(PDF) XRayLab White Paper

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XRayLab White Paper

International Commercial

Experiments Service

This project has received funding from

the European Commission’s H2020

Framework Program for research,

technological development and

demonstration under grant agreement

No. 666815

ICE Cubes

Title : XRayLab White Paper

Abstract : The XRayLab is a novel X-ray diffraction (XRD) facility for the International

Space Station (ISS) being developed by Space Applications Services.

This facility can be utilised for protein crystallography in space, and for a

wide range of scientific applications, that are yet to be determined.

The objectives of this white paper are to present the main characteristics

of the XRayLab, and to invite scientists and industry to propose

microgravity experiments to be performed using this facility.

Grant Agreement N° : 666815

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DOCUMENT APPROVAL SHEET

Name Company Signature and Date

Prepared by: T. Peignier Space Applications Services

PA Checked by: L. Tazi Space Applications Services

Approved by: M. Ricci Space Applications Services

Space Applications Services NV/SA Tel: +32-(0)2-721.54.84

Leuvensesteenweg 325 Fax: +32-(0)2-721.54.44

1932 Zaventem, Belgium Web: www.spaceapplications.com

This document is the property of

Space Applications Services NV/SA.

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DOCUMENT CHANGE RECORD

Version Date Author Changed

Sections / Pages

Reason for Change / RID No

1.0.0 23-May-2016 T. Peignier Initial release

1.0.2 27-May-2016 T. Peignier pp. 4-5, 7-12 Slight corrections and rephrasing

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Table of Contents

1 Introduction ................................................................................................................................. 1

1.1 Background ...................................................................................................................... 1

1.2 Scope ............................................................................................................................... 2

1.3 Applicable Documents ...................................................................................................... 2

1.4 Reference Documents ...................................................................................................... 2

1.5 Acronyms .......................................................................................................................... 3

2 The XRayLab ................................................................................................................................ 4

2.1 The XRayLab Facility ....................................................................................................... 4

2.2 The XRayLab Cards ......................................................................................................... 5

2.3 Operational Concept ........................................................................................................ 6

3 Applications/Uses ....................................................................................................................... 7

3.1 Original Application: XRD of Protein-Ligand Complexes ................................................. 7

3.2 Additional Applications/Uses .......................................................................................... 10

4 Conclusions ............................................................................................................................... 12

List of Figures

Figure 1: The International Space Station in orbit ................................................................................... 1

Figure 2: CAD rendering of the inside of the XRayLab facility ................................................................ 4

Figure 3: A schematic illustration of the method of forming droplets for protein-ligand complexes

crystallization in a microfluidic system (adapted from [RD13]) ................................................................ 8

Figure 4: XRD of the crystals: crystallization chamber mounted on a rotating goniometer .................... 9

List of Tables

Table 1: XRayLab characteristics ............................................................................................................ 5

Table 2: XRayLab performance requirements for e.g. protein crystallography ..................................... 10

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1 Introduction

1.1 Background

The International Space Station (ISS) is a great technical achievement, designed as a permanently

manned Earth-orbiting laboratory for carrying out long-term scientific research in the unique environment

of space [RD1]. Thanks to its high modularity, the ISS is able to support science in a wide range of

disciplines.

Figure 1: The International Space Station in orbit

Unfortunately, to make use of the ISS is still unappealing to a large number of potential users [RD2],

due to the burden of complex rules and long procedures associated with developing and operating

equipment on board the Station.

The policy of the European Space Agency (ESA) about the utilization of the Columbus module changed

recently, opening to the possibility of accessing the ISS on a commercial basis [RD3]. This shift in policy

of the various space agencies will allow for the establishment of new commercial services supporting

the performance of additional science and technological research and development (R&D).

One of these initiatives is the International Commercial Experiment Cubes (ICE Cubes) service, aimed

at developing a multipurpose facility and an X-ray diffraction (XRD) -dedicated facility to be

accommodated on board the ISS and used by industries, scientific and educational organizations, either

on a commercial base or in partnership with national and international space agencies.

For more information about the ICE Cubes facility and service, see www.icecubesservice.com (RD4).

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1.2 Scope

The present document’s objectives are to:

• inform the readers about Space Applications Services’ ongoing project to develop an XRD facility

to be operated on board the ISS;

• attract the attention of a large community of scientists and industries;

• stimulate the proposals for exploitation and utilization of this microgravity facility with experiments

stemming from different scientific disciplines.

1.3 Applicable Documents

AD1 N/A

1.4 Reference Documents

RD1 ESA. User Guide to Low Gravity Platforms, HSO-K/MS/01/14, Issue 3 Rev. 0. December

2014

RD2 ESF. Independent Evaluation of ESA’s Programme for Life and Physical Sciences in Space

(ELIPS), Final Report. ISBN: 978-2-918428-77-0. 2012 December 13. Available from:

http://www.esf.org/fileadmin/Public_documents/Publications/elips_01.pdf

RD3 ESA. Call For Ideas “Space exploration as a driver for growth and competitiveness:

opportunities for the private sector”. 2015 March 03. Available from:

http://emits.sso.esa.int/emits-doc/ESTEC/News/ESA_CFI_Space_Exploration.pdf

RD4 Space Applications Services. ICE Cubes: Fast-Track, Low-Cost Service For Small

Experiments To The ISS. [cited 2016 May 23]. Available from:

http://www.icecubesservice.com/

RD5 Carruthers Jr CW, Gerdts C, Johnson MD, Webb P. A Microfluidic, High Throughput Protein

Crystal Growth Method for Microgravity. PLoS ONE. November 2013;8(11):e82298.

doi:10.1371/journal.pone.0082298.

RD6 Ildefonso M, Candoni N, Veesler S. A Cheap, Easy Microfluidic Crystallization Device

Ensuring Universal Solvent Compatibility. Org Process Res Dev. April 2012;16(4):556-560.

doi:10.1021/op200291z

RD7 García-Ruiz JM, Otálora F. Answers to a questionnaire on the PharmaLab experimental

facility for Space Applications Services. December 2015

RD8 Anderson AC. The Process of Structure-Based Drug Design. Chemistry & Biology.

September 2003;10:787-797

RD9 DeLucas LJ, McPherson A. Comprehensive Evaluation of Microgravity Protein Crystallization

[Presentation]. Denver(CO): ISS Research & Development Conference. 2012 June 26

RD10 Takahashi S, et al. JAXA protein crystallization in space: ongoing improvements for growing

high-quality crystals. J. Synchrotron Rad. August 2013;20:968-973.

doi:10.1107/S0909049513021596

RD11 Arkray, Inc. Development of Innovative Biosensing System for Diabetes Care Utilizing Space

Environment - Participation in the High Quality Protein Crystal Growth Experiment at “Kibo”

in the International Space Station. 2014 September 25. Available from:

http://www.arkray.co.jp/english/ex/release48.html

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RD12 Gerdts CJ, Elliott M, Lovell S, Mixon MB, Napuli AJ, Staker BL, Nollert P, Stewart L. The

plug-based nanovolume Microcapillary Protein Crystallization System (MPCS). Acta Cryst.

D64. 2008;1116-1122. doi:10.1107/S0907444908028060

RD13 Li L, Ismagilov RF. Protein crystallization using microfluidic technologies based on valves,

droplets, and SlipChip. Annu Rev Biophys. 2010;39:139-158.

doi:10.1146/annurev.biophys.050708.133630

1.5 Acronyms

AD Applicable Document

EC European Commission

ELIPS European Programme for Life and Physical Sciences

ESA European Space Agency

ESF European Science Foundation

FM Flight Model

GM Ground Model

ICE Cubes International Commercial Experiment Cubes

ISS International Space Station

MPCS Microcapillary Protein Crystallization System

N/A Not Applicable

PCG Protein Crystal Growth

RD Reference Document

R&D Research and Development

SBDD Structure-Based Drug Design

TBC To Be Confirmed

XRD X-Ray Diffraction

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2 The XRayLab

As part of the ICE Cubes programme, being developed by Space Applications Services with the support

of the European Commission (EC), the development of the XRayLab facility represents one of the core

assets the programme wants to offer to potential users.

The primary function of the XRayLab is to perform in situ X-ray diffraction (XRD) measurements and

this technique can be used for a wide range of applications, e.g. for protein crystallography in space.

The technological core of the XRayLab is an XRD instrument and an exchangeable sample

dispenser/container (so-called ‘XRayLab Card’).

The in-orbit operations of the XRayLab will not rely on the astronauts (except for the Card exchanges).

They will be monitored from ground and/or automatized to the maximum possible extent.

2.1 The XRayLab Facility

Figure 2: CAD rendering of the inside of the XRayLab facility

The XRayLab will mainly consist of:

• an X-ray source (and associated optics to filter and focus the beam)

• an X-ray detector (and associated electronics)

• a beam stop to block the direct beam

• a single-axis rotation goniometer, mounted on a two-axis alignment stage

• an optical sample alignment and inspection system

Optical alignment and

inspection system

X-ray source

XRayLab Card mounted on top of the

goniometer and positioning system

X-ray detector

X-ray beam

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• a Card holder providing mechanical and electrical interfaces, on which the astronaut will

mount/unmount the exchangeable XRayLab Cards (cf. §2.2) containing the sample(s) to be

diffracted

• an adaptable system allowing for power and closed-looped command and control of e.g. micro-

pumps and/or temperature-controlled areas inside the mounted XRayLab Card

• a data acquisition, transfer and management system

• a radiation shielding structure

• a thermal control system

The principal characteristics planned for the XRayLab facility are summarized in Table 1 below.

Characteristics Value

X-ray source technology microfocus sealed tube

X-ray source anode material copper

X-ray source wavelength 1.54 Å

X-ray source beam size 110 to 250 µm

X-ray beam divergence 5.0 to 7.5 mrad

X-ray source flux density 0.5 to 1.4 · 1010 ph/s·mm²

Detector resolution 1024 x 1024 pixels

Goniometer rotation range > 360 °

Goniometer minimal incremental motion 0.62”

Alignment stage travel range 13 mm

Alignment stage resolution 4 nm

Table 1: XRayLab characteristics

Because of the limited data bandwidth of the ISS, only a subset of the generated data (diffraction pattern

images) can be downlinked to Earth via near real-time telemetry.

Depending on the overall data size, the rest can either be downlinked to the ICE Cubes mission control

centre (and made available online to the scientists) after the end of the experiment, or it can be

transferred onto an external memory device (e.g. flash memory drive or removable hard disk) for

download to Earth at the earliest possible opportunity.

2.2 The XRayLab Cards

The XRayLab Cards are the dispensers/holders of the samples to be X-ray diffracted. They are

exchangeable by design, so as to accommodate the widest variety of experiments possible.

Depending on the Card design and the samples characteristics, one single Card may contain up to

several hundreds of samples to be diffracted.

As the Card design is purposely highly flexible, each Card can in principle be custom designed and

manufactured, either by the scientists themselves, or by Space Applications Services, in collaboration

with the interested scientists. The Card design will only be limited by:

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• its mechanical interface (to fit in the goniometer),

• its electrical interface (if needed, e.g. for power and closed-looped control of micro-pumps and/or

temperature-controlled areas inside the Card),

• the overall dimensional envelop (as a first indication, in the order of 10cm x 6cm x 6cm)

The three above-listed limits will be defined further to receiving requirements from the scientific and

R&D community interested in making use of the XRayLab (cf. §4).

The Cards will be launched separately and will be manually placed inside the XRayLab (and removed

from it) by the astronauts. As a first indication, manual Card exchanges on orbit could happen from 3 to

12 times a year, depending on the operational constraints.

Depending on the experiment needs, the Cards can be launched refrigerated or frozen, installed in the

launcher few hours before launch (late access) and quickly removed from the launcher upon its docking

to the ISS (on-orbit early retrieval). If so required, Cards could eventually be physically brought back to

Earth.

In the case of protein crystal growth (PCG) related experiments, the XRayLab Cards are considered to

be microfluidic systems, as these allow the implementation of different crystallization techniques, such

as the batch technique (already demonstrated on board the ISS, [RD5]), but also the free interface

diffusion and the counter-diffusion techniques.

Undeniably, droplet-based microfluidic systems have proven to be more effective in PCG compared with

conventional micro-batch method. The advantage is that single crystals can be grown in nanolitre-range

droplets, thus enabling large volume of experiments under identical conditions and requiring negligible

consumables [RD6].

Furthermore, microfluidic systems in space may have other interesting applications not only for proteins

but also for pharmacological compounds and other small molecules [RD7].

More details about the design of a microfluidic Card for a specific application are given in §3.1.3.

Additional Card designs will be elaborated to suit the diverse scientific needs of the various experiments

to be performed using the XRayLab facility (cf. §3.2).

2.3 Operational Concept

Prior to launch, the scientist will fill in one or several Ground Models (GMs) of the Card with samples

and/or necessary consumables. Tests will be performed on Earth inside the XRayLab Ground Model to

determine e.g. experiment parameters, data collection strategy, etc.

Further to these ground tests, the scientist will fill in the Flight Model (FM) of the Card. If needed, the

XRayLab Card can be launched refrigerated or flash frozen. Upon arrival on board the ISS, the Card

will be mounted inside the XRayLab Flight Model by the astronaut. The ground team at Space

Applications Services will then initiate the experiment.

Every XRD image will be stored locally on the XRayLab facility. As stated in §2.1, a subset of the

generated data will be downlinked to Earth via near real-time telemetry, for e.g. inspection by the

scientists. If required, the experimental parameters can be refined or changed via near-real time

telecommand.

After the end of the experiment, all data will be made available to the scientists, either using the faster

but limited downlink capabilities of the ISS, or through physical download to Earth of an external memory

device at the earliest possible opportunity.

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3 Applications/Uses

The original concept of the XRayLab was targeting the research in the pharmaceutical field (hence its

initial name of “PharmaLab”), with the aim to apply the X-ray crystallography technique to protein-

pharmaceutical compounds molecular complexes crystallized in orbit, in order to elucidate the rigid

protein atomic configurations, and identify the protein-ligand docking relationships.

However, thanks to its main technical characteristics, it became apparent that the XRayLab could also

help scientific research in adjacent fields, such as in the investigations of protein-nucleic acids

interactions, molecules’ biosynthesis, or X-ray crystallography studies of colloidal / soft matters.

Additionally, one of the attractive aspects of the XRayLab is that the XRD will be performed in situ, thus

precluding any possible negative impact on the diffraction quality of the samples that could come from

space to ground transportation.

3.1 Original Application: XRD of Protein-Ligand Complexes

3.1.1 Background

Since its start during the mid-1980s, the process of rationally designing new pharmaceutical products

has achieved significant success and has led to new areas of research such as structure-based drug

design (SBDD). As one of the main approaches in many industrial drug discovery programs, the SBDD

field flourished in parallel with advances in protein crystal growth (PCG) techniques and computational

speed as well as the explosion of genomic and proteomic data [RD8].

Despite these achievements, the future of SBDD remains dependent on accurate models of protein

structures and the understanding of lead compounds to investigate binding mechanism. As one method

of protein structural identification, the X-ray crystallography technique has become an integral part of

SBDD. Since the majority of the currently known protein structures are determined by X-ray

crystallography, this technique can either elucidate rigid protein atomic configuration or it can also

identify the protein-ligand docking relationships.

However, some proteins are more difficult to crystallize in suitable size and sufficient quality due to

buoyancy-induced convection and sedimentation of crystals’ nuclei in the 1g environment. On board the

ISS, microgravity offers an ideal setting where these proteins are able to grow in homogeneous

crystalline formations with fewer lattice defects [RD9]. Such high-quality crystals will permit XRD to

produce more accurate models (R-factor less than 25%) [RD8] of the macromolecular structures

compared to those obtained from less well-ordered crystals grown on ground.

3.1.2 The Role of Microgravity in Protein Crystal Quality [RD7]

The quality of a protein crystal depends certainly on the conditions under which it grows. In the

microgravity environment, the lack of convection and sedimentation phenomena results favourable for

the growth of high quality protein crystals. Furthermore, the selection of the crystallization technique,

the value of supersaturation, the rate of increase of supersaturation, the mass transport regime in the

solution and the growth mechanisms by which the crystal grows are important in addition to the quality

of the solution from which it grows. It is currently accepted that a mass transport scenario controlled by

diffusion may favour the diffraction quality of protein crystals. And this is the reason –pure fluid

dynamics– why microgravity plays a role in the area of protein crystallization.

The relative importance of diffusion and convection in crystallizing solution is defined in fluid dynamics

using dimensionless numbers such as the Grashof number, which gives an account of the ratio between

the buoyant forces and the viscous drag forces.

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GrN = L3

⋅

α

⋅

Δc

⋅

g

⋅

ν -2

where g is the gravity acceleration, ν is the kinematic viscosity, α is the volume expansion coefficient,

and L is the characteristic dimension for the container. From this equation, it is easily deduced that

buoyancy motion can be reduced by lowering the value of g or L, by increasing the viscosity of the

solution and by locating the growing crystal in the upper part of the container. L is the characteristic size

of the reactor (the size of the drop or the diameter of a capillary or microfluidic chamber).

It is clear from the above equation that both microgravity and microfluidics play in the same direction.

Buoyancies forces become predominant in the crystallizing solution either by lowering the value of g or

the value of L.

It should also be noted that the signal over noise statistics in diffraction data depends on the number of

scatterers in the beam, so larger crystals can produce better data (at least within the 50‐500‐micron

range of crystal size commonly used in protein crystallography).

3.1.3 PharmaCard

One of the most promising aspects of microgravity research is related to the possible biomedical

advancements coming from the study of space-grown protein crystals [RD10, RD11].

In this respect, in parallel with the facility, some Cards are being developed to be able to grow large and

well-ordered crystals prior to XRD. Explicitly, the XRayLab Card designed for this specific application –

purposely called ‘PharmaCard’– will consist of a microfluidic system including:

• Fluid reservoirs including but not limited to protein and fragmented compounds in solution, buffer,

precipitant, fluorinated carrier fluid, cryoprotectant (TBC);

• Fluid distribution system controlled by independently operated micro-pumps;

• Microfluidic capillary system in which droplets can be generated (cf. Figure 3), each representing a

microbatch-style crystallization experiment [RD12]

• Waste reservoir where the processed crystals can be discarded.

Figure 3: A schematic illustration of the method of forming droplets for protein-ligand

complexes crystallization in a microfluidic system (adapted from [RD13])

The PharmaCard is currently in its preliminary design phase and will be further refined in collaboration

with scientists/industries interested in developing such an experiment. As such, detailed characteristics

such as dimensions, materials, pumping rates, etc. are under finalization.

As a first indication, the capillary diameter for this application is thought to be 250 µm minimum, but

nothing precludes other sizes.

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The elucidation of the crystals of the protein-ligand molecular complexes will be achieved through the

X-ray diffractometer (cf. §2.1) in order to characterise the binding configuration and then the structure-

activity relationship of the lead compound on the target protein. The PCG workflow will be entirely

contained inside of the sealed microfluidic system and each crystal will be introduced to the X-ray beam

and rotated to collect diffraction patterns from all necessary angles, with a target resolution of 2.0Å (see

Table 2 on page 10).

Figure 4: XRD of the crystals: crystallization chamber mounted on a rotating goniometer

3.1.4 Operational Concept of a PharmaCard Experiment

Prior to launch, the scientist will fill in the PharmaCard with aqueous protein and fragmented compound

buffered solutions along with all necessary consumables. The PharmaCard will immediately be either

refrigerated or flash frozen. Upon ISS arrival, the Card will be thawed, and the ground team at Space

Applications Services will initiate the process of molecular interaction between the compound’s

fragments and the target protein at a set temperature. Immediately after, the ground team will activate

the droplets formation, and monitor the crystallization process via near real-time telemetry.

Once PCG has completed, the droplets will be pushed one by one into the X-ray beam path and, upon

successful crystal quality inspection (based on optical microscopy images), XRD of the crystal under

investigation will commence with each diffraction image stored locally by the XRayLab facility.

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After the end of the experiment, all data will be made available to the scientist, either using the faster

but limited downlink capabilities of the ISS, or through physical download to Earth of an external memory

device (e.g. flash memory drive or removable hard disk) at the earliest possible opportunity.

3.2 Additional Applications/Uses

3.2.1 Protein Crystal Growth

There is no doubt that an understanding of how crystallization takes place in space will be needed in

the near future. Crystallization is such a universal process that space cannot be explored without a deep

knowledge of how molecules join themselves under microgravity to form crystals, from nano- to metre-

size scale [RD7].

Since the XRayLab Cards are purposely exchangeable, their design can be highly flexible.

As such, the most obvious complimentary uses of the XRayLab are in the fields of chemical/structural

biology, molecular biology, genetics, bioengineering and synthetic biology (e.g. to solve the molecular

structure of proteins/enzymes, DNA, RNA, chromosomes structures and their mutations, NA-protein,

protein-protein, or protein-antibodies interactions), as well as potential material sciences structural and

functional analysis. All these scientific fields could benefit from using the XRayLab.

For these types of experiment, only small adaptations of the Card design as presented in Figure 4 will

be required, such as:

• the content of the wells themselves (one could even contain a gas, in order to generate bubbles),

• the number of wells,

• the micro-pumps,

• the consumable fluids,

• the diameter of the capillary,

• the presence of temperature-controlled areas.

More drastic changes of the XRayLab Card could also be implemented to accommodate for e.g. free

interface diffusion and counter-diffusion experiments.

Performance requirements Value

Maximum unit cell size 200 Å

Mosaicity 0.1-1.0 °

System resolution 2.0 Å

Accuracy l/σ (highest resolution shell) 2

Completeness (highest resolution shell) 90%

R-merge 10%

Table 2: XRayLab performance requirements for e.g. protein crystallography

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3.2.2 Other Uses

Virtually any sample dispenser/container which fits inside the XRayLab and which can hold the

sample(s) at the focal point of the X-ray beam can be developed.

The scientific and R&D community is thus prompted to suggest experiments in all possible fields of

exploitation and studies.

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4 Conclusions

The XRayLab facility for the ISS is currently under development. It will allow in situ XRD of samples,

such as protein crystals, in microgravity. These samples will be held in exchangeable XRayLab Cards,

to be launched separately, at room temperature, refrigerated or frozen, according to the scientific

requirements.

Dedicated XRayLab Cards, such as microfluidic systems, can be manufactured, meeting the XRD

workflow allowed by the facility.

Various scientific fields could benefit from the exploitation of the XRayLab capabilities for both

fundamental and applied sciences. The XRayLab may be utilized for pharmaceutical drug design and

development applications, biotechnology investigations, material sciences (colloids / soft matter

crystallography) experiments, etc.

The scientific and R&D community is encouraged to consider the utilization of the XRayLab and

to propose additional fields of exploitation and studies.

For additional information, contact xraylab@spaceapplications.com, and for an overview of the general

characteristics of the ICE Cubes service, visit www.icecubesservice.com (RD4).

XRayLab White Paper

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