Contribution to this year’s CLOVES Family Conference

On 07.08.2021, I was given the opportunity to present at this year’s CLOVES Family Conference. This offered me the rare chance to interact directly with PROS (PIK3CA-related overgrowth spectrum) patients and their families, and offer them some of my (limited) knowledge in return for all their support.

Communication of complex science to non-scientists is no easy task but certainly one that we ought to take seriously as researchers. It is our responsibility to ensure that individuals directly or indirectly affected by our work are fully aware of its meaning and, especially, its limitations. It is not merely a sign of professional credibility. It is a sign of respect for the people who 1. inspire our research on a daily basis; 2. contribute to it financially, one way or another.

This belief in humble and honest communication about science, not just with the public but also with other scientists, was largely given to me by my PhD supervisor, Prof Robert Semple, who also deserves most of the credit for my knowledge about PROS and overall research in this area.

The aim of my talk was not only to highlight current research and unanswered questions in PROS, but also what the limitations of available experimental model systems are. I feel rather strongly about the need for such clarification. Nowadays, scientific publications – before and after peer review – are easily accessible, yet it takes a lot of critical thinking and background knowledge to assess the presented findings. Even for a scientist, the sheer number of publications in any given field is often bewildering and impossible to keep up with. Most papers are therefore unlikely to be evaluated beyond titles and abstracts. As I told the patient community, titles, abstracts and even entire publications can often be misleading and inflate the importance of their findings. This is the result of an academic evaluation system where being “first” and “flashy” matters more than being “right” and “rigorous”. To help patients/patient relatives with critical assessment of “PI3K” publications of relevance to PROS, here is a bullet point summary of some of the “tools” I mentioned in yesterday’s presentation:

1. If it sounds too good to be true, it probably is. Unless claims about treatments and even cures were evaluated as part of a controlled phase 3 clinical trial (and certainly not just in cells or mice), I’d advise a healthy dose of scepticism, with some tentative optimism.
   
2. There is no such thing as the perfect model system. All current model systems used in PROS have advantages and disadvantages. My presentation gave some clues as to what those are. Watch out for studies that are only mouse or only 2D cell culture. This information is typically provided in the method’s section. While the conclusions of such studies may be perfectly valid for the mouse or the particular cell type under investigation, extrapolation to the human disease may not be possible. Basically, a mouse is not a human, nor are cells grown in highly artificial culture conditions in the lab. PROS is a case-in-point – it has been very difficult to model the human overgrowth in mouse models. Currently, the best mouse mimic of the disease is not based on a PIK3CA gene that occurs in nature. Cell biology knowledge obtained from this model will therefore warrant replication in a complimentary, “natural” cell model system.
   
3. Findings that have been reproduced across a range of different assays, and even better – across different publications/scientific groups, are more trustworthy than those based on a single assay. Granted, this can be difficult for a non-scientist to gauge, but the number of distinct headings in the method section and the diversity of scientific figures may serve as (imperfect) clues.
   
4. Be careful not to extrapolate findings from bona fide cancer studies to PROS. While both cancer and PROS may share the same PIK3CA mutations, the contexts are very different.

The point of the above is not to dismiss PROS/PI3K research. Quite the contrary.

There is so much good research in this area, and it would be a shame if it were to be drowned out by less reliable findings. Hopefully, some of the above tips will allow patients and their families to distinguish signal from noise.

The full presentation, including a recording that is slightly longer (35 min) than the original talk, is now openly available via my Open Science Framework presentations site. Feel free to use and abuse as long as the CC-BY license is observed! 🙂

“Organopoly”: combining fun and knowledge about the wonderful human body

What makes up a human body? What are the names of the different organs and what are their functions? What is good and bad for the body? Find out answers to all of these questions whilst playing “Organopoly” with us. Organopoly is an interactive and eye-catching educational game that introduces children and adults alike to key human biology knowledge as well as information related to lifestyle choices and disease prevention. To promote this resource to Cambridgeshire families with children 9-16-years-old, we will be running a whole-day game event at Ross Community Centre from 10 am – 4 pm on Saturday 14 October. Two games will be played in parallel with maximum 8 players per board. Each game session will last 2h30min, with the option to attend the morning or the afternoon session. Free versions of the game and additional educational resources to take home will be provided at the end.

Ross Street Community Centre is easily accessible by car or bike. A small car park and cycle racks are available in addition to free on-street parking locally. All rooms are wheelchair-accessible.

The event is free of charge, but bookings are mandatory for individual players (bookings are not required for attending family members). This event is supported by the Royal Society of Biology Regional Grant Scheme.

Watch out for us on Twitter via @RalitsaMadsen and/or #Organopoly.

Modern peer review, science communication and this week’s science news

Modern peer review

At the time of writing this blog post, I am enjoying the lunch provided by the organisers of a workshop on “How to get the most out of modern peer review?” (it is being filmed so you can benefit from it, too!). I have learned a lot, and some things are worth sharing. The first presentation by Wei Mun Chan, Editorial Manager at eLife, offered valuable insight into consultative peer review where reviewers engage in a discussion with each other and feed back to the editors. The final decision letter and the author feedback is also openly accessible to promote greater transparency. This is just one example of a great initiative to promote faster peer reviews, less bias during the process and increased transparency. On to the second presentation, Dr Sabina Alam from F1000 introduced their open-science publishing platform where the paper/data comes first, followed by a transparent peer review process. The whole life-cycle of the paper can be followed openly by the readers who are also invited to comment and review the paper publicly. F1000 allows the publication of multiple types of data, including single findings, as long as it is reported correctly and meets scientific standards. So if you have old reagents gathering dust in the lab and projects that were terminated prematurely, why not share it with the rest of the world? Someone might be able to take it up and build on your efforts. You will get recognition for it, too! In the same vein, F1000 promotes the dissemination of scientific posters and PowerPoint slides; these do not undergo peer review, but are assigned a DOI and are therefore citable – GREAT!

Next we heard from Dr Laurent Gatto from the Proteomics Research Unit here at Cambridge. He gave us some tips for good reviewing, and you can view those online as Dr Gatto shares his material openly. In summary, make sure that the data is always there, that the names and numbers match up, that the metadata is available and the science reproducible!

The final talk before lunch was given by Tom Culley, Marketing Director at Publons. This is my first encounter with Publons, and I am impressed. What a great initiative to give scientists recognition for their peer review work! This can only improve the quality of the published science because reviewers have an incentive to do well and will be recognised for it. Publons creates a complete track record of all your reviews and you can even add past reviews to obtain the deserved credit for them. Another great initiative to foster trust and integrity in research!

I am looking forward to the last sessions and a workshop by Dr Varsha Khodiyar, Data Curation Editor at Scientific Data!

Writing for non-scientists

I have recently had to write a grant application which forced me to think carefully about wording when describing my research to the general public. I quickly realised that I will need much more trial-and-error experience to become as good as my supervisor (who has the added benefit of being a clinician who talks science to non-scientists all the time!). Luckily, there are many good guides available on the internet, and I have just come across a very useful collection provided by eLife on how to write plain language summaries! Looking forward to putting these into practice as I will be writing a guest blog for the Biochemical Society which is quite exciting.. Also, if I have time, I would really like to have a go at writing a story for the Biochemical Society’s Science Communication Competition!

Finally, a bit from the research world…

I haven’t had a chance to look at these in detail yet, but here are some papers that caught my attention this week. Fingers crossed for solid data reporting!

Phosphorylation of the exocyst protein Exo84 by TBK1 promotes insulin-stimulated GLUT4 trafficking (http://stke.sciencemag.org/content/10/471/eaah5085)

Dynamics of embryonic stem cell differentiation inferred from single-cell transcriptomics show a series of transitions through discrete cell states (https://elifesciences.org/content/6/e20487)

Synergistic drug combinations for cancer identified in a CRISPR screen for pairwise genetic interactions (http://www.nature.com/nbt/journal/vaop/ncurrent/full/nbt.3834.html)

Lysosomal cholesterol activates mTORC1 via an SLC38A9–Niemann-Pick C1 signaling complex (http://science.sciencemag.org/content/355/6331/1306)

Large-scale design of robust genetic circuits with multiple inputs and outputs for mammalian cells (http://www.nature.com/nbt/journal/vaop/ncurrent/full/nbt.3805.html)

The cold-induced lipokine 12,13-diHOME promotes fatty acid transport into brown adipose tissue (http://www.nature.com/nm/journal/vaop/ncurrent/full/nm.4297.html)

New Year, new blogpost, new language: my project in Danish!

For friends and family in Denmark (+ any other interested Danish readers), finally a description of what I spend most of my wake hours doing. I hope it makes sense!

Hver gang jeg kommer hjem til Danmark, bliver jeg mødt af velmente spørgsmål og bemærkninger vedrørende min forskning:

”Hvad er det præcist, du laver?”

”Er det ikke diabetes, du forsker i?”

”Du finder vel sikkert kuren mod kræft!”

”Ej, det lyder godt nok specifikt og komplekst.”

Det er skønt, at folk er oprigtigt interesserede i mit arbejde! Og det er på tide, at jeg takker for interessen ved at trylle mystikken væk og give jer alle en (forhåbentligt) forståelig beskrivelse af, hvad jeg bruger de fleste af mine vågne timer på.

Tænk dig først tilbage til den tid, hvor du lå gemt i din mors mave. Er det ikke utroligt, at sammensmeltningen af en ægcelle og en sædcelle på 9 måneder kan føre til fødslen af en oftest velskabt menneskebaby? Utallige komplekse processer finder sted i løbet af denne udvikling, hvor en enkelt celle bliver til en hel organisme bestående af op mod 10000000000000 celler organiseret på en helt bestemt måde. Hvad er op og ned, venstre og højre? Hvor skal de forskellige organer placeres, og hvor store skal de være?

Vores tidlige udvikling er derfor et godt eksempel på, hvorfor det er vigtigt, at vækst er nøje reguleret helt nede på cellulært niveau. Modsat er kræft et eksempel på, hvor galt det kan gå, når cellers vækst pludselig ikke kan holdes i skak. Typisk sker det, fordi vores celler med alderen akkumulerer flere og flere fejl i sit DNA (”computerkoden”), hvorved diverse vækstregulerende mekanismer går tabt, mens andre bliver forstærket. Det kan kun ende i en katastrofe, når bremserne ikke virker, og speederen er i bund.

Det viser sig, at der på verdensplan findes sjældne individer med fejl i dette vækstprogram – fejl, som har fundet sted meget tidligt i fosterudviklingen. Disse mennesker har ikke kræft, men er ved fødslen kendetegnet ved abnorm vækst, som fortsætter livet igennem. Det var et gennembrud, da min vejleder og hans team in 2011 opdagede, at en af de mest hyppige programmeringsfejl i kræft også er årsagen til disse sjældne vækstsygdomme. Det drejer sig om en genetisk mutation – en stavefejl i DNA’et – i lige netop den del, der koder for proteinet PIK3CA (de fleste gener koder for proteiner, og proteiner udfører de fleste funktioner i vores celler).

PIK3CA er ikke et tilfældigt protein. Det fungerer som tænd-knappen for cellens vækst, stofskifte, deling og bevægelse. De omtalte genetiske ”stavefejl” fører til, at PIK3CA er aktivt hele tiden, eller med andre ord: tænd-knappen sidder fast. Konsekvenserne er til at få øje på. Den første patient, som blev diagnosticeret med denne mutation, har to ben, der hver især vejer over 50 kg. Til sammenligning er hendes overkrop overraskende tynd. Som følge af, at den genetiske fejl opstår under udviklingen, er der altså ingen garanti for, at det er hele kroppen, der kommer til at lide af abnorm vækst. Vi har derfor at gøre med et helt spektrum af sjældne patienter, hvor nogle kun har en enkelt finger, der er for stor, mens andre kæmper med alvorlige misdannelser omfattende hjerne og blodkar.

Formålet med mit projekt er at forstå, hvorledes de forskellige genetiske ”stavefejl” i PIK3CA omprogrammerer en celles udvikling og vækst. For at komme så tæt på den tidlige udvikling som muligt bruger jeg pluripotente stamceller, dvs. celler med potentiale til at blive til enhver anden celle i menneskekroppen. For at få stamceller med de rette genetiske fejl, kan man benytte sig af to forskellige teknikker. Den ene er at få en vævsprøve fra patienten og omprogrammere hudceller tilbage til stamceller – en metode, der førte til udgivelsen af en Nobelpris! Den anden teknik benytter sig af nutidens biologis mest revolutionerende redskab (en kommende Nobelpris): CRISPR. CRISPR kan sammenlignes med en saks, der er i stand til at klippe meget præcist i DNA’et i lige netop dét gen, man ønsker at ændre. Man lapper derefter DNA-bruddet og indsætter samtidigt den ønskede ”stavefejl”. Voilá – jeg har de celler, jeg skal bruge! (Helt så let er det heller ikke, og det tog mig et helt år at nå dertil!)

Min forskning er betydningsfuld, fordi den nye viden potentielt kan føre til udviklingen af nye behandlingsmetoder for sjældne patienter med abnorm vækst. I bredere forstand vil vi lære noget fundamentalt om udviklings- og vækstkontrol på cellulært niveau. Sidst men ikke mindst vil denne viden bidrage til en bedre forståelse af individuelle kræftgeners virkningsmekanismer.

Mange, der kender mig, tænker sikkert: ”Det har godt nok ingenting med diabetes at gøre.”

Og så alligevel – det har i den grad noget med det at gøre. Den hyppigste form for diabetes, Type 2, er en stofskiftesygdom karakteriseret ved manglende evne til at fjerne sukker fra blodet, fordi bugspytkirtlen ikke er i stand til at producere nok af hormonet insulin og den smule, der stadig bliver lavet, er ikke længere i stand til at virke på de muskel- og fedtceller, der skal optage sukkeret. PIK3CA er et af nøgleproteinerne, der gør en celle i stand til at respondere på insulin: ved at optage sukker og vokse. PIK3CA orkestrerer derfor cellens stofskifte, og mit projekt giver mig den unikke mulighed for at få et indblik i de underliggende mekanismer.

Det er vildt spændende. Og krævende! Dog er jeg taknemmelig for at kunne sige, at jeg bliver betalt for at lave noget, som jeg elsker, som er sjovt, og som har en mening – for mig personligt, og også for de patienter, der bliver berørt af det.

Developing that incurable curiousity, life-changing events and decisions: the bumpy road to my life as a scientist

I made the decision to start my own little science blog after attending a Wellcome Trust meeting for 1st year PhD students yesterday. The purpose of my blog will be to engage the public with my life as a biomedical PhD student, hopefully inspiring others to follow the same path. But who am I and how did I end up in one of the world’s best universities? The following is a personal insight into my life and why I believe that anyone with a passion to learn, access to the right mentors and most importantly – perseverance – can make it this far and beyond. If you desire something deeply, chase that dream, don’t let it go.