Phage Therapy in the Year 2035

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HYPOTHESIS AND THEORY

published: 03 June 2020

doi: 10.3389/fmicb.2020.01171

Edited by:

Andrzej Gorski,

Polish Academy of Sciences, Poland

Reviewed by:

Stephen Tobias Abedon,

The Ohio State University,

United States

Ronen Nissan Hazan,

The Hebrew University of Jerusalem,

Israel

*Correspondence:

Jean-Paul Pirnay

[email protected]

Specialty section:

This article was submitted to

Antimicrobials, Resistance

and Chemotherapy,

a section of the journal

Frontiers in Microbiology

Received: 27 February 2020

Accepted: 07 May 2020

Published: 03 June 2020

Citation:

Pirnay J-P (2020) Phage Therapy

in the Year 2035.

Front. Microbiol. 11:1171.

doi: 10.3389/fmicb.2020.01171

Phage Therapy in the Year 2035

Jean-Paul Pirnay

Laboratory for Molecular and Cellular Technology, Queen Astrid Military Hospital, Brussels, Belgium

The emergence of multidrug resistant bacteria in both community- and hospital-

acquired infections is recognized as a major public health threat. Phage therapy is

increasingly mediatized and researched as an additional tool for combatting antibiotic

resistant infections. However, phages exhibit a number of properties that differ from

antibiotics and hamper their development as pharmaceutical products and their

application in therapy. This paper advocates a paradigm shift in the development and

application of infectious disease therapeutics to cater for personalized phage therapy,

which could be realized by the year 2035. More speciﬁcally, it presents a sustainable

and ethical supply chain of instant synthetic phages, based on a community effort,

supported and steered by public health organizations, and managed by a platform

combining Artiﬁcial Intelligence (AI) and Distributed Ledger (DL) Technology.

Keywords: infectious diseases, antibiotic resistance, antimicrobial resistance, phage therapy, synthetic biology,

artiﬁcial intelligence, machine learning, distributed ledger technology

PREFACE

This paper oﬀers a personal vision of what might be needed for phage therapy to ﬁnally break

through as a mainstream antibacterial tool. It is inﬂuenced by historical and recent failures and

uncertainties in the phage therapy ﬁeld and aims at ﬁnding solutions based on future and emerging

technologies that are supposed to model the science and society of tomorrow.

PHAGE THERAPY

Bacteriophages (phages) are the viruses of bacteria. Since time immemorial they have controlled

the growth and spread of their bacterial hosts. Bacterial viruses are the most ubiquitous lifelike

entities in our biosphere. There are an estimated 10 million-fold more viruses in the oceans than

there are stars in the universe and if all the phages on Earth were stacked on top of another, this

tower would stretch further than the nearest 60 galaxies (Suttle, 2013). They can easily be found

wherever bacteria thrive: in sewers, rivers, or patients’ urine and stool. Phages of human bacterial

pathogens are most often composed of an icosahedral head, a sphere with 20 ﬂat faces made of

proteins and containing a nucleic acid genome, to which a protein tail is attached. When a strictly

lytic phage adheres with its tail ﬁbers and spikes to the surface of its target bacterium, the syringe-

like tail sheath contracts and the tail core is driven through the bacterial cell wall, injecting the

phage genome into the periplasm of the bacterial cell. Immediately, the bacterial DNA and protein

synthesis machinery is hijacked to build copies of the phage. Some phages cut the bacterial DNA

into pieces. After a latent period of minutes to hours, the newly formed phages burst out of their

bacterial hosts, which are killed in the process. The phage progeny, which can run into the hundreds

per bacterium, then go oﬀ to ﬁnd new host bacteria to infect. As such, phages can be considered

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as self-replicating antimicrobials. Importantly, phages have

evolved to only infect certain target bacteria and are harmless to

mammalian cells.

Early evidence of viral-like agents with antibacterial activity

was reported by the English bacteriologist Frederick Twort,

and by the French-Canadian microbiologist Felix d’Hérelle

in 1915 and 1917, respectively (Sulakvelidze et al., 2001). In

1919, d’Hérelle exploited for the ﬁrst time the therapeutic

potential of phages when he used them to cure a boy suﬀering

from dysentery in Paris. Phage therapy was immediately

recognized as a therapeutic approach to treat bacterial infections

and commercialization of phage therapy preparations was

undertaken by several companies, such as L’Oréal in Europe and

Eli Lilly Company in the United States (Sulakvelidze et al., 2001).

In 1923, the Georgian microbiologist Giorgi Eliava founded the

Eliava Institute in Tbilisi, Georgia, devoted to phage therapy

research. It was the start of extensive phage therapy research

and development in the former Soviet-Union. However, early

uses of phage therapy were often unreliable and research into

antibiotics had also been ongoing. The successful use of penicillin

during the Second World War and its subsequent worldwide

marketing led Western scientists to lose interest in phage

therapy. Soviet researchers, in contrast, continued to develop

phage therapy and to publish their results, but due to the

Iron Curtain their knowledge and experience did not spread

across the world (Sulakvelidze et al., 2001). At the dawn of the

third millennium, the increasing health burden of infections

with antibiotic resistant bacteria (Cassini et al., 2019) incited

a renewed worldwide interest in phage therapy as a viable

additional tool to the clinical management of bacterial infections

(Thiel, 2004). All over the world, phage therapy centers are being

set up, following in the footsteps of the Eliava Institute and the

phage therapy unit at the Hirszfeld Institute in Wrocław, Poland

(Miêdzybrodzki et al., 2012).

THE YEAR 2035

Fast forward to future Earth of 2035, a gloomy world

characterized by human overpopulation, major ecosystem

disruptions, global warming, and xenophobia.

While soaking in his bath, Dr. John Iverian, a retired

microbiologist, suddenly felt an extremely painful sting in the

back of his neck, followed by a sound like a small plane’s

propeller. He screened the environment and in the corner of

his eye he saw a weird large insect with long creepy legs and

antennas sitting on the wall next to his designer bathtub. Osuri,

the home management system of Iverian’s loft in the center of

Antwerp, identiﬁed the insect as the brown marmorated stink

bug Halyomorpha halys, which had spread across the world.

Osuri’s report, projected on one of the bathroom’s video screens,

mentioned that people, who were bitten, initially experienced a

small red sore in the bite area of their skin. When left unattended,

the bite wound would swell and produce puss. Tired and muzzy,

non-chalant Iverian stepped out of his bath and went to bed.

He had decided not to perform the elaborate wound treatment

procedure, which had strongly been advised by Osuri. Early next

morning, however, the bite had turned into a necrotic wound

showing clear signs of infection.

Anxiously, Iverian activated his Phage-BEAM device. BEAM

stood for “Bedside Energized Anti-Microbial.” The device had the

size and shape of a shoebox, but with a more elegant and polished

look. The name of the device and its manufacturer were designed

in colorful letters on the side of the seamless white enameled

box. Iverian removed a swab from its sterile packaging and gently

passed it over the entire area of the wound, making sure that

the wound exudate thoroughly wetted the cotton wool tip of the

swab. When the swab approached the “insert sample” area of the

box, a tiny door opened as if magically, freeing a 10-inch high

hologram of a lab technician, named Marcia. She showed Iverian

where to dock the sample. Marcia was developed to guide the

clients through the test procedure. “For best results, please insert

a new phage bio-ink cartridge, Dr. Iverian,” Marcia said. Just as

it used to be for yesteryear’s 2D printers, the cost of the bio-ink

cartridges was almost as high as the cost of the Phage-BEAM

device itself. According to “Business Insider,” phage bio-ink was

the second most expensive liquid on Earth, behind Chanel No.

8. Luckily, as one of the inventors, Iverian had obtained the

right to always have the most recent version of this device at his

disposition, including a continuous supply of reagents, for free.

Iverian knew perfectly how the device worked, so he did not

need Marcia’s help. First, DNA was extracted from the swab tip

and the metagenome—all the genetic material present in the

sample, including the infecting bacteria—was determined. Next,

these genetic data were sent to a secured “Phage XChange” server

where a complex AI-driven algorithm predicted the genome

sequence of the phage that was most likely to lyze the infecting

bacteria identiﬁed in the metagenome and was supposed to elicit

the weakest immune reaction in the patient. The phage genome

data were sent to the Phage-BEAM device, which ﬁrst synthesized

the phage genome and then the phage, using a proprietary

bacterium-free phage production system.

Within 1 h after sampling, the device would produce a ready-

to-use therapeutic phage product. Results of the step-by-step

procedure would be transmitted to the enormous home video

screen in Iverian’s living room. Sitting in his LC2 armchair,

listening to Mozart’s Great Mass in C minor, Iverian anxiously

waited for the results to come in. He had a bad feeling about

this. The result sent shivers down Iverian’s spine. Bacterial

pathogen identiﬁed: Streptococcus pyogenes strain FE-2033! Osuri

immediately activated the infection alert protocol, sending a

message to the World Center for Disease Control and projected

worrisome background information on the lethal ﬂesh eating

bacterial strain, which was considered an imminent threat to

public health since 2033. For a moment, Iverian considered

excising the infected wound and some surrounding healthy tissue

with a kitchen knife, but he calmed down and decided to wait

and apply the imminent Phage-BEAM product. An hour later,

the Phage-BEAM device had produced synthetic phages. These

phages were then mixed with the isolated bacteria, in a validation

module, to test their in vitro eﬃcacy. Fifteen minutes later, the

green light was given for Iverian to commence treatment. Iverian

applied the phages in a slow release hydrogel-based wound

dressing, which had ﬁrst been mixed with the concentrated

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phage suspension produced by the Phage-BEAM device, and

also contained synergistic antibiotics. The hydrogel temporarily

relieved the pain, which further calmed him. Iverian repeated

application of the phage and antibiotic-loaded hydrogel once a

day. Wound infection improved within 24 h and after 7 days the

wound was almost completely healed. Iverian’s potentially life-

threatening infection was successfully treated, timely and without

leaving his home. But, for many previous decades, it had not

been certain that phage therapy would break through to become

a broadly applied and clinically useful antibacterial tool. The

medical world had taken a while to realize that phage therapy

did not need to be identical to antibiotic therapy, and this mainly

because of the peculiarities of the active agents, the phages.

SOME RELEVANT PECULIARITIES OF

PHAGES

Phages exhibit a number of properties that diﬀer from antibiotics

and hampered their development as pharmaceutical products

and application in therapy. First, they tend to be speciﬁc

about which bacteria they infect. They will at best target a

considerable part of one single bacterial species, but at worst

they will infect only a small number of strains within one

species. Therapeutic phages can thus be selected to mainly kill

one bacterial species, or a clinically relevant subgroup thereof,

and spare the patient’s beneﬁcial bacteria (e.g., the gut, skin, or

oral commensal ﬂora). Most routinely employed antibiotics, in

contrast, have a broad spectrum of activity, which can cause

“collateral damage” to the patient’s commensal microbiomes,

which in turn can result in adverse eﬀects such as the selection

of antibiotic resistant bacterial species (e.g., Clostridium diﬃcile)

or antibiotic-associated diarrhea (Jernberg et al., 2010). The

drawback of phage speciﬁcity is that the infecting bacteria need to

be identiﬁed before starting phage therapy. In empirical antibiotic

therapy, in contrast, broad-spectrum antibiotic cocktails that

aﬀect a multitude of Gram-positive and Gram-negative bacteria,

and diverse fungi are typically used. When more information is

known (e.g., from bacterial culture), treatment may consist of

narrow-spectrum antibiotics, which more speciﬁcally target the

bacteria or fungi identiﬁed to be causing disease.

Second, bacteria and phages are involved in a host–

parasite relationship. Strictly lytic phages are ubiquitous in the

environment and require the death of their bacterial host to

complete their life cycle. Without hosts, phages cannot exist.

Phages impose selection for resistant hosts, which in turn

impose selection for eﬀective phages. This results in what is

called “antagonistic coevolution,” an arms race between bacteria

and phages, characterized by reciprocal evolution of bacterial

resistance and phage infectivity (Buckling and Rainey, 2002).

Just as with most antimicrobials, bacteria will thus also become

resistant to phages (Luria and Delbrück, 1943; Schooley et al.,

2017), but, in contrast to static antibiotics, phages have the

capacity to overcome bacterial resistance (Buckling and Rainey,

2002). There are nevertheless indications that bacteria and phages

will not indeﬁnitely increase their respective resistance and

infectivity (Fortuna et al., 2019).

PHAGE THERAPY APPROACHES

At the time of the phage therapy revival in the early 2000s,

two distinct phage therapy approaches had been developed

(Pirnay et al., 2011). In what could be called the one-size-ﬁts-all

approach, deﬁned broad-spectrum phage cocktails, which were

supposed to target the majority of bacteria suspected to cause

certain infectious diseases, were applied. These predeﬁned broad-

spectrum phage cocktails were developed, produced, and tested

within the current pharmaco-economic models, which had been

designed to cater for “static” drugs such as antibiotics. However,

truly broad-spectrum phage cocktails, active against most Gram-

positive and/or Gram-negative bacteria commonly encountered

in infectious diseases needed to contain large amounts of phages

and turned out to be very diﬃcult to develop. It was feasible

to develop narrower spectrum phage cocktails, active against

one or a few bacterial species, to be used in certain indications

and minding that the infecting bacterial species were known

in advance. For some bacterial species, such as Staphylococcus

aureus, phages showing an exceptionally broad host range had

been isolated and characterized (Vandersteegen et al., 2011). In

PhagoBurn, a randomized controlled trial, success in achieving

sustained reduction in Pseudomonas aeruginosa burdens in burn

wounds was linked to initial susceptibility to the phage cocktail

(Jault et al., 2019). However, one-third of the included patients

were shown to harbor pre-existing P. aeruginosa strains resistant

to the phage cocktail, which consisted of no less than 12

lytic P. aeruginosa phages. In addition, phage cocktails that

were initially designed to be eﬀective needed to be regularly

updated (e.g., supplemented with new phages) in response

to the emergence of phage resistance or the involvement of

newly circulating clinically relevant strains. Finally, it was not

known if confronting bacteria with high concentrations of

ﬁxed phage cocktails would cause the emergence, spread and

persistence of bacterial phage resistance in hospitals and in the

environment, similar to what had happened upon the massive

use of antibiotics.

In personalized phage therapy concepts, one or more phages

were selected from a phage bank, or from the environment,

and possibly adapted (in vitro selection of phage mutants

exhibiting increased infectivity) to more eﬃciently infect the

bacteria isolated from the patient’s infection site (Friman et al.,

2016). Some phage therapy centers set up and maintained large

therapeutic phage banks, which were regularly updated with

new phages, widening and adapting the host range of the bank

to the ever-changing bacterial populations. Personalized phage

therapy approaches were potentially more sustainable, as only

the infecting bacterium is targeted, resulting in less selection

pressure toward bacterial phage resistance. However, they were

also more elaborate and logistically complex than one-size-ﬁts-

all approaches, with bacterial strains and matching phages being

sent all over the world (Figure 1). Moreover, precision medicine

concepts were, in general, not compatible with most medicinal

product (drugs in the United States) development and licensing

pathways, which required several years and millions of euros

(dollars) to complete, and this for every phage in the bank

(Verbeken et al., 2012).

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FIGURE 1 | International transfers of phages from (red arrows) and to (blue arrows) the Queen Astrid Military Hospital (QAMH) in Brussels in view of clinical

applications over the period 2015–2020. On the national level, phages were dispatched from the QAMH to ﬁve university hospitals (not shown). In addition, the

selection of matching phages often encompassed the transfer of the patients’ bacterial isolates, and ﬁve international patients (two from France, two from the

Netherlands, and one from Tunisia) were transferred to Brussels for phage therapy.

ENTER SYNTHETIC BIOLOGY

With the onset of the third millennium, synthetic biology

approaches had been increasingly developed to reduce the

speciﬁcity of phages and the emergence of bacterial phage

resistance (e.g., structure-guided design) (Pires et al., 2016;

Dunne et al., 2019). For instance, yeast-based platforms for phage

tail ﬁber protein switching were elaborated to engineer hybrid

phages with more predictable and extended host range (Ando

et al., 2015; Yosef et al., 2017) and genetic engineering strategies

(e.g., CRISPR-Cas editing tools) were developed to address other

aspects such as negative patient-phage interactions (e.g., anti-

phage immune response) (Brown et al., 2017), the potential

emergence and spread of bacterial phage resistance mechanisms,

and the release of harmful bacterial contents such as endotoxins

(Hwang et al., 2018). Synthetic phage genomes needed to be

rebooted to produce phage oﬀspring (Barbu et al., 2016; Pires

et al., 2016), through transformation of Escherichia coli or Listeria

monocytogenes L-forms (Kilcher et al., 2018), or using cell-free

transcription-translation (TXTL) systems (Rustad et al., 2018).

Western regulatory frameworks had gradually started to cater

for precision and personalized phage therapy approaches using

naturally occurring phages (Pirnay et al., 2018), engineered

phages (Dedrick et al., 2019), and synthetic phages.

The development of ad hoc and on-site therapeutic phage

production devices, such as Phage-BEAM, did not run smoothly,

Iverian recalled. To start with, it required artiﬁcial intelligence

(AI)-based in silico phage matching and design. Deep learning

(Martorell-Marugán et al., 2019), a subset of Machine Learning,

was chosen to search for links between bacterial genomes and

infecting phage genomes, because it was easier to scale to bigger

number of samples. For instance, deep learning methods did

not require so-called feature extraction, which would require

gene/protein level annotation of phage and bacterial genomes

and would limit predictions to certain known relationships

between bacterial and phage features, such as phage tail ﬁber

structures binding to speciﬁc bacterial cell wall receptors. As a

down side, it needed to be powered by a continuous supply of

massive amounts of data, linking lytic phage genomes to host

bacterial genomes, and that’s where the shoe pinched. Whole

genome sequencing had slowly percolated into the practice

of clinical microbiology (American Academy of Microbiology,

2016), but research institutes and pharmaceutical companies

were not keen to submit their data to a single centralized

database, and no investors were found willing and able to

acquire the available data and/or to produce suﬃcient amounts

of new data. A second obstacle that had to be overcome was

the unavailability of quick, reliable, and aﬀordable synthesis of

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large DNA molecules. Initial DNA synthesis techniques were

based on organic chemistry and produced relatively small DNA

molecules. The de novo synthesis of phage genomes required

assembling several genome fragments (Barbu et al., 2016; Pires

et al., 2016; Lemire et al., 2018) in the yeast Saccharomyces

cerevisiae, using yeast artiﬁcial chromosomes (Ando et al., 2015),

or chemical assembly (Gibson et al., 2009). The development

of a new technique to synthesize DNA, based on DNA-

synthesizing enzymes found in cells of the immune system

(Palluk et al., 2018), facilitated phage genome synthesis. Finally,

some hurdles had to be overcome to develop generic cell-free

phage production systems able to produce phages in high titers

and exhibiting the same levels of bacterial infectivity as their

natural analogs.

THE BREAKTHROUGH

The major problem was that it turned out to be very diﬃcult

to collect the massive amounts of linked phage and bacterial

genome sequences necessary for the deep learning AI algorithms

to predict and/or design phage sequences with a therapeutically

acceptable level of accuracy. Iverian remembered that the real

breakthrough came when the not-for-proﬁt organization “Phage

FIGURE 2 | Vision of how the phage supply chain might be organized in 2035. AI, artiﬁcial intelligence; ATGC, DNA sequence; BEAM, bedside energized

anti-microbial; DL, distributed ledger; IoT, Internet of Things; P, PhageCoin; WHO, World Health Organization.

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XChange” launched its global phage governance platform of the

same name to create an eﬃcient, standardized, sustainable, and

ethical phage supply chain (Figure 2). Phage XChange mainly

consisted of an AI module and a Distributed Ledger (DL)

(Thiebes et al., 2020). The platform’s AI module analyzed linked

phage and bacterial genomes to predict and design potent phages

for clients. It also predicted which bacterial pathogens needed the

most urgent attention, based on the Internet of Things (IoT) and

Big Data and information provided by international public health

organizations, such as the World Health Organization (WHO)

and national Centers for Disease Control. These data steered

the system toward the isolation and characterization of the most

urgently needed phages.

The platform’s DL module ensured a suﬃcient, qualitative,

and recorded input of linked phage/bacterial genome sequences

to the AI module and ditto supply of phage sequences to

clients, in compliance with the provisions of the Nagoya protocol

(Expert round table on acceptance and re-implementation of

bacteriophage therapy et al., 2018). The DL immutably recorded

all stakeholder (e.g., suppliers of data, sequencing services, and

clients), transaction, and contract details. It also recorded the

exact quality, speciﬁcations, and weight of the supplied material.

An algorithm determined the non-redundancy and estimated

the weight (e.g., the virulence and host range of the phages)

and desirability of the submitted material. Phages targeting

emerging bacterial pathogens were of course most wanted.

Most patent issues were obviated. The DL acted as a payment

ledger to assure that all parties were paid timely and fairly.

A number of PhageCoins (the platform’s crypto currency) were

attributed to the suppliers in relation to the quality, weight, and

desirability of the supplied material. Clients extracting prediction

results (phage sequences) through the DL paid an amount of

PhageCoins, proportionate to the estimated value of the phages.

These PhageCoins were used to maintain the DL, to assure a

suﬃcient and continuous inﬂow of material, and to expand phage

virulence and host range data (matching phages to bacteria). An

additional injection of funds and incentive to supply material

was found in producers and suppliers of all kinds of goods.

With the instantly earned PhageCoins, phage suppliers could

buy online all kinds of products at strongly reduced prices,

from laboratory- and school equipment to sports items. These

goods were provided through corporate sponsorship. Several

established companies sponsored PhageXchange in exchange of

tax reductions, publicity, and the image of a socially responsible

brand. The weight of the supplied material, and thus also

its value, were initially undervalued, but were re-evaluated at

regular intervals (iteration) and suppliers were attributed more

PhageCoins when warranted. Even though useful from the

moment it was introduced, the platform only became really

successful when it was put under the protection of the WHO,

in analogy to the worldwide system of traceability, transparency,

vigilance, and surveillance of Medicinal Products of Human

Origin (Warwick et al., 2013). A formal agreement between Phage

XChange and the WHO increased international conﬁdence in

the long-term sustainability of the platform and protection

from unethical commercial exploitation. The search for potent

therapeutic phages soon became a community eﬀort aimed

at solving the antibiotic resistance crisis, with independent

“phage hunters,” schools, scout groups, villages on the banks

of the Amazon River, etc., isolating and submitting phages to

Phage XChange, in exchange of PhageCoins. At the margins of

this, various companies and institutions developed peripheral

equipment and services, such as phage isolation kits and

sequencing and phage synthesizing platforms (e.g., the Phage-

BEAM device). In anticipation of these devices, intermediary

solutions were oﬀered, whereby the phages themselves were

obtained through the DL.

EPILOG

This view on the future of phage therapy provides an optimistic

ending to the antibiotic resistance crisis. The ad hoc and

on site production of synthetic phages, linked to a global,

community-based, phage management system, turned out to

be a welcome and aﬀordable (for social security systems)

extra weapon in the ﬁght against antibiotic resistant bacterial

infections. However, it was not a magic bullet; it was a synergistic

supplement to established antimicrobials. The instant and cell-

free production of synthetic phages, whether designed or not, had

considerable advantages over classically produced (in bacterial

hosts) natural phages:

(i) There was no need to maintain physical therapeutic phage

banks and to dispatch the patient’s bacterial isolates and the

matching therapeutic phages all over the world.

(ii) Synthetic phages against bacteria causing eminent public

health threats, such as the 2011 E. coli O104:H4 outbreak in

Germany (Merabishvili et al., 2012), or bacteria (suspected

to be) used for bioterrorism (Joñczyk-Matysiak et al., 2014)

could be timely produced on site.

(iii) Phages against bacteria causing potentially lethal diseases,

for which no non-lethal production host strains were

available and whose propagation used to require biosafety

level-3 (bsl-3) bio-containment precautions, could be

synthesized in bsl-1 conditions.

(iv) When no phages could be isolated from sampling sites,

for instance, because the bacterial host strains used in the

isolation techniques were not susceptible to the desired

phages, (predicted) phage genomic sequences, extracted

from metagenomic data (Reyes et al., 2010; Amgarten et al.,

2018), could be used to produce synthetic phages.

(v) Synthetic phage preparations contained no (or smaller

amounts of) molecules that could have a negative impact

on patients (e.g., endotoxins).

(vi) Devices were adapted to produce synthetic phages

during extended space travel and space colonization

(Taylor and Sommer, 2005).

There is little chance that these predictions will come true.

It is probably too shortsighted to think that a community-based

eﬀort, supported by public health organizations and managed by

a global, sustainable and ethical platform, could be at the heart

of a solution to the current worldwide antibiotic resistance crisis.

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Some parts of the proposed system, such as cell free production

of synthetic phages using a bedside device, have a reasonable

chance of being realized, while other elements, such as

corporate sponsorship, will likely remain limited to the

realm of science ﬁction. You may say that I’m a dreamer,

so feel free to wake me up in 2035 to confront me

with reality!

AUTHOR CONTRIBUTIONS

J-PP conceived the vision and drafted the manuscript.

FUNDING

Publication costs were covered by “Société Scientiﬁque du

Service Médical Militaire – Wetenschappelijke Vereniging van de

Militaire Medische Dienst”.

ACKNOWLEDGMENTS

The personal vision, or dream, developed in this manuscript

came about as a result of interactions with many fellow

researchers over the past 15 years. It is impossible to name

them all, but it would not be fair to take all the credits alone.

Therefore, I decided to acknowledge some of them here (in

alphabetical order), with the risk—or better, the certainty—

of forgetting some important inﬂuencers: Joana Azeredo, Nata

Bakuradze, Bob Blasdel, Dimitri Boeckaerts, Angus Buckling,

Yves Briers, Pieter-Jan Ceyssens, Nina Chanishvili, Laurent

Debarbieux, Sarah Djebara, Dorien Dams, Daniel De Vos,

Quirin Emslander, Alan Fauconnier, Ville Friman, Andrzej

Górski, Téa Glonti, Nino Grdzelishvili, Serge Jennes, Elene

Kakabadze, Betty Kutter, Rob Lavigne, Cédric Lood, Alice

Maestri, Khatuna Makalatia, Maya Merabishvili, Tobi Nagel,

Thomas Rose, Patrick Soentjens, Michiel Stock, Rüdiger Trojok,

An Van den Bossche, Mario Vaneechoutte, Gilbert Verbeken,

and Kilian Vogele.

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Conﬂict of Interest: The author declares that the research was conducted in the

absence of any commercial or ﬁnancial relationships that could be construed as a

potential conﬂict of interest.

The handling editor declared past co-authorship with the author.

of the Creative Commons Attribution License (CC BY). The use, distribution or

reproduction in other forums is permitted, provided the original author(s) and the

is cited, in accordance with accepted academic practice. No use, distribution or

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