Harnessing forces: an interview with Lining (Arnold) Ju

Harnessing forces: an interview with Lining (Arnold) Ju

September 14, 2016

On reading that the 21st century would be known as the century of biology, mechanical engineering graduate Lining (Arnold) Ju decided to pursue a PhD in biomedical engineering. He is currently a postdoc at the Heart Research Institute and a lecturer at the University of Sydney in Australia, where he studies how platelets sense mechanical forces and how problems in this process can lead to various blood diseases.

Arnold JuArnold Ju. Image: Jason Jia

What drove your interest in science?
When I was at elementary school in the early 1990s, China was still quite poor. For example, there were a few days every month when the supplies of water and electricity to my home were cut. Around that time, there was a lot of social media discussion about a national development strategy driven by science and technology. This made me believe that science can help us escape poverty and improve our quality of life. 

Did you always plan on following a research career? 
When I finished my PhD, I thought about joining a biotech company. But I heard that company life is quite structured and disciplined, which didn't suit my personality. I like to try challenging things and to think "outside the box". Moreover, I was deeply influenced by Steve Jobs’ commencement address at Stanford. I thought I should keep trying to extend the boundary of human knowledge, and so I decided to do a postdoc and stay in academia. 

In your recent paper in eLife you report how mechanical forces act on a molecule in a platelet and are sensed and converted into biochemical signals. Why is it biologically important to understand how mechanical forces affect single molecules?
In all forms of life, survival is based upon the ability to respond to environmental pressures, including diverse sets of mechanical forces. For example, these forces play an important role in shaping, developing and maintaining tissues. As a fundamental question, how individual “mechanosensor” proteins sense force and convert it into biochemical signals that can influence cell behaviour is poorly understood. The main reason for this is a lack of tools that can study the relationship between binding kinetics, protein conformation and signalling in the normal cell environment and concurrently measure the dynamics of this system. 

How would you summarize the main findings of your paper?
We developed a nanotool called a biomembrane force probe (BFP) that shows how single molecules sense mechanical forces in real time. The probe is much more widely applicable than existing nanotools: it works with almost all membrane receptor systems and, most importantly, can be used in experiments on live cells. Using the BFP, we developed a clearer understanding of how platelets sense the mechanical forces they encounter during bleeding and start the signalling process that leads to blood clotting. The structural insights we gained may help to design a generic mechanosensory machine. 

Why would we want to build such a machine? 
The next generation of biotechnology allows people to design synthetic receptors and engineer customized cell sensing and response behaviours. Having the ability to build synthetic mechanosensory proteins will be even more powerful as it will give us another degree of freedom for controlling cell behaviours mechanically. At the moment, a big application for this concept is immunotherapy: reprogramming immune cells to sense and destroy cancers.  

What are the other medical implications of your findings?
The formation of blood clots inside vessels – thrombosis – contributes to the world’s most deadly diseases, including cardiovascular disease, sepsis and cancer. The drugs that are normally used to prevent these platelet clots, such as aspirin and clopidogrel, do not work well in conditions that produce high shear forces, as seen when blood flows through narrowed vessels or past clots in large arteries. Understanding the way in which mechanosensing mechanisms affect how platelets form clots will help researchers to identify new treatments and preventative measures for cardiovascular diseases. 

Are you currently working on anything that follows up on those results?
Yes. After I finished my PhD I wanted to find out whether these biophysical insights have biological significance. Therefore, I joined a platelet biology and thrombosis lab to work on animal experiments. I am working to develop ways to study mechanosensing under both physiological and pathological conditions using animal models. I’m also performing drug tests using a few inhibitors that target the platelet mechanosensing pathway.

What else are you working on at the moment?
In another aspect of our study, we discovered that a mutation associated with a bleeding disorder called Type 2B von Willibrand disease prevents the platelet mechanosensing molecule from efficiently converting mechanical signals into biochemical signals. Starting from this, I am thinking of developing a point-of-care approach for diagnosing blood diseases and performing tests on samples taken from patients. The good news is that my current supervisor has established a consortium that allows me to directly work with clinicians and translate fundamental biological insights into potential real-world solutions.

What is a normal working day like for you – for example, what did you do yesterday?
In the morning, I organised a journal club, checked mice in the animal facility, prepared blood samples and isolated platelets. I then performed experiments all afternoon, until 6pm. In the evening, I drove home from work, performed data analysis, wrote emails and planned experiments for the following day.  

What has been your most thrilling moment in your research career?
When my work was accepted by eLife. And when the National Science Foundation in the US selected my work as the top story.

And the most discouraging?
A million rejections before eLife accepted my work. 

How long did it take to get the paper published? 
It took three years to generate the results and one and a half years to write the manuscript, pass through all the rejections and get the paper accepted.

Who has most influenced your career so far?
My Ph.D. supervisor Prof. Cheng Zhu. He told me “less complaints, more efforts”.

If you could travel back in time to when you started your PhD, what advice would you give yourself?
Not to be scared of leaving my comfort zone. Amazing things happen at the cutting edge. 

And if you could travel five years into the future, what would you hope to find yourself doing?
I hope I could find myself staying in science and working towards translating the fundamental discovery in my eLife paper into some real-world solutions for cardiovascular diseases. 

In your opinion, what changes would most improve the way that science is done today?
Reform the current peer review process and stop evaluating scientific success by impact factor. We also spend too much time writing grants, rebutting reviews and completing lots of non-scientific paperwork.  

And what would most improve the professional lives of early career scientists?
Improving stipends or providing more sources of funding for early career scientists. This may prevent some good people from leaving science. Unfortunately, the current funding environment and living pressures are not favourable to young scientists. 

Having moved from the US to Australia, have you noticed any differences in how science is performed and supported? 
Compared with the US, Australia has a smaller research community. The good thing is that there is less competition; the bad thing is that peer communication is quite difficult. The funding mechanism is also different. Unlike the US, where it is possible to gets funds in almost all areas of research, Australia only funds a few prioritised research areas that have most impact on the country. 

Do you find it easy to get the work-life balance right?
I’ve found it more and more challenging. When I started my PhD I was single. I used to stay in the lab until midnight in order to get the answers to intriguing scientific questions. Now I’m married, I find it impossible to work in that way. 

What are your main interests outside of science?
Travel. I enjoy visiting different countries and experiencing different cultures. 

What would we be surprised to learn about you?
In the second year of my PhD, I went to a small town at the US-Mexico border to renew my student visa. Unfortunately, due to a problem with the paperwork, I was stuck there for two months. It was the wrong decision at the wrong time in the wrong place, because my trip coincided with the period when the drug war was escalated at the border. My ignorance put me into the most dangerous moment in my life. During that time, a local Mexican family accommodated me. In return, I helped their business by selling tacos and lumberjacking. In the end, I survived in Mexico, got my paperwork processed and returned to my PhD life in the US. Otherwise, the eLife study would never have happened. 

Lining (Arnold) Ju CV

2015 – present: Postdoc, the Heart Research Institute; Lecturer, the University of Sydney, Australia
2014: Postdoc, Monash University, Australia
2008 – 2013: PhD in Biomedical Engineering, Georgia Institute of Technology and Emory University, USA
2011: Visiting Scholar, Oklahoma Medical Research Foundation, USA
2004 – 2008: BS in Applied Mechanics, Peking University, China