Interview with Science Minds

Recently I was interviewed by Vinoy Vijayan for his excellent Science Minds podcast. 

You can download the interview here, if you are interested in a discussion on science careers, different pathways to take in science, mentorship and diversity in science.

Diabetes: the fragile beta cell model

In the current issue of Trends in Molecular Medicine, we put forward the evidence for and against the beta cell fragility model, where innate defects in beta cell survival drive both type 1 and type 2 diabetes.  

Read: Liston, Todd and Lagou (2017). "Beta cell fragility as a common underlying risk factor in type 1 and type 2 diabetes". Trends in Molecular Medicine. 

New insights in genetic defect allow prevention of fatal illnesses in children

A team of scientists led by prof. Adrian Liston (VIB–KU Leuven) and prof. Isabelle Meyts (UZ Leuven – KU Leuven) were able to characterize a new genetic immunodeficiency resulting from a mutation in a gene named STAT2. This mutation causes patients to be extremely vulnerable to normally mild childhood illnesses such as rotavirus and enterovirus. Prof. Liston’s comprehensive analysis of the genetic defect allows clinicians to provide children with the proper therapies before illnesses prove fatal. The findings of the research have been published in the Journal of Allergy and Clinical Immunology.

Recent advancements in technologies and tools now make it possible for researchers to identify extremely subtle defects of the human immune system. In the past, many patients with “hidden” immunodeficiencies, or defects that were not obvious from the outset, often become extremely ill or die before their genetic disorders are diagnosed. Prof. Liston and his lab were able to identify a gene mutation causing an immunodeficiency that can be fatal during childhood, enabling children to be diagnosed, monitored and preemptively treated for the disorder.

Immunodeficiency disorders are not rare

Ranging from disorders as severe as the well-known “bubble boy” to nearly impossible-to-detect ‘hidden’ defects, immunodeficiencies are more common than scientists previously thought. Immunologists and geneticists have only just begun to scratch the surface when it comes to defining these latter types of immune disorders, which can be specific enough to make sufferers highly susceptible to just one or two types of diseases.

Prof. Adrian Liston (VIB-KU Leuven): “I wouldn’t be surprised if, when we finally do complete the identification of all genetic immunodeficiencies, we discover that up to 1 in 100 children are affected. The ‘hidden’ ones are especially insidious, because they do not present as obviously as other genetic immune disorders. In our study, one of the patients did unfortunately die before a diagnosis could be made. The other patient is alive and well, and now that she has been diagnosed, she is being carefully watched. We can do something about most immunodeficiencies – if only we can identify them.”

Severe common illnesses may signal immune disorder

Prof. Meyts, lead clinician for the patients, stresses the importance of assessing the severity of childhood illnesses on the part of parents, suggesting that parents look for helpful information online and raise the possibility of a potential genetic immunodeficiency with a pediatrician.

Prof. Isabelle Meyts (UZ Leuven – KU Leuven): "When an otherwise healthy child experiences extremely severe infection with a common pathogen, like influenza or the chickenpox virus, or whenever a child is particularly vulnerable to infection with a single pathogen, an underlying defect in the immune system is likely. Likewise, a family history of a child succumbing to infection should alert the family and the clinician. Identifying the causative gene defect allows for genetic counseling of the family and for preventive measures to be taken."

Unraveling ‘hidden’ immunodeficiencies

The potential future avenues for this research are numerous and extremely relevant to current medicine. Prof. Liston’s lab has developed a unique immune phenotyping platform and gene discovery program that can help identify previously unknown immune system defects and inflammatory diseases, leading to novel new treatments that can be administered in a timely way.

Prof. Adrian Liston: “We seek to identify every possible cause of genetic immunodeficiency so that every child displaying warning signs can be tested and treated before it is too late.”

Journal club: A new hint to the evolution of the nucleus?

One of the fundamental divisons of life is between prokaryotes and eukaryotes. Prokaryotes, including both Archaea and bacteria, have a very simple cell, with no major subcellular compartments. Eukaryotes, essentially all over living things (plants, animals, fungi, amoeba, etc), have much more complex cells, with a nucleus and dedicated organelles (mitochondria, chloroplasts, etc).

Exactly how eukaryotes evolves from prokaryotes is one of the biggest questions in evolution. It is clear that some organelles, such as mitochondria and chloroplasts, evolved by endosymbosis. Essentially, one bacteria swallowed another, which survived inside and took on specialised functions. The nucleus has been a bigger mystery, with no clear preceeding structure in prokaryotes to build upon. Until now. In the lastest issue of Science, Chaikeeratisak et al discover a nucleus-like structure in bacteria. Interestingly, the structure is not part of the bacteria's normal lifecycle, instead it is assembled by a virus, bacteriophage 201φ2-1, as a structure for DNA replication and transcription, after which the RNA is sent to the cytoplasm of the bacteria for translation, exactly as occurs in eukaryotes.

There are many fascinating angles to this paper. Why does bacteriophage 201φ2-1 assemble this structure? Is it to protect the phage genome from bacteria attack by restriction enzymes and the like? Most importantly, could similar viruses have been the origin of the eukaryotic nucleus? One can easily imagine an ancestral prokaryote becoming permanently infected by such a virus, and rapidly evolving useful functions for a nucleus of its own. 

Read the paper: Vorrapon Chaikeeratisak, Katrina Nguyen, Kanika Khanna, Axel F. Brilot, Marcella L. Erb, Joanna K. C. Coker, Anastasia Vavilina, Gerald L. Newton, Robert Buschauer, Kit Pogliano, Elizabeth Villa, David A. Agard and Joe Pogliano. 'Assembly of a nucleus-like structure during viral replication in bacteria'. Science  13 Jan 2017: Vol. 355, Issue 6321, pp. 194-197

To post-doc or not?

This Nature Biotechnology paper has an interesting analysis of American biomed PhDs who chose to post-doc or not. Essentially, doing a post-doc is essential for an academic position, but it actually lowers net salary outside of academia. How well this translates to other countries is not clear - American post-docs are paid much lower salaries than some other countries, but it is worth a read.

This was my favourite paragraph:

"Ex-postdocs continued to earn less on average than non-postdocs ten or more years postPhD. In-fact, ex-postdocs gave up 17–21% of their present value of income over the first 15 years of their careers. This suggests that postdoctoral education is inconsistent with a model of human capital investment. Instead, it indicates that postdoc positions work as tournaments, where individuals compete for an increasingly limited number of tenured/TT jobs by signaling their ability and commitment through long hours in laboratories and years spent underpaid."

Sounds about right. Except that it forgets to mention some of the great things about doing a post-doc. You can easily relocate and live for a few years pretty much anywhere in the world. It is like starting your PhD over again, except you are actually competent at your job, you don't have to write a thesis, and you can leave whenever you feel like. You meet great people that are in research for the love of it, and you will keep some of the most valuable contacts you ever make for the rest of your career. 

Science career advice, age 5

Want to be a scientist?

Like to solve problems?

Good at maths?

Patience?

Like to experiment?

Want to be a doctor?

Like to help people?

Not afraid of blood?

Good listener?

Like to study?

Want to be a professor?

Like to read?

Like to teach?

Patience?

Good memory?

Effecting change as an animal rights advocate

I have been an animal rights advocate for my entire adult life. I am also a medical researcher, specialising in the translation of advances from mouse immunology to patients. I am a vegetarian, for ethical reasons, and yet I am director of the mouse genetic engineering service at KUL. How can one be an advocate for both animal rights and for the use of animals in medical research?

Few would argue against medical research. Who wants a life that is nasty, brutish and short? When I first entered medical research I considered starting in a research project that did not use animals, so that my dual passions did not come into conflict. In the end, however, I decided to work on a mouse model of Multiple Sclerosis – scenes of which would certainly be confronting if shown to the public out of context. I did so because I could not bear to be a hypocrite, willing to take advantage of the outcomes of laboratory animal use, but not willing to get my own hands dirty. Since then, advances in Multiple Sclerosis research in mice have resulted in better treatments for patients, with new medications capable of adding decades of healthy life to the millions of sufferers. Who would be willing to deny their loved ones access to these medicines, despite the work being based on animal models?

At the same time, few would argue against animals having rights. We no longer throw cats from the belfry in Ypres, or other such wanton brutality that was once commonplace. Cruelty against pets is now criminal and farms are inspected for the treatment of livestock. The most intensive protections for animals are reserved for animals in medical research. In order to even start research on mice I have taken countless training courses and filled in hundreds of pages of animal health assessments. My mice are kept in conditions that would be luxurious for wild mice, and have daily health checks by trained staff. The use of each individual mouse is assessed by an external ethics panel, including an ethicist and a veterinary surgeon. I assure you that nothing as brutal as a mouse trap or rat poison would pass muster, let alone the conditions that wild mice endure daily!

Animal research is the bedrock of medical research. Even as we continue to refine, reduce and replace animals in research, we need to accept that all of our advances rest upon work done in animals. At the same time, and rightfully so, laboratory animals have the strongest legal and ethical protections of any animals in our society.

This is not to say that animal use in medical research cannot be improved. Not all researchers have a full awareness of the responsibility that comes with animal research, and violations of animal rights do occur. But the worst thing that we can do would be to reverse progress with a knee-jerk reaction. Attempts to reduce animal research by increasing bureaucratic burden simply de-emphasize the most important regulations. An extra tax on animal use in medical research will need to be paid by reducing the number of trained staff caring for the animals. Public condemnation of animal researchers in the media shuts down dialog. We need to increase, not decrease, communication between animal rights advocates and medical research advocates. Animal rights groups that demand absolutes only make progress more difficult for moderates. Those of us willing to proceed with mutual respect know that the only way to continue the steady improvements in laboratory animal conditions is to increase openness and transparency. If you are an animal rights advocate that actually wants to effect change, I encourage you to work with, instead of against, medical researchers. We will listen. 

Hoe kan iemand tegelijk opkomen voor dierenrechten als voor het gebruik van proefdieren?

Knack:

'Het ergste wat we kunnen doen is om in een paniekreactie alle vooruitgang te blokkeren', schrijft professor Adrian Liston (KU Leuven en VIB). Hij roept de dierenreachtenactivisten daarom op om de dialoog aan te gaan.

Al heel mijn volwassen leven zet ik me in voor dierenrechten en dierenwelzijn. Ik ben ook een medisch onderzoeker, gespecialiseerd in het vertalen van nieuwe immunologische inzichten van muizen naar patiënten. Ik ben vegetariër, om ethische redenen, en toch sta ik aan het hoofd van de dienst voor genetische manipulatie van muizen aan de KU Leuven. Hoe kan iemand opkomen zowel voor de rechten van dieren als voor het gebruik van dieren in medisch onderzoek?

Bijna niemand is tegen medisch onderzoek. Wie wil er nu een hard en kort leven? Toen ik voor het eerst als onderzoeker aan de slag ging overwoog ik een project waarbij geen proefdieren werden gebruikt, zodat mijn twee overtuigingen niet met elkaar in conflict kwamen. Uiteindelijk heb ik toch besloten om te werken op een muismodel van Multiple Sclerose of MS - proeven die zeker confronterend zouden overkomen als ze uit hun context aan het publiek getoond zouden worden.

De reden voor mijn besluit was dat ik niet schijnheilig kon blijven, enerzijds bereid om mee te profiteren van de resultaten van proefdieronderzoek, maar niet om mijn eigen handen vuil te maken. Sindsdien is er heel wat vooruitgang geboekt in het MS-onderzoek. Dankzij dierproeven zijn er nu betere behandelingen en nieuwe geneesmiddelen die miljoenen patiënten heel wat extra gezonde jaren opleveren. Wie wil hun vrienden of familie deze geneesmiddelen ontzeggen, zelfs al is het werk gebaseerd op dierlijke modellen?

Uitgebreide regelgeving voor proefdieren

Tegelijkertijd is zo goed als iedereen het er over eens dat ook dieren rechten hebben. We gooien geen katten meer van het belfort in Ieper, of andere van die brutaliteiten die onder het mom van traditie jarenlang gebeurden. Dierenmishandeling is nu gelukkig strafbaar en de behandeling en huisvesting van vee op boerderijen wordt nauwlettend geïnspecteerd. De meest uitgebreide regelgeving op het vlak van dierenbescherming is weggelegd voor proefdieren in medisch onderzoek. Vooraleer zelfs maar te mogen starten met muizenonderzoek heb ik talloze opleidingen gevolgd en honderden pagina's medische keuringen en ethische dossiers ingevuld.

In vergelijking met wilde muizen, leven mijn muizen in luxueuze omstandigheden, en hun gezondheid wordt dagelijks gecontroleerd door opgeleid personeel. Het gebruik van elke individuele muis wordt beoordeeld door een externe ethische commissie, met inbegrip van een ethicus en een dierenarts. Ik kan u verzekeren dat niets zo brutaal als een muizenval of rattengif die commissie zou passeren, laat staan alle andere ongemakken die wilde muizen dagelijks te verduren krijgen.

Dierproeven vormen de basis van medisch onderzoek. Zelfs wanneer we doorgaan met het verfijnen, verminderen en vervangen van dierproeven moeten we accepteren dat al onze nieuwe wetenschappelijke inzichten berusten op werk verricht bij dieren. Tegelijkertijd hebben proefdieren de sterkste wettelijke en ethische bescherming van alle dieren in onze samenleving, en terecht ook.

Dit wil niet zeggen dat het gebruik van proefdieren in medisch onderzoek niet verder kan worden verbeterd. Niet alle onderzoekers zijn zich volledig bewust van de verantwoordelijkheden die dierproeven met zich meebrengen, en schendingen van de rechten van dieren komen helaas voor. Maar het ergste wat we kunnen doen is om in een paniekreactie alle vooruitgang te blokkeren. Pogingen om dierproeven te verminderen door het verhogen van de bureaucratische lasten zorgen er gewoon voor dat er minder aandacht geschonken wordt aan de belangrijkste regels. Een extra belasting op dierproeven in medisch onderzoek zal worden betaald door het verminderen van het aantal opgeleide medewerkers die zorgen voor de dieren.

Onderzoekers publiekelijk veroordelen in de media sluit de deur voor iedere dialoog. We moeten zorgen voor meer, niet minder, communicatie tussen voorstanders van dierenrechten en van medisch onderzoek. Dierenrechtengroeperingen met absolute eisen maken vooruitgang enkel moeilijker voor gematigden. Diegenen onder ons die bereid zijn om door te zetten met wederzijds respect weten dat meer openheid en transparantie de enige manier zijn om de levensomstandigheden van proefdieren te verbeteren. Als u een dierenrechtenactivist bent die echt verandering teweeg wilt brengen, dan moedig ik u aan om mee te werken met medische onderzoekers, in plaats van tegen ons. Bij ons vindt u alvast een luisterend oor.

Adrian Liston is professor aan de KU Leuven en VIB. Hij staat aan het hoofd van de afdeling genetische manipulatie op muizen.