Applications of space-industry technologies to the life sciences

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Applications of space-industry technologies to the life sciences Space technology could provide many opportunities for the biosciences. Discussion of the applications of space technology to the life sciences are often largely confined to the application of orbital research facilities to fundamental research, particularly protein-crystallization studies that lead to solution of the protein structure. In this article, I speculate on the future of this and other applications of space to biotechnology. Two-hundred years after the introduction of microgravity-fabrication techniques, with the drop-shaft manufacture of lead shot, the 1980s saw a wave of enthusiasm for protein crystallization in long-term microgravity facilities in orbit’. However, orbital microgravity has only given the clear technical advantage that was predicted by space enthusiasts in -25% of experiments (Box 1). The biotechnology community has been disillusioned by the huge cost of launches that have yielded modest results, and so it has not been an enthusiastic supporter of space-based facilities. However, such support is critical at a time when budgets for space R&D are being cut, and plans for major projects such as the Alpha Space Station risk being cancelled (reviewed in Refs 7, 8). The pharmaceutical industry is also under heavy financial pressure: the German and Italian pharmaceutical markets suffered a 30% shrinkage in 1993; the UK and French markets are static; and the US market has faced unfriendly scrutiny. Longterm, speculative research effort is being cut, and effort is being redirected into generating core business profit. However, all is not bleak for space research. Leading pharmaceutical companies recognize that the future profits are driven by existing drug-discovery and development programmes, and the shorter the development time, the better their overall profitability (Fig. 1). If the space industry can argue convincingly that their R&D facilities can reduce time to market for new compounds, then it will find a ready market and vociferous support in the pharmaceutical and biotechnology industries. 0 1995,

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So, can these two high-technology industries - the space industry, the darling of the 196Os, and the biotechnology industry, the icon of the 1980s - collaborate in this decade? This article speculates on some of the more plausible synergies. The advantages of space Table 1 lists a few of the lifesciences research projects in the public domain that are based on spaceindustry technology, and their reliance on specific technologies. The majority of the projects can be performed using ground-based facilities that simulate conditions of altered gravity - indeed, most of the projects listed were carried out in such facilities. Investigation of the effects of gravity on plant growth are typical of such experiments: the use of a clinostat mimics the absence of gravity by its rotation, ensuring that no cell experiences a net gravitational force. In general, an experiment is only worth doing in space if space enables one to control a critical parameter better than it could be controlled on the ground. Without this advantage, the experimenter has no benefit for the substantial cost of putting experiments into space. This includes both the obvious financial cost and the technical cost of simplifying an experiment so that it can be fitted

into a small space, survive launch (and often survive storage for months or years while waiting for launch), and operate without the scientist to monitor its progress. Even such standard biochemical techniques as column chromatography or gel electrophoresis use marker dyes, which the experimenter checks visually to confirm that the experiment is running to plan. Although such checks are apparently simple, they are, in fact, very difficult to duplicate with a machine. Parameters that make such ‘simplification’ of the experiment worthwhile include those that are most economically performed in space, such as: (1) Exposure of very small samples, such as seeds or bacteria, to the highenergy radiation environment of space. For large samples, it is more economic to use ground-based reactor or accelerator facilities. (2) Long-term exposure of large systems, such as whole organisms, or major laboratory facilities, such as protein-crystallization-device robots, to low-acceleration environments (‘microgravity’) in air. Short exposure times can be achieved much more cheaply by using drop tubes or sounding rockets (see Table 2). Accelerations of lg are only relevant to quite large systems. Very small systems, such as viruses or bacteria are not seriously affected by gravity”; however, the same is not true oflarge collections of small objects, such as collections of organisms (for example, microbial ecosystems) or bulk solutions of macromolecules. It was the

Box 1. Proteins used in crystallization experiments US shuttle and Russian Mir missionsa Albumin(humanserumIb Aldosereductase Antibody Fabb Anti-chymotrypsin D-Alanineualanine ligase Aspartaseb Aspartatereceptor Bacteriorhodopsin Beta lactamase Canavalinb Catalase Diacetinase ElastaseIpigIb Growthhormone(human) Beta-hexosaminidase Histidase

on the

Interferonalpha Interferongammab lsocitratedehydrogenaseb lsocitratelyaseb Lac repressor-DNAcomplexb Lathyruslectinb Luciferase Lysozyme Neuraminidase (influenza) Phospholipase A2b Reversetranscriptase(HIV) Ribosomes(bacterial) Tetrahydrofolatesynthetaseb Transferrin(human) Tryptophan-tRNA synthetase Trp repressor-DNAcomplexb

aData from Refs 2-6. bThese proteins gave significantly better crystals when grown in microgravity than in equivalent ground-based experiments using conventional equipment. TIBTECH JANUARY 1995

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bio topics what can be done on Earth. Each project is different, but a few examples will illustrate how the guidelines listed above can be applied.

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Plot of profitability as a percentage of turnover for Glaxo, Astra, Pfizer, Roche and Ciba Geigy against: (a) time-to-market (time In months between filing of US patent and first product US launch date, averaged for ten drugs per company); (b) R&D expenditure; and (c) R&D expenditure as a proportion of pharmaceutical sales. There is a clear correlation between profitability and time-to-market only. hope that bulk solutions would show fewer convection effects in space than on Earth, and hence proteins would be able to crystallize more evenly, that motivated researchers to try to crystallize proteins in space. (3) Low aton-density. This can be achieved in small volumes on Earth; however, space has essentially unlitited volume, where the density of matter is as low as a few hundred atoms per cm3 (near the Earth) (Ref. 12). For large-scale synthesis or screening of exotic chemicals, such a large-scale ‘vacuum might be valuable. Other potentially useful aspects of the orbital environment are largescale exposure to extreme UV or IBTECH JANUARY 1995 WOL 13)

X-ray radiation fields, and the ability to accelerate objects to high relative velocities over large distances. In all cases, it is the stability of the space environment that is critical. High velocities can be achieved in gas guns on the ground, as can exposure to X-rays for short periods of time, and relatively small volumes of vacuum can be generated using vacuum pumps. Some workers claim that space can provide higher quality vacuum than is possible on the ground: a recent experiment achieved 1 O-l-’ torr aboard the shuttle (atmospheric pressure = 750 tot-r) (Ref. 12). Thus, space industries (and biotechnologists) must ask themselves what should be put into space, and

crystallization

The use of space for protein crytallization is the best-known application oforbital facilities. Scientists can only maintain a sample in free fall for the time it takes to crystallize a protein by getting it off the Earth. There was a strong belief that, in the absence of convection currents and contact with container walls, protein crystals would grow larger and with fewer defects in space than was possible on the ground would be able to be grown in space. This idea has now been tested extensively. Protein-crystallization ventures, such as the European Space Agency (ESA) Advanced Protein Crystallization Facility are already part of the established programme for future US space-shuttle launches, and progranunes such as the Eureca satellite, which was launched and retrieved from orbit in mid-1993, are continuing microgravity experiments’i. Experiments have also been carried out on the Russian space station, Mir (Ref. 2). (The Russian Biocosnios satellite, a much smaller vehicle than Eureca, performed similar experiments, but not protein-crystallization specifically experiments.) In addition, several companies are developing protein crystallization as a corrirnercial service, acting as an interface between US (BioServe Space Technologies, University of Colorado, Boulder, USA), Russian (Payload co, Systems Inc., Boston, MA, USA)‘j or Japanese (Space Technology Corporation)” sub-orbital or orbital facilities. The results have been disappointing (see Box 1). In only a few cases have protein crystals that are any better than those made under lg on the ground been produced. In some instances, although the proteins had been crystallized in Earth-based laboratories, no crystals were generated in space. There could be many reasons for this, but the most likely explanation is that the need to ‘sinplify’ protein crystallization to get it into orbit had adverse effects on the complex and difficult experimental procedures that outweighed the potential benefits of crystallizing in free fall. Crystallographers now view orbital crystallization as a very expensive extension of what they already

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bio topics Table 1. Experiments carried out during long-term space-based research programme Subject

Experiment

Technique

Numerousproteins Escherichiacoli

Proteincrystallization Effect on growth Cellmembranepermeability Effects on movement Effects on movement Effects of radiation(fast protons) Effects of radiation Activation measurement Cultureunderreducedstress Cultureand cell growth in vitro

Various,in orbitallaboratories(seeBox 1) Culturein satellite,analysison ground ShuttleBiorack Microscopyin orbitalfacilities Microscopy Short-termorbit in satellite Long-termexposureandcytology Cellculture undercentrifugation Cellculture in orbit Low-shearcell-culturesystems(groundbased) Cellculture undercentrifugation Clinostat

Paramecium Chlorella Arabidopsisseeds Plant-cellchromosomes Humanlymphocytes Musclecells Bone-marrowstemcells Nerve-cellsynapses Plant-callus culture (severalspecies) Plant-roottips A431 carconimacells Japanesetree frogs Spiders Various(Dictyostelium, Euglena,mammaliancells) Amphibian-egg development (Xenopus) Fish Rat Humancircadianrhythms Humans

Synapticageingand development Effects of gravity on plantgrowth Effects of gravity on developmentof geotropism Growthcharacteristicsunderhighg Dynamicbehaviour Web-spinning behaviourunder microgravity Sensitivityof mechanicalstress sensormechanisms Effects of varying gravity

Clinostatandorbital growth experiments

Orientationbehaviourin microgravity Muscledegenerationunderlack of muscletension Effects of removalof normalentraining stimuli Couplingof perceptionand movement undervarying g

Orbital laboratory Hind-limbsuspension on Earth

Cellculture undercentrifugation Orbitallaboratory Orbitallaboratory ShuttleBiorack Centrifugeand soundingrockets

O;$al facilities(alsoabandonedmines Hypdrbolicaircraft flight

a Data from Refs 9, 10.

know: the more ways you try to crystallize something, the better the chances ofobtaining ‘authentic’ crytals that can be used for X-ray structural studies. A full-scale space station acting as a permanent home for scientists in space could overcome the problems of needing to ‘simplify’ experiments for launch into orbit. The construction of such a facility was once viewed as an inevitable step in humankind’s expansion into the universe: now it appears to be only a long-term possibility. The Mir space station, which was in low-Earth orbit for several years during the 198Os, was the core of such a facility, but was nearly abandoned on the fall of the Soviet Union. The USA, with European collaboration, has been planning a permanent manned space station called Freedom, but the end of the Cold War has meant that the plans have been scaled down and are under continued threat of cancellation. Europe’s contribution to the station, an R&D laboratory called

Columbus has, for the past five years, been alternatively cut from the plans and reinstated: at the moment it is in limbo. The Freedom and Mir programmes have now been combined into the concept of a joint station, provisionally called Alpha (Ref. 16). Currently, the role of this station in research, and Europe’s contribution to it, is undefined. In the absence of a full-scale orbiting research facility, research has continued on smaller, shorter-term missions. The US shuttle has been home to the International Microgravity Laboratory (IML) for several missions. The IML has contained the protein-crystallization experiments, as well as more newsworthy payloads, such as spiders and Japanese tree frogs. Most of IML’s capacity is taken up with studies in physics and physical chemistry. The Eureca satellite is a more ambitious Eurowhich is pean science facility, launched into orbit by the US shuttle and then retrieved on a subsequent flight. Again, the exper-

iments on Eureca’s first flight in 1993 centred on the physical and earth sciences, as it is still difficult to design entirely automatic life-science experiments that run for months without any operators, can be packaged into a satellite, and are also scientifically interesting. Testing on the ground On the ground, the facilities that are used to develop, test and prepare payloads and people for space could also be used for life-science research. For example, recent results suggest that relatively low accelerations (5-108) enhance protein crystallization”. It would be possible to run an entire crystallization series at log if a centrifuge large enough and stable enough could be found - and it can, in several ground-based testing facilities. The CF-18 centrifuge at the Gagarin Space Centre (Moscow, Russia) has already been used for some preliminary crystallization experiments’*, as has the French LCPC 5.5m centrifuge at TlBTECHJANUARY1995WOL13)

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bio topics Table 2. Duration of exposure to ‘space’ (primarily microgravity) using different methods Method

Duration of experiment

Drop tube/drop shaft KC-135 (hyperbolic aircraft flight) Sounding rocket Satellite: Biocosmos (Russia) Space plane: Shuttle (NASA); Hermes spaceplane (European Space AgencyT; H-l 1 Orbitingplane(JapanY Spacestation: MIR(Russia);Freedom (USA-Europe)” Highaltitudesatellite(e.g. long-duration exposurefacility)

10 seconds 90 seconds 500 seconds 1-5 days 2 weeks Indefinite,probably around1 year Indefinite,>5 years

aFacilities notbuilt yet.

Nantes”. This illustrates that ‘space technologies’ mean ‘in orbit’.

the point need not

Cell culture in free fall Another type of study that takes weeks or months to complete, and is influenced by gravity, is the study of growth or differentiation. Wholetissue or organism studies involving microgravity are probably the most likely applications of space facilities, including studies of growth, development and degeneration of mammals in conditions where there is no net stress on the tissues from having to stand up (or lie down). Several centres are looking at such applications, including one of the NASA Centers for Commercial Development of Space (CCDSs), based at Penn State University (PA, USA)h. Some work in this direction has already begun, with studies of bonemarrow stem cells in low-shear bioreactor921. This work, which can easily be carried out on the ground, could lead to the reconstruction of bone marrow in vitro. If current cellculture results are indicative, this hagile tissue will take weeks to build, and could not be constructed in a gravity field. Once constructed, however, the marrow is more robust, and could conceivably be used for treating diseases such as osteoporosis, anaemia and immune disorders. Even if this proved im-practical, studying how complex tissues form could shed light on how differentiation malfunctions in disease. Tissue healing can be very difficult to study in animal models, as healthy animals do not accurately mimic aged or ill humans**. Removing the gravitational stimulus to grow from muscle, and particularly bone, could turn a healthy mouse into an approxiTBTECH JANUARY 1995

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mation of an osteoporotic human7. Neurological anatomy, recently decried by Crick and Jones as being the Cinderella subject of the neurosciences*s, could also benefit from the ability to grow cells in realistic threedimensional networks that are free of supporting synthetic polymers. This may have implications in the future for new therapies for diseases that involve aberrant neural development and degeneration. Microgravity as a cell-culture environment has previously been suggested as an application of space research. However, the emphasis has been on isolating cells from their artificial culture environment. Lymphocytes are activated by plastic, for example, and culturing them under high g force increases the activation24. (Exactly what activates the lymphocytes is not known, but it is related to the charge pattern on the plastic surface, as coating the plastic with thick layers of hydrophilic polymer removes the effectz4.) In principle, culturing lymphocytes in free fall should simulate more accurately the conditions that they encounter in the body. However, the applications of microgravity go beyond this as, in their normal environment, most cells are not only not in contact with plastic, but are in contact with many other cells and with the extracellular matrix that they synthesize. This tissue context is extremely difficult to mimic in vitro in the absence of complete tissue explants. In orbit, however, cells could be allowed to assemble themselves into tissue-like assemblages without being subjected to sedimentation, gravity-induced strain, shear strain from rotating reactors, or polymeric supports.

An additional, entirely speculative, idea is to allow cells to grow along the air-medium interface of ‘foamed’ structures, which are stable in free fall but not on Earth. Japanese microgravity missions’s have produced analogous foamed-metal structures in microgravity: foams are unstable during formation, but as the metal solid-&es they become rigid. No-one knows what an analogous cell-filled foam would be like, but it would be interesting to find out. From cells to tissues There are many applications of the idea of separating cell types from their parent organisms, while at the same time removing any gravity-induced strain. Applications in bone-marrow stroma synthesis and neuronalnetwork analysis have been mentioned as research topics. Other applications, such as artificial skin and connective-tissue formation and woundhealing models are being studied by Clontec (Palo Alto, CA, USA), Convatec (Princeton, NJ, USA), and Merocel (Mystic, CT, USA) (Ref. 6). The same techniques could generate valuable products, as bone marrow for transplant is a rare and extremely costly commodity, and divisioncompetent neuronal tissue for experimental treatments of, for example, Parkinson’s disease, is unobtainable from humans in many countries. Whether tissues or tissue replacements produced in conditions of free fall will have real value as a therapy remains to be seen: their structure may be adapted to space, and not to Earth-bound humans, and so they may only be of interest for research purposes. However, the limited amount of information available on how cells behave in free fall suggests that this is an interesting avenue to explore. The economics of producing tissue replacements in orbit are also attractive. The enormous price per gram of bone marrow suggests that cell biology could form a bridge between the use of orbital facilities for research and their use for production. Databases Some fundamental research knowledge could be obtained from existing space-related research databases, whose size makes the European Molecular Biology Laboratory (EMBL) DNA-sequence database look minute. ESA provides an online Information Retrieval Service

‘Don’t tell me someone’s

(IRS) with -130 separate databases25. However, these are bibliographicaltype databases, not compilations of data generated by the space industry itself. Databases of information that the space programme has generated itself (either in space or on the ground) could also provide valuable data for the healthcare industry (for example, the extensive information obtained on astronauts before, during and after space-flight). Space flight causes unique stresses on humans who are extremely healthy to start with. As well as loss of muscle and bone-mass, which mimics changes in later life, space flight results in unique changes in physiology, such as Combined Injury Syndrome (CIS) (Ref. 269, which is defined as a drop in the total number of lymphocytes, to below 40% of normal, and is caused by synergistic combinations of conventional injury and relatively low levels of radiation. To date, space-medicine efforts have focused, not unreasonably, on protecting the astronauts from such problems, but as a spin-off have generated data that could be relevant to many more-commonplace diseases. Data from the CIS space programme could be unusually valuable in this respect, as Mir astronauts have ‘flown’ for far longer periods of time than US or European ones2’.

left the lid off the Japanese

Modifications to the data-collection procedures on existing programmes, which would add virtually no extra mass to the payloads, could provide a wealth of additional data of commercial value from future missions, enhancing understanding of the regulation of muscle, bone and haematopoietic differentiation. Other features of space As discussed above, if space itself is to be a valuable scientific resource, then it must be because it provides an environment that cannot be duplicated on Earth for long periods. Two other features that might be considered are high-energy radiation fields and extremely low atom-densities. Agricultural biotechnology could benefit from the bizarre genetic effects of ultra-high-energy radiation to generate new genotypes (by far the largest source of new crop varieties is still ‘traditional’ genetics). NASA’s long-duration exposure facility (LDEF) (Ref. 28) experiments are an example of this type of application, and illustrate that, while it may not be economic to loft a tree into orbit, it often is worthwhile launching a few seeds. However, experiments with bacteria” do not suggest that space is unusually mutagenic. The low atom density in space produces some exotic chemicals,

tree frogs again!’

which could lead to avenues of chemical research not previously explored by chemists unused to an ‘empty’ test tube being really empty. In one sense, mining space as a source of novel chemicals has already begun: the fullerenes were discovered as a by-product of just thinking about what elemental carbon could form between the stars”. The experience of fullerene discovery shows that, once discovered in space, it may well be cheaper and easier to synthesize a new compound on Earth. There is a close analogy with exploiting fungal and plant sources to discover drugs, but using chemical methods to manufacture them. Telecommunications and sensing One attribute of space - the ability to shoot things very fast across huge distances - is not of obvious use to biologists. However, it is the basis of the remote-sensing industry and a large portion of the telecommunications industry. These areas of space endeavour lie halfway between ground and orbit: the biologists do not need to be in the satellite, nor to place samples there. Here, the existing infrastructure of space flight can be used by the biotechnologist. Telemetry and telecommunications are the standard products of the space industry, amounting to TlBTECHJANUARY1995b'OL13)

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biotopics USg62.35 billion sales in 1991. While existing telecommunications links are usually sufficient for exchange of research and project-management data in biotechnology companies, this may not always be so: it was rumoured that EMBL was seriously considering having a dedicated satellite link to distribute the exponentially growing EMBL DNAsequence data library, such was their frustration with the expensive German PTT telecommunications system. (In the end, they opted to move the data library to the new EBI in Cambridge, UK, instead.) At least one water company in the UK runs a water-processing plant in the USA by remote telemetry, showing that more-imaginative use of telecommunications is a realistic possibility. Remote sensing will be more interesting to agrochemical companies looking for local conditions in which pathogens do, or do not, affect crop plants, enabling millions of square miles to be monitored in one experiment. The same logic could apply to ‘ethnopharmacology’, the search for drug candidates among traditional herbal remedies. Screening the rainforest for local variations in mineral or vegetation characteristics could pinpoint areas where the local ecology differs from surrounding areas, and could thus indicate a different potential herbal pharmacopoeia. This is a much mot-r efficient method of searching than asking every medicine man in the Amazon basin about their lifetime of experience. The Landsat satellite [run by the semi-private company EOSAT (Washington, DC, USA) since the mid-1980slnn, and the French SPOT satellite can provide a wealth of highly detailed images for use in such applications. Studies of this sort have already shown that orbital-mapping data can differentiate different types of heather in Scotlandj’ and different forest types in Michigan3*. Fanciful futures? Further in the fixture, can we speculate on some radically new ways of using space? At the moment, pharmaceutical research has used space only when the orbital facilities are already there, and fitted into existing programmes of discovery. This is a low-investment, low-risk, low-return path, and many argue that the limits of existing discovery systems are already in sight. A step TIBTECH JANUARY 1995 (VOL 13)

change in technique, in which space technology is a central part of the discovery process, rather than an alternative way of doing essentially ground-based procedures, could provide new avenues for drug discovery. Such ‘step changes’ step outside the linear improvements that are part of continuous science. They allow the discontinuous changes in approach to a problem, which Thomas Kuhn has called ‘scientific revolutions’. Step changes could use any of the features of space mentioned above. Large volumes of vacuum suggests the possibility of developing highresolution X-ray or neutron microscopes, based on the projector principle. Extensive microgravity could be used in the separation of objects that would normally fall at an appreciable rate. Separation of multicellular organisrns on the basis of charge or magnetic field sounds fancifill only because we are not used to scaling up procedures that work perfectly well on viruses to protozoa or algae. On Earth, that is fancy: in space, it could be a highly effective practicality. Pilot experiments have already been carried out on board the US Spacelab flown on the shuttle in June 1993. The experiments listed in Table 1 only represent a small start in this direction, as they tend to answer questions that are already being asked. We need to ask: ‘What kind of new question can we ask, and answer, using space?’ Ultimately, the new applications, both on the ground and in space, will have to come from a consideration not of how the two industries as they are can fit together, but how they can be developed to fit together. This should take into account whether a project needs some of the expertise built up in the space industry (which is on Earth), some specific piece of equipment (which may be on Earth), or whether you really need the expense, inconvenience and time delay of getting an experiment into space itself. This type of forward planning in the management of technology is d&cult, but it is going to be increasingly valuable for the pharmaceutical industry. In addition, if the political noises that beset the space programmes of Europe and the USA are a guide, it is going to be vital to the survival of some of the more visionary parts of the space industry.

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