of "information" in organisms and in computers, and how to translate between them. A society that uses information technology to interweave all its parts requires new systems for generating, distributing, and storing power, but batteries will be only one part of these systems.

Chemistry has always been the invisible hand that builds and operates the tools, and sustains the infrastructure. It can be more. We think of ourselves as experts in quarrying blocks from granite; we have not thought it our job to build cathedrals from them. Whether we choose to focus on the molecules, materials, and tools that are at the beginnings of discovery, or bring our particular, unique understanding of the world to bear on unraveling the problems at the end, is for us to decide.

I believe that everything from methane to sentience is chemistry, and that we should reexamine our own assumptions concerning the boundaries of our field. Examining the broader assumptions that follow may provide some stimulus to do so.

## Assumptions

## I. We Are Mortal

We assume we are mortal: we will die. We know that from experience, albeit the experience of others. But die of infec-tious what? One hundred years ago, now, it is a relatively minor problem. now, it is a relatively minor problem. Most of us now alive will die of cardio-vascular disease, cancer, Alzheimer's dis-ease. diabetes degenerative disease. Re-gardless of the details, we die of old age. disease was a major cause of death;

We know, however, that some cells age differently than others. Transformed cells single-celled age (al-though differently are they in some organisms are than sense not others. an that immortal Transformed organism); replicate by division have a kind of immortality. pro-long There life: are caloric strategies deprivation that strongly does so in mice and fruit flies, and probably also does so in man. Inheritance certainly makes a difference.

Molecular biology has begun to illuminate each of our infirmities and to suggest remedies. Cardiovascular (CV) disease is already following the path combina-tion of of infectious medications disease: that control the blood pressure, cholesterol re-duettist inhibitors; and concentrations others aspirin) (HMGA-CoA and that the control clot-ting of blood is decreasing mortality as a result of CV disease; these benefits will increase when treatment begins earlier in life, before the damage is done. Understanding the role of free radicals in damage to tissues can help to limit injury after blockage to a blood supply. Infectious disease may also play an important role in the damage to the intima of the blood vessels, and help to initiate plaque formation. Changes in lifestyle—eating less fat and red meat. smoking fewer cigarettes—contribute to limiting injury. Many of the causes of CV disease seem understandable, and. in principle, controllable. Minimize these causes, and when these medical strategies engineered dys-functional finally organ immunologically fail, with replace one from to the a pig resem-ble a human, or regenerate the organ possi-bility entirely. that There CV disease—now seems a realistic the largest single cause of death—may cease to be a significant contributor to mortality.

Angew. Chem. Int. Ed. 2004, 43, 3632-3641

## I. We Are Mortal (cont.)

If CV disease were marginalized, other diseases would take center stage. Cancer is next in line, and is a much. enor-mous much more advances difficult in cancer problem. biology The have taught, if nothing else, how complicated cancer is. Cancer is fundamentally a cumulative derangement of the genome within a population of cells. By the time the disease is detectable, there is usually already extensive damage to genes and molecular-level chromosomes. cancer understanding explains The why growing, of success the etiology in cancer of therapy has been so halting.

While genomics has so far primarily been useful in understanding, rather than in treating, the disease, it offers many suggestions for the future. There are many genomic defects that are common among cancers: damage to the signaling pathways responsible for control of the cell cycle; breakdown in the processes that check for genetic damage. and guide the damaged cell to break-down its own in death the pathways through apoptosis; that prevent cells from leaving their origin and colonizing other organs. Understanding the role of telomers—the chromosomal structures that count the age of cells by progressive shortening during each cell division— and resetting this internal clock may ap-proaches have important to cancer—especially consequences. New blocking factors that are essential for metastasis: preventing vascularization of tumors: developing viruses that are specific to tumor cells—all suggest new strategies for tainly control. appear; Other some strategies will certainly will cer- be useful. The nascent field of systems biology will help to coordinate these strategies.

For cancer (and perhaps for most presymptomat-ic diseases) detection) prevention may be (or more important than cure. Avoiding influences that cause genetic damage—most obviously. specific compounds in the environment or in foods (and especially in tobacco smoke) that rcact with DNA—and avoiding exposure to ultraviolet light or ionizing radiation may be the most cost-effective method of reducing this risk.

We certainly do not see an end to cancer. nor even. yet. a real beginning to its prevention and cure. We have, how-

molec-ular ever, ideas understanding an for enormously therapies. of expanded the disease, and

After cancer come the diseases of aging. The details of these diseases are even less-well understood than are those of cancer. For most, we have only hints suscepti-bility. expo-sure. of flood the of and infection, importance genetic genomic information environmental of programming. genetic will, A how-ever. emerge from studies of multiple human and non-human genomes; we can control many infectious diseases and environmental exposures; we will be able to reset biological clocks and repair begin-nings genetic of dysfunction. broad strategies We see to combat the the diseases of aging. although we have no idea of effective tactics.

These changes in the understanding of disease and aging, and of medical treatment, do not promise immortality. But, they are constructing, for the first time, a true molecular science of disease and of medicine. The change from empiricism to understanding, and from reaction to anticipation. forms the basis for a revolution in health care. As this revolution unfolds, it has the potential to transform society.

Immortality is not necessary to change the world: much less will do. How per-form if would the average our social life span institutions were 200+ years? What would happen if the period of female fertility were 100 years? How would we behave if life expectancy could be extended by a factor of five. but only the very, very rich could afford the extension? How would the world change if the difference in life span between first and third world countries were a factor of ten?

Chemistry is at the core of changes in biomedicine. Chemistry makes drugs an-alytical and vaccines. systems Chemistry that will enable makes detailed the Chemis-try genomic provides analysis the of understanding individuals. of the changes in molecules that accompany disease and aging. Chemistry identifies environ-mental (and damage. sometimes factors What that chemistry generates) lead to does the biological not do char-acteristics behavior—to now is to integrate with see cellular molecular-level the and picture organismic in the pointillist splatter of dots. Still, molec-

ular chemistry, molecular biology, and medicine are fundamentally the same im-provement mole-cules subject—the applica-tion of important that of understanding understanding human to life, health. and the to of the

## z Only Living Creatures Think; We Think
Best

We arc, at least in our own opinion. intelli-gent re-nowned other the crown and species. for versatile of creation: our We ability assume of species, the to that most subjugate and there is no threat to this position (barring the appearance of aliens, or some other incalculable improbability).

Will we continue to be unique? Is there another species that could become as intelligent as we are? It seems unlikely that other living creatures could bio-logical emerge we would evolution as superior probably is relatively intelligences: not be slow, kind and or hospitable to a potential competitor. emer-gence An alternative of another to the intelligent improbable animal (or insect, or plant) species is that the next silicon-rather sentience than on carbon-based. the planet might be

Individual computers probably do self-conscious) nec-essary not global currently information to be in intelligent the have way network—the the that complexity (or we at are. least As world the communica-tions assembled wide systems; web; high (or. universal bandwidth increasingly, connectivity—is as it or-ganic self-assembles, complexity oppor-tunity chemistry), (or perhaps to that use rivals there even the will phrase a certainty) exceeds be an from that for a or of each of us as individuals. A global, interconnected entity that operates at frequencies of petaflops will do things that we cannot begin to imagine. Why not think? Why not think about itself? Perhaps even think about us?

The probability of a new intelligence emerging by biological evolution is generation-al limited times by of the complex decades-long organisms, by the low rate at which new variants arise by mutation, and by the complexity and functional form of the central nervous system. Evolution and selection have taken millennia to jostle us into our

## z Only Living Creatures Think; We Think
Best (cont.)

present situation; I suspect it would require special circumstances for another to jostle us aside quickly. Our intelligence, adaptability, and self-awareness (aided by the chance development during evolution of an opposed thumb and an oddly positioned larynx) have enabled us to survive and out-reproduce many more voracious but less-intelligent and self-aware forms of life.

Computers operate by different rules, and without the constraints of biology. Computer cycles are much neurotrans-mitters change faster than through across the diffusion synapses evolutionary of in selection the brain; is much slower than change by adaptive com-puter reprogramming. large, interconnectivity and communication With the will Internet. among become nodes very very rapid.

Perhaps most importantly. the growth of complexity in the web is driven by us: a significant part of the creativity of the human race—perhaps en-ergetic, hundreds de-voted to purposeful of the thousands mission people—is of of making creative, now more competent components for the web, to commu-nicate enabling as those efficiently components as possible, to and to encouraging the resulting systems to perform their tasks with little or no soft-ware human agents, supervision. applets, As and we develop autonomous systems, we seek local performance: what global connectivity among these local systems will bring remains for us to experience.

We could ask at least four interesting questions sen-tience in computer about the networks. potential The for first question taken be-tween in-telligence. to complexity, mean concerns (The the word appearance the emergence, connections "emergence" of and is prop-erties in a complex system that we cannot predict from the properties of com-plex its individual must a system components.) be to think? How ... to become sentient? Can we—scientists, and especially chemists. who generally are committed reductionists—predict complex behaviors based on knowledge of simple components? Understanding complexity has not been a strength of reductionist science. A second question concerns the basic requirements for "intelligence". Are complexity and den-

sity of connections enough, or is there something about the human brain that intelli-gence? makes it I personally uniquely capable doubt that of there is in-side anything my skull special other about than the its wetware complexity, which it is internally connected, and its the three-dimensional density with experi-ence: ability I to doubt, modify but itself cannot through disprove, that self-consciousness. there with the are relationship quantum A third subtleties between question to deals intelli-gence correlation, and self-awareness. or is self-awareness Is there a intelli-gence? some-thing the delicate different A fourth issue in character question of the relation than touches on be-tween life and intelligence. We speculate endlessly sys-tems, and about whether evolution biological in living evolution leads inevitably to intelligence. What about in-telligent intelligence web would without certainly life? not An be alive in any sense a biologist would recognize.

poten-tial We of have computer opinions networks about to the support sentience, humans, Self-awareness and but is probably not not all knowledge. not that unique is Homo to sapiens is self-aware. A porpoise or a chimpanzee is probably self-aware. A human fetus is certainly not self-aware: a baby grows into self-awareness; an Alzheimer's patient grows out of it. Can we guarantee that a computer system would not grow to be self-aware? I doubt it.

Would we even know if some future version of the world wide web had developed self-awareness? I suspect that we would not, at least for a long time. Our ability to imagine existences not our own is profoundly limited. The ability of a silicon-based intelligence— one inhabiting a distributed web of mag-netoresistive cunningly satellite doped repeaters, films, crystals of optical and and giant "thinking" fibers and gradients, elec-trons—to through the imagine food, flow and of a world photons sex seems of water, and equally salt improbable. in-telligences did If aqueous become and aware silicon of one another, it is not clear what the outcome would be.

What does this have to do with chemistry? Probably everything. One

of hu-mans the face great is intellectual to understand challenges intelligence as a property that emerges from the what-ever interactions they of are, molecules are not (which, intelligent). Chemistry is familiar with complexity. but has not yet embraced the task of understanding the forms of complex behavior that can emerge from large groups of molecules, or of systems (for example, cells) formed from molecules. In studying intelligence in a complex system. our own intelligence is probably the best example with which to begin. This effort is the best preparation we can presently imagine for an encounter with another intelligence. whether met on our else-where. own planet or encountered

## Redrawing the Line between
Living and Dead

## 3. Animals and Machines are Different

Humankind tends to categorize. Among the categories that have been separate in the past have been "living" and "nonliving". and "animal" and "machine". An animal is a biological entity made of tissue and bone. It is born of other animals, lives, and dies, and has characteristics that are what they are by inheri-tance. virtue In of the evolution past. we and have genetic not designed animals, although their performance may in a few cases have been optimized empirically through domestication and selective breeding to meet certain of our needs. Since we and animals arc alive, we recognize various degrees of ethical responsibility toward them.

A machine is qualitatively different: an object of metal, ceramic, and plastic, which we design and build de novo. We now to-ward feel machines. no ethical responsibilities

This convenient distinction between animal and machine is beginning to fail at several levels. In the most biological sense, we are developing the ability to develop-ing specify design biological animals. the characteristics tools We that are rapidly will enable animals us to a of in way similar to that in which we specify al-ready ani-mals the characteristics for use the genetic same sorts engineering of machines. of tasks with as We we use

## 3. Animals and Machines are Different (cont.)

mechanical engineering with machines. compo-nents We have of one chimeras species that into build another: we ani-mal re-engineer can to add resemble entire or delete subsystems that genes: of another. we of one can We are learning how to modify the surface antigens of one species to make its organs compatible with transfer into another species. We have taken the first steps in learning how to regenerate organs from stem cells, and perhaps to de-differentiate differentiated tissue. and then regrow it into regenerated parts. We arc developing a toolkit that de-sign is making of animals possible using the machinelike pans that can range from nucleotide sequences to whole organs.

Most of this work has, of course, been focused on objectives in biology and biomedicine. As the capabilities of biology extend, however, the idea of animals (or insects) for other uses quickly follows. Animals as sensors— that is, as "canaries"—is now plausible. unques-tionably chem-ical Plants chemical reactors and already transformations. microorganisms for alternatives carrying We are out know to some that selective breeding can produce unusual plants and animals; applied biology can only increase our skills at "species consid-er—perhaps engineering". species-engineering will We will hove for ultimately ourselves. to consider— Were we to cmbark on mulligenerational space flight, would we be better off with phys-ical artificial form. gravity or with and a physical our current form better adapted for low gravity, high radiation, envi-ronment and whatever the ship other could aspects best of provide? the

More radical, but much earlier in development, is work intended to fuse the world of man and machines. Current technology builds implantable sensors to control cardiac rhythm and glucose levels. Cochlear implants help the deaf to hear. The targets are becoming more in-sects ambitious: and rats electrodes that begin implanted to control in their motion or relay information about their environment; retinal chips to provide trans-duce sight for thought the blind: directly systems into mechanical that motion. For the more distant future, the goal is direct, efficient. communication between human brains and machines.

These efforts point toward an extraordinarily complex (and perhaps unachievable) future goal: the ability to connect brain and computer directly—that is, to allow information flowing in the nerves of an organism to shift directly into information flowing as electrons or photons in a computer. The technological barriers to this kind of fusion of animate and inanimate are immense, but do not violate any fundamental physical laws, and do not seem ultimately insurmountable. Progress in solving some of them—for example, in developing interfaces that are biocompatible—has been rapid; progress towards others—for example, learning how to transfer information between neural and silicon-based systems—has been slow. Given the unarguable fact that biology and information technology have been the scientific revolutions of the last half of the 20th century, it is almost certain that the 21st century will see their overlap and fusion.

What are the major technical problems? One must learn the code used in the brain and the nerves to convey, process, and interpret information; (we already know the code used in computers, since we designed it); one must learn how to build a physical interface between the two-perhaps between nerves and microelectrodes. One must learn how to convert between the currencies used by the neurons to transfer information-ion gradients across membranes and pulses of neurotransmitters in synapses-and the currencies used by silicon-based systems-electrons and photons. The goal of direct communication between human brain and computer also faces a serious problem of dimensional translation: computers are now intrinsically 2D in their architectures, and brains are 3D. We have no solution yet to the problem of making a sufficient number of the correct kinds of neural-to-computer connections. Perhaps growing specialized neural tissues to act as connectors-that is, genetic modification of the human to fit better to the computer-will be the final approach.

With a capability to build hybrid systems—systems containing not just two kinds of biological molecule or tissue, but systems containing some components that are biological and

others that are silicon—the issue of whether computer networks might emerge as sentient entities capable of competing with humans could become moot: one could imagine wetware and silicon co-developing, and a blurring of the concepts of "animal" and "machine" and "alive" and "dead" in a way that is unimaginable now.

Many of the most important of these problems ultimately have components that arc molecular. Although molecules may be only a part of the systems that transmit and interpret information in organisms, building interfaces between the living and nonliving. and designing translators to bridge the languages of inti-mately ions and upon electrons, chemistry. both The depend tools for Biocompat-ibility neu-ral genetic manip-ulation tissues of is engineering genetic a will molecular require materials. of chemical specialized and materials problem.

certain-ly The see 21st us redraw century will the almost line between "living" and "dead," and many of the mo-lecular. tools to do so must ultimately be

## 4. Human life Is Invaluable

The idea of a long, healthy life fits neatly with the assumption of western civilizations that life is invaluable, and that prolonging it, when possible. is a in-creasingly moral obligation. in conflict This with obligation the need is to limit the costs of medical treatments. to balance bene-fits, and the to distribution stabilize population of health levels. We may be forced to confront the value of prolonging life on two fronts:

objec-tive First, of a as long, we move healthy toward life, we the already see that there is an interval where life can be prolonged, but only at great expense. and not necessarily with high quality. If, for example, we can extend life through combinations of artificial devices (artificial joints and organs). immunosuppres-sion, xenotransplantation, and organ regeneration, the cost immuno-logical to the patient crisis and may constant be a life flirtation of with infection. We may be able to buy a longer life, but only an expensive and uncomfortable one. As biomedical sci-

## 4. Human life Is Invaluable (cont.)

ence makes it possible to patch up (but not cure) many previously terminal inter-ests conditions, seems inevitable. a serious collision of

Second, and more complicated, are the demographic consequences of reaching the technical goal of building prolonga-tion popula-tion pro-longs a something medical control of healthy life capability give: span. requires life. birthrate, there Balancing arithmetically that must greatly and be either that limitations on birthrates or limitations on life spans. We may find that we have a choice: "New life or old?" Placing termination of life—killing a person— on the same footing as birth control—an everyday part of recreational sex— would mean a fundamental shift in values.

## Sorting Humans

## 5. All Are Born Equal

An assumption in many western societies is equality at birth: equal rights under law, and equal access to opportunity. This assumption is respectful of the individual, and there have been no means—or no means that we have chosen to validate and adopt—of quan-

tifying inequality. Genetics has the potential to change our convenient inability to measure innate capability; cognitive science and psychology will also contribute.

## re-sist Pandora opening could the not box.
Can we?

Genomic analysis of individuals is just dawning. The first complete maps of the human genome are still being refined, and the task of associa-tion correlating of single and genes confirming and gene the clusters with the characteristics of individuals has begun. It is the "Panama Canal" project of modem biology. Eventually there will be a highly profitable shipping pheno-typic trade oceans, between but the now genomic there and is a lot of mud to move and many mosquitoes to swat. We do not know how complicated the task will be: it is possible that the characteristics that make us what we are will be determined by single proteins or relatively uncomplicated clusters of pro-

teins, and that genomics will open a ca-pability; window directly it is more onto probable behavior that and these characteristics reflect the behavior of complex biological systems, and will require many decades to decipher. In improve-ments any event. in even the relevant with dramatic technologies— both for the collection of the needed biological anal-ysis—the information task of correlating and for its genetic constitution with the potential strengths re-quire centu-ries) and weaknesses of decades work. (hut of probably individuals not will

This enterprise—the mapping of under-standing genomic information of capabilities, onto weaknesses an and po-tential bchaviors—has, for enormous good. of course, It will the be one foundation for medical science; it will help individuals to understand where they might be susceptible to damage expo-sure; through it will disease allow or them environmental the opportunity to identify and exercise their strongest capabilities.

It will also change society if used to If chil-dren—according classify it is very individuals—especially easy to to these collect capabilities. genomic information about individuals, will we be able to resist the temptation to use

this information to un-derstand as much about them as possible? Not

just their susceptibility
to emphysema from
abil-ity smoking, to handle but the their stresses
of office work, combat,
or marriage? Or their

potential to be good parents? Or to pay traffic tickets on time? Or to have a sense of humor? We are incorrigibly curious and mischievous Pandora could not resist opening the box; will we do any better?

For good or evil, chemistry is a devel-opment central player of analytical in this project. systems The that allow rapid. accurate, inexpensive analysis of intimate-ly the linked genome areas of individuals; of functional the genomics and proteomics that will associate genes en-vironmental bio-logical with components proteins function; to influences—from and stress, the proteins correlation and from with stress- of food

induced chemicals to disease or dysfunction—will all depend centrally on chemistry to build the tools to study genomics, proteomics, and metabolism...

...and, eventually, to sort human
beings according to their characteristics
and potentials.

## 6. We Are Individuals, and Privacy is
Important

We are accustomed to thinking of ourselves as individuals and as such we individuali-ty: value freedom the accoutrements of choice, privacy, of lack of control by others, self-determination. We are individuals in the sense that we choose our own paths; we keep our own secrets: we are unpredictable to others.

We arc individuals partly by choice, and partly by accident: we are not able to read the thoughts of others, nor to control their thinking. Characteristic of technol-ogy the revolutions and in genetics in information is that they have the capability to provide information about individuals in such abundance and detail be-come cell-phones global able assis-tants; that to privacy moot. these technology communicate and other phones Many and microelectronic in unpredictability of arc with which us a now step anyone everyone have toward on the is a globe, at any time, using sound. sight, and data, by portable communications systems. The global positioning system (GPS) and related systems allow us to determine positions: with a simple transponder, it will allow others to sur-veillance—by determine from unpiloted,long-endurance our monitors positions. inside Universal buildings; vehicles outside buildings—will one day allow our continuous-ly. actions A history to be of monitored our behaviors and actions can be stored in large databases. Genetic analysis has the potential to predict capabilities, susceptibilities, and patterns of behavior. Sociology and psychology, as they become sciences. will help to connect the dots between molecules and behaviors, and between individuals and crowds and societies.

It may be that it is still impossible to read our minds; but if it is possible to know our positions and circumstances to watch and record our activities, to

## 6. We Are Individuals, and Privacy is
Important (cont.)

know our intrinsic capabilities, and to communicate with us at all times, it may be unnecessary actually to read our minds: all the information that is needed to predict our behaviors may already be available.

Many of the major technologies human-kind needed from to a begin society to of transform individuals to a kindof hive-animal are, in practical fact. already available, albeit in the form of high-den-sity early information prototypes: surveillance, GPS, storage; systems very sensors genetic for remote for testing. One essential technology that is not available is portable power. It is possible that we may develop methods of providing power wirelessly inside buildings and in cities as we now provide light; beyond enclosed spaces, devices for generation and storage of power will be required. To be in constant electronic communication indi-vidual carry devices requires that broadcast, that the but en-ergy broadcasting density of requires any battery power. that The we can imagine will not fill this need: what is required is either a direct, low-temper. ature hydrocarbon fuel cell, or more exotic power sources: perhaps small nuclear power sources, or methods of extracting electrical energy from the metabolism of individuals. That extra cake for dessert might power more minutes communica-tion! of high-bandwidth

## Infor-mation The Democratization and Expertise of

## 7. Experts Know Best; Doctors Control the Medical System

knowl-edge We belongs assume to that experts. specialized I do not expect

my auto mechanic—an expert in his own field—to do Diels-Alder reactions. We depend on experts, and on their ability to use their expert knowledge to our benefit.

We are. understandably. especially ex-perts—doctors—in interested we all become in the sick: workings the we medical all of age. the system: The prototyp-ic medical guild—one profession controlled has been a by highly trained individuals, who establish the standards that others must pass to join.

Doctors also control most of the aspects of medicine: information about disease and treatment; approval of new drugs and new methods of treatment; and access to drugs. Although those who pay for medicine (in the US HMOs, or health maintenance organizations, and insurers) are challenging this system, doctors still largely run medicine. This system has many good features, and some bad ones as well.

An interesting consequence of the development of the world wide web is the ability of individuals with common interests to find and communicate with one another. There are few individuals who are as motivated as those who are sick (or who believe that they are sick) and who wish to be well. The development of web-based medicine allows these individuals to talk to one another, and to share opinion, gossip, and fact without formal medical supervision. They can often buy drugs that are not approved by the medical establishment, and they can experiment on themselves: the sales of “nontraditional” medicines is now claimed to be comparable to that of medicines that have regulatory approval. It is common for a physician to be faced with a patient carrying a thick folder of computer printouts describing the disease. In short, the medical profession is losing its control of the flow of authoritative medical information, and to an extent, of the course of medical treatment taken by patients.

Medicine is changing, and doctors must keep up with an enormous volume of information. Patients have as much access as doctors to much of the information, and often a more intense motivation to assimilate it. They may be better informed than their doctors, and collectively they can call on an extraordinary breadth of expertise. The Internet allows information—true, false, untested—to flow internationally without professional or peer supervision. Nontraditional and unapproved drugs are readily available.

The democratization of information and expertise that springs from the world wide web, and the power of groups of motivated amateurs to strike out on their own in technical subjects, is weakening the authority of "experts" in society. Travel agents are a disappearing breed—one can order tickets on the

web. Accounting programs are replacing tax accountants. A free-form community of hackers and programmers developed the Linux operating system. Computers routinely land commercial airliners. The environmental and consumer advocacy groups that so bedevil technology (sometimes to excellent effect) are highly skilled in collective expertise and collective action. Doctors are losing their grip on their profession. Even universities are beginning to worry about their monopoly to certify expertise.

Of course, someone still has to hold the scalpel and the bedpan. Or some thing: the hand wielding the knife could well be a machine's.

## The Globe

## 8. Earth Will Remain Habitable

environ-ment Although and global discussions warming of are the endless, to much of the world the problems these phrases represent are still abstract. The first-world countries have not slashed their use of fossil fuels: the third-world countries continue to reduce forests to wastelands; and coal is the fuel of choice for some of the largest economies of this century. for some of the largest economies of this century.

-there seems to be growing agree-ment that anthropogenic contribu-tions—carbon dioxide, soot, methane, others—to the atmosphere are signifi-cant, and are increasing global temper-atures signifi-cant, others—to the absence and relative are the increasing to of dioxide, atmosphere what these they soot, global contributions. would are methane, be in signifi-cance There of is this no increase agreement in temperature on the on society. The temperature of the Earth has gone through a set of sawtooth excursions over the last millennia: we are now in an exceptionally warm period in this normal climatic cycle in any event, and despite our mischievous efforts plane-tary scale, to achieve temperatures warming may on again a fall in the future.

But what happens if the assumption that the Earth will remain habitable (or mamma-lian at least life as as accommodating it now is) proves to wrong? prob-ably Changes be relatively in the environment slow; even if will we melt the west Greenland ice sheet, it seems

## 8. Earth Will Remain Habitable (cont.)

unlikely that we will tip the balance of the planet so that Earth becomes Venus (although we would submerge New York and Tokyo). We would adjust.

Other changes—for example, those resulting from all-out nuclear war or a large meteor strike—would probably give us much less time to adapt, and far fewer options.

insur-ance How policy, much and of of a what technological nature, should fun-damentally earth? we have There against change are events many the that habitability possibilities might of to reduce carbon emissions significantly: replacing gasoline engines with efficient diesels, developing highly efficient fuel cells, developing solar and wind power optimally. and reintroducing nuclear power are four. Industrial solutions to pollution would proceed more rapidly if there were active investment in "green" invest-ment technologies, is primarily and a the matter rate of of the regulation and public policy, albeit complicated by the fact that regulations apply locally within countries, but the problem is global.

Technical issues are less important than political ones in nuclear matters, and we have not begun to take the problem of a meteor strike seriously.

## 9. Nations Are the Most Powerful of
Human Organizations

The world is now organized into nations—social and political entities with defined geographical boundaries. Nations made sense in a world in which wealth was based on natural resources, fertile land, water, and people. Wealthy nations were those that could lay claim to vast natural resources, and had access to trade routes: wealthy nations were also those that could afford to wage war.

It was easy to keep score with nations as central political entities. The ground has however, shifted. It is more important now to be able to control and use information than to mine bauxite or diamonds. It is more important now to have a highly educated population than large reserves of coal. The fluidity of information,and the difficulty ofowning opportuni-ties and containing for small it, groups also opens of people. The Internet allows almost any group of

infor-mation, people access and at to floods almost of no useful cost. The technology of information has redefined infor-mation wealth—from and services—and material goods thus to makes the centrality of nations—which control physical space but not information space—open to question.

As for war: The cold war was a period in which the two most powerful nations competi-tion conven-tional ostensibly lines: faced with one organized another armies along and in a weapons. The armies were never used directly, surro-gate although conflicts they were in Korea. employed Vietnam. in and Afghanistan. Ultimately, however, the conflict proved to be economic: the US out-spent won, in the significant Soviet Union. part because it

sys-tems, As and information, people become information central to wealth, large countries (especially those housing open societies) become more vulnerable to cyber attacks. The US and the Soviet Union also had a virtual monopoly on strategic nuclear systems weap-ons, sponding for many especially monopoly years: those they in have terrorist for no biological cone- weapons. Joshua Lederberg has said "biological weapons enable a single man to wage war," and biological and cyber attacks—plausibly originating in small countries or in nonstate entities such as criminal, religious, or ideological groups. or even, perhaps. corporations— now rank with nuclear attacks in the risk they hold for society.

Technology has started a shift away from nations as the central political alli-ances, entity economic to supranational regions. entities: multinational reli-gions. corporations, It has posed capitalist risks to groupings, the developed countries. which value openness and capitalism, and which require relatively few barriers to the movement of people. information, and goods for efficient operation. This openness of western societies makes them difficult to defend. Developing new technologies to defend against these new threats—sensors, drugs, and defensive agents for use against biological threats; software agents and security systems to protect computer networks—are important compo-nents problems in chemistry. and all have central

Deciding how much protection is "enough", and how much is "too much"—that is. deciding how to value security and privacy when the two are in soci-ety. conflict—is a broader question for

## Not Everything is Built on Sand

Is there nothing that is secure, then? The answer is. of course, that we do not know, but a number of assumptions seem most unlikely to fall. We assume that it is impossible to read minds, or to teleport physical objects, or to move faster than the speed of light in vacuum. We assume that time can not be made to run in reverse, and that the major laws discovered by physical science over the last several centuries will continue to be true: water at room temperature will not spontaneously separate into steam and ice; objects will not spontaneously rise against gravity; we will not discover a source of energy for free. The second law of thermodynamics will continue to describe the world in which we live. Not everything is built on sand.

## Are There Questions We Should
Not Ask?

Is "big" science—science that changes the world—good for the world it changes? I am constitutionally an optimist, and would answer "Usually 'yes'". We (at least in the developed world) live longer than our forebears. devote less of our lives to personal under-stand survival; the suffer world less more from fully; disease; have more time to spend building society and appreciating existence. I believe that science has generally worked for the common good in the past, and will continue to do so in the future. Still. science and technology will unlock some doors we may not choose to open.

in-evitably Science brings that ethical changes issues. the Building world a microfluidic system for analysis of the human genome may be no more or less challenging technically than building a better catalyst for the production of polyethylene, but it is more important for society.

## Are There Questions We Should
Not Ask? (cont.)

We scientists do have something special to contribute to discussions of the outcomes of science. We know some things that will be done before they are done; we know some things that cannot be done at all; we can speculate about things that mightbe done. We can alert our neighbors to the possibility of change. and be a part of discussions and decisions that encourage the good. and avoid or forestall the bad. We can try to prevent fear of new ideas from blocking beneficial technology. In choosing to work on problems with the potential to change society, we should. ideally. accept an obligation to help society understand how it might benefit. and what it might pay, for that change.

We can suggest what doors can be opened, and what might wait in the rooms behind them. Our neighbors will decide for their own reasons whether they would like to open these doors and move in.

Finally: Is there science that must not be done? There are easy cases—I can see no redeeming virtue of publicly available research that develops strains of anthrax that are resistant to multiple antibiotics—but much of research is not easily classified as "good" or "bad".

Chemistry contributes broadly to the foundations of technology, and thus it is particularly difficult to guess its future impact: a new chemical reaction might be used to make a cancer therapeutic or oppor-tunities a chemical that weapon. seem within Some of the the reach of investigation, if not within the reach of sub-stantially solution—technologies prolong life, or that develop might new forms of life, or lead to sentient systems that rival us in intelligence—will do both good and harm. At the very minimum,

those of us who pursue these problems should accept an obligation to explain to our fellow citizens fully and clearly what we are doing, and why, and (to the limited extent we can) with what possible outcomes.

Humankind will do what it will do, but at least everyone should understand—in so far as is possible—what the choices are, and what the consequences might be. Chemistry, if it takes more interest in (and responsibility for) the full scope of programs—from molecules, to applications, and to influence on society—may be able to use the very breadth of its connections to technology to help in this explanation.

After that, the surprises take over. The last, most realistic, assumption may

conse-quences be that the will ultimately law of unintended apply.

Published Online: June 24.2004

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