Lena Ho: In pursuit of small but mighty peptides

Written by Nicole Lim, Senior editor

If Lena Ho asked you to wait for just five minutes while she quickly runs to the lab, you’d often end up waiting half an hour. If she asked for 30 minutes to finish something off, you’d better find a comfortable spot to while away a couple of hours.

But if she asked you to wait for an hour or two, “then don’t bother,” laughed Ho, remembering the conversion chart her now husband developed during their dating days when they were both graduate students at Stanford.

Such was the pull of the lab, the latest data, the desire to crack the problem.

“I was addicted to new data,” confessed Ho, who is now an assistant professor with Duke-NUS’ Cardiovascular and Metabolic Disorders Programme where she leads the endogenous peptide lab.

“Since then, the nature of my work has changed. My work is no longer at the bench, but I still feel excited about the work in the lab,” said Ho. “I still work all the time, but instead of producing the data with my own two hands, I coach and mentor budding scientists in my lab to generate the exciting findings.”
 

Growing up, logically

Ho grew up in a family full of engineers. Her father was an engineer. Her uncle too. By the age of eight, her older brother, too, showed signs of following in their footsteps.

“I didn’t have the same inclination,” said Ho.

Instead, she wanted to explore stage acting.

“I remember watching Les Misérables for the first time after reading the book and it made a big impression on me,” she recalled. She also played the piano and was in band during high school.

“But I didn’t have any talent. I wasn’t dramatic enough,” Ho deadpanned.

She did, however, have a few true talents up her sleeve. She excelled at chemistry, which comforted her with its logic and certainty, and was enchanted by the endless possibilities of biology.

After a short-lived attempt to pursue medicine because she turned out to be too fearful of cadavers, Ho headed to the US to study life sciences. There, she found her home: the lab. After class, during summer breaks, Ho squeezed lab time in whenever she could.

“That was the first deterministic turn in my life,” said Ho. “There was no turning back.”

Those college and graduate school years were some of the best in her life. Without other commitments and with a brain hotwired for learning, she soaked up all the opportunities available to her—taking courses simply because they interested her—and abandoned herself to her research.

Although she pursued her PhD in an immunology lab, Ho embraced technologies outside of the field to solve her question—all in pursuit of more data and a better understanding of the mysteries of some of the human body’s most complex systems.
 

Back on home soil

With a stellar track record from Stanford, the returning A*STAR scholar was quickly recruited into the lab of Bruno Reversade at the Institute of Medical Biology. There, she was given what seemed like a hopeless task: to characterise a tiny, remote part of the genome, thought to be junk RNA devoid of any function. Yet, this so-called long non-coding RNA somehow kept cropping up in early human development.

“It was an ambitious project [that] people before me had tried only to run into walls,” said Ho, who was delighted to be challenged like this.

For two years, she hit one dead end after another, experiment after experiment.

“But Bruno was so convinced that we were going to discover something groundbreaking that it kept me motivated,” Ho said.

What also helped was that she wasn’t afraid of the unknown, learning new techniques, starting over—all in the hunt for knowledge.

“Lena is a gifted experimentalist who is comfortable moving out of her lane, taking a risk and pursuing—and mastering—sophisticated techniques to get data,” said Ray Dunn, a neighbour and collaborator at A*STAR at the time, who worked with Ho on parts of the project.

After shooting in the dark for years, the first breakthrough came when Ho found that far from being junk, this tiny nugget of a genome did some heavy lifting during human development and pregnancy. 

“It turned out to be the source for a small peptide,” said Ho.

That discovery broke the dam. From there, Ho and her colleagues established that the resulting peptide—a tiny signalling molecule—was essential for the development of the heart and other cardiovascular tissues. While the peptide was mostly found in blastocysts—some of the earliest cells that make up the body—it was also expressed in some adult cells like the placenta, where it was found to protect mothers against preeclampsia.
 

Finding her niche

With that experience under her belt, it was time to set up her own team. To do that, Ho took the pragmatic step of first identifying her own niche.

“I did a very simple analysis by looking at the different cell compartments and the distribution of proteins by size,” explained Ho. “What I found was that the mitochondria were very skewed towards a smaller size proteome.”

The last remnants of humans’ bacterial origins turned out to be crammed with these tiny strings, made of fewer than 100 amino acids. All of which were peptides that have not been widely studied.

Ho found her niche characterising these unknown molecules. And a home at Duke-NUS, where she’d made a deep impression even before signing on the dotted line.

Owen Rackham, a fellow assistant professor at Duke-NUS, distinctly remembers their first encounter—over coffee at the old Housemen Canteen—where the conversation stretched for hours.

“At that point, not many people had been looking at these small open reading frames,” said Rackham, who together with his then-office partner, Sebastian Schaeffer, were keen to catalogue these sources of peptides. So, when they heard that Ho was interviewing at Duke-NUS, they seized their chance.

“After our chat, I remember hoping that she would move here,” recalled Rackham.

The trio now has an atlas of small open reading frames—or smORFs—in different cell types under review with a journal. But more than just a paper, they have a symbiotic relationship where Rackham and Schaeffer share details of the small open reading frames they discover and Ho investigates their function.

“She is one of the leading people in the world on smORFs. It’s amazing that she sits four offices away from me,” mused Rackham.

Professor Pat Casey, Senior Vice-Dean for Research at Duke-NUS who was similarly impressed, added: “What struck me most when I first met Lena was both the depth of understanding of her field of research and the clear excitement in her voice when she discussed her work. She exuded confidence without arrogance, and it was clear that she was going to be a winner.”
 

Following the ripples

While Ho remains a basic scientist focused on the fundamental mechanisms that underpin human biology such as metabolism and inflammation, she is acutely aware of the ripple effects that well-directed discoveries trigger.

“I want my lab to always be a leader in discovering basic mechanisms while at the same time applying what we find to help people with diseases—in our case, mitochondrial diseases.”

Mitochondrial diseases are inherited disorders that range from fatal illnesses to long-term deficits in motor ability and degenerative diseases of the heart and brain.

“We want to know whether what we find can help to alleviate these diseases,” said Ho. “So that we can be proud of what we do beyond the papers we publish.”

Connecting the dots between the lab work and human conditions is a particular talent of Ho’s, according to her colleague and collaborator Ashley St John: “She’s good at extending the observations from the data to what their significance is downstream. She bridges multiple fields and brings together concepts that are hard for people to see the connection immediately.”

With that skill, it came as little surprised that Ho was among 26 young investigators who were selected last year for their excellent track record to join EMBO’s life sciences community. Ho is the only representative from Singapore in her cohort.

 “I am looking forward to the annual meeting where we get to meet the other fellows, establish new networks,” said Ho.
 

Setting her own code

Beyond the awards that Ho has received (which also include National Research Foundation and Howard Hughes Medical Institute fellowships), what attracts people to is that she’s fun to work with. She’s generous with her time and knowledge and always interested in the science.

“People gravitate to her because she’s very easy going and approachable. Even though she has a rockstar reputation and is at the top of her game professionally, she will sit with you and patiently work through your data’s kinks,” observed Dunn, who is now an associate professor of regenerative medicine at the Lee Kong Chian School of Medicine.

And she remains undaunted by new technologies, keeping her finger firmly on the pulse of the scientific community here.

“Lena is very knowledgeable about the latest technologies available and always willing to learn and apply new ones,” confirmed St John, an associate professor with Duke-NUS’ Emerging Infectious Diseases Programme.

“She’s also usually one of the first people to know about something that’s new in Singapore.”

But not all aspects of becoming a principal investigator or PI have come easy. In fact, the transition has been one of the most challenging moments in Ho’s career so far. From focusing exclusively on science, Ho’s responsibilities have expanded to include mentoring, HR and administration.

Motivating people who have very different perspectives was also a challenge for Ho as she moved into the role of principal investigator. But like the earlier challenges, she has risen to meet it head on—with a little unexpected help from her fun-loving nine-year-old daughter.

“She is very different from me and I had to find out how to bring out the best in her,” said Ho, who hopes to nurture her daughter to grow into someone who does the right thing to the best of their ability. “Her idea of success may not be the same as mine, but I’ve learnt to celebrate with her.”

Now, she deftly juggles her expectations and priorities with those of her team while supporting them when things haven’t turned out the way they had hoped.

“My mantra is ‘It is what it is’,” said Ho. So, if the data doesn’t support their project’s hypothesis, they instead focus learning how to frame the next hypothesis better.

Reflecting on the qualities that she hopes to nurture in others, Ho summed it up as: “Be tenacious and persistent. Be the best you can to those around you. That is how you leave your mark and make a difference to people around you. And be happy.”