Interview: insights from a career researching the protein corona and combating academic bullying

Can you share a turning point in your work as a scientist?

The first turning point was when I decided to immigrate to the USA 9 years ago. My work in regenerative medicine and nanomedicine requires crosstalk between different experts. However, the crosstalk between experts was not so great – not like today. By training, I'm a material scientist and my master of science was in biomedical engineering, but I needed to get training from other fields. So I traveled a great deal, visiting labs in Ireland and Switzerland and then in the USA.

My main lab was in Tehran, Iran, but due to sanctions and many other difficulties, we were not able to achieve a useful level of interdisciplinary crosstalk. We also did not have sufficient facilities or funding to perform high-quality nanomedicine research. I decided to leave my well-established lab and the position I had held for almost 5 years as an assistant professor at Tehran University of Medical Sciences and migrate to the USA. I started over with a postdoc at Stanford University and then went to Harvard Medical School, where my last position was assistant professor. The entire process of emigration and starting over was certainly a major turning point.

Another inflection point was starting work in the field of academic bullying. Having worked at a range of different universities, I was surprised at how common it was to witness people suffering from what we call academic bullying and harassment. In 2018, I wrote a very short piece for Nature as a corresponding letter to the editor [1]. It was only a few paragraphs describing the difficulties that international students have in reporting academic bullying to their institutions. However, interestingly, the volume of the response I received from this very short piece was far beyond all the feedback I've received from all my papers in the fields of nanomedicine and regenerative medicine combined.

I believe that we scientists share the mission of maintaining honesty and integrity while improving science to make the world a better place for everyone. I began studying academic bullying in part to make it less taboo, because when I talked with other scientists, I realized that almost every one had either experienced or witnessed these behaviors. Everyone knows that we have this problem, but no one wants to talk about it for fear of retaliation or any number of other reasons. That was the next turning point in my scientific journey.

Can you outline what your lab is currently working on?

In the field of nanomedicine, we continue to work on improving the robustness and reproducibility of nanomedical data, as we have been doing for almost 12 years [2]. We are looking for ways to modify assays, characterization approaches and methodology to obtain better data, such as ensuring that we are not unintentionally introducing errors. For example, back in 2009, we started modifying toxicity assays because they were developed for toxicity evaluation of chemical compounds and other types of materials, rather than nanoparticles. When someone wanted to use a toxicity assay for nanomedicine, a specific modification was needed for each type of assay to avoid errors. For example, one commonly used assay for assessing cells' metabolic activity is MTT assay [2]. For many it is the standard assay of the cytotoxicity or compatibility of a product, but research over the past decade has shown that many nanoparticles interact with assay compounds to generate data errors. Thus, we are trying to improve the accuracy of these assays.

We also seek to modify current methodologies and characterization techniques for protein corona formation and analysis. We want to ensure that our identification of the biological identity of nanoparticles is robust and reproducible by others, and not compromised by protein contamination. Having accurate information helps to define the biological fate of the particles and to add value to protein corona data.

To date, protein corona has mostly been considered a source of complications in nanomedicine [3]. For example, if someone makes a targeted nanoparticle and uses antibodies, aptamers or any targeting species on the surface, protein corona can shield them and cause mistargeting. As another example, if someone develops a nanoparticle for drug delivery, the protein corona can add an additional barrier and alter the drug-release profile seen with in vitro evaluations.

Now we are broadening our focus to include the potential advantages offered by the protein corona. In 2014 my team defined the concept of disease-specific or personalized protein corona [4]. This means that plasmas from different people produce protein coronas that reflect the health conditions of those individuals, suggesting the use of protein corona for disease detection. Such methods could also support many other techniques such as proteomics approaches for finding biomarkers [5]. Other groups are also working on using protein corona data for development of new therapeutics. However, all such projects first require accurate data.

Our research seeks to understand what affects protein corona and how it can be analyzed in a robust way to allow those data to be used by other scientists [6,7]. We are examining whether and how various plasma factors such as sex, age and health status affect the protein corona. We also continue to propose methodologies to avoid protein contamination when preparing the protein corona [8].

Very recently, we identified another major factor affecting outcomes of protein corona research. Experts in the field are now adept at characterization techniques, checking the size of the protein corona and obtaining profiles of protein coronas using gel electrophoresis techniques, but the bottleneck remains mass spectrometry. Many labs send their prepared corona-coated nanoparticles to an external mass spec lab for analysis of the type and abundance of proteins on their surface.

To assess variability among mass spectroscopy centers, we sent the same aliquot of identical particles to different core facilities around the USA. The results were shocking: though over 4000 total proteins were identified, fewer than 75 of those were shared by all cores. That means only 2% of the data were reproducible across cores [9]. Our findings suggest that protein corona datasets should not be compared across independent studies and more broadly may compromise the interpretation of protein corona research, with implications for biomarker discovery as well as the safety and efficacy of nanoscale biotechnologies.

In the area of academic bullying, we are now focused on i) how targets can protect themselves [10], ii) better understand the reasons that enables bullies to thrive in academia [11] and iii) strategies that can bring other stakeholders to the discussion to seek solutions [12]. For example, we continue to discuss the issue with various funding agencies. We also constantly ask journal editors to join the discussion because we believe them ideally positioned to increase awareness among a wide range of communities. However, their current understanding is that academic bullying is not a concern among their audience; if they come to understand that academic bullying can cause plagiarism and data falsification, they will be more likely to see it as a relevant problem. We continue to point out why they should also be part of the conversation in addressing academic bullying.

Your research has included work on the importance of sex in assessing nanomedicines such as your paper published in Nature Communications in 2021 [13]. Could you elaborate on this please?

We began looking at sex differences in nanomedicine back in 2016 using samples of the placenta layer taken from male and female newborns. We wanted to have access to earlier-stage, sex-specific cells that have not been exposed to many sex-specific hormones, to determine how sex may affect the cell's interaction with nanoparticles.

The outcomes we published in 2018 were very interesting, as they showed that the uptake of nanoparticles by male and female cells – and the very structure of male and female placenta-derived cells – was different [14]. For example, we noticed that the distribution, characterization and thickness and shape of the actin filaments and microtubules were different in male and female cells. We posited that this affected nanoparticle uptake, as female cells have three-times more uptake than male cells. That is just one example of why sex is a critical consideration in using nanomedicines as therapeutic agents.

This effect adds to sex imbalances in clinical trials, where many researchers mostly consider males because there are fewer complications for the outcomes they are measuring. In our Nature Communications paper, we took a closer look at other factors that may affect nanoparticles when they interact with male and female cells or biosystems [13]. For example, we found corporate data suggesting that the plasma from males and the plasma from females have significantly different proteins.

This is extremely important because the composition of the protein corona depends on the composition of the plasma. Significant differences in plasma produce significant variations in the corona profiles or biological identity of nanoparticles. This means, for example, that the safety, therapeutic efficacy and biological fate of those particles would be different in males and females. There is already a strong call for development of sex-specific nanoparticles as a prerequisite for safe and efficient nanomedicine therapies for all.

We propose that, like other parameters such as age, health status and general robustness of data, sex also needs to be considered as a key factor in developing safe and an efficient nanoparticles for both sexes.

Finally, where do you think that the field of nanomedicine will be in 10 years' time?

The extremely broad spectrum of possible applications of nanomedicine makes predicting its future very difficult. But at least in terms of the biological identity of nanoparticles, I think that in 10 years many nanomedicine-based diagnostics and therapeutics will have sprung from a deeper understanding of the protein corona. Perhaps that will include supporting immunotherapy approaches or diagnosing diseases at their very earliest stages. Many companies have already begun work on the early detection of disease using nanoparticles. I would also predict that the information and data we derive from better understanding the protein corona will yield significant improvements on both diagnostic and therapeutic fronts over the next 10 years. It could also help spur the development of disease-specific and sex-specific nanodiagnostics and nanotherapeutics.