Lok Shee Mei under the microscope | MEDICUS 2023 Issue 4

Lok Shee Mei under the microscope: the biologist cooking up a storm in her lab

By Dr Chua Li Min, Science writer

“If I were not a structural biologist,” mused Lok Shee Mei, “I would probably have become a chef. I love cooking!”

In the kitchen, the self-taught chef experiments with flavour and texture to make her dishes just right. The mother-of-two is famous for her melt-in-the-mouth beef noodles and fragrant ginseng chicken soup.

“My son is my top fan. He says I cook the best and prefers home-cooked food to dining out at a Michelin star restaurant!” she laughed.

And like her cooking skills, Lok, who is a renowned structural biologist and professor in the Emerging Infectious Diseases Programme, has acquired much of her scientific expertise, through trial and error and by finding the best person to learn from.

“What stands out about Shee Mei is that she knows what she wants and is determined to get it,” shared Indiana University Professor Marc Morais, who met Lok while they were both postdoctoral fellows almost 20 years ago.

Her recipe for success?

“I tell myself: ‘Don’t worry, I can do this’,” said Lok.

And with that approach, she has solved structures of viruses causing diseases like dengue and Zika, providing vital intel that can be used in antibody or drug design to limit the spread of the diseases or to lessen their severity.

“I love structures. They don’t lie, because you can literally see how the virus or protein looks like. Your interpretation may not be correct all the time, but your result is always right,” said Lok, who leads the virus structure and function lab.

“Our role is to find out how nature evolves,” she added. “It’s a very sacred job.”

Choosing science (logically)

Lok was a playful child, spending all her free time before classes in the sports hall.

“I would put my bag down immediately after reaching school for a game of badminton,” she confessed.

Once in the classroom, however, she became fascinated with the sciences that could show her more about the world she lived in. From atoms to biology—everything intrigued Lok.

“I was mostly a science and math person,” said Lok. “I found the theories and concepts very logical, which appealed to me.”

Although easily distracted, when exams were around the corner, she would hit the books, armed with the study hacks from her older sister. “She set a really good example for us. She always excelled in her work, but also took the time to teach and encourage us. She was my role model,” said Lok.

What also made the difference, Lok believes, was her passion for the subjects, in particular science: “I need to be interested to do well.”

While Lok excelled in maths and science, languages were “not really my forte”, she shared. “The first time I realised I couldn’t really speak English well was during my oral exam,” added Lok, who worked hard to improve her English after that fateful test for her Primary School Leaving Examinations.

“So I didn’t end up going to what most people would consider an ‘elite’ school at the time,” she said. Despite that, Lok did well enough to enroll on the sciences at school.

And by the time she completed her “O” levels, Lok was certain that it was a path she wanted to pursue—studying biotechnology at Ngee Ann Polytechnic before completing her undergraduate studies in microbiology at the Queensland University of Technology. “I am just in awe at how nature drives things into the way they are while keeping everything in balance,” said Lok.

Solving puzzles from the structural realm

It seemed that Lok was en route to becoming a microbiologist until she hit upon a realisation while working on her undergraduate research project studying the dengue virus.

“What stands out about Shee Mei is that she knows what she wants and is determined to get it.”
Prof Marc Morais

At that time, Lok was searching for specific regions, or residues, on the virus that could shed light on why some dengue variants could escape the body’s immune system.

“We only managed to identify one residue, and we couldn’t even tell where this residue was binding to on the antibody,” recalled Lok.

So when she came across a structural biology paper which answered that question, Lok was awestruck: “The paper showed everything—you could see every single detail. It made me think: ‘Why am I doing this? I should do something else’,” she recalled.

Putting that thought into action, Lok took the plunge and pursued a project based on X-ray crystallography for her PhD at the National University of Singapore. “X-ray crystallography enables you to visualise objects down to 2.4 angstroms, which is as small as atoms and molecules,” said Lok. That is a ten-billionth of a metre.

But before she could reveal the structure of her protein-of-interest, she first had to become adept at growing crystals of it, a tedious process that took her multiple rounds of trial and error. “It’s like mining for diamonds, because it’s so hard to get the crystals,” she explained.

“Once you have the crystals, you shoot them with X-rays to get a diffraction pattern which is used to generate a detailed three-dimensional map of the protein’s structure.” Perfecting the right conditions for that to happen took time but she succeeded eventually, graduating from her PhD studies with a published paper in the bag.

Learning from the best

But learning about x-ray crystallography wasn’t enough for Lok. She wanted to master the technique. So, Lok embarked on her postdoctoral research in the lab of Michael Rossmann, who was widely regarded as the best in the field.

“Most people join the lab to become better structural biologists, with no great attachment to their project. But Shee Mei was really driven by this opportunity to learn structural biology while still studying the dengue virus, largely due to the impact it has had on her country,” shared Morais, who was Lok’s colleague at the time.

“It was a very, very difficult decision,” shared Lok. “I had to leave my husband and my daughter, who was 4 years old at the time because I couldn’t afford to have them join me.”

To complicate matters, not everyone around her supported that decision, believing that Lok should have stayed home to care for the family instead.

But Lok’s husband felt otherwise, encouraging her to seize the opportunity: “Parenting is a partnership and this opportunity was huge for Shee Mei. It was a no brainer.”

“It was probably tougher on her than on us,” he added.

So she made the trip to the Rossmann lab in Purdue University, Indiana, USA in 2004: “It was the best lab in the world and it turned out to well worth every minute spent.”

From shooting X-rays to electrons

By the time Lok was setting up her own lab in 2009, another innovative new technique that showed greater potential for solving large assemblies had been developed: cryo-electron microscopy, or cryo-EM for short. “It can solve really, really big structures instead of just small proteins. And you can solve structures that are almost in a native condition. So you can visualise the entire virus,” explained Lok.

There was no question that she was going to master this technique. “Most scientists tend to focus on what they are good at, but Shee Mei has little hesitation when it comes to incorporating a new technique or approach in her lab,” remarked Morais.

Once again, she hopped on a plane, this time to Houston in Texas, to the lab of Professor Chiu Wah. There, she spent three months learning from Chiu, a pioneer in the field who is now at Stanford.

“I brought back a treasure trove full of programmes and learnt how to manage and use the microscope. His way of screening samples was also a lot more efficient, so we adapted that for our lab’s workflow as well,” said Lok. “I was very, very excited when we obtained the first data set in seven-angstrom resolution!”

But it wasn’t all smooth sailing initially.

“She is really aggressive about moving towards her goals and I see her as an outstanding representation of what a strong female scientist should be.”
Assoc Prof Ashley
St John

Chiu’s microscope, which was manufactured in Japan, was different from the Dutch model in Singapore, which meant the buttons on both instruments were named and positioned differently. So it took nine months for Lok to map the buttons and fully train her lab technician in operating the microscope.

While it was tedious, it was a necessary move, explained Lok: “Because we’re solving structures to really high resolution, we need to align the microscope really well.”

And that was not the only challenge: the lab technician whom she had trained for months left. Once again, her husband, a trained microbiologist, volunteered to help, formally joining her lab.

“We did fight a bit initially, but things worked out in the end,” she mused. “He’s very responsible and he takes excellent pictures.”

Since then, the duo, joined by the rest of the Lok lab, has taken on many challenges.

Structural changes in the dengue virus when exposed to a higher temperature of 37 degrees Celsius observed using cryo-EM // Credit: Lok Shee Mei

“Work is one of the shared interests my parents have and it has brought them closer to each other because they understand each other’s work so well,” observed Lok’s daughter, Miss Ng Ee Chern.

Witnessing the dedication her parents pour into their work also taught her something else: “I learnt that hard work is essential to achieve what you want, and usually the effort that you put into your work will pay off,” said Ng, now a fourth-year medical student.

Professor Lok Shee Mei (second from left) with her daughter, Miss Ng Ee Chern (left), and husband and son, on a family holiday // Credit: Lok Shee Mei

Staring the Zika virus in the face

Hard work like the commitment required when racing an international competition to reveal the structure of the Zika virus that was causing an outbreak half-way around the world.

“I remember reading about the Zika outbreak in Brazil on the BBC back then,” said Lok, who wasted no time in writing to her collaborator in the USA to request for a strain of the virus, before assembling a five-member crack team to solve the structure of this flavivirus.

They were in a head-to-head race with another group. And watching time trickle by as they waited for their precious cargo to clear customs was agony; all of them well aware that the other group’s head start was stretching farther by the day.

Lok and her team didn’t publish first. But they did publish in Nature. “We were given one chance to revise our work. So we were going back and forth, like every two days with the reviewers,” recalled Lok. “The overwhelming stress led to canker sores in my mouth at the end.”

But it is a moment Lok still looks back on with immense pride. “That was the fastest we had ever gone,” she said, of her lab’s herculean efforts in giving the world a first glimpse of the virus and its defenses in a record four months.

And publishing second had one advantage. “We did some additional biochemical assays to study the stability of the virus at different temperatures, which might tell us a little bit more about how the virus is able to survive in semen, saliva and urine,” said Lok.

For her impactful contributions, Lok received the prestigious NUS Provost’s Chair Professorship in 2021.

“She is really aggressive about moving towards her goals and I see her as an outstanding representation of what a strong female scientist should be,” said Associate Professor Ashley St John, Lok’s colleague from the same Programme.

The structure of the Zika virus that Lok and her team solved using cryo-electron microscopy // Credit: Lok Shee Mei

The structure of the Zika virus that Lok and her team solved using cryo-electron microscopy // Credit: Lok Shee Mei

Caring for the people around her

But it is not just research that Lok cares deeply about, but also the people around her.

St John, who sits just a few doors down the corridor from Lok, knows that she can count on her anytime.

“She might come across as kind of tough initially, but once you get to know her, she’s very quick to give advice and even to call you on the weekend just to ask how you are doing,” said St John, who now regards Lok as a good friend. “She always makes it clear that you’re never wasting her time. And she makes it her role to give advice to people because she cares deeply about their development as scientists.”

And that includes going through every single paper with her team before it is published. “My team members and I sit next to each other for months just to do that,” said Lok.

Lok with her team member in the lab

“As a principal investigator, I have a responsibility to get my lab people the best job in the future so everything that comes out from my lab must be high quality,” she added. “Their success is also my success.”

It is also why Lok is always encouraging them to learn a new skill—after having been there and done that. “Everybody deserves to do what they like to do,” she said.

Taking that next big step

Always ready to embark on her next adventure, Lok has her sights set on the next big thing in structural biology: solving the structure of a virus inside a cell or protein, which would enable scientists like her to study a virus’ interaction with a cell.

“So you can see how the virus binds, how it moves and into which organelle,” said Lok, her eyes lighting up. It is a step up from the current technique, which allows scientists to observe purified viruses in isolation.

“I am very honoured that I will get to see this exciting development in my lifetime,” said Lok, who is planning to use this improved method to uncover the secrets of how viruses like the dengue virus attack. “That is my ultimate dream—to tell the complete story of how a virus infects the cell.”

Knowing that what she discovers could benefit human health someday is what keeps Lok going: “When we make a huge leap in helping people understand key principles in our field, that is the best part of my work.”