FRANK WILCZEK
Physicist, MIT; Recipient, 2004 Nobel Prize in Physics; Author, Fantastic Realities

Physics Will Not Achieve a Theory of Everything

I'm optimistic that physics will not achieve a Theory of Everything.

That might seem an odd thing to be optimistic about. Many of my colleagues in physics are inspired by the prospect of achieving a Theory of Everything. Some even claim that they've already got it. (Acknowledging, to be sure, that perhaps a few i's remain to be dotted or a few t's to be crossed.) My advice, dear colleagues: Be careful what you wish for. If you reflect for a moment on what the words actually mean, a Theory of Everything may not appear so attractive. It would imply that the world could no longer surprise us, and had no more to teach us.

I don't buy it. I'm optimistic that the world will continue to surprise us in fascinating and fundamental ways.  

Simply writing down the laws or equations is a long way from being able to anticipate their consequences. Few physicists—and no sober ones—seriously expect future work in fundamental physics to exhaust, for example, neuroscience. 

A less literal reading of "Theory of Everything" is closer to what physicists who use it mean by it. It's supposed to be a theory, not really of everything, but of "everything fundamental". And here "fundamental" is also being used in an unusual, technical sense. A more precise word here might be "basic" or "irreducible". That is, the physicists' Theory of Everything is supposed to provide all the laws that can't be derived logically, even in principle, from other laws. The structure of DNA surely emerges—in principle—from the equations of the standard model, and I strongly suspect that the possibility of Mind does too. So those phenomena, while they are vastly important and clearly fundamental in the usual sense, aren't fundamental in the technical sense, and elucidating them is not part of a Theory of Everything. 

I think we're about to enter a new Golden Age in fundamental physics. The Large Hadron Collider (LHC), which should begin to operate at CERN, near Geneva, starting in summer 2007, will probe the behavior of matter at energies higher than ever accessed before. There is no consensus about what we'll find there. I'm still fond of a calculation that Savas Dimopoulos, Stuart Raby and I did in 1981. We found—speaking roughly—that we could unify the description of fundamental interactions (gauge unification) only within an expanded version of relativity, which includes transformations of spin (supersymmetry). To make that dual unification we had to bring in new particles, which were too heavy to be observed at the time, but ought to be coming into range at the LHC. If they do exist we'll have a new world of phenomena to discover and explore. The astronomical riddle of dark matter could well be found there. Several competing ideas are in play, as well. The point is that whatever happens, experimenters will be making fundamental discoveries that take us by surprise. That would be impossible, if we had a Theory of Everything in the sense just described—that is, of everything fundamental.

In recent months a different, much weaker notion of what a "Theory of Everything" might accomplish has gained ground, largely inspired by developments in string theory. In this concept, the Theory provides a unique set of equations, but those equations that have many solutions, which are realized in different parts of the Universe. One speaks instead of a multiverse, composed of many domains, each forming a universe in itself, each with its own distinctive laws. Now even the fundamental—i.e., basic, irreducible—laws are beyond the power of the Theory to supply, since they vary from universe to universe. At this point the contrast between the grandeur of the words "Theory of Everything" and the meager information delivered becomes grotesque.

The glamour of the quest for a Theory of Everything, or a Final Theory, harks back Einstein's long quest for his version, a Unified Field Theory. Lest we forget, that quest was fruitless. During his great creative period, Einstein produced marvelous theories of particular things: Brownian motion, the photoelectric effect, the electrodynamics of moving bodies, the equality of inertial and gravitational mass. I take inspiration from the early Einstein, the creative opportunist who consulted Nature, rather than the later "all-or-nothing" romantic who tried (and failed) to dictate to Her. I'm optimistic that She'll continue to surprise me, and my successors, for a long time.

DAVID DEUTSCH
Quantum physicist, Oxford University; Author, The Fabric of Reality

About Whether Solutions in General Are Possible

They always are. Why is that important? Firstly, because it is true. There is no anthropocentric spite built into the laws of physics, mandating that human improvement may proceed this far and no further. Nor is the dark, neo-religious fantasy true that Nature abhors human hubris, and always exacts a hidden price that outweighs any apparent success, so that 'progress' always has to be in scare quotes. And secondly, because how we explain failure, both prospectively and retrospectively, is itself a major determinant of success. If we are optimistic that failure to improve ourselves always means failure to find the solution, then success is never due to divine grace (nowadays known as 'natural resources') but always to human effort and creativity, and failure is opportunity.

LEON LEDERMAN
Physicist and Nobel Laureate; Director Emeritus, Fermilab; Coauthor, The God Particle

The Coming Revolution in Science Education

I am optimistic about science education! I knew I should have had a
psychological check-up, be tested for delusional fantasies, my PhD revoked in a public ceremony with the breaking of my pencils. After all, in 1983, we were officially declared "A Nation at Risk".

Commissions galore like the 1999 Glenn Commission was entitled "Before it is too Late"; Education Commission of the States "No Time to Waste", The Hart-Rudman Commission which came close to recommending that the budgets of Education and Defense be swapped!

Eminent CEO's like Bill Gates (Microsoft), Craig Barrett (Intel), Louis Gerstner (IBM), Norman Augustine (Lockheed Martin) i.e. Corporations which depend on rationality for their profits, all agree that our system of 50 independent States, 15,000 school districts, 26,000 high schools etc etc has failed catastrophically to educate our students for life and work in the 21st century. But the good news is that the portent of our failed educational system as it impacts our health care, our economy, our culture and our status in the globalized world is finally becoming clear, clear to parents, clear to economists, clear, gasp! even to members of the Congress!

Somehow, we have created a sputnik-like climate warning of a powerful enemy...not the Soviets but even more worthy of a war we must declare and win: The War on Ignorance.

Out of Sputnik came the National Defense Education Act of 1958, NASA and a renewed determination to modernize science education, but also the conjugate communication skills, foreign languages and a need for public science literacy.

Can one imagine parents who know the earth revolves around the sun?

And for all of the Edge scientists, an audience who might read their stuff? Now there is wild optimism!!

JILL NEIMARK
Science Journalist; Co-author, Why Good Things Happen To Good People

The Human Epigenome Project

There are maps, and then there are maps. We're embarking on a kind of mapmaking that will usher in new ways of understanding ourselves-a map that can explain why identical twins are not truly identical, so that one succumbs to schizophrenia while the other remains cognitively intact; why what your mom ate can save or sabotage your health (as well as that of your children and your children's children); and how our genetic fates can be tuned by such simple universals as love or vitamins.

It's The Human Epigenome Project (HEP). It's the next step after the Human Genome Project, which in itself was as audacious as the Apollo space program or the Manhattan Project, mapping 25,000 genes and the 3 billion pairs of bases in our DNA. And yet, what The Human Genome Project mapped is like land without borders, roads without names, a map without movement. Genes are silent unless activated. To have them is not necessarily to be under their influence.

"Land lies in water, it is shadowed green," begins Elizabeth Bishop's classic early poem, "The Map." The double helix lies in the epigenome like land lies in water. The epigenome is a flute playing a tune that charms the snake-coiled snake that is the code of life-and the snake spirals upward in response. A long bundle of biochemical markers all along the genome, the epigenome responds to environmental signals and then switches genes off or on, upregulates or downregulates their activity. And in that change lies a great part of our destiny.

In 2003, in a widely discussed experiment, scientist Randy Jirtle of Duke University Medical Center in Durham, North Carolina, showed that he could change the activity of a mouse's genes by giving supplements to its mom prior to, or during, very early pregnancy. A mouse with yellow fur, whose offspring would normally also be yellow, will give birth to brown-furred babies if fed a diet supplemented with vitamin B12, folic acid, betaine and choline. Even the offspring of the mom's offspring will be born with brown fur. The genes themselves have not changed at all, but their expression has, and that lasts for at least two generations. And a fungicide used on fruits led to sperm abnormalities in rats-abnormalities passed down at least four generations. This gives us insight into nature's ways: apparently she figures any change in the food supply will last a while, and isn't just a seasonal fling.

Then, in 2004, Moshe Szyf, Michael Meaney and their colleagues at McGill University in Montreal, Canada, showed that love can work in a similar way. If mothers don't lick, groom and nurse their babies enough, a molecular tag known as a methyl group-a tiny molecule made of three hydrogen atoms bound to a single carbon atom-is added to a gene that helps regulate an animal's response to stress. In pups that aren't nurtured properly, the methyl group downregulates the genes' activity for life. The pups have higher levels of stress hormones and are more afraid to explore new environments. What is nature saying? If a mom didn't attend to her newborn much, it's probably because the environment was hostile and stressful. Better to be vigilant and cautious, even afraid. Later, Meany and his colleagues showed that a common food supplement could do exactly the same thing to the genes of well-licked and nurtured rats. Once the pups were three months old, researchers injected a common amino acid, L-methionine, into their brains. This methylated the same gene, downregulated it, and turned the rats into anxious wallflowers.

Last June, the European Human Epigenome Project published its first findings on the methylation profiles, or epigenetics, of three chromosomes. The push to map the epigenome is on. In the last few weeks alone I've seen very different epigenetic stories coming across the science wires. From the University of Texas Medical Branch at Galveston came the news that breastfeeding protects children who are genetically susceptible to repeated ear infections because of common variants in their genes. The tendency toward ear infections runs in families, and researchers found the culprit in two gene variants that increase inflammatory signaling molecules in the immune system. Remarkably, breast milk seemed to permanently quiet the genes, so that even later in childhood, long after the children had stopped breastfeeding, they were protected from recurrent infections.

In research from the Universidad Nacional Autonoma de Mexico and the Instituto Nacional de Cancerologia, Mexico, epigenetic drugs are now being studied in breast, ovarian and cervical cancer. These drugs affect genes that, when reactivated, help regulate cell proliferation, cell death, cell differentiation, and drug resistance. They're cheaper than designer-name cancer drugs, and might help increase survival rates.

Even water fleas are joining the epigenetic act. In a December study from the University of California at Berkeley expression of genes in water fleas changed in response to common contaminants. Water fleas are regularly used to monitor freshwater toxicity, usually with a "kill 'em and count 'em" approach. Researchers found that copper, cadmium and zinc decreased expression of genes involved in digestion and infection. Screening like this might help industry assess and avoid particularly toxic contaminants.

Epigenetics offers us a different kind of map. One where we can zoom in and zoom out. A map of many colors, with street signs so we can navigate, routes that we can choose, destinations that we can change. Maybe the gene isn't selfish. Maybe it's actually sensitive. "More delicate than the historian's are the mapmaker's colors." So concludes Elizabeth Bishop's poem, and the epigenome may prove to be one of the more beautiful, delicate, subtle maps of all time.

JOICHI ITO
Founder and CEO, Neoteny

Emergent Democracy and Global Voices

I am optimistic that open networks will continue to grow and become available to more and more people. I am optimistic that computers will continue to become cheaper and more available. I am optimistic that the hardware and software will become more open, transparent and free. I am optimistic that the ability to for people to create, share and remix their works will provide a voice to the vast majority of people.

I believe that the Internet, open source and a global culture of discourse and sharing will become the pillar of democracy for the 21st Century. Whereas those in power as well as terrorists who are not have used broadcast technology and the mass media of the 20th century against the free world, I am optimistic that Internet will enable the collective voice of the people and that voice will be a voice of reason and good will.

MARK PAGEL
Evolutionary Biologist, Reading University, England

The Limits of Democracy

Some historians think the idea of democracy arose in the Greek soldier-sailors of the 7th to 4th centuries BC who manned the trireme warships. Up to sixty men—a deme—rowed these daunting three-tiered ships. Their effectiveness in battle depended upon precise and coordinated teamwork; the phrase 'pulling together' may have its origin in the triremes. Deme-ocracy arose when the rower-fighters realized that the same kind of coordinated pulling together that powered the boat could be used to influence which battles their masters had them fight and the conditions of their service. Herodotus records that up to forty triremes were used when Samos invaded the Egyptians—a lot of voting oarsmen. Modern democracies owe a debt to the actions of these wretched fellows whose fates were gambled by rulers who did not always have the rowers' best interests at heart.

In spite of this, and two and a half thousand years on, I am optimistic that the world is glimpsing the limits of democracy. I speak of democracy in its wider manifestations, and not just as government. The common idea of democracy—that everyone has a 'right' to be heard—naturally flourishes among the smallest collections of people that can organise themselves into a group. To survive, these groups compete for what they see as their share of the pie. Look no further than the ultra-democracies of some Western European nations, deadlocked coalition governments legitimized from systems of proportional representation that reward small special interest demes. Look to the intolerance that arises when this or that group asserts rights over this or that groups' rights. Look to 'focus groups'. Look to a state of numerical populism in which the most votes or text messages or viewers is what is to be delivered, crowned or sold. In the artist Paul Klee's words "democracy with its semi-civilization sincerely cherishes junk". Strong words perhaps, but there is that old saying about decision making by committee.

The British playwright Dennis Potter in a public speech not long before his death defended the BBC—a decidedly undemocratic and state-owned institution—for its very lack of populism. To Potter the role of the BBC was to decide for the rest of us the standards of what should be deemed good art, drama, history and reporting, and to challenge us intellectually and aesthetically. A dangerous state of affairs? Elitism? Maybe. But I am optimistic that people are recognising that democracy simplistically applied, without an eye on the larger Project, can easily descend into an ochlocracy ruled by the groups that shout the loudest. Even by the middle of the 19th century Disraeli was saying "the world is wearied of statesmen whom democracy has degraded into politicians".

A hopeful sign: some nations and especially some American states are researching new low carbon-footprint technologies and voluntarily committing to what will be burdensome and expensive climate-change targets. In most cases they are doing so without any democratic mandate. They realize that there may be larger and longer term stakes to play for than the 'right' to behave as one pleases or to have what one wants. Maybe you know of other examples.

STEVEN STROGATZ
Applied mathematician, Cornell University; Author, Sync

Why Do We Need to Sleep?

In the coming year, we're going to witness a breakthrough in our understanding of what sleep is for.

It surprises most people to learn that this is even a question. Every other basic bodily function—like eating, drinking, breathing, urinating, or defecating—has a pretty clear purpose. Our bodies and brains need food, water, and oxygen to stay alive and to replenish themselves, and if they didn't rid themselves of the byproducts of this metabolism, we'd be awash in our own toxic waste. Likewise, sleep must be for something important. We all spend decades in this strange state, immobilized, unconscious, and vulnerable. But what exactly does sleep do for us?

Parents tell their children they need to sleep because they're tired and need to rest. But of course rest is not good enough. Lying still for eight hours is no substitute for sleep. My own mother had a different theory. She said I needed to sleep because I had too much "sleepy gas." It had been building up all day long, and so I needed to sleep to get rid of it. In fact, scientists observed a long time ago that if you keep a sheep awake continuously for several days and then inject some of its cerebrospinal fluid into another, well-rested sheep, that sheep will fall right asleep, presumably because some naturally-occurring sleep substance had reached a soporific level in the donor. But this line of research never quite solved the puzzle. Although a number of putative sleep substances have now been identified, we're not sure how they might work biochemically, or how sleep (as opposed to mere rest) might break them down.

Other sleep-deprivation studies done in the early 1980's took a more brutal approach, keeping rats awake for weeks until they died from a lack of sleep, and then looking for the precise cause of death. Such studies (now outlawed) could not pinpoint any specific culprits, such as particular organ failures. One striking observation, however, was that the rats ate much more than normal and yet wasted away. Their metabolism seemed to be wrecked. So maybe sleep is for energy regulation, in some unspecified way. Other popular theories are that sleep is for tissue repair, or immune function, or for consolidating learning and memory.

The new development, and the cause for optimism, is an original approach to the problem that makes the first quantitative, testable predictions about the function of sleep. Two physicists, Van Savage (Harvard Medical School) and Geoff West (Santa Fe Institute), have analyzed how sleep varies across mammals of different species. Normally physiological time ticks slower for bigger animals. For example, elephants live much longer than mice and their hearts beat much slower. The interesting thing is that both animals' lifetimes and pulse times scale in the same way with their body mass—in direct proportion to their mass raised to the 1/4 power—with the curious implication that the hearts of mice and elephants will typically beat the same number of times in their lifetime.

What is so strange about sleep in this regard is that it behaves differently from all other physiological times. It's backward. Mice sleep longer than elephants, not shorter—about fourteen hours a day compared to four. Savage and West interpret this as evidence that sleep is related to cellular repair. They note that cells produce destructive byproducts, such as free radicals, in the course of normal metabolism, and they hypothesize that sleep somehow helps repair the damage that ensues. (In this view, the mouse needs to sleep longer to clean up all the byproducts generated by its revved-up metabolism.). Then, using classic laws about how metabolic rate varies across different species, they derive mathematical predictions about how sleep duration should vary with an animal's size. But which size is most relevant—brain size or body size? The key is that they are not proportional. If sleep is for repairing the brain, Savage and West derive one prediction; if it's for repairing the body, they derive a different prediction. When they finally confront their model with the available data, they infer that sleep is mainly for repairing the brain, not the body. So much for beauty sleep.

LARRY SANGER
Co-founder, Wikipedia

Humanity's Coming Enlightenment

I am optimistic about humanity's coming enlightenment.

In particular, I am optimistic about humanity's prospects for starting exemplary new collaboratively-developed knowledge resources. When we hit upon the correct models for collaborative knowledge-collection online, there will be a jaw-dropping, unprecedented, paradigm-shifting explosion in the availability of high-quality free knowledge.

Over the last few years I have received an increasing amount of mail from researchers who want to build dynamic, efficient, and enormous new knowledge resources that follow the wiki model. I believe researchers are drawn to the wiki model because they naturally love several ideas suggested by the model: working closely with large numbers of their colleagues spread over the world; updating shared knowledge on the fly and avoiding costly duplication of labor; presenting knowledge systematically and in all its glorious complexity; and providing clear and compelling free access to important knowledge of their fields to a world that, in many cases, desperately needs such access. These features make the wiki model exciting.

Researchers—scholars, scientists, professionals of all sorts, and indeed, all folks who love books—are, as I say, drawn to the wiki model of strong collaboration in growing numbers. It's an accident of history that methods of strong collaboration online began among programmers and then spread into use by a completely egalitarian community, Wikipedia, and its many imitators. The next step in the evolution, which we are now witnessing on many fronts at once, is the adoption of wikis, and similarly dynamic and efficient "Web 2.0" methods of strong collaboration, by knowledge workers, or (as in the case of my new project, the Citizendium) huge open communities that are gently guided by experts.

I think the most fantastic knowledge resources of the near future will not be encyclopedias or textbooks. They will be brand new sorts of resources, never before possible because they require the participation of thousands, or even millions, of users. What—for example—can that quantity of people do with millions of free books at their fingertips?

Assuming as I do that expert-guided but public participatory free knowledge projects are feasible, and that—after becoming convinced of their tremendous value—millions of intellectuals from around the world will begin spending significant amounts of time developing them together, my considered view is that we are approaching a kind of intellectual revolution:

• The time spent in library, reference, and literature research will be shortened by orders of magnitude, as increasingly detailed indexes and various kinds of maps of the literature are made available, as brilliant new search methods become available for the entire contents of enormous libraries, and as literature reviews (and similar resources) at all levels of specialization are constantly updated.

• Indeed, due to these coming sea changes in the way the results of research are accessed, we might well see new and more efficient methods of presenting novel research to the world than the traditional peer-reviewed research paper. (I suggest nothing in particular here, but as a general point it seems not unlikely.)

• In many fields, especially in the humanities and social sciences, what today appears to be "cutting edge" thinking will be placed into an easily-accessible historical context. It will appear as so much scholarship properly does appear: old ideas warmed-over. I think the embarrassing ease of access to historical precursors and related work will lead scholars in these fields to focus on hard study, consolidation, systematization, and maybe even teaching. Actually, I don't think that. That would be too optimistic.

• There will be—as is already becoming the case—a newly global research community that has a presence coextensive with the Internet itself. This, even more than the advent of the Internet itself, has the potential to bring scholars from developing nations around the globe into the world of research as nothing ever has before. A well-educated, well-plugged-in intelligentsia from every uncensored place on the map could have many remarkable effects.

• Perhaps more important than any of the above, the ease with which information is accessed by teachers and students will require a complete and long overdue rethinking of the methods of education. What happens to education in a world in which not only *some questionable* information is available pretty quickly (as is now the case via Google and Wikipedia), but in which the most "officially" reliable information is available practically instantly to everyone? What would teachers do with their students if class were held every day in the middle of the largest library in the world?

Those are my expectations, and to have such expectations is of course to be very optimistic.

I should add that it seems the management of these information resources will have tremendous power, due to the tremendous value of their resources. So I hope that these managing bodies or persons will use their power according to the love of free speech, Western democratic republican principles of governance, and the rule of law.

BARRY SMITH
Philosopher, School of Advanced Study, University of London; Coeditor, Knowing Our Own Minds

Attempts to Dictate Our Tastes, Our Preferences, Our Culture, Our Media, Our Political Policies, Or Moral Choices Are Bound In the End to Fail

At first, my suggestion may sound rather pessimistic, but what I am optimistic about is that ultimately monopolies fail. By which I mean, attempts to dominate our tastes, our preferences, our culture, our media, our political policies, or moral choices. Restless creatures that we are, we seek out variety and difference, opportunities to extend the scope of our thinking and to exercise discrimination and taste. This may make us hard to satisfy, but, ultimately, it is this lack of satisfaction that leads to progress and spells the end of hegemonies in ideology, religion, or science.

John Stuart Mill wondered whether each of us would rather be the pig satisfied or Socrates dissatisfied, and at times it may seem as though a lot of people have chosen the former. But that is only in the short term. Long term, we have no choice but to be dissatisfied when things are constant and unchanging. The satiety of our appetites, the endless repetition of the same thoughts and feelings, will, eventually, in all but pathological cases, lead us to move on in mind and seek fresh inputs. To begin with, people may readily sacrifice their freedom for comfort, but increasingly the absence of change, the monotony of surroundings and routines will lead to acute discomfort and the search for something new. That is why I am optimistic that people who are fed a constant diet of the same ideas, the same foods, the same TV programmes, the same religious or political dogmas will eventually come to consider other possibilities, will switch off, change allegiance, and think differently for themselves. It may take time; after all, some people’s threshold for boredom is higher than others. But change and a moving on will be inevitable. The lesson is already being learned in the corporate world where monopolies try to cope with this by diversifying their range of services. Their chance of survival will depend on how cynically or sincerely they respond to this restless aspect of the human mind. We are used to hearing how bad the diet of television or Hollywood movies is, and how people have come to expect less and less. But I think the opposite is true. People are increasingly switching off and staying away from the familiar and undemanding shows and films that lazy television executives and film producers offer. Instead, space has opened up for intelligent and entertaining programmes and for independent film-making. It is here, at the creative end of the culture, that big popular success is to be found. In similar vein, the increasingly global market has led to a firmer appreciation of the interestingly local ones. And I am optimistic that people, through boredom and the need for something new, will seek out better, not worse experiences.

Human cognition depends on change and movement in order to function. Evolution has built us this way. Try staring at a blank wall for several seconds without blinking and you will find the image eventually bleaching until you can see nothing. The eye’s visual workings respond to movement and change. So too do the other parts of our cognitive systems. Feed them the same inputs successively and they cease to produce very much worth having as output. Like the shark in water, we need to keep moving or, cognitively, we die.

Science, too, represents the greatest advert for our unquiet natures. For as soon as a theory or school becomes the established orthodoxy, creative minds begin to explore the possibility that we must begin from completely different starting assumptions, and seek novel interpretations of the data. Without this constant movement to resist acceptance and stasis we would not have the advances or excitements that fundamental science can provide. That said, we must not overlook the role that luck plays in great discoveries either. But even with a lucky finding we must be capable or recognising and seizing on it if we are to develop insight for large-scale revisions to our thinking. The possibility to revise, rework, and reconsider depends on this sometimes uncomfortable fact about our natures and our need to search for something fresh.

So far, I have been stressing the positive aspect of the restless mind but there is a paradox in our nature and our restless search for change. For unless we countenance change for change’s sake, or the relativist doctrine that anything goes (—and I don’t) how do we preserve the very best of our thinking, select better quality experiences, and maintain our purposes, directions and values?  How do we avoid losing sight of older wisdom while rushing towards something new? It is here, perhaps, that our need for variation and discrimination serves us best. For the quick and gimmicky, the superficially appealing but weakest objects of our thinking or targets of desire will also be the least substantial and have an essential blandness that can tire us quickly. Besides, the more experience we have, the larger the background against which to compare and judge the worth or quality of what is newly encountered, and to decide if it will be ultimately rewarding. Certainly, people can be fickle or stubborn, but they are seldom fickle or stubborn for long. They will seek out better, according to what they are presently capable of responding to, and they will be dissatisfied by something not worthy of the attention they are capable of. For this reason attempts to dictate their tastes, cultural goods, ideologies or ideas are bound in the end to fail, and about that, and despite of many dark forces around us, I am optimistic.

IAN WILMUT
Biologist; Cloning Researcher; Roslin Institute, Edinburgh; Coauthor, The Second Creation


Research in Biology and Medicine Will Provide the First Effective Treatments for Many Diseases

I am optimistic that during this new century research in biology and medicine will provide the first effective treatments for many diseases, although we cannot predict when they will become available and in some cases it may take several decades.

A greater number of new treatments may well be developed than was introduced during the twentieth century. I make this judgment not only on the basis of a simple extrapolation from developments in the past, but also on a consideration of the new understanding that is being established at present and of the revolutionary techniques that are emerging. Consider as examples the potential value of the genome mapping projects, stem cells and the techniques to assess many thousand small molecules for their ability to have desired effects upon human cells in laboratory test systems. All of this is underpinned by rapidly advancing molecular biology providing essential understanding of the mechanisms that regulate cell function.

Entirely new opportunities are being provided by the mapping of the genomes of people, other mammals and a variety of infectious agents that cause human diseases such as malaria. Although we now know the entire genetic sequence of a small number of people and have new estimates of the number of genes in the human genome, we have a great deal to learn about the role of specific gene products and the mechanisms that ensure appropriate functioning of the genes. Those actively involved in this aspect of research believe that this stage in the development of human genetics will be far more demanding and take far longer than the mere mechanical reading of the sequence. However, it will in the end be very rewarding.

It has been appreciated for sometime that some human diseases result directly from differences in DNA sequence, but despite considerable research efforts only a small number of causative mutations have been identified. Modern, rapid sequencing techniques will greatly facilitate these analyses in the future. However, it is likely that in a far greater number of cases sequence differences make people comparatively vulnerable to disease, but are not directly causative of that disease. These associations will only be revealed by large-scale studies in which the genomes of hundreds, perhaps thousands, of people are determined while also monitoring the incidence of diseases in that population. This may make it possible to provide accurate warnings to people that they are vulnerable to specific diseases, while also offering advice on life style and medication to reduce that risk.

In time information of this kind may also greatly increase the accuracy of selection of appropriate medication for particular patients. At present an adverse response to medicines is a major cause of death or the need for hospital treatment, even if the medicine is appropriately prescribed and taken. This is because of differences between people in the response to drugs. It is probably fanciful to think of tailoring medications for each person, because this implies a full knowledge for every person of their likely response to and metabolism of every compound that might be considered as a medicine. However, it does seem likely that understanding of these mechanisms will lead to improved design and selection of new compounds.

A great deal has been made of the potential use of stem cells or their derivatives to replace those lost in degenerative diseases that reflect the death or malfunctioning of specific cell populations. Diseases that are considered suitable for treatment in this way include Parkinson’s disease and other neurodegenerative diseases, juvenile diabetes, spinal cord injury, liver damage resulting from hepatitis or solvent abuse. In their haste to consider this use of stem cells, the potential benefit of using such cells for drug discovery and toxicology studies is overlooked. Drug assessment will be markedly more accurate as cells become available that are representative of the critical tissues of a variety of different people.

In some cases, the cells will be genetically identical to those of patients with an overt inherited condition. There are a number of potential sources of such cells, but at present the most likely seem to be embryo stem cells because they are known to have two key characteristics. They have the ability to form all of the different tissues of an adult and they are able to multiply almost indefinitely in the laboratory. In practice this means that researchers will have the opportunity to study genetically identical cell populations again and again over a period of years and to examine their response to potential drugs. 

This is not known to be the case for any cells taken from adults. The gene sequence known to be associated with a specific disease may be introduced into existing cell lines to create a population of cells that would be expected to exhibit the characteristics of the disease. Alternatively, it may be possible to use somatic cell nuclear transfer from a patient with an inherited disease to obtain embryo stem cell lines having that characteristic even if the causative mutation is not known.

In some cases similar research may be provide an understanding of the molecular mechanisms that regulate the function of stem cells in a tissue. In time, this may make it possible to stimulate the replacement of damaged or lost cells from endogenous stem cell populations in the patient. There would be many practical advantages in being able to use this drug-based approach to cell therapy. The alternative will be to produce cells of the required type from embryo stem cells, in sufficient number that they can replace the lost cells. When they have reached the appropriate stage of their maturation these must then be inserted into the damaged tissues in such a way that they are able to integrate fully into that tissue and restore normal function. While it is likely that each approach to cell therapy will be used for some diseases, there are clearly many potential benefits to a drug based therapy.

I am optimistic that research has the potential to provide these new opportunities, and many more not described. However, I am concerned that society tends to be frightened by innovations while taking for granted the treatments that are available. We would make the most rapid progress if we recognized that it was earlier research that led to the present treatments and if we were excited by the challenges and opportunities that will arise from new research.