Conferences

I have very recently been to a conference in Australia. As a PhD student, attending conferences is a big perk: I get to go out of my department bubble and see what is done and more importantly how it is done in other labs. In my specific case, it’s even a bigger advantage as I am the only person studying animal models of multiple sclerosis, and the only person studying so many innate immune receptors in my building (and, as far as it feels, in this city). I got some interesting warnings regarding the technical difficulties of my research and I have learned a few things that in hindsight are not that new but I had never given much thought about.

I have attended this conference series before. In fact, I have been there for the last 3 editions: in Germany, Israel and Australia. Organisation wise it does not differ much from event to event and the poster sessions are also always quite a mess. Small rooms, no space between posters, too many posters per session, you name it. This time I had to pitch my poster just before my allocation session. Where did this fail? There were three groups pitching at the same time, in the same hallway, during apero. Regardless to say that 1) no one could hear each other, 2) no one make an effort to go watch the pitches. I felt quite useless there. No feedback on the pitch either.

The positive aspect of this conference was location. Most people find it very far to travel to Australia from Europe, therefore most Americans who would collaborate with European labs also did not attend. This brought the challenge of finding topics and speakers to fill in the program. Most new topics were presented by Canadian and Australian researchers. There are a few interesting things going on, specially when it comes to the immune component of psychiatric and other neurological diseases. Will stay tuned to this in the following years.

 

A Ciência ao serviço da História

No meu primeiro texto fiz referência que, não raras vezes, a interface ciência-humanidades apresenta um interessante potencial para ser explorado. A forma mais visível de tal exploração será, talvez, o ramo de História da Ciência, mas há outros exemplos que ilustram os benefícios desta simbiose.

É o caso que hoje aqui trago em que antigos manuscritos foram decifrados graças à aplicação de modernas tecnologias. Claudius Galenus, também conhecido por Galeno, foi um médico romano de origem grega do século II cuja influência no conhecimento médico e farmacológico perdurou durante largos séculos. As obras de Galeno encontram-se agrupadas na colecção “Galenic corpus” sendo que, ao longo dos tempos, várias traduções foram sendo feitas ajudando na sua disseminação na Europa e Ásia.

É o caso de “On the Mixtures and Powers of Simple Drugs” que, no século VI, foi traduzido para a língua siríaca característica do Médio Oriente. Lamentavelmente, no século XI, seguindo os costumes da Idade Média, os pergaminhos com a obra traduzida foram usados como um palimpsesto, ou seja, procedeu-se à remoção do texto original para a escrita de novos textos (no caso, religiosos).

É aqui que as técnicas hoje disponíveis entram em cena e, no último mês de Março, uma equipa de investigação do Stanford Synchrotron Radiation Lightsource (SSRL, Califórnia, Estados Unidos) conseguiu aceder ao texto de Galeno graças ao uso de radiação de sincrotrão. Para tal, começaram por usar diferentes tipos de radiação electromagnética (radiação visível, ultravioleta e infravermelha) o que permitiu uma identificação parcial da obra. O uso da técnica de fluorescência de raios-X complementou a anterior abordagem tornando possível distinguir os dois textos nos pergaminhos pelas diferentes propriedades de fluorescência apresentadas pelas respectivas tintas usadas que diferem no conteúdo em metais (nomeadamente ferro, zinco, mercúrio e cobre).

A análise do texto de Galeno será certamente útil para melhor caracterizar o conhecimento médico da época reforçando a importância destas abordagens. Pormenores adicionais podem ser encontrados online (https://www6.slac.stanford.edu/news/2018-03-22-hidden-medical-text-read-first-time-thousand-years.aspx).

Does Aspirin protect against Alzheimer’s?

For this week I had decided to read and summarise a paper published in J Neuroscience, about the protective role of aspirin in Alzherimer’s Disease (AD). I saw a link highlighting this paper on Facebook and could not immediately get access to the full text (paywalls). I did not even read the full title, but I already had 1 question: “did they check by correlation studies if there’s less people chronically taking aspirin, among those with AD? When I finally saw the full title of the paper, I realised that the study was more precise: “Aspirin induces Lysosomal biogenesis and attenuates Amyloid plaque pathology in a mouse model of Alzheimer’s disease via PPARα”.

Here I got a bit doubtful if I should still read the paper for this blog. But I persisted. My main concern being: why this particular pathway? The answer, which gets obvious mid-paper is: the authors seem to have worked on this one molecule before. But the rational to have chosen Aspirin as treatment seems to have a logical argumentation.

Stepping back: Alzheimer’s disease is caused by accumulation of Amyloid-beta (Abeta). This is a protein that can aggregate with others of the same type in such unbreakable structures that the aggregates are known as plaques. In general, protein aggregates would normally be broken down by the cell machinery: e.g. proteasome and lysosomes, but in AD it seems that this machinery is not working, or is not efficient enough. The authors point out that aspirin has been shown to increase the production of lysosomes.

For this study, the authors follow up on this increase of production of lysosomes by aspirin.

They started by adding Abeta to cells and then aspirin and check that indeed, cells treated with aspirin have less Abeta because 1) they take in less Abeta from the solution and 2) they get rid of the previously taken in Abeta, faster. To check the cause of this clearance, the authors checked for lysosome numbers and saw that it was increased in cells treated with aspirin. Moreover, they hypothesised this was due to new production of lysosomes and therefore looked into known transcription factors (TF) that promote lysosome biosynthesis. Having identified TFEB, they looked for enhancers of this TF and this was when they identified the PPRE site, and went on to study PPARs (Peroxisome proliferator-activated receptor), the pathway they have been familiar with. The next step in this paper is to distinguish between PPAR alpha, beta and gamma, by coupling Abeta-incubation with aspirin treatment in the presence and absence of inhibitors of these 3 molecules: meaning that the authors were able to see that when PPAR alpha was blocked, then aspirin treatment did not lead to increase lysosome production and Abeta was not broken down efficiently.

Pathway-studies done in cells is very useful to pin-point all the players in a certain process but it is not always a good model of the real situation. Therefore, the authors have used a mouse model of AD to test aspirin treatment in vivo: mice with 5 mutations in the Abeta production pathway, that are known to cause familiar AD in humans. These mice develop AD “spontaneously” after a certain age. Thus, once the mice had developed AD, the authors have treated these mice with aspirin, as well as a new set of mice that have the 5 mutations associated with AD and are deficient for PPARalpha. The conclusion is that in the group of mice that are deficient for PPARalpha, the accumulation of Abeta plaques is higher, because the same aspirin treatment is not effective anymore.

So, my question remains: is there a correlation in humans between those taking aspirin and decrease risk of Alzheimer’s disease? This study does not address that.

What this study points at is to a link between PPAR alpha mediated increased lysosome production after treatment with aspirin.

 

Notes & References

Transcription Factor (TF) – protein capable to bind to a sequence of DNA and therefore regulate gene expression.

Enhancer region – sequence of DNA to which TF bind.

Soldados (semi)desconhecidos da Ciência

Os grandes feitos e avanços da humanidade devem-se, na sua generalidade, a um conjunto mais ou menos alargado de pessoas. No entanto, é frequente que apenas os maiores líderes fiquem registados na História o que, convenhamos, acaba por ser natural. A Ciência segue esta mesma regra como facilmente se conclui olhando para os Prémios Nobel: cada vez mais, os laureados representam uma vasta equipa de trabalho.

Assim sendo, é também possível encontrar na História alguns investigadores que “ficam para trás” em dadas descobertas. O caso de Rosalind Franklin na descoberta da estrutura do DNA é particularmente mencionado entre os cristalógrafos e talvez um dia o aborde neste espaço. No entanto, o “feliz” contemplado de hoje é o naturalista galês Alfred Russel Wallace (1823-1913) já que se cumprem precisamente 160 anos da apresentação pública do seu trabalho sobre a evolução das espécies a 1 de Julho de 1858 à “Linnean Society of London”.

Não pretendendo entrar em detalhes biográficos, as observações e pesquisas de Wallace sobre diferentes espécies levaram-no a ser correspondente de Darwin cujo prestígio era já então reconhecido. Nos inícios de 1858, Wallace preparou um ensaio intitulado “On the Tendency of Varieties to Depart Indefinitely From the Original Type” que Darwin recebeu no dia 18 de Junho do mesmo ano. Constatando grandes semelhanças entre as suas teorias (não publicadas) e aquelas descritas por Wallace, Darwin pediu conselhos a Lyell e Hooker que resolveram apresentar os trabalhos dos dois autores em simultâneo embora realçando o trabalho de Darwin. A partir daqui, “o resto é História”: a obra “A Origem das Espécies” foi publicada no ano seguinte fazendo de Darwin o grande obreiro da teoria da selecção natural e relegando Wallace para segundo plano.

Não sendo um caso crítico – os contributos de Wallace foram e continuam a ser, apesar de tudo, reconhecidos – é ilustrativo que, não raras vezes, “estar no sítio certo, à hora certa” é essencial para se conseguir importantes conquistas e reconhecimentos. Uma máxima que, sem surpresas, é tanta vez aplicada também no dia-a-dia.

How I chose it

I am (still) interested in the role of the immune system as the poisonous environment in which ageing and neurodegenerative diseases (e.g. Alzheimer’s disease) develop. Thus, to me it was very important to do a PhD in the field of Neuroimmunology. There are a few places in the world where this field thrives, and I had excluded outside Europe (the daily live seems to be quite different from here) and South Europe (don’t like the weather). Scandinavia is too dark in winter, and I am a person that tends to see the world through darker glasses anyway. Central Europe comes as solution.

But I refused to work one more day for free (did that for 10 months) or for a stipend: I wanted to pay taxes! Paying taxes makes me believe I have a proper job, a job that will secure my retirement, my illnesses and even my maternity leave. This is only possible in a few countries: Switzerland is one of them.

There’s a hub for neuroimmunology in Zurich, so I applied here.

When I came for the interview I did not ask

  • How many PhD/master students are you supervising?
  • What do you expect from me in the next 4 years?
  • What do you expect from this project for the next 4 years?
  • How big do you expect the lab to become?
  • What techniques can I learn that will distinguish me from the competition when applying for a new job?
  • What can I bring to this lab, from all the things I have learned?
  • Who is my “go-to” person in case I have questions with data analysis?
  • How reliable is this model? How appropriate is this model to study this condition?

I just read the project description. I talked to the Professor, the 2 junior PIs, and the PhD student that I would replace. I was very happy with what I heard and I had a very positive feeling that our way to go about life matched. I chose the lab because it was quite small (but it tripled in 2 years) and because the project was pretty solid (actually, the model was not working), and just needed some molecular characterisation that I could do (still haven’t done it) and eventually I could starting exploring other angles and putting together bits and pieces.

For some of those questions I got to see/experience the answers in real life and the others I have eventually asked. Other important questions are not to be asked, but to be answered by the PhD candidate:

  • What do you want from your PhD?
  • Do you want to supervise a master student?
  • What do you want to learn that will make you a suitable candidate in your next job? This could be a super-fancy technique, a coding language, or organizational skills.
  • What do you have in your portfolio that you are confident with, and can use as a “reliable, always working method”?

In my case, I wanted to learn immunology, specially about the immune system. This is difficult on a daily basis because the project tends to be way more narrow than the general knowledge in immunology I would like to acquire. I don’t mind supervising master students, but I do not have a structured project they can pursue on their own. I would like to acquire good knowledge of FACS and CyTOF and my go to method is qPCR. It always works.

What should you know before choosing a lab

My PhD wasn’t easy and neither was my master. So, you may ask, if my master was “painful” why did I go for a PhD? First of all, I’m crazy, I admit. But I thought that the PhD couldn’t be worse than my master. Wrong! I think it was different but it wasn’t “great”… Do not misinterpret me, I end up having results to publish but they only showed up really late… Nevertheless, after a PhD mourning period (as my PhD supervisor calls it) I realized that I still love science and I actually think I can do science for the rest of my life.

I presume that at least 50 % of PhDs recognize themselves in this story. During my master and PhD (especially when I was struggling with the pain of no results) I would have several talks with my colleagues about how to choose the best project/lab. I now realize that at the time that we have to choose the lab/project most people don’t know exactly what they should pinpoint as key aspects to consider.  Thus, looking to what was my friends experience and mine, I believe that there are some key points that you should take into consideration when choosing a lab and project to work on!

Starting with the field of study (neuroscience, stem cells, immunology…), when students are choosing a lab/project they tend to think that the field of study that they pick is what will define their future path. Well, I believe that is not true! What will define you is your skills! Of course, the field where you will be working on is important, but it will be the combination of what you know theoretically and experimentally that will make you unique. So, don’t forget to ask yourself, if I choose this lab/project what will I learn? Don’t focus your choice only in the field of study.

What about the supervisor? To choose a “good” supervisor you should know yourself! A good supervisor for me doesn’t mean is a good supervisor for you. Why? Because people give importance to different supervisor personalities and methodologies. For example, if you are an open mind you don’t want to choose a supervisor that is closed mind. You should try to know with the lab members how is the supervisor for example in terms of methodologies – do you have to do exactly how he/she says or do you have freedom to design an experiment to accomplish a specific goal previously discussed? Does he/she tries to understand your results when they do not fulfill the work hypothesis? Is he/she able to change the working hypothesis? These are some of the examples that you should consider. Someone told me once “you should choose a supervisor that you admire as a scientist”.

And what about coworkers? I think is obvious that you will take advantage of a lab where people discuss ideas, results and problems! Believe me, you will find so many problems along the way, if you are surrounded with open minds that are problem solvers you will be in good hands! Of course, you don’t know that for sure but you can always have an idea about it when talking with them. Oh, and make sure that there is a “friendly” environment!

Finally, the project per se! As mentioned above, make sure that your project will make you have a hand full of skills. Nevertheless, if you are starting your PhD and you would like to design your own project, make sure that you are engaged in a lab colleague’s work. That will make you learn the lab procedures, you will help on his/her experiments which means you probably win co-authorship on his/her paper and importantly these will give you solid bases of a good PhD hypothesis because you will have then increased your know-how on the subject of study.

At the end, balance the pros and cons of the labs that you are considering and good luck on your choice!