Lena Ho studied biochemistry at the University of Wisconsin–Madison, USA, funded by a scholarship from the Singapore Economic Development Board. Lena then joined the lab of Gerald Crabtree at Stanford University for her PhD, where she investigated the function and mechanism of chromatin remodelling proteins in the epigenetic regulation of embryonic, haematopoietic and cancer stem cells. She then moved back to Singapore for a postdoc in Bruno Reversade's lab at the Institute of Medical Biology, A*STAR, where she found that some non-coding RNAs can in fact encode short peptides, exemplified by her discovery of the peptide hormone ELABELA. In 2017, Lena became Assistant Professor at Duke–NUS Medical School and the Institute of Medical Biology, A*STAR, where her Endogenous Peptides lab currently focuses on secreted and mitochondria-localised peptides to uncover new paradigms in cell biology and improve cardiometabolic and immune health.
What inspired you to become a scientist?
In school, I think as early as third grade, we started to have time in our schedule when we could go to a designated space and grow plants or look at mould on bread under a simple microscope. I grew up in Asia, so we had very limited resources, but this sort of hands-on learning really piqued my interest in science. Then, I attended college in the USA to study biochemistry, and whenever I had free time, I would go and find a job and really enjoyed the ability to be independent. It was different from class, where I was told what to study in a textbook; in the lab, I could decide what question I wanted to ask and figure out how I wanted to do an experiment. Since my scholarship was provided by the Singapore Economic Development Board, which at the time supported the training of Singaporean people in science so that they could make informed decisions on scientific investments, I started a job for them after my undergraduate studies. But I couldn't enjoy it, because it didn't have much freedom or require creativity – so that's how I found out that I'm not meant for this type of office job. I got permission to leave early and start my PhD, where I was surrounded by scientifically excellent and creative people. So, from then onwards it was a very natural thing for me to become a scientist – I'm actually the first one in my family; everyone else is an engineer!
Why did you decide on the academic career path instead of science in industry?
That's a more difficult question. I think I was always enamoured with the idea of being an academic professor, and that's how I ended up here. But I also think it's very different for this generation of scientists, and if I were finishing my PhD now, I would give it much more serious thought. When I graduated, there weren't as many attractive options in industry as there are now.
What is the main theme of your lab and the scientific questions you are trying to answer?
We want to understand why our proteome employs so many small proteins called micropeptides, which are smaller than 100 amino acids. We have a track record of taking a peptide and figuring out what it does mechanistically, which is very satisfying, but we also want to find more general principles regarding their biology. We'd like to know whether they have specialised functions that larger proteins can't perform, or if they are made and degraded in a similar way to larger proteins.
How did you start working on micropeptides, which at the time was an entirely new paradigm?
This actually happened serendipitously. A large number of micropeptides come from regions of the transcriptome that were thought to be non-coding, or from UTRs of canonical RNAs. I started working on long non-coding RNAs (lncRNAs) in 2010, and then it was very hot to look at their developmental functions. We spent quite some time studying a specific lncRNA, and as we were playing with the gene, we noticed that there was a highly conserved open reading frame. Most lncRNAs have two to four open reading frames, so it took about two years to convince myself that there was really a protein encoded in that transcript. The next breakthrough came when we figured out that the peptide was secreted, and we then found the receptor it was signalling through. So, the peptide is none other than ELABELA, also known as Toddler. Around that time, Jonathan Weissman's lab had really popularised ribosome profiling, and many labs were seeing a lot of translation happening outside of the canonical translatome, so it was clear that there were plenty of micropeptides to be discovered.
It's therefore remarkable that another group made the same discovery at a time when there were barely any micropeptides with known functions
This was a huge coincidence, and we couldn't believe it! Alex Schier's lab found Toddler while looking for non-annotated translated open reading frames, whereas we just stumbled upon it, but we only learned about each other at the very end. It's quite seldom that you get independent discoveries that really point to the same thing!
Your research on micropeptides has led you to work in different biological contexts, such as vascular biology, immunometabolism and mitochondria. Do you enjoy this diversity, or can changing fields become overwhelming?
Both at the same time, and I would say that this type of research is not for everyone. I've interacted with some people during my career who said that the uncertainty of the field is crazy and asked why I'm doing this to myself. But if you look at the trajectory of my career, I've changed fields pretty much at every single juncture, so I think this suits me really well. You can never get comfortable, because you constantly have to learn new things. The other advantage is that you go into a field without a priori assumptions. I think this has enabled us to be innovative, because we don't have a hypothesis that we're trying to prove, so we very strongly rely on the data to tell us where to go next. The risk is that you might not become an expert in any one process or molecule; I try to overcome this by finding someone to work with who I trust and who is an expert in the new field we are venturing into.
“[…] we don't have a hypothesis that we're trying to prove, so we very strongly rely on the data to tell us where to go next.”
Thinking back to the time you started your lab, what were the biggest challenges you had to overcome?
Before starting my lab, I didn't know that I was going to be working on mitochondria. So, I literally started from scratch and had difficulty describing what we do in the lab to new recruits. A main challenge was figuring out what kind of skills and infrastructure we needed and then hiring the right people. And then there were of course all the challenges that come with trying to break into a new field, including having your papers considered seriously – especially coming from an Asian country – and establishing a name in the field.
Do you still do experiments yourself?
The truth is, I would really like to tell you that I'm still doing experiments, but I haven't been able to find time to do an experiment from beginning to end for quite a while now – I'd find myself taking shortcuts or doing one part of the experiment and then getting someone to cover for me, which I then stopped because it felt a bit like a waste of everyone's time. Still, I often think it would be great to block three months in my calendar to get back to the bench, but this is quite tricky at this stage of my career. I definitely still do a lot of data analysis though, and can't imagine having it otherwise!
What is the most important advice you would give to someone about to start their own lab?
I think you need to be able to decide and have a good ‘nose’ for what's a significant research question to work on, even before you invest too much time into it. Unfortunately, as the scientific environment is super competitive now, you have to be very judicious in what you choose to do. Something I'd tell young researchers who are daunted by how difficult the academic career trajectory is, is to never underestimate the possibility of making a really significant discovery – and it's always really refreshing when I see someone with a genuine excitement for scientific discovery. I think that if you are good and have an enquiring mind, you don't have to worry – just give it your best and it will all work out!
“[…] never underestimate the possibility of making a really significant discovery […]“
How do you balance being a scientist and a mother? And do you think universities are providing enough support for scientists with families?
In Asia, the assumption is that your mom or dad will help you with the kids, and we are very much lacking the support structures that exist, for example, in European countries. Fortunately, here in Singapore we have live-in helpers to take care of the house and basic needs of kids, which I make use of, and this has been very beneficial. Regarding how to strike a balance, this is hard to answer, and I think you just have to find creative ways to get things done; I'm also noticing that as my daughter grows older, her needs are changing. So, it's important that I carve out protected time with her; for example, on Saturday mornings we always play tennis together and then have lunch afterwards.
Finally, could you tell us an interesting fact about yourself that people wouldn't know by looking at your CV?
There's an artistic side of me that I never got to properly develop. I play the piano, but it was always a dream of mine to be a violinist; so during COVID, I picked up playing the violin. This was a bit daunting at my age, but it's never too late to learn a difficult skill. I also think that because our world is evolving so quickly, learning new things is becoming a fundamental life skill everyone needs to have. Learning to play the violin also keeps me humble; my teacher, who is a young adult, is very patient with me, so in situations when I would get frustrated about a student not understanding something that I find simple, I remember to see it from their point of view and have more empathy.
Lena Ho's contact details: Duke–NUS Medical School, 8 College Road, Singapore 138957, Singapore.
Lena Ho was interviewed by Máté Pálfy, Features & Reviews Editor at Journal of Cell Science. This piece has been edited and condensed with approval from the interviewee.