Science | DEZERAECOX

Terrific TDP-43 Talks in Trieste

Wed, 11 Oct 2023 12:58:17 +0000

Terrific TDP-43 Talks in Trieste

As you may know, I am currently a Lady Edith Wolfson Junior Non-Clinical Research Fellow at the University of Cambridge. My work, supported by the MND Association, seeks to develop new tools that enable us to evaluate models of MND we use in the laboratory for research and therapeutic testing. I have been focused on a protein, one of the fundamental building blocks of every cell in our body, which goes rogue in up to 97% of people living with MND. This protein is called TDP-43. It forms clumps (”aggregates”) in specialised brain cells called motor neurons, and is thought to be intimately linked to the death of these cells which underlies all forms of MND.

Recently, I had the privilege of attending the held at the beautiful Stazione Marittima in Trieste, Italy. As the name implies, this meeting was the first of its kind specifically seeking to bring together people from all around the world whose work is focused on TDP-43; from how it is encoded in our DNA, to how the protein is produced, regulated and functions in healthy cells, to how failures of its function can lead to disease. In contrast to traditional meetings focused on a specific disease or cellular phenomenon, there was a uniquely singular focus on TDP-43 and all aspects of its biology.

The meeting was opened by local host Emanuele Buratti. Dr Buratti treated the audience, spanning students to established giants of the field, to a trip down memory lane. Sharing photos of original results and hand-drawn annotations from his lab books from the late 1990’s, Buratti gave early context to a field that has gone on to span more than two decades. It set the scene for a fantastic program featuring presenters from around the globe who would go on to describe novel experimental approaches, advances in our understanding of how TDP-43 relates to MND, and new therapeutic strategies that are gaining traction toward clinical trials. Recounting it all would take longer than the meeting itself (unfortunately a case of ‘you had to be there’!) but I am delighted to have the opportunity to share a snapshot of some of the outstanding science with you.

An early highlight came in the form of a potential new therapeutic strategy, described by James Shorter in his presentation “ (Dis)solving the problem of aberrant protein states“. Recent work from Shorter’s team has focused on the normal function of TDP-43 in cells which involves the separation into a distinct phase, similar to how oil comes together to form droplets in water. If TDP-43 stays in this separated state for too long then it can turn into elongated aggregates similar to those associated with MND. Shorter’s team have , another fundamental cellular building block, to manipulate the phase formed by TDP-43 and reverse the abnormal phases. In theory, this could prevent or even reverse the characteristic clumps formed by TDP-43 in those living with MND - an exciting proof of principle that offers a promising potential new strategy toward viable therapeutics.

Competing for best pop-culture reference, Michael Ward introduced us to the TDP-43 Multiverse during his talk titled “ Functional genomic strategies to identify regulators of neuronal TDP-43 biology”. Just as big data has taken the world by storm, biology is now generating and exploiting bigger datasets than ever before. Ward’s research encourages us to ‘think bigger’ when it comes to TDP-43. Using computational tools, including different cell types and a range of biological molecules such as DNA, RNA and proteins, in an attempt to unravel the chaos that erupts in neurons when TDP-43 function is lost. The resulting data atlas may let us pinpoint the effects of losing TDP-43 function that are specific to motor neurons, a key mechanism of MND that remains unknown.

Late on the second day, Alyssa Coyne presented “ Large scale analysis of sALS and C9orf72 ALS/FTD iPSNs reveals defects in TDP-43 function repaired by genetic therapies”. In essence, a tour de force analysis of the collection of cell models created from people living with MND, which are an invaluable experimental tool. Alyssa asked a simple question, which is similarly at the heart of my research: How good are these models at capturing what we see in real people? One of the principal functions of TDP-43 is in processing RNA. RNA plays a vital role in our cells by converting the instructions from DNA to make proteins. TDP-43 processes a collection of different RNAs, which form a characteristic signature. Looking at the signature in cell models and comparing them to those of the corresponding donor allowed Coyne’s team to establish that signatures are variable between patients, just like fingerprints, but that cells can faithfully recreate the signature of their matched donor. These signatures together pointed toward defects in how molecules move within cells in MND. When TDP-43 is dysfunctional, it is found to move from the DNA storehouse - the nucleus - into the larger cell body, where it forms clumps. , again offering hope of a new potential target for therapeutic intervention.

Last but not least, the poster session — where many early career researchers showcase their work — is always a firm favourite, and this one did not disappoint. With the backdrop of a stunning sunset, attendees were treated to some stellar discussions from the future of the field. Carlo Scialò shared his progress towards the ultrasensitive detection of TDP-43 in nasal swabs; Oscar Wilkins described a new computational tool, SpliceNouveau, to help design next-generation therapies; and Diana Arseni described her groundbreaking work delivering an atomic-scale picture of the shape TDP-43 adopts when it forms the toxic aggregates found in MND. Such sessions are an invaluable opportunity to make connections, discover new technologies, and see ‘fresh-from-the-bench’ science.

In all, this really was a fantastic event spanning all manner of biochemical, biophysical, and clinical approaches to understanding TDP-43, a molecule at the heart of MND. I learnt more than I thought possible and am so grateful for the opportunity to immerse myself in this welcoming and exciting research community. I have no doubt that the collaborations forged throughout the meeting will drive TDP-43 research forward, and I can’t wait for the 2nd conference on TDP-43 function and dysfunction in disease in a few years’ time!

Can’t get enough TDP-43? Find out more about my research , or check out the complete conference program . For anyone interested in the next iteration of the meeting, stay tuned - I look forward to seeing you there!

This post was developed with editorial contributions from Charlotte Roy from the , who supported my attendance at this meeting. A version of the post first appeared .

Investigating the Investigators: 2020 Edition

Tue, 16 Mar 2021 19:00:00 +0000

Investigating the Investigators: 2020 Edition

Each year the Australian National Health and Medical Research Council award a set of Fellowships to outstanding scientists. As an Early-Career Researcher, you might say I have a vested interest in understanding the picture these outcomes paint for my ability to pursue a research career in Australia. I’ve written extensively about how the outcomes reflect trends of the scheme as a whole (you can find a detailed description of the , and a ). But this still begs the question: just what does a successful Investigator look like in my field and at my career stage in 2020? And perhaps even more importantly for you, what did a successful application look like amongst your peers? So, this year I’ve decided to put the data in your hands!

Introducing the portal

Meet : a collection of interactive datasets underlying the NHMRC outcomes across four key metrics - Research area, Geography, Seniority and Gender. You can now explore how the Fellowship scheme has evolved with time, how the most successful research hubs are distributed, and what characteristics are typical of successful applications within each funding tier. The landing page includes everything you need to know to get started, as well as some resources for the extra curious among you.

A few words on why…

These Fellowships are the life-blood of many Australian researchers, and are always hotly-contested tickets for emerging and established researchers alike. Astoundingly, given the absolute reliance on data when it comes to everyday science, very little is done with the outcome data beyond cursory summaries of gender and career stage equity. Researchers deserve to know what the overarching trends are and how the scheme has evolved. Now, the interactive and wholistic nature of the datasets means that you no longer have to take my word for it (or anyone else’s for that matter!). In addition, my hope is that the portal will be a step toward maximizing access to actionable insights for researchers looking to develop their future funding strategy.

Final thoughts

Researchers are already busy preparing applications for the next round of Investigator Grants which close in just a few short weeks, and this year the stakes are perhaps higher than ever before. As , external funding sources will be paramount. For ECRs especially, the next few years look bleak as we are at without dedicated support.

With outcome data directly in the hands of researchers, everyone has the opportunity to make data-driven decisions about where their energies are best spent next application season. Most importantly, these data offer us as a community the opportunity to evaluate how well the scheme outcomes are aligned with our priorities for supporting innovative and emerging researchers as the future of Australian science.

So, without any further ado…. If you haven’t already, head on over to . Happy exploring!

Are you thinking of applying in the next round of Investigator Grants? Did any of the datasets surprise you, or were they helpful in your decision of whether or not to apply? Head over to the , or let me know on !

Image credits: inspecting gears with magnifying glass | @ pluyer via

Lorne Proteins 2020

Sat, 08 Feb 2020 05:19:01 +0000

Lorne Proteins 2020

If you’ve landed here after checking out my poster , welcome. If you stumbled here by accident, the more the merrier. Either way, thanks for stopping by!

I hope you found something interesting or useful, and enjoyed hearing about the work we are doing to develop new tools for measuring proteostasis. If you have any questions, want to know more about what we do, or simply want to get in touch, you can find me on twitter head over to the .

For anyone who wasn’t at the conference, or didn’t get a chance to say hi, I have included a brief run-down (and tried to skip over most of the gory – boring, technical – details!).

What’s all this proteostasis business?

Cells have an extensive quality control network responsible for maintaining their molecular machines, including synthesis, folding, degradation and transport

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. Collectively, this machinery is known as the proteostasis network. Proteostasis imbalance results in protein misfolding and aggregation, the central molecular signature of neurodegenerative diseases such as Alzheimer’s and Parkinson’s.

We lack knowledge of which proteins in the cell become vulnerable to improper folding during proteostasis imbalance. One measure of protein foldedness is the extent to which a protein can be unfolded thermally or with a chemical denaturant such as urea. Until recently, it has been difficult to track foldedness in cells due to sheer complexity of the many ten’s of thousands of proteins and proteoforms needed for our cells to function.

To overcome this, this work specifically aimed to:

Devise a chemical biology and proteomics approach to monitor the foldedness of the proteome.
Determine the influence of pharmacological agents that unbalance proteostasis on proteome foldedness.

What is tetraphenylethene maleimide, other than a tongue twister?!

Tetraphenylethene maleimide (TPE-MI) is a dye (tetraphenylethene maleimide) that becomes fluorescent when it binds to reactive thiol residues

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. Buried, reactive thiols are the most buried residue of all amino acids in globular (properly folded) proteins. Monitoring the exposure of these thiols using TPE-MI gives us a sensitive way to probe foldedness in complex mixtures.

To test this strategy, we used a purified, well-studied protein – β-lactoglobulin. We know both the sequence and 3D structure of this protein, and its behaviour in a range of denaturants is known. β-lactoglobulin has 5 thiol residues, of which two pairs are bonded and the remaining one (Cys121) is buried in the core of the folded protein. As β-lactoglobulin unfolds in increasing concentrations of denaturant, we get a corresponding increase in TPE-MI fluorescence.

But what about the giant protein soup our cells make, I hear you ask…

While TPE-MI can reliably tell us about the unfolding of a single, purified protein, our cells are jam-packed with thousands of copies of thousands of different proteins. How can we possibly know which proteins TPE-MI is binding to?

Enter: proteomics. This revolutionary tool is a workflow based on mass spectrometry which can report back on the composition of complex mixtures – both which proteins are present, and the relative amount of that protein. The basics of this technique are beyond the scope of this post, but if you are looking for more details check out the resources section below

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. I have included a brief explanation of the method we use below, which relies on isotopically labelling cells in culture before lysing, denaturing and labelling with TPE-MI. Proteins are digested (chopped up) into regular, smaller pieces before analysis via mass spectrometry.

Using custom software, we can identify and quantify protein pieces. Unfortunately, we cannot identify the protein pieces specifically labelled with TPE-MI, but instead, we look for the loss of those pieces. We can do this for many many proteins and start to understand the concentration at which specific proteins unfold. We can even start to understand intricacies in unfolding for separate protein domains.

How does this help us understand disease mechanisms?

This new method now provides a way to monitor how the stability of proteins (measured how much denaturant it takes to unfold them) changes under conditions of proteostasis impairment that are present in disease. For example, we are now investigating the changes in proteome foldedness when we inhibit hubs of the proteostasis network such as molecular chaperones. How do the proteins that rely on specific molecular chaperones to be folded change when those proteins are no longer active? What if we stop the cell from degrading old proteins? Or from decorating their proteins with extra modifications that mediate structure and activity like phosphorylation? Defects in this machinery are common in neurodegenerative protein aggregation diseases and we now have the tools to start tackling these questions.

References and handy links

Chiti F, Dobson CM (2017) . Annu Rev Biochem 86: 27–68.
Chen MZ, Moily NS, Bridgford JL, Wood RJ, Radwan M, Smith TA, Song Z, Tang BZ, Tilley L, Xu X, Reid GE, Pouladi MA, Hong Y, Hatters DM (2017) . Nat Commun 8: 1–10.
Lottspeich, F. (2009). . In Proteomics (pp. 3-10). Humana Press.
Graves, P. R., & Haystead, T. A. (2002). . Microbiology and molecular biology reviews, 66(1), 39-63.

That’s all from me for now. Still can’t get enough or want to know more? Simply want to get in touch? Find me on twitter head over to the - love to hear from you! Now, back to the beach 🏄🌴☀️ !

BioInfoSummer 2019

Sun, 29 Dec 2019 09:28:44 +0000

With half my home state on fire and the lead up to Christmas, this post has been in the works for a few weeks. But here it is - better late than never! My brief recap of my recent adventure to BioInfoSummer 2019.

Conference details

Title:

Date: December 2nd - 6th 2019

Location: University of Sydney, Australia

Overview:

BioInfoSummer brings together advanced undergraduate and postgraduate students, researchers and professionals from the mathematics, statistics, medical sciences and information technology disciplines. Attendees develop bioinformatics skills, national networks and employability. The central themes of the 2019 conference were Epigenetics/genomics, Single cell omics, Mass spec analytics and BioCAsia/precision medicine.

Overall thoughts and impressions

Of all the conference travel I have done this year, BioInfoSummer was the closest to home and the furthest from a normal conference. The wide applicability of omics techniques meant a broad spectrum of research topics presented by a diverse collection of researchers with a common love for data analysis. In addition, being targeted at students and early-career researchers meant the dynamic of the seminar sessions was quite different - an atmosphere in which students were comfortable asking questions and driving the discussion around world-leading best practices in the field of bioinformatics. This was supported by plentiful and generous travel scholarships boosting the participation of interstate early-career researchers.

Even though my research has been edging into bioinformatics for a little while, this was my first formal foray into the community. While I was a little anxious about being immersed in a new group of people, luckily bioinformaticians are a friendly bunch! This meant that the workshops had a welcoming feel, creating a safe space to actively try out the techniques presented during the morning symposium sessions.

Last but not least, the location and timing of BioInfoSummer meant that they were able to share sessions and speakers with , and were followed directly by . This enriched the sessions and provided even greater diversity and networking opportunities. This truly was a fantastic blend representative of the bioinformatics scene in Australia. I cannot recommend enough for new PhD students or post-doctoral researchers new to bioinformatics in it’s many incarnations.

Lessions learnt

1. Bioinformatic techniques for proteomic analyses lags behind the trail blazed by genomics - this was evident in the distribution of the program, but also attendees. However, I also think that…

2. The distinction between proteomics and genomics is sometimes unhelpful - similar underlying data structures make some methods applicable to both, and leveraging the substantial ground that has been covered in genomics will assist in the rapid progression and development of proteomics methods.

3. Single cells are the future, but not the complete story - innovations in single-cell proteomics and ongoing developments in single-cell RNAseq will continue to push the boundaries of our understanding of biology on the smallest scales. However, one of my favourite talks of the conference was on the value of bulk methods in an era of single-cell capabilities. And I agree - these methods should be applied as appropriate and often one and inform the other.

4. Seeing is believing - two-dimensional imaging mass spec and spatial transcriptomics are the next frontier. With these techniques, we are starting to understand the spatial distribution and cooperation of cells in health and disease.

5. The future is now - the big data buzzword - everyone will have heard the term big data. This is becoming more the norm than the exception, even in biological research. This has meant that method development and bioinformaticians are in high demand, and become recognised as an integral part to any research project. This was exemplified by one of the conference keynotes, in which the speaker discussed the essential skills for a bioinformatician in the next five years; many of these included the ability to wrangle, access and store large amounts of data, as well as being able to leverage this data for biological insight.

6. Unexpected acquaintances - I travelled to Sydney expecting to know no-one. In a classic small-science-world moment, within five minutes of arriving I ran into a post-doc from another research group in my building! While we had met and talked a little previously, the chance to spend a week nerding out over data analysis and coding methods was the perfect way to get to know each other better. In fact, this was one of the best parts of the conference. As well as this, I met a handful of people from my alma mata who grew up in a similar corner of the world as I did.

Take home resources

There were too many great resources to share them all, but if you’re looking for tutorial style activities then the Material for each of the is a great place to start. Other than this, below are a few of the packages, tutorials or databases that I am keen to check out after hearing about them during the conference:

’s featured workspaces demonstrate common genomic analysis pipelines deployed using data and tools available on AnVIL.
is a portal to a series of public experiments describing mouse and human stem cells and how they differentiate to become mature cells, tissues and organs.
is a collection of lightweight and handy tools for Python that help to handle various sorts of proteomics data.
: A Python Library for High-Throughput (Phospho)proteomics Data Analysis
The repository contains a list of open source Python tools for Proteomics analysis. The list is very likely incomplete and we are happy to take pull request with new tools.
The workflow management system is a tool to create reproducible and scalable data analyses. Workflows are described via a human readable, Python based language.
workflow: differential discovery in high-throughput high-dimensional cytometry datasets

These will hopefully give you a flavour of the overall themes covered at the conference, but if you are new to the world of bioinformatics I thoroughly encourage you to get involved next year. The conference is slated to be held next December in Canberra, so keep an eye out for the official announcement!

Overall, BioInfoSummer was a great opportunity to connect and build community with like-minded people. I was so lucky to be supported by an AMSI ChooseMaths travel award - without their support, I could not have travelled to attend the conference and I cannot thank them enough for their support of Women in STEM. If you are new to or interested in the world of bioinformatics I whole-heartedly recommend checking it out next year!

Image credits:

Investigating the Investigator Grants 2019

Mon, 30 Sep 2019 01:26:50 +0000

Introduction

The hottest topic on Australian researchers lips this month has been the recent NHMRC Investigator Grant announcement. After all the commotion around the new scheme and the distribution of research dollars, I set about flexing my data-science muscles to see what the outcomes of the scheme were overall, and what a successful application might look like for the next round.

What are Investigator Grants?

If you are a scientific researcher in Australia, chances are you were aware of the NHMRC announcement a few weeks ago of their latest round of funding. For those who are outside health-focused research, this was a highly-anticipated announcement after a complete re-structure of the NHMRC Funding Schemes over the previous year. The reform included replacing the Fellowship system (funds to support individual researchers to establish their own research programme) under the unified banner of Investigator Grants.

Historically, previous incarnations of these Fellowships (Early Career, Career Development and Research Fellowships) have supported the very best and brightest researchers in Australia with varying levels of lottery-luck in their award. Importantly, having been successful at the first rungs on the Fellowship ladder, researchers were then much more likely to gain the next level of support. Therefore, the award of these Fellowships to emerging researchers is a crucial support system that could make or break a career.

In particular, the lists better support for Early and Mid-Career Researchers (EMCRs) as a key goal of their reform:

Early and mid-career researchers are being discouraged from pursuing a research career.
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In response to these issues, NHMRC reviewed the structure of its research funding and has reformed its grant program.

NHMRC, 2019

Why the fuss?

For researchers who spend many (many) weeks (months) working on the application for these schemes, the outcomes are of intense interest. The research funding environment in Australia is extremely competitive, and often the difference between funded and not funded can be little more than pot-luck. Early reports during the peer review process this year suggested that the new scheme had an abundance of issues and was likely to be even more of a lottery than previous years.

After the announcement, scientists flooded Twitter with their thoughts, interpretations and statistical analysis of the overall outcomes. There were many deserving people who were lucky enough to make the grade this time around. However, there were also an abundance of leading researchers who missed out and cursory analyses highlighted an abundance of inequities and unforeseen results of the reform.

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Many of the numbers you will see online come from the key performance data released by the NHMRC (data on gender, age and state awardee rates has been made available since at least 2013). It is my firm belief that, as scientists, we should use science (including data science) to drive our decision making. The trends reveal biases/underlying issues in the grant scheme, and provide rationale/direction for additional reform. In addition, the profile of previously successful applicants can help researchers like myself understand how we fit within the scheme and, according to whether (or not) we fit the profile, inform our decision to apply in the next round (which is not that far away!).

Crunching the numbers

Most of the raw data used in this analysis came from the . I collected some extra data on the Field of Research codes and individual researchers from additional sources including the and .

After initial cleaning of the raw data, I decided to equate the new and old schemes by ‘matching’ the tiers as best as possible. According to a fact sheet provided by the , equivalent schemes are as follows: Early Career Fellowships map to Emerging Leadership level 1, Career Development Fellowships map to Emerging Leadership level 2, and Research Fellowships map to Leadership levels.

Due to differences in eligibility (according to years post-PhD) as shown above, the correlation is not perfect. But it serves the purpose of being able to compare as the NHMRC intended at least.

For the nitty-gritty details of the number crunching and visualisation techniques that went into the makings of this post, be sure to check out the post soon. If you’re simply here for the pretty pictures and insights, read on!

Key insights

Overall trends

At first glance, it appears as though the new investigator scheme has seen an injection of more money into the Fellowships portion of NHMRC funding. However, this funding includes more money per person at the upper tiers without a substantial increase in the number of applications funded. Moreover, the number of successfully funded applications and dollars was skewed toward the Leadership levels with an overall decline in the number of level 1 and 2 (Emerging Leader) applications funded.

The decline in the number of applications funded was matched by a substantial increase in the number of applications submitted, leading to a nosedive in the success rates particularly in the EL2 and L1 brackets. This increase in applications was thought to reflect the changes in eligibility structure meaning everyone had a go and often at levels far below what was appropriate for their research experience. The NHMRC is reported to be hopeful the number of applicants will decrease in the next round (thus artificially inflating the success rate).

Location, location, location!

With the conglomerate of research institutes, personnel and equipment in Melbourne, it has always been tough to beat in funding success. The same was true of this year, with Victoria the overwhelming leader in the number of awarded applications and second-highest success rate. In fact, Victoria received more than 45% of the awarded Fellowships in 2019.

The large number of applications originating in Victoria, coupled with their high success rate, suggests that not only is there a critical mass of outstanding researchers concentrated around the Melbourne biomedical hubs, but that they benefited immensely from the support processes in place in the lead up to submission. Hopefully, other institutes around the country can find value in their strategies for the following rounds.

Gauging the gender gap

Gender has always been a touchy topic when it comes to Fellowship funding in Australia, especially at the later stages of academia. There were concerted efforts made to target gender equality in the new scheme. However, at first glance, there was an enormous bias in the total number and dollars awarded. In fact, this disparity is the worst that the Fellowships scheme has seen in the last five years.

If we dig a little deeper, it becomes clear that this skew is due mainly to biases in the upper tier of the scheme. In fact, at the first and second tiers (level 1 and 2), there has been progress toward equality and, in some cases, even over-representation of women for the last five years. However, the successful males outnumber females two to one at the highest tier (level 3).

Two to one. The new scheme, if anything, has made this worse with the proportion of awards for women the lowest it has been since 2015. This points toward a systemic issue with how relative to opportunity is assessed and the lack of support for women entering the upper echelons of academia that is still ingrained in the research culture in Australia. Moreover, the extended 5-year term of these awards means that these differences will permeate University faculty for many years to come.

Titles and track records

As a general benchmark, academic titles say something about a researcher’s seniority. Considering the distribution of titles among successful awardees, there is a clear trend toward more and more senior researchers finding success at lower levels of the Fellowship scheme. For example, Associate Professors have taken a share of the level 1 funding for the last two years and for the first time, there was an Emeritus Professor awarded level 3 funding in 2019.

Similar trends can be seen in the track record of successful awardees, especially their publication history. While this is imperfect due to author name mismatches, overall the median number of publications for level 2 awardees has held steady around 50. In contrast, level 3 saw a sharp increase this year for the first time. The median number of publications for level 1 awardees has also steadily increased, meaning that to be competitive ECRs now need on average twice as many publications as they did 5 years ago.

With the revamp of funding levels and removal of specific ‘years-post-PhD’ ranges for level 1 and 2, this was always a concern. While I have (many, many) issues with using the years-post-PhD award as a ruler to measure relative success, at the bare minimum I do believe this distinction helped stratify junior researchers in the eyes of reviewers and assisted their assessment relative to opportunity. Unfortunately, the lack of boundaries this year left many researchers unsure of the appropriate level of funding they should apply for and moreover allowed many to take advantage of the lower levels in the scheme. This placed a large responsibility on reviewers to fairly evaluate an individuals trajectory against others with up to 10 years longer in research. A big ask!

Trendy topics

With every application, researchers include up to five keyword phrases describing the focus of their proposed research. By looking at the most popular keywords, I wanted to understand the research themes attracting the most funding and potentially consider how this has evolved over the last few years.

2015 keywords

2019 keywords

Interestingly, the top five keywords for the previous five years have typically been some iteration of health, disease, biology and cancer. While these seem very general, reading between the lines reveals a transition from ‘disease’-driven research to ‘health’-centric. Interestingly, epidemiology has emerged as a prominent focus this year. Cancer research has also held a steady proportion of funded applications, suggesting an area of high priority either among reviewers or impressive researchers embedded in this field.

What is unclear from these trends is the type of research being funded in these proposals. This is captured in the NHMRC reporting process as ‘broad research themes’. Traditionally, fundamental (Basic) research has held a large share of the total funding. However, the last five years have seen a steady decline in this proportion and a corresponding increase in the more translational themes.

In particular, clinical medicine and science enjoyed a sizeable bump in the proportion of funding awarded such that it has almost reached parody with basic science. This likely stems from the strong emphasis on ‘research impact’ that permeates all aspects of the new scheme, and at face value is not terribly alarming. However, our translational research must be underpinned by quality fundamental understanding and our ability to fund this type of research from the NHMRC scheme appears to be questionable in the future.

What does this mean for science, and ECRs, in Australia?

Overall, there has been a shift toward more senior and established researchers in all three levels of award. This is not merely a consequence of the new scheme, but has definitely been accentuated by it. This is likely reflective of the desire to invest in researchers who can demonstrate their previous impact has a direct and immediate public benefit.

This is also reflected in the share of the pie gobbled up by each of the four broad research areas, where Clinical and Medical Science has seen a steady increase at the expense of Basic Science.

While I made every effort to take a comprehensive snapshot of the available awardee data, these insights were limited in part by fragmentation of the data. The raw data provided by the NHMRC includes summary totals e.g. by gender or by state, but often the per-applicant information, due to obvious privacy reasons, is not available.

Some of the missing data, such as the years-post-PhD for successful applicants, could, in theory, be provided anonymously and would provide tremendous insight for potential applicants. At this stage, the closest proxy for years post-PhD is the mean age of awardees (although this as a measure is complicated by relative to opportunity). This year the mean age for level 1 awardees increased from 35 in 2018 to 37, agreeing with the overall sentiment of increasing seniority among successful applicants. With the restructuring in 2019, the NHMRC has all but done away with the ECR funding dedicated for those entering the postdoctoral workforce and require us instead to relying on the provision of project funding by senior researchers for many years before being deemed worthy and ‘impactful’.

There have been a number of statements released by associations commenting on this and other perceived failures of the new scheme, and suggesting changes to overcome these issues. For example, the released a host of recommendations aimed at alleviating many of the pain points ranging from the application structure to review processes. However, the short turnaround time (given applications for the next round open tomorrow and close in a little under two months) means that these recommendations are extremely unlikely to be implemented until next year. Moreover, this is a general and of research funding schemes world-wide. At this point, like so many other ECRs in my position, it is now time for me to think about whether my time, energy and effort are best placed in the hands of the NHMRC, other Australian funding schemes or - like so many in my position - whether I should instead focus on opportunities abroad. In the spirit of data-driven decision making, hopefully these insights have helped guide your thoughts as they have mine.

Resources

The original data was sourced from the
For more on the initial guidelines provided during the scheme restructure, check out the
Author track record information, including publication number and field-weighted citation impact, were collected from . If you are considering an application in the upcoming round, it’s a great idea to benchmark yourself against previous successful applicants.
For more info on the specific number crunching and data visualisation techniques used here, don’t forget to keep an eye out for my post.

Are you thinking of applying in the next round of Investigator Grants? Did any of these stats surprise you, or were they helpful in your decision of whether or not to apply in the next round? Head over to the , or let me know on .

Image credits: inspecting gears with magnifying glass | @ pluyer via

FASEB Protein Aggregation Conference 2019

Sun, 30 Jun 2019 04:29:41 +0000

After a science career spanning a decade without having attended an international conference, I have been fortunate enough this year to speak at not one but two! What follows is a not-so-brief rundown of my second international conference, what I learnt along the way and where I am hoping to take these lessons.

The benefits of a niche, narrow-focused conference

From the very first keynote speaker (shout out to Judith Frydman - what a powerhouse for proteostasis research), it was clear to me that this was going to be different to almost any other conference I have attended in the past. This conference (and in fact, the same is true for most FASEB themes) was very targeted around a single area of biology (protein aggregation), meaning that the talks were all very focused and relevant for all attendees. Indeed, the tight-knit and collaborative nature of this community was exemplified by the fact that each speakers acknowledgement slides listed at least one - normally many - other attendees.

It was so refreshing and heartening to see a dedicated community of brilliant researchers converge around this problem with a singular view to solving the puzzle of disease-associated aggregation. As well as this, there was a broad range of techniques on display and I felt that I left with a fantastic cross-section of the breadth of work being done in the field, both for pathogenic and functional amyloid aggregation, ranging from single-molecule through structural, cellular and whole-organism studies right up to clinical trials. Importantly, plenty of researchers presented unpublished data (presumably due to the diminished need for an extensive background in this audience, who are likely to have seen the speakers published works) that I would otherwise not have seen for many more months/years if the paper is held up during publication.

For me personally, this conference represented the intersection of my PhD work (centred on aggregation of a specific protein) and my current postdoctoral work (focusing more broadly on proteostasis and its role in disease-associated protein aggregation). So much has happened in the field since my PhD and it was pure bliss getting to nerd-out surrounded by like-minded people. I was surprised more than once at the new connections my brain was able to find in this setting. I found that by listening to many perspectives/methods targetting similar biology, it was easier to start to integrate those complex ideas rather than reading the papers in isolation. Aside from this, for the junior attendees like myself this conference made for a fantastic job market, with many lab heads in our field advertising positions.

Lessons learnt

A good and engaging speaker is one who is in tune with the audience, including their level of engagement, and who respects the time of the audience by sticking to their allocated slot.
Aim to engage. In a small group such as this, you will inevitably run into many of the high-profile speakers - maybe even at the breakfast table! - so it is essential to have attended and engaged with their talk. Bonus points for devising an intelligent question to follow up on their presented material!
The “comment and a question” audience member will always elicit a collective groan - don’t be this person!
Conference organisation is no small feat - but inevitably the strength of the organisation team will impact on the general experience. In this case, a lack of confirmed program less than a week out from the conference was not a good sign. Missteps in the organisation led to the chaotic herding of humans to food and coffee breaks and program potluck ensued when the speaking slots were revised on day one of the conference.
Location, location, location: Snowmass was an incredible conference location. A small ski village easing into the break between winter ski and summer hiking seasons, there was plenty of sunshine and a brisk breeze all set in front of a stunning snow-capped mountainous backdrop. A huge highlight of the conference was the relative isolation which, while difficult to travel to and from, heightened the sense of community and connectivity between attendees. Spending time immersed in the location will strengthen your connection to that conference. Snowmass made this particularly easy, with plenty of Springtime hikes, walks and sunshine on display.

The who, what, when and where of woeful wifi - an outstandingly woeful conference internet connection elicited plenty of complaints throughout the week. However, I did feel was more engaged with talks that I might not have otherwise prioritised, as it was much more difficult to multitask with attention-sucking admin jobs like email. While sticking almost 100 researchers in a room for large swaths of the day that does not have reliable internet is probably a recipe for disaster, it certainly supports the age-old adage of ‘unplugging’ during seminars/conferences to be emersed in the research at hand.
Chairing is caring - an experienced chair who takes control of a session, including speaker introductions and managing question time, can have a profound impact on the speakers and attendees. It is not a job that should be taken lightly. It is worthwhile paying attention next time you have the chance to observe an adept chairperson, taking note of the often unseen acts that contribute to a flawless, inclusive and positive conference session.
The diversity debate among question askers - it struck me how often the same group of 5 - 10 people in a room of ten times that many were always the ones to ask questions. I have never taken to the microphone at a conference to ask a question of the speaker. Not due to lack of ideas - I will often have a list of question ready and waiting to be addressed - but I always lack courage in a room filled with ’experts’ and my imposter syndrome keeps my butt glued to the seat. Is this maintained as some kind of PI-ready test you have to pass? Throughout this conference, I ruminated on the idea of how to engage people other than those that are brave enough to take to the microphone - there are plenty of free crowdsourcing options out there ( and to name a few), and yet I have not seen a single conference where this is adopted. I am keeping a keen eye open for an opportunity to put this inclusivity initiative into action.
By far the biggest take home from this conference was that everything which seems so significant before leaving for the conference (poster prep, student meetings, experiments, slides, …) will no longer be so important once you arrive, and will be overcome by things like remembering faces of people you meet, feeling comfortable in a room of strangers, testing the confines of your comfort zone and nailing your two-minute “who I am” pitch. I am still working on perfecting these aspects of conference attendance!

Personal perspectives

“Growing a pair” is a lifelong process: it is important to make the most of opportunities at a conference (which can often be once-in-a-lifetime combinations of people, place and perspectives) while understanding and appreciating your limits.
Finding your people and your place: while engaging with diverse people is a key goal of attending any conference, recognising that you need smaller groups and its OK to need more relaxed time (e.g. spending time with small group of colleagues for drinks at a local bar instead of the crowded networking events.

The psychology of ideas: you know that feeling when your idea is discussed during a meeting, and the academic goes on to believe it was theirs? For the first time ever, a senior academic articulated to me their inability to discern where an idea comes from, and it was enlightening. In contrast to my previous reactions, this wisened academic encouraged me (and the other early career researchers present) to hold firm when this happens and to realise that it is most often without malice but simply a product of the multitude of ideas and meetings senior researchers attend every day.
The importance of a mentor in science: it’s no secret. In fact, any time I have spoken to an academic about their career path and trajectory they speak constantly about the different mentors that smoothed their journey. But this conference, I spent a bit of time reflecting on the importance of proactively approaching search for good mentor-mentee relationships. Having mentors that enter your career organically is important, but you should also identify and target strategic additions to your ’team’ of mentors.
Who am I? Every successful and prominent researcher to take the stage at this conference began with “My lab works on…”. It is important to define this early on, and I am very aware of this hole in my current career focus.
The value of contemplation: Conferences have been one of the few times this year that I have taken the chance to sit and think - really think - about science (and life and decisions). While I would like to bring more of this deep contemplation to my every-day science, I am learning to accept and expect these events to be heightened moments of reflection and embrace the soul-searching mood!
Trading hats: with a few days set aside before and after the conference for travel, it was incredible to put on my long-lost tourist hat and enjoy the sights, sounds, smells and sensations of being in a new country. This experience reminded me of how lucky I am to have the opportunity to do this as an academic, and that I should more often take time to reflect on that privilege.

Overall, this conference was a tour-de-force of world-leading experts and cutting-edge research, and included several abstract-selected talks from ECRs (including myself!) that together comprised a diverse and wellbalanced program in a stunning location. Were you in Snowmass this June? Get in touch via and let me know what you thought of the FASEB Protein Aggregation Conference!

Banner image credits:

EMBL Proteomics in Health and Disease Mechanisms 2019

Sun, 24 Mar 2019 07:19:06 +0000

Last year I had the privilege and pleasure to attend (and present at) four scientific conferences. This year is shaping up to be just as wonderful, as I have been lucky enough to attend two conferences is as many months, marking the start of what I hope to be a productive year ahead. Here is a little about my recent European adventures, including my first oral presentation at an international conference.

Conference details:

Title:

Date: 7th - 9th March 2019

Location: Heidelberg, Germany

Overview:

Focused on the application of proteomics to cell biology and unraveling disease mechanisms by addressing conceptually novel ways to study long-standing questions in these fields. As most proteomics-based conferences tend to focus on analytical chemistry, the selection of biological topics is usually uneven. Therefore, this unique conference aims to showcase biology applications and build bridges to the disciplines where the technology’s promise is still not nearly fully realised.

There’s a first time for everything!

This was my first truly international conference. What do I mean by that? I have attended and presented at several Australian national conferences consisting of international speakers, but was yet to have travelled overseas to visit a conference in another country. Unfortunately, our isolation makes such an undertaking on a student or starting post-doctoral salary near impossible. In this case, I had been madly applying for every pot of travel funding I could find for the last year, and in a fantastic “it-never-rains-but-it-pours” moment I received all three of the grants I applied for! This meant I was able not only to travel halfway around the world and attend a pre-eminent conference in my field, I could also afford to visit some long-term collaborators for a week afterwards. All together, the two weeks of travel were almost entirely covered and this meant that instead of being consumed with the cost of my every move I could actually focus on the science.

Overall scientific programme and conference feel

Not only did I get to hear about all the amazing developments at the forefront of proteomics research worldwide, I also got to showcase some of my work to leaders in the field. This was an incredible opportunity, and while I was a little disappointed with my talk (owing to sub-optimal preparation and a large dose of nerves), I received overall positive feedback. As well as this, there was so many advances in techniques and biological understanding that I would have never come across on my own, at least not within the next 12 months while the papers are being sucked down the peer-review black hole!

As well as a stunning program, I feel I must give a bonus shout out to the EMBL organising team. Everything ran smoothly, was well organised and timed, and was superbly catered. There was also a small enough number of participants and a well-balanced program between students, post-doctoral researchers, principle investigators and moguls of the field. A conference I would highly recommend to anyone interested in the biological applications of advanced proteomics techniques.

So conferences are just an excuse to travel?

Conferences are the life-blood of academic knowledge sharing. You might think the enormous volume of published literature would be the best source of the up-to-date goings-on of the science world, but sadly in most circumstances you’d be wrong.

I have written before about the importance of conferences, particularly for those of us a little isolated outside the major American and European science hubs. This is because these conferences are essential for establishing and maintaining connections with colleagues, and for hearing about the cutting edge research being done in your field all over the world. As I alluded to above, unfortunately by the time most manuscripts have made it through the academic publishing process, six to twelve months have past (sometimes more) and there are more new and exciting developments already happening (with the advent of preprint servers such as BioRxiv this will hopefully change, but more on that in a later post).

For these reasons, conference attendance in particular for early-career researchers, is about so much more than the travel. Sure, it helps if the places you are visiting are enticing and if you can spare a few days afterward to explore, but the invaluable aspects of conference attendance always take precedence.

Lessons learnt

As my first international meeting, I learnt some new lessons about attending (and making the most of) conferences abroad.

1. Multiply your typical organisation time by at least double. International travel, in addition to conference attendance and accommodation, requires a significant investment of time and energy to plan and book a reasonable itinerary.

2. Departure day is not that far away. I realised after madly rushing to finish my slides on the 14 h flight from Australia to my stopover, that I had perhaps underestimated how quickly my departure date would approach. I was so focused on tackling the seemingly all-so-important last minute experiments and meeting with my students to plan their activities while I was away, that the very reason for my trip got pushed to the side. The result was a less-than-flattering performance during my presentation, and a general feeling of exhaustion throughout the conference which dampened my social spirit. Consequently, I did not proactively initiate many interactions with other attendees, and therefore failed to make as many useful contacts as I otherwise could have.

3. Do your research, researcher! This mostly relates to scoping out the program beforehand. Sure, reading the headline speakers you should be able to identify any leaders that would be good to hear from. But more than this - look over the abstracts, and pinpoint those which are relevant, interesting or potentially useful. To assist this process, concurrently search the presenter in PubMed to get a handle on their other research. Unfortunately, an abstract may not do justice to a programme of scientific discovery, however reading the most recent/most cited articles will help you highlight not-to-miss talks. In addition, I got caught out this conference by an invited speaker whose most recent papers have been instrumental in my project design. Unfortunately, I recognised the first author’s name, and not the speaker (who was senior author on the papers in question) and therefore missed an initial opportunity to discuss this work in depth with the driving principle investigator. Having then done my homework, I was able to make this crucial connection.

4. There will be other conferences, but this is a once-in-a-lifetime experience. Sure, there will be uncomfortable moments, especially attending a conference in a foreign country surrounded by unfamiliar languages and faces. But the best in life happens outside your comfort zone. Unfortunately, it took me a significant portion of the short three-day meeting to push my comfortable boundaries, and after the first two days I left feeling as though I had not taken enough advantage of the opportunities a small meeting with superstars-of-the-field presents. I was disappointed in the impression I made over these two days due to my lack of will power to engage in the social activities, and this was compounded by the feeling of responsibility to those who had funded my trip (including the conference organisers, with a very generous stipend). Ultimately, by the end of the conference, I gathered the seeds of a few meaningful connections to chase up by email - and the very important lesson to make more of these meetings in person in future.

Final thoughts

There are plenty of downsides to science (hellloo no job security, poor work-life balance etc) and travelling (long-haul flights, little sleep, $$$) - but conferences provide a great opportunity to combine the best of both. I would thoroughly recommend this conference, or any in the series of , for early-career researchers looking for an excuse to visit Europe and beyond.

Have you attended any other international conferences or EMBL events you can recommend? Find me on or head over to the to tell me more!

Many thanks to the generous funding provided by the Bio21 Institute Post-doctoral Fellows Travel Grant, the University of Melbourne Faculty of Dentistry, Medicine and Health Early-career Researcher Travel Award and the EMBL Corporate Partnership Programme Travel Grant. Without these initiatives, this travel would not have been possible and I am so very grateful for the opportunities provided by these funds both at the conference and beyond.

Image credits: EMBL Conference logo sourced

#LorneProteins2019 & #FASEB2019

Mon, 11 Feb 2019 06:07:09 +0000

If you’ve landed here after checking out my poster or the , welcome. Thanks for stopping by!

Just can’t get enough of the pretty pretty science? You can find details about the work I presented on my poster here. For anyone who wasn’t at these conferences, or didn’t get a chance to say hi, I have included a brief run-down (and tried to skip over most of the gory - boring, technical - details!).

Now - onto the science!

Setting the scene.

Cells have an extensive quality control network responsible for maintaining their molecular machines, including synthesis, folding, degradation and transport

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To overcome this, this work specifically aimed to:

Devise a chemical biology and proteomics approach to monitor the foldedness of the proteome.
Determine the influence of pharmacological agents that unbalance proteostasis on proteome foldedness.

What is tetraphenylethene maelimide, other than a tongue twister?!

Tetraphenylethene maelimide (TPE-MI) is a dye (tetraphenylethene maelimide) that becomes fluorescent when it binds to reactive thiol residues

\[2\]

To test this strategy, we used a purified, well-studied protein - β-lactoglobulin. We know both the sequence and 3D structure of this protein, and its behaviour in a range of denaturants is known. β-lactoglobulin has 5 thiol residues, of which two pairs are bonded and the remaining one (Cys121) is buried in the core of the folded protein. As β-lactoglobulin unfolds in increasing concentrations of denaturant, we get a corresponding increase in TPE-MI fluorescence.

But what about the giant protein soup our cells make, I hear you ask…

Enter: . This revolutionary tool is a workflow based on mass spectrometry which can report back on the composition of complex mixtures - both which proteins are present, and the relative amount of that protein. The basics of this technique are beyond the scope of this post, but if you are looking for more details check out the resources section below

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Using custom software, we can identify and quantify protein pieces. Unfortunately, we cannot identify the protein pieces specifically labelled with TPE-MI, but instead we look for the loss of those pieces. We can do this for many many proteins and start to understand the concentration at which specific proteins unfold. We can even start to understand intricacies in unfolding for seperate protein domains, such as in the example below where different reactive thiols give information on specific domains of Hsp70.

How does this help us understand disease mechanisms?

References and handy links

Chiti F, Dobson CM (2017) Annu Rev Biochem 86: 27–68.
Chen MZ, Moily NS, Bridgford JL, Wood RJ, Radwan M, Smith TA, Song Z, Tang BZ, Tilley L, Xu X, Reid GE, Pouladi MA, Hong Y, Hatters DM (2017) Nat Commun 8: 1–10.
Lottspeich, F. (2009). In Proteomics (pp. 3-10). Humana Press.
Graves, P. R., & Haystead, T. A. (2002). Microbiology and molecular biology reviews, 66(1), 39-63.

That’s all from me for now. Like the pretty pictures? Still can’t get enough of the science? Simply want to get in touch? Find me on twitter or head over the to page - I’d love to hear from you! Now, back to the beach 🏄🌴☀️ or the snow-covered mountains 🏔️⛷️!

Magnified 2018

Tue, 05 Jun 2018 07:53:54 +0000

The Illawarra Health and Medical Research Institute (IHMRI), in association with the School of Arts, English and Media at the University of Wollongong (UOW), are hosting a fundraising exhibition featuring images from the work of researchers and students, in support of Motor Neuron Disease (MND) research at IHMRI. This is a cause quite close to my heart, and as an alumnus, I was lucky enough to be invited to contribute. I actually had a heap of fun choosing my artwork (you can check out my submissions below) and for all the details on when and where you can find the exhibition head . Works in the exhibition will be on sale to the general public, with all proceeds going towards Motor Neuron Disease (MND) research at IHMRI. What better reason do you need to pick up some fantastic sciart?

Decoding Proteostasis

Proteins are the major cellular building blocks fundamental for most basic operations sustaining life. Most proteins need extensive management by the cell’s proteostasis machinery to maintain their proper shape. Proteostasis imbalance can cause neuronal death, leading to neurodegenerative disease. Various cellular stresses, such as inhibiting housekeeping functions or dismantling structural components, can differentially impact neuronal health. Understanding changes in each individual protein (columns) within a cell as it responds to different stresses (rows) highlights how different stress types influence proteostasis. Revealing common vulnerable pathways, by decoding this ‘proteome barcode’, will help focus future therapeutic targeting on neurons weakest links.

The twists and turns of proteostasis

Misfolded proteins aggregate into elongated fibrils (yellow/green ribbons), which cause neuronal death and lead to neurodegenerative diseases like MND, Parkinson’s and Alzheimer’s disease. Using powerful microscopes, we can watch how the molecular chaperones (red), part of the cells proteostasis defence network, attach along the fibrils, helping to protect the neurons from these toxic tentacles.

the nomadic scientist: blessing or curse?

Thu, 05 Apr 2018 10:36:32 +0000

From the very beginning of my undergraduate degree, I knew that I wanted to pursue research overseas. Not so much a permanent relocation, but I was very keen to leverage the international nature of science to see the world. I secured a post-graduate position with a group leader who was open and supportive of this goal, and was instrumental in helping me go abroad during my PhD research. What followed was a whirlwind trip to Cambridge, UK, where I worked on acquiring a new technique to add to my developing skills arsenal. Despite the short stint, it was hands down the most personally and professionally life changing experience.

This is not to say that my home institute isn’t producing to good science - it is - but through this experience I was immersed in a city bursting at the seams with passionate experts, cutting-edge research and world-leading techniques. To say I fell in love would be an understatement. The cohesiveness and intertwined networks I observed whilst there were an incredible, eyeopening window into the collaboration that comes from bringing together world-leading experts from a broad range of disciplines in a melting pot dedicated to the pursuit of knowledge.

After returning to Australia, I worked towards the holy grail - thesis submission - and dreamed of the postdoctoral jobs I could chase internationally. One year on I am still here, and in a position I am thoroughly enjoying, but you better believe I still have my eye on an overseas position in the next 5 years. I do wholeheartedly believe that a diverse research training period is a critical foundation for a well rounded researcher, giving context and cultivating understanding of the abundant theories and approaches one can take to answer the big scientific questions. Diverse experiences offer the chance to explore the problem at hand from a new perspective, leading to unique insight.

And as excited as I still am about all the places science could take me in the next few chapters, my extra-continental daydreams have been tainted with an air of urgency of late. I am beginning to feel as though, with the current funding climate, the only way I am going to get a foot in the door is to do my time in a country where the pay is less, the work-life balance a little more unbalanced and my family a little(lot) further away. Even worse, I am acutely aware that in this situation I am the privileged one. Assuming I am lucky enough the secure a position in a good lab group in my area of research, I have very few restrictions or barriers to relocation. Sure, money is always an issue. And there might be a few personal hiccups (my partner is not infected with my incurable case of wanderlust), but I am (relatively) young, without kids and with no significant financial constraints (other than the misguided hope to someday get on the property ladder).

Many of my colleagues, and friends, do not enjoy the same level of flexibility.

And so, I suppose this post is more about what you think - is it possible to progress in the Australian scientific research landscape without being a nomad, at least for a little while? And what effect does this have on the diversity retained in the upper echelons of the academic institutions?

Manuscript: The sticky cell savers

Wed, 14 Mar 2018 09:01:25 +0000

All great wines and whiskys are matured, some for many many years. Ageing in this way allows time for complex chemical interactions that improves their quality. Although the maturation process for my latest scientific publication wasn’t quite as long as a quality (traditionally 12 - 21 years, in case you were curious), there were times where it felt as though I was never going to get to crack open the barrel! But, we are - and with that, the remainder of my PhD research is finally published.

I will do my best to not bore you with the details, and instead try to distil 4 years of research, experiments, writing, revisions, more experiments and more revisions into a succinct description of why this paper is important. But first, if you haven’t already found it, I recommend looking here for a little context.

AIM: To examine the ability of the small heat shock molecular chaperone proteins to interact with higher order aggregates (oligomers and fibrils) of alpha-synuclein, whose aggregation is associated with Parkinson’s Disease.

NOTABLE METHODS: Single molecule total internal reflection fluorescence (TIRF) microscopy - allows us to visualise directly the chaperone proteins interacting with fibrillar alpha-synuclein, reactive oxygen cell toxicity assay to monitor the impact of fibrillar alpha-synuclein on live cells in the presence and absence of chaperone.

THE BEST BITS: Directly visualising the interaction between a small heat shock molecular chaperone protein and alpha-synuclein fibrils. While this wasn’t the version that made it into the manuscript, it’s one of my personal favourite science images so far!

TIRF image of fibrils (blue, green, yellow), with bound chaperone (red)

TAKE HOME MESSAGE: Small heat shock proteins have multiple mechanisms of interacting with potentially toxic proteins. These molecular chaperones are well-suited to intervening at various stages in the aggregation pathway to protect cells from toxicity.

If you’d like to read the full article, or maybe check out a few more pretty pictures, you can find it .

lifeguards of the cell

Sun, 11 Mar 2018 09:39:27 +0000

I believe communicating science with a broad and diverse audience is our responsibility as researchers. One of my most important audiences has always been my friends and family, many of whom didn’t do or don’t remember a single high school biology lesson. Needless to say, they’ve been a great testing ground for honing my elevator pitch - and I’ve discovered a neat metaphor makes it so much easier to describe complex scientific concepts without the dumbfounded look that normally accompanies any mention of protein homeostasis at family BBQ’s. Thankfully, our beach side home of Wollongong provides plenty of inspiration!

My scientific passion is understanding how each cell in our body achieves the world’s greatest balancing act - keeping all of its basic building blocks, proteins, in their correct three-dimensional conformation and therefore a functional state. Cells have an intricate network of ’lifeguards’, the proteostasis network, who monitor the proteins (or swimmers), keeping them folded and active or sending them to be degraded when they are no longer functional or needed. When there are disruptions to these lifeguards, the swimmers begin to drown (misfold) and can take others down with them (non-functional proteins accumulate) - at which point our cells begin to die. In the case of neurons, this cell death manifests as diseases like Alzheimer’s, ALS and Parkinson’s disease. It is therefore immensely important for us to understand why proteins begin to drown, how the lifeguards work and what contributes to their failure.

Much of my PhD work centered on one type of lifeguard - the small heat shock molecular chaperones. These lifeguards essentially patrol the beach, watching the swimmers, and spring into action when they detect a swimmer in trouble (a misfolded protein). Unfortunately they don’t have the ability to completely rescue a drowning swimmer (refold the protein), but they are quite good at bringing them back to the clubhouse and keeping them safe until help arrives (holding the protein in a folding-competent state). I focused my research on understanding how the small heat shock proteins help the swimmers (do they give them a life-ring? a pair of floaties? when do they hand them over to the experts?), and whether there was anything they could do once the drowning swimmers started to accumulate.

As a result of my PhD research, we now know that there are many ways the small heat shock proteins can interact with a particular type of swimmer (a-synuclein, whose misfolding and accumulation leads to Parkinson’s disease). Understanding these fundamental mechanisms is a crucial step in developing therapeutics to target the cellular lifeguards, to help treat or cure the diseases that result from their failure.

Lorne Conference Series 2018

Sun, 11 Feb 2018 05:31:58 +0000

At this point, I think I have written more about conferences than anything else. I am sure you are thinking that is all scientists do - Don’t be fooled! I have been incredibly fortunate to get to so many conferences in the last few months, culminating in two iconic fixtures in the Australian protein science conference circuit - Lorne Proteomics and Lorne Protein Structure and Function. I wont belabour the point about how important or valuable these conferences are (at this point, it gets kind of redundant!), but I will give a quick overview of my experience of the Lorne Meetings 2018.

First, it is important to understand the origins of the Lorne meetings. Starting out in the 70’s as a humble symposia, the Protein Structure and Function Meeting this year celebrated it’s 43rd installment. It is now at the centre of five consecutive meetings that run throughout February in the lovely beach town of Lorne, Victoria, covering Proteomics, Proteins, Genomes, Cancer and Immunology. I have been to a few of the Proteins meetings throughout my PhD, but this is the first time that I have attended two of the Lorne meetings back to back. It gave me a unique perspective on the similarities and differences of each meeting, and I benefited from each in wildly different ways.

A nice feature of the Lorne meetings is that the experience starts during the transit to Lorne. This year I traveled with one of my supervisors, and it was a great opportunity to have some one-on-one time. If you ever get the chance to travel with your academic mentors, I highly recommend grabbing it with both hands! It is through these conversations that you can get to know the person behind the science, and the politics behind the academic. For me, these conversations have been a highlight over the years, and this was no exception.

The first in my lineup was Lorne Proteomics. Given proteomics a very new skill to me, this was a great opportunity to get up-to-date knowledge from leaders in the field and help cement my growing understanding of best proteomic practices. I felt very alone and new to this crowd, with only one or two familiar faces in 240 delegates. However, I was lucky to be a speaker selected from abstract (a fancy way of saying I applied with a description of my research, and they chose me as one of the ~60 presenters). This was a true treat, as it was a great way to introduce myself and my work to a completely new network of scientists. I got some great feedback and a brand new approach to my project. What struck me most about this conference was the diversity of science that was covered in the talks. Being primarily a technique based conference (as opposed to a biological theme as with the Proteins meeting), there were marine biologists, physiologists, ‘method’ologists (mass spectrometry, crystallography, electron microscopy), molecular biologists, statisticians and mathematicians. It was a great overview of the scope of disciplines in which proteomics and associated techniques are both indispensable and actively developed.

An interesting side-note to this conference was the inclusion of the Annual General Meeting for the Australasian Society of Proteomics. This was my first foray into Society politics and management. It was a really great opportunity to observe the inner workings of the society and see where I could potentially get involved in the future. There were rumblings of an ECR-led program for Lorne Proteomics 2020, so stay tuned!

Barely a few hours after the close of the Proteomics meeting, the Proteins delegates descended on Lorne. The faces were more familiar and, for someone who enjoys the sensation of routine, everything felt a little more like ‘home’. The first night featured one of my favourite sessions - the Leach lecture, in which an emminent Australian Protein Scientist is awarded the lecture and intertwines personal experience with scientific detail. This year’s lecture was given by Ray Norton, and he did not disappoint.

Ray Norton on his journey, quoting John Lennon (or more accurately Readers Digest!)

“Life’s what happens when you’re busy making plans”

— Dezerae Cox (@dezeraecox)

Other notable sessions included the Student & Invited Speaker lunch, where I was a ‘facilitator’ (my job was to help stimulate conversation across the table). As well as the great opportunity students had to interact with our international visitors, there were two keynote speakers. First, Liz Miller gave a great summary of her science journey - how she had landed in her first post-doc, managed to coordinate two academic careers across the globe, and how she had taken advantage of the often serendipitous nature of science. Her take home message was planning moves in science takes time, so start looking and thinking about it early. This was echoed by Nobel Laureate Richard Henderson, whose take-home message was to do almost as much research into the paths you can take, and the places you can go, as actual science itself. I think, in our current scientific and political climate, that these messages could not be more timely for students to hear from leaders in our field.

Last but not least, I had the chance to catch up one-on-one with two of the international speakers. Building on my confidence from the Proteostais and Disease Symposium, I took this opportunity to get their input on my current project, their thoughts on my career goals and their advice on moving forward over the next few years. I am truly amazed, and incredibly grateful, for the generosity of experienced researchers in offering their mentorship to me as a young Early-Career Researcher - it turns out that sometimes all you have to do is ask.

It goes without saying, that if you ever have the chance to get to one of the Lorne Conferences you wont be disappointed. Hopefully I’ll see you there next year!

Advanced Scientific Programming in Python Summer School

Thu, 25 Jan 2018 23:10:08 +0000

Another post, another conference!

This time it was the Asia-Pacific “ . A full 6 days of intensive training in the programming language Python, designed to extend my amateur skills and give me more tools to analyse my data.

And boy, did it deliver - kicking off with some free swag!

The formal sessions started with a welcome from the school’s founder, Tiziano, who’s first iteration of the school was over a decade ago. His opening remarks really resonated with me:

In industry there are normally teams tackling a problem. and it is important to be kind to your teammates by writing nice code and documenting well. In science, we often work alone on our own data, and that teammate is your future self. This week is all about being kind to your future self.

Each of the main sessions targeted a specific element of scientific program in python (from GitHub to tidy data in pandas to plotting with MatPlotLib to parallelization to packaging to cython). The tutors would spend a few minutes making sure our basic knowledge was up to speed, before taking those concepts and extending them beyond what I had ever considered possible from my programming life!

A huge part of the success of the school was pair programming. The school provided one computer between two, all formatted identically and containing all the necessary applications for the week, with which we were to work in pairs to solve the lecturer’s exercises. This was a completely new experience for me - not only had I never worked with anyone else collaboratively in a coding environment, I was not accustomed to sharing my code with anyone! I have always been shy of sharing my programs, feeling like they were amateur and ‘half done’. Now, not only did my partner get to see the ‘final’ product, they would get to watch my thoughts take shape on the page! As terrifying as it sounds, I really did learn a lot from observing others and from their input as we worked together.

To consolidate our knowledge, on the final day we were split into teams where we would collaborate using our newly minted GitHub skills. The goal was to program two pacman bots which would be pitted against the other teams in a tournament - not only did I have a great team, and a great time learning to work with the bots, but we WON! This meant the delivery of swag #2: a signed copy of “Elegant Scipy”!

With tutors from Europe, New Zealand, South America and Australia, we were spoilt for expertise. Most surprisingly (and delightfully) of all was that the student profiles were just as diverse! Over the course of the conference, I worked with a particle physicist, a plant biologist, an engineer, a medical radiation physicist and a virologist. Not to mention the age, cultural and gender diversity - the group of students was a beautiful reflection of the diversity of the scientific community.

I can honestly say I felt so privileged to be selected (the conference was free to a limited number of students), and it was hands down the most practical and valuable conference for developing skills I have ever attended. If you ever have the chance to go, I cannot recommend it enough.

Happy programming!

ideas on what helps and hinders symposium speakers

Mon, 27 Nov 2017 20:28:25 +0000

During the recent , a friend was scheduled to give a talk about her work. Sitting in the audience watching a parade of marvellous speakers is a special kind of torture, when you are convinced you could not possibly achieve a similar performance. I should know - until the very last year of my PhD, I was not a very talented communicator either. However, after a venture overseas and a stint in a different lab, I found my voice. I wouldn’t say I’m brilliant (far from it), but I have realised the importance of this aspect of science communication and worked hard at being able to at least stomach the idea.

My friend asked how I’d done it. How do you overcome the paralysing fear most people associate with public speaking? I didn’t really have an answer for her at the time - I encouraged her to be confident, which is of course the main ingredient. However, I have thought about it since then, and while watching the remaining conference talks I came across a few things that as an audience member I think can make or break a presentation.

1. Don’t repeat your talk name and title - people can read the program and your first slide (we are mostly smart cookies after all), and it is the job of a good session to chair (also presumably a smart cookie) to give those details when they introduce you. Instead, open by thanking the organisers for the opportunity to present some exciting new work, and a one line teaser to grab the audience - tell them why they should pay attention RIGHT NOW, and not wait until five minutes into your talk. If you don’t have them at the beginning, there will be no getting them back.

2. Oh, you’re skipping your introduction? Because EVERYONE ELSE has given this intro? At a conference specifically about your topic? NO WAY?! Think about your audience early on in the talk’s preparation stage and don’t be afraid to adjust on Day 1 of a three day event. If available, check out the program/other abstracts early, highlight talks with relevance to yours and gauge the level of any remaining introduction that you will need to give. Being able to refer to someone else’s intro not only shows you have engaged with the symposium but also gives you more time to go through the exciting bits (your results!)

3. Keep it simple, stupid. Most of the time you will have a very short window in which to convey your story, which will inevitably be the result of months and months of your blood, sweat and tears. Trying to cram too much into this time window makes your story confusing and hard to follow (10 tiny bar graphs on one slide, anyone?) and people will loose interest. Focus on a simple message, tell people what they need to understand that message, tell them what the message is, then reiterate why your message is important. Simple. As a bonus, people will chase down details with questions, avoiding the dreaded crickets-and-tumbleweeds at the end of a particularly confusing or dense talk.

4. Following on from this, constantly telling people you don’t have time to present this, that or the other (in an effort to keep the slides simple), sounds arrogant and selfish - figure out a story that you CAN tell in the allocated time and reiterate that you are happy to talk details during the breaks.

5. Fake it till you make it. This one has stood the test of time, and for good reason. So much of our perception of a good presenter is taken from their physical cues - and that stems entirely from confidence. If you are nervous beyond belief and terrified of doing something wrong, that will inevitably come through in your body language. If you own your talk and your work, that will come across instead. I think of this like you are the pilot of a plane - if you sound scared and uncertain, your passengers are going to be unsettled and anxious, leading to this cycle of negative reinforcement. If instead you get on the PA system, calmly detail the weather or flight plan (how would they really know how high you’re going to fly??) and make them believe you are in control of the situation, your passengers (the audience) will be calm and the atmosphere relaxed. Everyone will make it out alive and live happily ever after. Or so we hope.

Got any good tips that I’ve missed? Let me know your secret ingredient!

Proteostasis & Disease Symposium 2017

Mon, 27 Nov 2017 09:55:59 +0000

The last week saw me spend more time speaking than I can recall in recent memory, all thanks to the . A blur of yummy food, wonderful people, stunning views and cutting edge science - all the makings of a good conference. If you don’t believe me, you can see what others thought here:

There are many, many meetings of scientists all over the world scattered throughout the year, but this particular conference will always have a soft spot in my heart. It is in my hometown (the absolutely stunning Wollongong), hosted by my alma-mater, and is the perfect way to showcase my science, show off my old stomping ground to international guests and catch up with my scientific family.

There was a good mix of invited international speakers, presentations selected from abstract submissions and poster presentations from PhD students at various stages. All of the talks described essential research techniques and reported positive outcomes. Truly inspiring talks that fired up my brain with new and interesting ideas, drawing spiderwebs of connections and blossoming collaborative projects.

This is part of the reason why I really enjoy scientific conferences. These opportunities are a great time to take stock of my own research and think more about how it fits within the wider field. Often, scientific research can be draining. A mass of rejections, failed experiments and job insecurity can make it difficult to remember why it was I chose this path in the first place. However, conferences are a way to reinvigorate my scientific curiosity, and many times have been the cure to a significant slump.

I mentioned that I spent a great deal of the conference talking. Having moved away at the beginning of the year, this conference was my first opportunity to catch up with people from my old institute. More importantly, though, I made a conscious decision to gain as much as I could from the three day event by focusing on my networking skills. I was determined to move on from being the shy PhD student hoping to fade into the background, and made it my mission to engage with the international guests of various levels at every opportunity.

I was lucky enough to spend a significant amount of time chatting with two of the senior researchers. I can honestly say, although at times terrifying, that this was one of the most rewarding experiences of my career so far. Despite being ‘celebrities’ of the field, they were extremely personable and made for engaging dinner conversations. More than that, they were both forthcoming with experience and advice, and offered carefully considered critiques of my research.

For those lucky enough to be blessed with the self-confidence to be unfazed by encounters with important mentors, this may not seem like a big deal. I can assure you, for me and many others, it takes a vast amount of courage and persistence - but the reward is also much much more satisfying. Feeling as though you have made a new connection with a likeminded peer or professor in your field is truly an accomplishment. Knowing that you are able to achieve something you set your mind to has a funny way of boosting your confidence, and an even funnier collection of flow-on effects.

Returning home, I am happy and excited for the week ahead. Armed with my new-found confidence and three potential new collaborations, tomorrow is the start of one of few weeks left in the year. I don’t know about you, but I’m going to make the most of it!