Exploration is an important survival strategy in evolution. Themigration of expansive species depends on exploring their immediate or distantsurroundings for new food sources or safe habitats; it can also come as aresult of population pressures or environmental changes. The human species hasadded another reason for exploration, namely curiosity. This intellectual urgeto explore the unknown led the great European explorers to the Americas,Australia and Antarctica between the fifteenth and seventeenth centuries.Inquisitiveness about nature is also the driving force behind humans exploringthe polar caps, climbing mountain peaks and diving into the abysses of theoceans. Now, the ultimate frontier to explore in the twenty-first century isspace. Astronomical observations and satellites have already yielded immenseknowledge about our solar system and the universe beyond. But thesetechnologies can provide only a limited picture of what is out there;eventually humans themselves will have to travel to other planets toinvestigate them in more intimate detail. Tremendous advances in rocket andspaceship technologies during the past 50 years, driven mainly by nationalsecurity considerations, the need for better communication or a desire toobserve environmental changes and human activity on the ground, have made itpossible to send humans into near-Earth orbit and to the Moon. Conceivably,these advances will eventually make it possible to transport astronauts toother planets, and Mars in particular (Fig. 1).

But there are significant differences between exploring Earth andexploring space. First and foremost, space is an unforgiving environment thatdoes not tolerate human errors or technical failure. For humans leaving Earth'sorbit for extended periods, there are even more dangers. One is the nearabsence of gravity in space; the presence of high-energy, ionizing cosmic ray(HZE) nuclei is another. Because both zero gravity and cosmic rays would havesevere health implications for astronauts on a Mars-bound spaceship, we firstneed to investigate their effects on cells, tissues and our hormonal and immunesystems. However, although we are able to produce HZE nuclei on Earth and studytheir effects on biological material, we cannot simulate extended periods oflow gravity and their additive effects on cells and tissues. Thus, theInternational Space Station (ISS) will have an enormously important role inassessing the health dangers for humans in space and in the development ofpotential countermeasures.

There is much information on the adaptation of astronauts to zerogravity (0g) in space and on their return to 1g on Earth.Nevertheless, our understanding of these effects is not complete; nor havecountermeasures to mitigate them been identified.

Observations of astronauts travelling on the Space Shuttle and Russiancosmonauts' long-term visits to the Mir space station indicate that time spentin 0g has serious effects on bone and muscle physiology and thecardiovascular system. For instance, the return from 0g to 1gleads to an inability to maintain an appropriate blood pressure when in anupright position—orthostatic intolerance—and insufficient bloodflow to the brain. Astronauts returning from orbit therefore have to rest forseveral minutes, and the time needed to normalize their blood pressureincreases with the time spent in 0g. This could mean that astronautstravelling to Mars—which would take at least one year in0g—would need considerable time to readapt to gravity afterlanding there or after their return to Earth, unless we find a technologicalsolution to the creation of artificial gravity on a spaceship. Moreover, thereare other cardiovascular effects, such as cardiac arrhythmia and atrophy, thatneed to be studied in more detail before we can ensure the safety of astronautson a Mars mission. Other effects of extended time in low gravity are loss ofbone mass and muscle deterioration. Without adequate countermeasures, thesecould impair the ability of astronauts to perform necessary functions on aspacecraft or on the surface of Mars.

The second main danger for human travellers is the presence of theaforementioned HZE nuclei in cosmic rays, because of the ionizing effect thatthey exert on atoms or molecules. Although they do not reach the Earth'ssurface because they are either absorbed by the atmosphere or deflected byEarth's magnetic field, there are already some experimental data on thecancer-inducing properties of electrons, neutrons and protons in cosmic raysand other potential deleterious effects on biological material from numerousEarth-based experiments on laboratory animals. In addition, studies of theeffects of the atomic bombs dropped on Japan in 1945 pro-vided further dataabout the health dangers of radiation and high-energy nuclei.

However, cosmic rays are quite different from nuclear explosions becausethey include considerably higher numbers of HZE nuclei—leftovers fromcollapsing stars and supernova explosions that were thrown into space.Curtis & Letaw (1989) estimated that on athree-year Mars mission, about 30% of cells in the body will be traversed byHZE nuclei withZ values—the number of protons—between 10and 28, and that virtually all cells will be traversed by nuclei withZvalues between 3 and 9. These traversals result in numerous ionizing events, orhits, on cellular molecules. The biological effects of HZE nuclei on cancerinduction, the central nervous system, the immune system and the eyes are notwell known, nor have the interaction of radiation effects at 0g beenstudied. Consequently we need to conduct many more experiments on Earth as wellas on the ISS before the health and safety of astronauts travelling to Mars andbeyond can be assured.

Another, not yet seriously investigated, problem in addition to thedirect damage of cells is the more general effect of space radiation on theimmune system.Toddet al. (1999) estimatedthat the probability of the immune system's being affected is equal to or evengreater than the probability of inducing mutations. The problem of estimatingthese indirect radiation effects is compounded by the fact that the dose ratesof HZE produced in experiments on Earth are relatively high, whereas the doserates in space—except for the intermittent but rare solarflares—are rather low. However, even such low doses could createsignificant complications through what is described as the 'bystander effect'in which cells—bystanders—that are not directly affected byradiation can be affected by neighbouring cells that have been hit and die orare mutated. The mechanisms for such effects involve cell–cellcommunication and the release of toxic products from damaged cells. Thus, theeffects on tissue can be significantly larger than those estimated fromindividual cells, especially at low doses that affect only a fraction of cellsin a tissue. The dose–response curve might not be a straight line at allbut concave downwards, implying that the risks at low doses could be evenlarger than the risks estimated at the higher doses used in experiments onEarth (Brenner & Elliston, 2001). Consequently,additional experiments are needed to estimate the effects of low doses of HZEparticles on single cells and biological tissues or model organisms.

Simple experiments with yeast and bacteria on orbiting spacecraft haveshown that 0g does not significantly affect radiation responses. Butthese experiments have not been performed on higher organisms or biologicaltissues to investigate a potential synergism between radiation, 0g andthe stress of space travel on the immune system. These have to wait forcompletion of the ISS, but any further expansion of the space station is now onhold because of a shortage of funding, mainly because construction costs werehigher than initially estimated (NRC, 2003). As aresult, the installation of numerous facilities, such as habitats for animals,a radiation source and a 1g centrifuge, is well behind schedule, andanimal experiments, such as the effects of 0g on radiation effects,cannot be done.

Ironically, the health dangers of radiation in space only became anissue when the potential dangers of material brought back from space werediscussed. In 1975 I joined the Space Science Board of the US National ResearchCouncil (NRC) that considered, among other issues, the problem of whetherobjects returned from the Moon or elsewhere from space could harbourdeleterious organisms that would be hazardous to life on Earth. The appropriatesolution at that time was to isolate these objects and extensively sterilizethem with X-rays or ultraviolet radiation, or high temperatures. Because of myexperience with various hazards of radiation exposure, I was subsequently askedto join the Committee on Space Biology and Medicine of the Space Science Board,and acted as chairman of its Task Group on the biological effects of spaceradiation. The committee produced a document entitledRadiation Hazards toCrews on Interplanetary Missions: Biological Issues and Research Strategies(NRC, 1996;Setlow,1999) with various conclusions and recommendations. Two in particularare worth noting: 'The overall estimated uncertainty in the risks ofradiation-induced biological effects ranges from a factor of 4- to 15-foldgreater to a factor of 4- to 15-fold smaller than our present estimates becauseof the uncertainties both in the way HZE particles and their spallationproducts penetrate shielding and the quantitative way in which these types ofradiation affect biological functions', and 'Unless NASA obtains access to areliable source of HZE particles ... for a significant fraction of each year,it will take over 10 years, perhaps over 20 years ... to reduce the presentlarge uncertainties in particle transport behaviour and in the biologicalresponse functions'.

In response to the report, NASA and the Brookhaven National Laboratory(BNL) established a NASA-funded facility at BNL, the NASA Space RadiationLaboratory (NSRL), to produce HZE nuclei that mimic radiation in space.Commissioned in July this year, the NSRL will conduct ground-based experimentsto determine the biological effects of HZE nuclei and test appropriatecountermeasures to minimize the radiation levels in a space vehicle. Oneobvious way to reduce the number of HZE nuclei traversing a spacecraft would beto incorporate appropriate shielding. The usual types of shielding one thinksof would be heavy metals such as lead, or a lighter metal such as aluminium.However, although the flux of cosmic ray particles is readily attenuated bysuch shields, the particles split the nuclei in the shield, which producesenergetic spallation products—lower-mass nuclei—that also ionizeand act as an additional source of radiation.Figure 2shows the fraction of cells that escape traversal by HZE particles as afunction of the mass of an aluminium shielding and the time being spent inspace (Brenner & Elliston, 2001). The longerthe time spent in space, the more cells are hit—note that the mass ofshielding has only a negligible effect. Lead would be an even less effectiveshielding material than aluminium; in general, metals are very poorcountermeasures to protect against radiation. Lighter elements, such as wateror plastics, might therefore be much better shields without adding additionalmass to a spaceship. Future experiments to be performed at the NSRL willprovide further evidence on different shielding materials and their effects onbiological systems.

Understanding and evaluating the physiological effects of radiation andgravity require not only experiments on Earth but also extensive research onthe ISS with an adequate number of animals and/or human subjects (Fig. 3). However, further expansion and work on the ISS hasbeen stalled because of cuts in funding by NASA and, more recently, by the lossof theColumbia space shuttle in February this year. In addition, theISS faces employment problems. Originally, a crew of six or seven astronautswas planned for the ISS to maintain and run the station and to do scientificexperiments. However, the shortage of funds means that there are not enoughlarge space vehicles, such as space shuttles, available to transport crew,equipment and supplies and to serve as a rescue vehicle in case of a seriousaccident on the ISS. Hence, for safety reasons the crew size was reduced in2002 to three, because only the Russian spacecraft,Soyuz, was availableand that can carry only three crew members in an emergency.

The loss of theColumbia shuttle in February 2003 hasexacerbated this problem. As the crew size has been decreased from six tothree, most of the astronauts' time will be spent on operation and maintenanceof the station, which leaves little time for conducting scientific experiments.Without a significantly large infusion of funds to supply the equipment and tosupport a larger crew, the collection of basic information about the hazards ofspace travel will not be accomplished within the next 10–20 years. Wealso need a continuing, rotating crew of at least six astronauts to obtainepidemiologically significant data on the physiological and psychologicaleffects of 0g on astronauts and the efficacy of countermeasures. Unlessthese experiments can be done, it will not be possible to guarantee the safetyand well-being of astronauts on a three-year trip to Mars and back.

So, how can we satisfy our curiosity about the Solar System and beyond,and continue to investigate the nearest planets in more detail? There are threepossible solutions. The first, and most obvious, is to use unmanned spacecraftto investigate the planets' surface and to land, for example, on Mars orEuropa—one of Jupiter's moons—and return samples to Earth. Thismight very well be done within the next 10 years. The second solution is toprovide massively increased funding for the ISS. I cannot guess how much thiswould be, because, judging from past experience, there are large uncertaintiesin such estimates. And these funds would even eclipse the amount of moneyneeded for a spacecraft that could transport a crew of six or seven astronautson a three-year trip to Mars and back. In the present global economiccircumstances, this is certainly not feasible without significant physical andfinancial collaboration and cooperation among many countries. The thirdpossible solution is to construct new lift-off capabilities and a much fasterspacecraft to drastically reduce the time being spent in space and thus theradiation exposure (Fig. 2) and other stresses onastronauts.Science (2003) reported thatRussia is working on plans for a nuclear-powered spacecraft to accomplish thisgoal. However, it is hard to envisage take-off and landing scenarios that wouldsatisfy environmental concerns. Given the current situation, I therefore thinkthat we will need to upgrade the ISS further and will have to stick with robotprobes for at least the next 15 years before we can re-evaluate the rationalefor sending humans to Mars.