Page 1

Human Health

Research at the Paul Scherrer Institute


Contents 4 For good health

4 Proteins and cancer therapy

20 Diverse insights into the structures of life

4 New technology for new insights

20 Dynamics of the alveoli

4 Life sciences at PSI in numbers

21 Biopolymers for the food industry

21 Insights into the cell

6 Probing the structures of life – developing new drugs

22 Proton therapy – a success story

22 First patient treatment more

8 Machinery of life

8 Understanding proteins –

developing drugs

8 Proteins everywhere

10 A biotechnological revolution 12 Radiating medicines

than 30 years ago

23 Patient treatment and research,

hand in hand

24 From research to the business world – collaboration with industry and spin-offs

13 Targeting thyroid cancer

26 Hand in hand with industry

13 In the middle of the nucleus

27 Drugs from PSI research

13 A view into the organism

27 Better X-rays

13 Supplying the Aargau hospitals

27 Technical specialist for proton therapy

14 The latest technology for research and therapy 16 Big machines make the smallest visible

16 Deciphering the structures of life

at the particle accelerator

17 Developments from PSI make

new insights possible

28 Using innovations to found spin-offs

28 Developing and testing drugs

28 Promoted by the PSI Founder Fellowship

28 Better X-rays

28 Supporting users from industry

31 PSI in brief 31 Imprint 31 Contacts

18 The Swiss approach: high quality

3


For good health When researchers in pharmaceutical

Again and again, PSI researchers gain

about the protein activation – and do

companies develop new drugs nowa­

notice in expert circles for describing

it with a resolution at which the indi-

days, they rely on detailed scientific

proteins in an unprecedented degree

vidual atoms of the protein can be

findings about the causes behind par­

of detail and thus elucidate their func-

seen.

ticular diseases. PSI contributes to this

tionality. Among the proteins studied

Proton therapy shows how fundamen-

knowledge in multiple ways. For one

most intensively at PSI are those that

tal research in other fields can contrib-

thing, PSI researchers investigate fun­

control the process of vision as well as

ute to advances in medicine in aston-

damental structures of life and, on that

cell division.

ishing ways. When this treatment

basis, develop approaches for new

A second research focus at PSI is on

method was developed in the 1980s,

treatment methods. In addition, they

the development of radiopharmaceu-

PSI was the only institution in Switzer-

develop radiopharmaceuticals – radio­

ticals. These drugs, which for the most

land that possessed a suitable proton

active drugs with which certain tu­

part consist of a combination of a bio-

accelerator, which had been built for

mours can be localised and precisely

molecule that accumulates on tumour

physics research. Today hundreds of

destroyed.

tissue with a radioactive isotope, are

patients per year are treated here, in-

At the same time, the large research

used in hospitals for cancer diagnostics

cluding very many children. In addition,

facilities of PSI, which are unique in

and therapy.

PSI is a leader in the further develop-

Switzerland, are also open to research­

ment of this innovative treatment

ers from universities and industrial

method.

New technology for new insights

On the following pages you can learn

PSI in many third-party research re­

Still, PSI’s contribution to the under-

ness of this research for forward-looking applications in medicine.

enterprises who come here to study structures of vital biomolecules and medicinal agents. Thus there is a bit of sults and therapies.

standing of life processes extends far

Beyond that, there are patients who

beyond its own research: Numerous

profit directly from the work of PSI:

external experts in the areas of biology

people who are afflicted by certain

and biochemistry carry out experiments

kinds of cancer and are treated with

at the large research facilities of PSI.

the precise and gentle proton therapy

Among them are also, besides scien-

right on the campus of the Institute.

tists from universities, researchers from

more about the secrets of life that are elucidated at PSI, as well as the useful-

large pharmaceutical firms or emerging biotech companies – some of which

Proteins and cancer therapy

have been founded directly out of PSI. Through the interplay between their

In the fundamental research of PSI, one

own research and their ingenuity in

of the essential classes of basic biolog-

engineering, PSI experts advance the

ical building blocks plays the leading

development of these facilities in such

role: proteins, highly complex biomol-

a way as to ensure future progress in

ecules that control and carry out prac-

medicine. Thus the new X-ray laser

tically all metabolic processes as well

SwissFEL makes it possible not only to

as cell division in all forms of life. In

record static images of proteins, but

humans and animals they also form the

also to measure the ultrafast changes

support scaffolding of the cell and

in protein molecules after their activa-

transport materials within the cell.

tion and, in this way, to make a film

4

Life sciences at PSI in numbers Since 1984, more than 8,000 cancer patients, including 500 children, have been treated by means of the ultraprecise proton therapy. The share of PSI’s budget devoted to life sciences amounts to 24 percent. Since 2002, more than 5,600 protein structures have been deciphered at SLS.


Studies at the large research facilities contribute to our knowledge about the structures of life and establish the basis for new drugs. 5


Probing the structures of life – developing new drugs

Today as in the past, researchers in the life sciences spend much of their time in the laboratory. 6


7


Machinery of life Proteins are central building blocks of

wonder that medicinal treatment in

every living system. Like tiny, highly

most cases is aimed at proteins.

specialised machines, they perform

Each protein consists of a chain of

countless tasks in the living organism:

smaller molecules – the amino acids.

They break down materials and build

The arrangement of these amino acids

up others, form the support scaffolding

for every single protein is stored in the

of our cells, transmit information

DNA. But the order of the amino acids

within the body, and see to it that

isn’t the only thing that matters. It is

energy is stored up and made available

also important that this chain folds

again on demand. Although they are

correctly and in doing so forms its typ-

all assembled according to the same

ical three-dimensional structure, with

principle – from a chain of “standard­

various extensions and bulges. In ad-

ised” building blocks, the amino acids

dition, practically all proteins alter their

– they can have an almost unimagina­

shape when they do their work – so

ble variety of different forms. At PSI,

they have more than one structure

researchers decipher the structure and

each. Only when scientists know the

function of the most diverse proteins

three-dimensional structure of the pro-

and thus gain a better understanding

tein as well as how it changes can they

of life processes. With this knowledge,

really understand its function.

The receptor rhodopsin has seven spiral structures. It is located in the cell membrane (yellow background). Visible between the spirals, with a shape like a panicle of grapes, is the retinal, which reacts to light. The incidence of light causes the retinal to change its form and thus slightly shift the spirals. This allows a G protein (beige-grey structure) from inside the cell (turquoise background) to bind to the rhodopsin receptor. The G protein initiates a process that makes sure the information of the light signal is passed on to the nerve cells and finally to the brain. This process takes place constantly and at such a fast pace that our eyes can perceive changes in the environment instantaneously.

they contribute to the development of new drugs.

Practically all processes in our body are

Understanding proteins – developing drugs

regulated by proteins. These complex

At PSI, several research groups are in-

biomolecules can be thought of as tiny

vestigating the composition and func-

machines that take on the most diverse

tion of proteins. One area of focus is

tasks in the cells of our body. They

the so-called G protein-coupled recep-

make it possible for us to see, hear, and

tors – proteins that sit in the cell mem-

taste, and they take care that different

brane and see to it that information

areas of the body can communicate and

from the outside gets into the cell. A

coordinate with each other. All nutri-

familiar example of such a protein is

ents such as sugars, fats, and vitamins

the beta receptor of the heart muscle

are assembled or metabolised by pro-

– if molecules of the hormone adrena-

light-induced structural changes in an-

teins, as are likewise all cellular com-

lin from outside come into contact with

other G protein-coupled receptor, the

ponents including DNA, RNA, and pro-

such a receptor, they stimulate the

visual pigment rhodopsin. This receptor

teins themselves. Proteins also play a

muscle cells to beat more strongly. To

reacts to light and is responsible for

role in all diseases: For example, peo-

artificially reduce this effect, the recep-

the “translation” of the physical infor-

ple can become ill when their bodies’

tors can be blocked with the help of a

mation “light” into a biochemical sig-

proteins are malformed or when the

drug – a beta blocker. Overall, 30 per-

nal that can be transmitted to the nerve

organism is attacked by microorgan-

cent of all newly developed drugs at-

cells in the brain. The PSI researchers

isms, which again consist to a large

tack proteins of this family. Structural

are working to elucidate the exact de-

extent of proteins. Therefore it is little

biologists at PSI have determined the

tails of this process on the molecular

8


dation of the structure of tubulins in interaction with different agents at PSI enables the improvement or new development of active ingredients for chemotherapy. In addition, the tubulins are the basis for tiny, highly mobile hairs that enable locomotion in single-celled organisms and can also be found on certain tissue surfaces, as in the lungs, for example, where they transport mucus outwards.

Proteins everywhere Proteins are also crucial for the development of radiopharmaceuticals – these cancer drugs dock selectively on proteins on the surface of tumour cells and destroy them with their radiation. The research facilities of PSI, which are also open to researchers from all over the world as well as industrial enterprises, offer in part unique possibilities for determining the structure and function of proteins. Members of staff at PSI look after the external users during their experiments, and thanks to this experience they are able to constantly enhance the facilities. The central role proteins play for the effectiveness of numerous drugs also accounts for their economic signifilevel; among other things, the insights

ton� that holds the cell in shape and

cance. In the development of new

gained yield important information for

coordinates the machinery of cell divi-

drugs, many large pharmaceutical com-

the development of new drugs against

sion. During cell division, tubulin fibres

panies make use of insights into the

diseases that cause blindness.

pull apart the newly formed chromo-

structure of proteins that they have

Another example is the protein tubulin.

somes and distribute them between

obtained at PSI. The protein research

It forms thin fibres that take on various

the two new cells. The latter proves

environment at PSI has also generated

functions in the cells. The fibres serve

useful in chemotherapy, in that this

a series of spin-off enterprises, which

as tracks on which substances are

process can be interrupted with agents

for example develop active medicinal

transported within the cell, and they

that bind to tubulin and thus prevent

agents or support industrial users in

form an important part of the “skele-

the division of cancer cells. The eluci-

their own investigations at PSI. 9


A biotechnological revolution Gebhard Schertler is the head of the research division of Biology and Chem­ istry at the Paul Scherrer Institute PSI and Professor for Structural Biology at ETH Zürich. In this interview he talks about biological research at PSI and the future of drug development

Gebhard Schertler, one of the core competences of PSI is deciphering the structure of proteins. What makes pro­ teins so interesting? In biology, proteins make up the workbench of life. They are structural building blocks or active tools that transform materials or transmit signals. Therefore, they are central to understanding the essential processes of life. There’s a saying: “The language of life is chemistry.” And a great many proteins are catalysts, which enable or regulate this chemistry. What is the significance of protein re­ search for our everyday life? Fundamental biology is becoming ever more relevant for the development of new therapeutic options against diseases. Thus, the insights we are gaining about the structure of proteins help to develop better drugs – for example, against cancer or diseases of the eye. But there is even more potential: We are standing at the start of a technological revolution, which could be described as biological systems engineering. Proteins become components in new biological regulatory circuits. For example, today people are thinking about drugs that can be switched on or off with light. At the moment this is possible only to a limited extent, but it will likely become 10


very important in the future; projects at

The results of these studies then yield

ceuticals, radioactively marked active

PSI are providing the necessary research

clues as to which drugs are most suita-

ingredients , are being developed in

infrastructure for these developments.

ble for the treatment.

close collaboration with hospitals. These are used mostly in the diagnosis

The buzzword “personalised medi­

In this context, what does “rational”

of cancers, but also increasingly in

cine” keeps coming up in connection

drug design mean – and what would

therapy.

with the future of diagnostics and ther­

be the alternative?

apy. What is meant by this term?

In the past, the approach was to try to

Beyond that, what strategies do you

Personalised medicine has different

investigate thousands and thousands

follow within the life sciences research

aspects. On the one hand, it refers to

of chemical compounds in one big test-

at PSI? Is there a vision that guides the

a treatment that is tailored to one par-

ing procedure – in the hope of identify-

way?

ticular person – that can begin with a

ing, by chance, a single compound that

Strategically, we are at the moment

genetic test, or with the medical history

showed the desired effect. Yet this

strongly focused on making a contribu-

and imaging techniques: for instance,

“non-rational” approach didn’t stand

tion to personalised medicine. At the

when precisely defining, in the course

the test. Millions were invested – and in

same time, besides fundamental ques-

of proton therapy at PSI, the three-di-

the end, the successes were small.

tions in structural biology, we will give

mensional zone around the tumour that

Therefore, today, there is really no longer

priority to topics that have relevance

should be treated. On the other hand,

any alternative to rational drug design

for the pharmaceutical industry, and

you want to analyse a person’s genes

where, on the basis of a target molecule,

we will intensify our collaboration with

and environmental factors as com-

a suitable active ingredient is devel-

hospitals. It is important to understand

pletely as possible and thus find out,

oped. With this approach we have had

that the way we gain knowledge is

for example, whether cancer cells will

good experience with biological agents,

changing. Up to now it was possible to

respond to a particular hormone ther-

for example with antibodies. Once a

achieve major breakthroughs with in-

apy or not. For me, the essence of it is

target molecule has been rationally iden-

dividual experimental methods alone.

that in the end, after a precise analysis

tified as the cause of a disease, it can be

In the future it will become ever more

of the individual patient, an optimal

switched on or off with antibodies. There

important to find combinations of

treatment emerges.

are disadvantages of antibodies in that

methods that are best suited to solve

they generally need to be injected, and

a specific problem and to make new

And how are researchers at PSI con­

may activate undesired immunological

findings possible. Therefore, we invest

tributing to personalised medicine?

reactions. Therefore, most pharmaceu-

in a broad portfolio of methods. For

In our fundamental research, we are

tical researchers are always searching

one, PSI has recently built the free-elec-

concerned with how proteins interact

for soluble substances that can be taken

tron X-ray laser SwissFEL, with which

with each other. Through analysis we try

in tablet form. Here, too, there are major

the movement of proteins can be made

to determine which protein plays a cen-

advances – on the one hand through

visible in the form of, one might say,

tral role in a disease: This protein is then

structural biology, on the other through

‘molecular movies’. On another front,

called the target molecule, because it

computer modelling of proteins. It’s a

structural analysis by means of electron

becomes the attack point for the medi-

combination of practical experience and

beams is becoming increasingly impor-

cal treatment. The researchers here at

theory that pays off best in the end.

tant – here, too, we are working on new

PSI often play a very important role when

machines. One important goal for the

such a target molecule has already been

In what other areas is PSI developing

future is to determine the structure of

identified and subsequently needs to

personalised medicine?

proteins in their natural environment,

be investigated more precisely, whether

Above all, radiopharmacy should be

inside cells.

structurally, biophysically, or kinetically.

mentioned here, where radiopharma11


Radiating medicines

Radioactive drugs can help many patients afflicted with cancer. In a specially secured laboratory, PSI researchers are working on new preparations.

They are sometimes the last hope

Although it’s impossible to imagine

but over a long range. Then their signals

against cancer: radioactive agents that

modern medicine without them, in the

can be detected by sensitive measure-

find their own way to the tumour cells

public perception they lead a shadow

ment devices outside the body, thus

and fight the cancer inside the body.

existence: radiopharmaceuticals. These

providing information about structures

Other “radiating medicines” have

are medicines that incorporate a radio-

and processes in the organism. In most

proven their value as diagnostic agents:

active substance, which decays in the

cases a complex biomolecule that aims

In a PET scanner, for instance, they can

body and emits radiation. Radiopharma-

selectively for a particular target mole-

indicate if the brain is functioning prop­

ceuticals can be used in two ways: Either

cule on tumour cells serves as the carrier

erly. At PSI, more than 25 researchers

the radioactive substance delivers a lot

for the radioactive substance. The target

are engaged with radiopharmaceuticals

of energy in a narrowly defined area,

molecules are usually proteins, so the

– they develop new agents or produce

making it suitable for destroying a tu-

work in radiopharmaceuticals also fits

them for use in hospitals.

mour, or they emit radiation only weakly

in with the protein research at PSI.

12


Radiopharmaceuticals are studied, re-

ficult. Among the challenges were the

For one thing, to be suitable for a PET

fined, and even produced at PSI. Five

initial side-effects of the hormone-like

scanner, the sought-after radionuclide

work groups take part in interdiscipli-

protein, the accumulation of the radi-

must emit a specific kind of particle –

nary collaborations in the Centre for

opharmaceutical in healthy tissue, and

positrons. Also, it should decay more

Radiopharmaceutical Sciences, which

the necessity of optimising the produc-

slowly than the radionuclides currently

PSI manages jointly with ETH Zurich and

tion method.

being used. That’s because their ex-

the University Hospital Zurich. Physical,

tremely short decay time restricts the

chemical, biological, pharmaceutical,

distribution of the drugs, even within

and medical aspects must be consid-

In the middle of the nucleus

a country as small as Switzerland. So the PSI scientists are now testing a new

ered in equal measure when the goal is to produce a suitable drug for the

The approach of another research

candidate that satisfies both require-

correct application – timed just right

group at PSI is still a dream for the fu-

ments: scandium-44. They produce the

and matched with the individual pa-

ture: Their goal is to channel radioac-

radioactive material by bombarding

tient. When working with radioactivity,

tive drugs directly into the nucleus of

non-radioactive calcium-44 with pro-

high safety standards must be met.

a cancer cell. The radioactive substance

tons for 90 minutes. For that they use

Furthermore, the short shelf life of the

could then make a direct strike on the

a particle accelerator at PSI. Thus the

drugs due to radioactive decay must be

genetic material and thus prevent fur-

special infrastructure of the research

taken into account.

ther divisions of the cancer cell. This

institute may be opening the path for

would be similar in principle to the

a new radionuclide to serve all of the

usual chemotherapy to date, only much

hospitals in Switzerland using a PET

more selective and with many fewer

scanner.

Targeting thyroid cancer

side-effects. With terbium-161, the reIt can take many years before a drug

searchers have already found a suita-

has been developed to the point where

ble radionuclide. Its radiation has an

it can be used in clinical studies. One

extremely short range and results in a

successful example is 177Lu-PSIG-2.

high energy release. Now the radionu-

That’s the name given to a new PSI-de-

clide still needs to be coupled with a

For the development of new radiophar-

veloped radiopharmaceutical that is

suitable protein that can open the way

maceuticals, PSI has built up a labora-

directed at a special cancer of the thy-

for it through the nuclear envelope of

tory infrastructure that is unique in the

roid and its metastases. The cancer

the cell.

canton of Aargau and beyond. With

Supplying the Aargau hospitals

arises from the so-called C cells of the

that, it also meets the requirements for

thyroid – radio-iodine therapy does not

being permitted to produce the radiop-

help in this case. Since the end of 2016,

A view into the organism

the new preparation has been tested

harmaceutical 68Ga-PSMA, developed elsewhere, which it recently began

at the University Hospital of Basel

A radionuclide with completely different

supplying to the Aargau Canton Hospi-

within the framework of a clinical study.

characteristics has been sought after

tals in Baden and Aarau. With the help

It consists of a small protein that re-

by radiochemists at PSI, to improve the

of this agent, doctors can diagnose

sembles one of the body’s own hor-

availability of radiopharmaceuticals for

metastases of prostate cancer early and

mones together with the radioactive

so-called positron-emission tomogra-

initiate treatment in a timely way. Be-

substance lutetium-177. The small pro-

phy or PET. With a PET scanner, three-di-

cause of the short half-life of the iso-

tein docks selectively on receptors on

mensional images of the interior of the

tope employed, gallium-68, 68Ga-

the surface of the tumour cells. The

body can be produced, and biochemi-

PSMA is only usable for three hours and

radioactive substance, the so-called

cal processes in the organism can be

must therefore be produced near where

radionuclide, decays there and de-

made visible. Besides diagnosing tu-

it will be applied. With this work PSI is

stroys the cancer in a targeted manner.

mours and metastases, it can be used

helping to bypass a significant bottle-

As simple as this is in principle, how-

for example to detect pathological

neck in the drug supply in Aargau.

ever, the pathway to the drug was dif-

changes in the brain. 13


The latest technology for research and therapy

Only through teamwork can the complex experiments to determine protein structures at SLS be carried out. 14


15


Big machines make the smallest visible Deciphering the structures of life at the particle accelerator

ture of protein molecules in detail. At

With that, they help to better under­

The X-ray light for such experiments can

researchers can observe how protein

stand processes in organisms and es­

only be generated at complex large

molecules change their shape, thus

tablish the basis for the development

research facilities. PSI operates two

gaining a better understanding of their

of new drugs. Physicists and engineers

such facilities. The Swiss Light Source

function. SwissFEL represents a novel

work constantly to improve the meas­

SLS went into operation at PSI in 2001.

type of research facility – currently,

urement methods so that researchers

Here, at three measurement stations,

there are only four other facilities of its

can investigate ever more challenging

researchers can determine the struc-

kind worldwide.

At the large research facilities of PSI, scientists make structures of biomol­ ecules and biological tissues visible.

questions.

Proteins are highly complex biomolecules that are central for all of the processes in the human organism. For the development of modern drugs, it is often crucial to understand the structure of the proteins involved, yet these are only a few millionths of a millimetre in size and therefore too small to be observable with a light microscope. At present a strong source of X-ray light is usually required in order to decipher their structure. In the experiment, X-ray light shines through the proteins – that is, the light goes in at one place and comes back out again at another. Along the way, part of the light is diverted from its straight path. These diffractions are registered by a detector. From this information, with the help of sophisticated computer programs, the structure of the proteins can be determined. It is not possible to examine one individual biomolecule, though – what’s needed is a protein crystal in which many identical biomolecules are arranged in a regular three-dimensional pattern. The production of such crystals is an art in itself, which researchers in a special laboratory at PSI have perfected. 16

the end of 2016, the X-ray free-electron laser SwissFEL was inaugurated – here


Developments from PSI make new insights possible

The basic principle behind SwissFEL

tinuous beam of light, while SwissFEL

and SLS is similar: Both take advantage

emits short flashes of extremely in-

of the fact that fast electrons emit light

tense light.

when they are forced onto a curved

Among the 5,600 proteins whose struc-

To always keep up with the growing

path. In both facilities, a particle accel-

ture has been deciphered at SLS since

demands of the scientists, PSI contin-

erator first brings the electrons up to

it started operating are structures of

ually enhances the measurement

nearly the speed of light. In SLS, the

the visual pigment rhodopsin, which

equipment. So, for example, they work

accelerator is roughly circular and has

functions as a light sensor in our eyes.

to make the PSI-developed detectors

a circumference of 288 metres; in

Also the structure of the ribosome, a

that register the rays diffracted upon

SwissFEL, a linear accelerator around

large and very complex biomolecule,

penetrating protein crystals ever faster

300 metres long is used. A regular ar-

which in the cell is responsible for the

and more accurate.

rangement of many magnets then

assembly of other proteins, was re-

To be able to observe proteins in mo-

forces the electrons onto a slalom

solved in part with help from measure-

tion at SwissFEL, researchers at PSI

track, thus causing them to generate

ments at SLS. For this achievement, the

have refined the method of serial crys-

light. The characteristics of the light

Cambridge-based structural biologist

tallography and are leading partici-

depend on the details of the facility –

Venkatraman Ramakrishnan received

pants in the development of so-called

so SLS mostly generates a quasi-con-

the 2009 Nobel Prize in Chemistry.

time-resolved serial crystallography. Many small crystals of the same protein are X-rayed one after another with the

To ensure that the large research facilities can achieve their full potential, researchers develop and test ancillary devices that are employed at the separate experiment stations.

extremely short and intense light pulses of SwissFEL. Shortly before the measurement, the protein is activated with light at slightly different points in time. In each crystal, then, the protein is arranged in a different phase of the motion. When they are put together, the images generated in the process yield the desired “film�. In this way, an international team under the leadership of PSI researchers was able to produce a 3-D film in 2018 that revealed important insights into one of the fastest processes in biology. The researchers were able to show how different components of bacteriorhodopsin, a molecule activated by light, similarly to the human visual pigment, work together to make the process especially efficient. Since SwissFEL was not yet ready at the time of the experiment, the measurements were carried out at a comparable facility in the USA. Protein structures are not the only topic from the life sciences studied at the large research facilities at PSI. The composition and functionality of cellular components, biological tissues and whole organs, and of drugs as well, can be investigated at SLS or the Swiss Spallation Neutron Source SINQ. 17


The Swiss approach: high quality Physicist Oliver Bunk, head of the Lab­

methods are used at PSI to make bio­

processes of life. It is significant not

oratory for Macromolecules and Bio­

logical structures visible?

only for fundamental research, but also

imaging at the Paul Scherrer Institute,

Far more than one method. In the life

for the pharmaceutical industry. And

explains why so many researchers from

sciences, interesting phenomena occur

on a larger scale, it is possible here to

the life sciences prefer to come to PSI

on every level: That begins with atoms,

look at tissue samples, or to conduct

to conduct experiments.

which join together to form complex

experiments on living mice that con-

molecules, and extends to visible phe-

tribute to understanding and minimis-

nomena such as hand or mouth move-

ing the harmful effects of artificial res-

ments. One important method, on the

piration on premature babies.

Mr. Bunk, your area of expertise is

level of large molecules, is X-ray crys-

called “macromolecules and bioimag­

tallography. It yields the structures of

At SLS, you image molecules with in­

ing”. Could you please explain what

proteins, which take part in all of the

tense X-ray light. That requires re­

18


searchers from the life sciences – in­

son’s diseases. Here many of the re-

who can measure, and when, has to be

cluding for example biologists,

searchers don’t know anything about

regulated. We organise that through an

physicians, and pharmaceutical scien­

the possibilities of the X-ray method.

international committee. Two times per

tists – to collaborate closely with phys­

But the first pioneers are coming to us

year, academic users can submit pro-

icists and engineers. How is this coop­

– or also scientists whom we’ve made

posals. The have to describe, on two to

eration organised at PSI?

aware of the new methods.

three pages, what experiment they plan to do. The committee, which consists

In my team at SLS, we have a lot of physicists, because they’re good at

What special capabilities does PSI of­

of independent subject-matter experts,

building instruments. But for the appli-

fer its external users – for instance in

reviews and ranks the proposals. Then

cation, they then need to talk with

comparison to similar facilities world­

the best are granted beamtime at our

colleagues who are experts in the re-

wide? Why do researchers choose PSI?

facility.

spective fields about their research

At SLS we don’t offer all methods, but

questions and install special technical

what we do, we try to do very well – we

And what does it cost?

systems: Biological samples, for exam-

focus more on quality than quantity.

Academic users are not required to pay

ple, often need to be cooled to prevent

We’re not just good in instrument de-

anything. In return, they must publish

radiation damage. Or the samples have

velopment; we also provide good, col-

the results afterwards, so that they are

to be kept moist. Mutual exchanges

laborative user supervision. Often in

freely available to the scientific com-

across disciplinary boundaries are nec-

the Anglo-American regions, only tech-

munity. Industrial users who want to

essary to build the best experiments.

nical support is offered; the research

keep the results to themselves have to

Normally from our side there are mixed

is left to the users. By contrast we re-

pay. One hour of beamtime costs

teams of physicists and biologists on

cruit researchers for the User Office

around 1,000 Swiss francs. Large phar-

site at the so-called beamline. They are

who already have experience with the

maceutical companies book large al-

experts in the examination method,

facilities from their own experiments,

lotments of time with us at a somewhat

and they have built the experiment. As

who are now optimising these, and who

reduced rate.

part of PSI’s service for users, they work

would like to cooperate with the best

together closely with researchers who

researchers in the world for the ad-

Could you please explain, for example,

have requested beamtime to resolve

vancement of science. They are highly

how an experiment at SLS is typically

their own questions, whether they

self-motivated. One can’t help noticing

prepared, and how it then proceeds?

come from PSI or from outside. And

that very good scientific publications

From the idea to the publication, two

together they tackle the experiment.

come out of this – more than in com-

years can easily go by. When research-

parable facilities. High quality – that’s

ers have an idea for which some alter-

just the Swiss approach.

ation of the facility is anticipated, a

How would you characterise the re­ searchers who use SLS for experiments

preliminary discussion takes place on

in the life sciences? What fields do

Beamtime at the large research facili­

site. Otherwise they simply write their

these users come from? What kinds of

ties of PSI is limited, but in great de­

proposals and, in successful cases,

questions do they bring with them?

mand. How is it decided who, in the

receive an allotment of beamtime

Many have specialised in structural

end, will get to use the facilities?

within the next half-year – together

biology and come from academia –

We operate the beamlines 5,000 hours

with a contact on site who can be con-

from ETH Zurich and the EPF Lausanne,

per year, 220 days per year. When we

sulted by phone in the run-up to the

for example, but also half from univer-

are in operation, we work six days a

experiment. Then the experiment is

sities outside Switzerland – as well as

week, around the clock. Then once the

carried out – that can last between

from the pharmaceutical industry. For

experiments have started, they should

eight hours and an entire week, de-

these groups, X-ray crystallography is

not be interrupted; otherwise you

pending on the technique and how

an important part of their research, and

would have a lot of start-up time. And

demanding the experiment is. Then

they know a lot about the technology.

these are expensive machines that

comes the data analysis. Often addi-

But we also have exciting projects in

must be utilised as fully as possible.

tional measurements or laboratory

the area of neuroscience, for example

Nonetheless, we have considerably

studies are needed before the results

concerning Alzheimer’s and Parkin-

more demand than we can satisfy. So

can be published. 19


Diverse insights into the structures of life Determining the composition and func­

different points. From the results of

tion of protein molecules is the goal of

many individual measurements, a so-

most researchers who study the struc­

phisticated computer program deter-

tures of life at the large research facil­

mines the three-dimensional structure

ities of PSI. Yet the laboratories of PSI

of the tissue being examined. Besides

offer numerous other possibilities for

the special X-ray beam, the technical

investigations in the life sciences. With

requirements include for example a

X-ray light, for example, it is also pos­

mechanism for moving and positioning

sible to capture 3-D images of tissue

the sample with nanometre precision,

structures and make the processes in

a chamber in which the tissue can be

organs visible. Neutrons reveal the

deep-frozen before and during the

composition of thinner organic layers.

measurement, and the software that

That could someday help to ensure that

generates the 3-D images. The new

the body receives the correct dosage

platform, known by the acronym OMNY,

of drugs.

enables the examination of various types of tissue and thus can also be used, for example, for cancer research.

Doctors and medical researchers have

These methods have already shown

long wished for a method that would

their strengths in studies of bone struc-

give them three-dimensional images of

tures, which have yielded evidence for

tissue structures with an accuracy

research in osteoporosis, as well as in

down to a few nanometres. This could

investigations of brain samples that

be used to image, in samples of brain

enable new insights for the neuro-

tissue for example, clumps of proteins

sciences, in particular for Parkinson’s

such as are typical for Parkinson’s and

research.

other degenerative diseases. Here studies using modern microscopes yield information that is definitely im-

Dynamics of the alveoli

portant, yet the samples have to be prepared in a way that falsifies the

When children are born prematurely,

structures. To examine samples with a

their lungs are not yet mature. They

light microscope, for example, they

must then receive artificial respiration

must be dyed; only very thin slices of

in the incubation chamber. But it is not

tissue can be examined with an elec-

easy, for example, for neonatal medical

tron microscope.

staff to set the air pressure of the res-

In recent years scientists at PSI have

pirator correctly. With the pressure too

developed and perfected a method

low or too high, there is a risk of lasting

with which they can produce detailed

damage to the lungs. Therefore scien-

images of three-dimensional structures

tists are searching for methods that can

in a deep-frozen cube of tissue with an

simulate artificial respiration in animal

edge length of roughly one-tenth of a

experiments. They would like to be able

millimetre. In the process, X-rays from

to observe the tiny alveoli of laboratory

SLS illuminate the sample at many

mice live and in motion.

20


At one beamline of SLS that is special-

purpose is the Swiss Spallation Neu-

ised for generating detailed 3-D images

tron Source SINQ at PSI, which other-

of various materials, the first success-

wise mainly helps materials scientists

ful attempts to observe the alveoli have

inspect the atomic structure of materi-

now been made. While recording the

als. Food and nutrition researchers at

heartbeat with an EKG, the scientists

ETH Zurich have questions to clarify for

managed to consistently trigger each

which optical examination methods are

shot with a flash of X-ray light when the

inadequate. They want to know more

heart was in a relatively relaxed state,

about the characteristics of biopoly-

so that the image of the lungs would

mers that form a thin film on water –

not be blurry. The X-ray light has to act

only one to two molecular layers thick.

within just one to two milliseconds, or

How such films behave at different

else the image is fuzzy.

temperatures, at different degrees of

In the future, in vivo microscopy is ex-

acidity, and under the influence of di-

pected to help optimise artificial res-

gestive enzymes has already been in-

piration, but that’s not all. It should

vestigated at SINQ.

also clear up fundamental questions

Cellulose is one example of such a bi-

in lung physiology that have long been

opolymer. Researchers want to shape

waiting for answers. The same goes for

this roughage material in such a way

the question of what goes wrong on the

that drugs can be microencapsulated

level of the alveoli in diseases such as

in it, so that they only release their

asthma and pulmonary fibrosis. In this

active agent at body temperature. An-

work PSI’s cooperation partners are the

other goal is, by putting biopolymers

clinic for neonatology at Lausanne Uni-

into fatty foods, to ensure that they are

versity Hospital as well as institutes of

not digested in the stomach, but only

ETH Zurich and the University of Bern.

when they reach the small intestine. That way people would feel full more quickly and ingest less fat overall.

Biopolymers for the food industry

Insights into the cell

Not only X-rays but also neutron beams are employed at PSI for life science

In another project, PSI researchers are

experiments. The facility used for that

developing and building a novel apparatus that will make it possible for the first time to observe the structure of biological molecules in their natural

With an examination method developed at PSI, axons in a mouse’s brain – processes that guide signals from one cell to the next, shown here in blue – can be viewed in three dimensions.

setting – inside the living cell. This is a new kind of electron microscope that will employ electron beams to examine molecular structures.

21


Proton therapy - a success story First patient treatment more than 30 years ago

treatment of tumours that are located

cialised clinics, the Centre for Proton

In 1984, patients affected by an ocular

ample, as well as tumours in the areas

Therapy CPT at PSI has been offering

tumour began to receive treatment with

of the head, neck, pelvis, and spine.

this cancer therapy since 1984. More

protons at PSI. Today a good 200 pa-

Children in particular benefit from this

than 8,000 people, including more

tients with ocular tumours are still be-

form of proton therapy: Their organs

than 500 children, have been treated

ing treated at PSI annually. Since the

are very sensitive to radiation, and their

here since then. Alongside the treat­

end of the 1990s, the so-called

long life expectancy makes it important

ment of patients, an important focus

spot-scanning technique, which was

to minimise the risk of side-effects from

at CPT is on investigating and continu­

developed at PSI, has strongly ex-

the irradiation.

ally refining treatment methods.

panded the possibilities of proton ther-

In spot scanning – also called pencil

apy. This new method enables the exact

beam scanning – a highly focused pro-

Irradiation with protons is an especially conservative way to attack certain tu­ mours. In close collaboration with spe­

More than half of all cancers are curable today, and many patients owe their survival to radiation therapy. Besides the classical radiation therapy with X-rays or gamma rays, there is treatment with particle beams – often with beams of protons. They have the property that they hit the tumour very precisely and thus protect surrounding healthy tissue considerably better than other radiation therapies. For physical reasons, protons release their maximal energy very precisely at a predetermined point in the tissue. That in Switzerland proton therapy is based not at a hospital, but rather at PSI, is due to the long-standing experience here with generating beams of fast protons. Since 1974, a proton accelerator facility has been in operation at PSI that is used for experiments in physics and the materials sciences. It was also, in the beginning, the one that provided the beam for the treatment of patients. Since 2007, there is COMET, an accelerator especially optimised for cancer therapy, which was developed by a company together with PSI researchers. 22

deep within the body and difficult to reach, such as brain tumours, for ex-


ton beam, which at a thickness of five

method was available only at PSI. In

are not permitted to move during the

to seven millimetres is about as thin as

the meantime it has become the world-

irradiation. Adults are aided in this by

a pencil, scans the entire volume of the

wide standard in proton therapy.

an individual face mask, a dental night

tumour, point by point and layer by

Before proton treatment begins, the

guard, or a couch that fits the body

layer. Thus there is hardly any strain on

position and extent of the tumour must

exactly. Small children are given light

the tissue surrounding the tumour.

be precisely determined. Also, patients

anaesthesia, so that they lie quite still

Crucial for this is the technology for

for the duration of the irradiation.

steering the proton beam, which is housed in an installation weighing around 200 tons – the gantry. With millimetre precision, this colossal machine can be rotated around the patients. For more than a decade, this

Not only does PSI operate the only treatment centre for proton therapy in Switzerland, but PSI researchers have also done considerable work to advance the technology behind the method.

Patient treatment and research, hand in hand Alongside the treatment of patients, the researchers of CPT work to refine the method through a number of different projects. They are making proton therapy even safer and more efficient, and they take great care to make the treatment less stressful for patients. In addition, they are developing new technologies that should expand the range of applications for spot-scanning proton therapy. In the future, one new irradiation technique is expected to allow tumours in organs that are by nature always in motion – for example, the lungs with their airways – to be irradiated with protons. A great many experts work at CPT. Various teams concern themselves with service and maintenance for the highly specialised therapy facilities. Regular quality checks and inspections by the Federal Office of Public Health ensure its smooth and safe operation. The medical staff is not only specialised in the exacting treatment, but also in caring support for the patients. Close collaboration exists with special clinics throughout Switzerland – in patient care as well as in research.

23


From research to the business world – collaboration with industry and spin-offs

24


Before protein molecules can be examined at SLS, they have to be incorporated into crystals. Producing such crystals is an art that researchers in a special laboratory of PSI have perfected. 25


Hand in hand with industry

One technique that was developed for experiments at SLS is expected, in the future, to enable mammo­ graphy examinations that distinguish between diseased and healthy tissue better than the current method. 26


The fundamentals underlying most

users just send in their samples and,

oped and produced at PSI. The gap

new drugs or medical devices originate

at the end, receive a report with a de-

between two “lattice bars” is just a few

in publicly funded research institutions

tailed interpretation of the findings.

thousandths of a millimetre.

such as PSI. For example, pharmaceu­

In 2011, in collaboration with the Can-

tical companies investigate active in­

ton Hospital of Baden, researchers

gredients at SLS or use the under­ standing of life processes obtained at

Drugs from PSI research

succeeded in proving that the method is suitable for mammography, that is,

PSI for the development of new drugs.

Researchers at PSI investigate the mo-

X-ray examination of the female breast.

Other companies benefit from PSI in

lecular backgrounds of a range of dis-

Further clinical studies have shown that

that they utilise and build on technol­

eases and determine which specific

the new method promises a better way

ogy and know-how developed at PSI.

classes of substances could be used to

to discriminate between benign and

treat these diseases. With this funda-

malignant changes in the breast. To-

mental research, they establish the

gether with the electronics concern

basis for drug development, which can

Philips, the research group has now

then be pursued by the pharmaceutical

built an initial prototype for a mammog-

Someone being treated, for example,

companies. For example, a cooperation

raphy device suitable for application in

with a new drug for cancer may not

between PSI and Roche builds on PSI

hospitals and doctors’ practices.

realise that a large research centre such

research into hereditary degenerative

as PSI might have taken part in its de-

eye diseases. Within the framework of

velopment. And yet that’s the case:

this cooperation, the researchers have

Practically all large pharmaceutical

developed a method with which can-

firms in the world, and quite a few

didate agents for the treatment of these

smaller ones as well, use the Swiss

diseases can be identified. The goal is

The newest irradiation faciity, Gantry 3,

Light Source SLS to find new active

to develop drugs that slow down the

was built in a research collaboration

agents or to optimise known remedies.

progression of the disease and thus

with the firm Varian Medical Systems.

That’s because under the focused X-ray

help patients maintain their vision

The long-standing teamwork between

beam, their interaction with the body’s

longer.

the industry partners with their know-

Technical specialist for proton therapy

own proteins can be studied with pre-

how and PSI, with its expert knowledge

cision. This tight collaboration between

stemming from fundamental and ap-

PSI and the pharmaceutical industry

Better X-rays

will also continue at the X-ray laser

plied research for proton therapy, has been a major learning experience for

SwissFEL. Here it will be possible to

SLS has also inspired medical research

both partners.

follow the changes in the molecules

in the area of cancer prevention: PSI

In 1993 the firm Schaer Proton AG,

during such an interaction and thus

physicists discovered, shortly after the

based in Flaach in the canton of Zurich,

obtain further important information

turn of this century, how an exami­

worked with PSI to build the world’s

for the optimisation of the agent.

nation method that had previously

first treatment facility (Gantry 1) using

All industrial clients bear the costs for

been used only at the large research

the PSI-developed spot-scanning tech-

use of the facilities themselves. The

facility can also be carried over to

nique for proton therapy. For several

Swiss companies Roche and Novartis,

standard X-ray systems. This so-called

years, Schaer has been manufacturing

which have been present since 2002,

phase-contrast X-ray technique em-

almost exclusively systems and com-

even co-finance one of the three SLS

ploys properties of X-ray light that are

ponents for proton therapy and mar-

beamlines designed for protein stud-

disregarded in conventional X-ray ex-

keting these worldwide.

ies. In carrying out, evaluating, and

aminations. It makes it possible to

Thus the work of PSI benefits compa-

interpreting the measurement results,

clearly demarcate not only hard struc-

nies in Switzerland and people facing

pharmaceutical researchers from in-

tures such as bones, but also a variety

illnesses all over the world.

dustry are supported by PSI researchers

of soft tissues of the body. The X-ray

or by two specialised PSI spin-offs. This

beam must be guided through several

assistance extends so far that some

very fine lattices, which were devel27


Using innovations to found spin-offs Numerous discoveries that have been

company founders Martin Ostermaier,

actual medicinal agent. Thus the anti-

made at PSI in the field of life sciences

Luca Zenone and Aurélien Rizk as well

bodies can selectively transport the

have the potential to form the basis for

as the research head Maria Waldhoer,

agent to the diseased cell. With the

new drugs or medical technologies. In

InterAx has developed into a dynamic

antibody-drug conjugates produced by

some cases, the researchers responsi­

start-up that has aroused the interest

Araris, diseases such as cancer or in-

ble then decide to found a spin-off – a

of Swiss and international investors.

flammatory diseases and bacterial in-

company that further develops the re­

One of the first companies to have

fections can be fought more effectively

sults, translates them to practice, and

opened its offices in Park innovaare,

and with less side-effects in the future.

brings them to market. Other PSI spin-

the innovation park in the immediate

On his way to becoming a businessman,

offs relieve industrial users of substan­

vicinity of PSI, in 2015, is leadXpro. The

Araris founder Philip Spycher was sup-

tial amounts of the work involved in

leadXpro team develops new, cus-

ported by a PSI Founder Fellowship. This

carrying out their experiments at the

tom-designed agents for drugs that are

new funding instrument provides an

large research facilities of PSI. PSI ac­

expected to significantly improve ther-

18-month grant that supports young

tively promotes the founding of spin-off

apy for diseases such as, for example,

researchers and engineers of PSI on the

companies by its researchers.

cancer and infectious diseases. In do-

career path to entrepreneurship, not

ing so, leadXpro especially brings in its

only financially but also through coach-

staff members’ long years of experience

ing and consultation. Within this period

in two areas: the investigation of

the grantees must demonstrate the com-

Developing and testing drugs

G protein-coupled receptors, ion chan-

mercialisation potential of their busi-

The firm InterAx combines experimen-

nels, and so-called transporters; and

ness ideas and prepare an initial busi-

tal and computer-aided pharmacology

the use of the large research facilities

ness plan.

to support biotech and pharmaceutical

of PSI, such as the Swiss Light Source

companies in the development and

SLS and the X-ray free-electron laser

selection of substances that could be

SwissFEL. Currently leadXpro is work-

used as new drugs in the future. The

ing on joint projects with six industrial

technologies used rest on the founda-

partners from Europe and the USA and

In July 2017, the start-up GratXray was

tion of research results obtained by

in addition is developing its own agent

founded. Its goal: Develop, manufac-

Martin Ostermaier and Aurélien Rizk

pipeline.

ture, and commercialise devices that

Better X-rays

– two of the company’s founders – in

offer – thanks to phase-contrast tech-

the course of their work at PSI.

nology (see pages 26-27) – a method

Promoted by the PSI Founder Fellowship

for diagnosing breast cancer that is

target molecule proceeds over time.

Araris is among the latest spin-offs from

technique used today. In the same year

With the help of the experimental find-

PSI. It concentrates on establishing a

it was founded, the firm was honoured

ings, they can simulate the effect of the

novel manufacturing method that ena-

with the Swiss Technology Award.

agent with the help of specially devel-

bles the optimisation, development,

oped computer programs. These sim-

and production of high-potency medi-

ulations provide insights that are im-

cines: in particular, so-called anti-

portant for the development of the

body-drug conjugates. These consist of

agent but which cannot be obtained

an antibody – a complex biomolecule

using present-day experimental meth-

that docks on a particular target mole-

Two PSI spin-off companies – Expose

ods. Under the leadership of the three

cule with extreme selectivity – and the

and Excelsus Structural Solutions –

The researchers of InterAx first investigate experimentally how the interaction of a potential drug molecule with the

28

more both precise and less stressful for the patient than the mammography

Supporting users from industry


Numerous pharmaceutical companies investigate drugs or protein structures at SLS. Two specialised PSI spin-offs support them in these studies – they conduct the experiment and if required deliver a detailed report with the findings.

have taken on the job of supporting

out needing to send their own staff

the arrangement of active ingredient

researchers from industry in their stud-

members to Switzerland. If required,

molecules in drugs. That is important

ies at SLS.

the researchers at Expose also evaluate

because an undesirable arrangement

Expose, which was founded in 2008 by

the measurement results and provide

can have dangerous consequences and

PSI researcher Joachim Diez, assists

the customer with complete informa-

must be avoided at all costs. It can lead

industrial researchers who want to con-

tion about the structure of the molecule

to a faster than expected release of the

duct studies to elucidate protein struc-

under investigation. Expose employs

drug, in which case the patient can

tures. The scientists from Expose take

four people and is currently collabo­

rapidly receive a dose that is much too

over all tasks involved in the measure-

rating with 19 industrial partners at

high. Excelsus staff members act as

ment. For Swiss pharmaceutical com-

27 locations in Europe, North America,

scientific partners of the colleagues

panies, this means that they can get

and Asia.

from the pharmaceutical companies:

the measurement results they need in

Excelsus, which was founded by PSI

They carry out the measurements at

the shortest amount of time and thus

researcher Fabia Gozzo in 2012, offers

SLS, evaluate the results, and often

more rapidly advance the development

pharmaceutical companies studies at

suggest solutions for their research

of new drugs. Companies from more

SLS using the powder diffractometry

questions. Excelsus employs five peo-

distant regions, on the other hand, can

method. This method makes it possi-

ple. In May 2016, the company opened

have their samples studied at SLS with-

ble, among other things, to determine

offices in Park innovaare. 29


Aerial view of the Paul Scherrer Institute PSI. The circular building in the background is the Swiss Light Source SLS, on the west bank of the River Aare. The construction of the SwissFEL X-ray free-electron laser is located in the forest across the river, on the left of the picture.

30


PSI in brief The Paul Scherrer Institute PSI is a research institute for natural and engineering sciences, conducting cutting-edge research in the fields of matter and materials, energy and the environment and human health. By performing fundamental and applied research, we work on sustainable solutions for major challenges facing society, science and economy. PSI develops, constructs and operates complex large research facilities. Every year more than 2500 guest scientists from Switzerland and around the world come to us. Just like PSI’s own researchers, they use our unique facilities to carry out experiments that are not possible anywhere else. PSI is committed to the training of future generations. Therefore about one quarter of our staff are post-docs, post-graduates or apprentices. Altogether PSI employs 2100 people, thus being the largest research institute in Switzerland.

Imprint Concept/Text Judith Rauch/Dr. Paul Piwnicki Editing committee Dr. Paul Piwnicki, Christian Heid Photography and Graphics All Photos Scanderbeg Sauer Photography except: page 9: Dr. Ching-Ju Tsai page 18: Kellenberger Kaminski Photographie page 20: Dr. Sarah Shahmoradian page 30: Markus Fischer Design and Layout Monika Blétry Printing Paul Scherrer Institut Available from Paul Scherrer Institut Events and Marketing Forschungsstrasse 111 5232 Villigen PSI, Schweiz Tel. +41 56 310 21 11 Villigen PSI, February 2019

Contacts Head of Research Division Biology and Chemistry Prof. Dr. Gebhard Schertler Tel. +41 56 310 42 65 gebhard.schertler@psi.ch Head of the Macromolecules and Bioimaging Laboratory Dr. Oliver Bunk Tel. +41 56 310 30 77 oliver.bunk@psi.ch Head of the Centre for Proton Therapy Prof. Dr. Damien C. Weber Tel. +41 56 310 58 28 damien.weber@psi.ch Head of the Centre for Radiopharmaceutical Sciences Prof. Dr. Roger Schibli Tel: +41 56 310 28 37 roger.schibli@psi.ch

Contact for industrial companies that would like to conduct investigations at the large research facilities: CEO SLS Techno Trans AG Stefan Müller Tel. +41 56 310 54 27 stefan.mueller@psi.ch Head Corporate Communications Dagmar Baroke Tel. +41 56 310 29 16 dagmar.baroke@psi.ch


Paul Scherrer Institut  ::  5232 Villigen PSI  ::  Switzerland  ::  Tel. +41 56 310 21 11  ::  www.psi.ch

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