Lipi’s Tools for a Better Biology

WHO? Lipi Thukral, 32
WHAT? Computational structural biologist
WHERE? CSIR-Institute of Genomics & Integrative Biology (IGIB), Delhi

Reported by Nandita Jayaraj

“I used to hate standing up and doing experiments, absolutely abhor it. I thought that there should be some other way I can contribute…” – Lipi Thukral

**

There is a common perception that biologists can’t code and that’s alright because they don’t need to, anyway. Computational structural biologist Lipi Thukral’s academic journey was founded on the busting of that myth. “From the beginning, we are told that descriptions define biology. But that’s not how it is anymore. To convert our descriptive training to analytical training is a challenge but definitely a required skill for those of us doing science in 2016.”

Lipi makes an instant impression. She greeted me at the lobby of the swanky IGIB South Delhi campus with a firm handshake and a smile, warm and confident. I had to quicken my pace to keep up with her as she led me around her lab before we settled into an empty conference room to talk about her life and the events leading up to her becoming one of the youngest faculty members at the institute.

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Picking up the hints

“I was somehow always motivated by science… it sounds cliched now!” said Lipi, who was born in Rudrapur, a town in Uttarakhand. Her family moved a lot. She was schooled in Nainital, Kanpur, and Lucknow before they finally settled down in Delhi when Lipi was in her final year of schooling (12th standard). Driven by her interest in the subject, Lipi enrolled to do her Bachelor’s in biotechnology in Amity University. This was in 2001 when not many colleges offered a biotechnology course, but Lipi was sure she did not want to study classical biology.

But two months into her course, she began to get fidgety. “I realised this is not for me.” She laughed sheepishly, “I used to hate standing up and doing experiments, absolutely abhor it.” It may sound like a minor pet peeve, but in Lipi’s case, this was something of a turning point. “I thought that there should be some other way I can contribute [to science].”

“My father had inculcated in me the reasoning that if you are interested in something – like ‘a’, out of ‘a-z’ – then pick up the hints. Do everything you can to pursue ‘a’.”  Lipi did exactly that. One of her course subjects, bioinformatics, had intrigued her. She found it amazing that certain biological experiments too complicated to conduct in the laboratory could be carried out easily using computers. She decided she would do her best to understand these tools. When her father pointed out that there were programming classes close by, she jumped at the opportunity to learn.

After each day in college, from 6 to 8pm, Lipi immersed herself in the world of C and C++ programming. She admits that her evening education inspired her way more than the daytime one. “I was still very interested in biology, but now from a different perspective – not from standing,” she laughed.

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Lipi shows me around the labs

Bioinformatics. It doesn’t matter where.

Thanks to her coding training on the side, Lipi was crystal clear about what she wanted to practise – computational biology. Not everyone agreed. “In 2004, everyone questioned my choice to go studying bioinformatics. They told me it is not a subject worth studying. ‘Study microbiology, biochemistry, immunology… biotechnology! Why don’t you do biotechnology?’ they said. None of my classmates understood my decision,” recalled Lipi. She was unperturbed by the exaggerated opinions because she understood bioinformatics was a great tool for overcoming experimental techniques. She knew that with it, she could employ computational techniques to better understand biology.

Lipi’s philosophy has always been to focus on the subject of her passion, rather than the place of study. She pursued her master’s in bioinformatics in Banasthali University, a women-only institution in Tonk, Rajasthan, known for its computer department, instead of opting for a more conventional course at one of the so-called elite institutions in the country.

At Banasthali, Lipi was faced with an interesting scenario. It’s difficult for students to get permission to leave the campus, but the campus is huge and within it, there was complete freedom. “We’d have classes at 7, 8, 9 pm and they promoted computers in hostel rooms. I found this environment very conducive for studying,” said Lipi.

Bioinformatics had just begun its big boom, and faculty at Banasthali were struggling to keep up with the hype. Lipi did her bit. “I was bad at theory classes but I would do all the practicals.” During this time, she started a website called ‘Lipi’s Bioinformatics World’. She admitted this to me rather embarrassedly (“it’s not updated and full of crappy stuff right now”), but when I pointed out to her that this sort of initiative is quite admirable for a student of science, Lipi agreed.

Project & a paper

In her final year, Lipi was offered a place to do a project in France but she chose to do a project under IIT Delhi’s B. Jayaram instead as his topic of research interested her more. Jayaram was using supercomputing to solve the ‘protein folding problem.

The protein folding problem

protein_folding_schematicProteins are made up of compounds called amino acids which are chained together in a specific sequence. The sequences, however, are not linear; they exist twisted and turned in specific contortions that determine the protein’s function. Hence, the shape of a protein is valuable information to have. We know how to take a protein sample and determine its sequence, but to be able to deduce what 3D shape this sequence will take has been a challenge.

Bioinformaticians like Jayaram develop software (his is called ‘Bhageerath’) that can predict what shape a protein will take, with just the sequence information as input. In his lab, Lipi was assigned to write an algorithm to predict the types of ‘loops’ a protein’s structure could contain. She succeeded, and the resulting tool called ‘ProRegIn’ was released and published in the following year. Lipi, thus, managed to have a paper published as the first author at the end of her 6-month Master’s project. This marked her official entry into the world of research.

“Now, on the other side, I’m stunned by how casually students approach projects,” commented Lipi. “I understand that competitive research labs have limited seats, but one has to be more tactful – writing comprehensive emails, meeting the supervisor, actually knowing the research problem the PI (principal investigator) is working on, is mandatory.” She emphasised the importance of a ‘prepared’ email. “It’s just a way of distinguishing yourself from the rest of the application. If I spot one such application among ten, it will make my day.”

[Lipi’s sentiment reminded me of something TIFR neuroscientist Vidita Vaidya (who was also the one who nominated Lipi for The Life of Science) had tweeted a few months back.]

An unexpected turn

After a successful project, there was no doubt in Lipi’s mind that she was going to pursue a PhD next. She chose the US as her preferred destination and began to get her applications ready. But applying to foreign universities is an expensive affair, much more so ten years ago than it is today. “It was financially a bit difficult time for my family and my ten applications cost about Rs 50,000. And all this for no sure-shot output! Yet, they were very supportive,” she said. Then, something unexpected happened. “Someone – some Indian researcher I did not know – found my website (Lipi’s Bioinformatics World) interesting and randomly emailed me. He asked me what I was doing now.” The stranger-wellwisher also turned Lipi’s attention to cutting-edge research being done in two German universities and suggested that she apply there too.

Lipi was completely awe-struck at the research being done at one of the labs led by computational biophysicist Jeremy Smith at Heidelberg University. She applied for a position and made it. Fortunately, her five years of PhD in Germany ended up being some of the best of her life. “It was a very international lab. Jeremy hired men and women equally, was very open and a progressive leader.” Lipi also became a fluent German speaker.

Choosing to come back

All these years, Lipi missed one person sorely. “My boyfriend, who I met in IIT, was in India. I was devastated [to leave him] but I told him I can’t do anything, I have to go and do my PhD,” she shrugged. “He is as supportive as my parents but so many years of long-distance relationship is very difficult.” Lipi came back to see him once or twice a year. “I could have saved all that money instead but relationships require effort. If not, they will fall apart.”

Lipi finished her PhD when she was just 26 years old. She returned to India and got married. She decided that she would stay and become part of Indian academia. Was that not a difficult shift? Yes, affirmed Lipi. The conventional path for an Indian to be part of the academia seems to involve a PhD abroad, followed by a postdoc and then return. “I decided I would just prove this wrong. I would do a good postdoc in India and get to a faculty position. Once you publish. Who will say no to you?”

She received a huge shot in the arm by winning the Department of Science & Technology’s INSPIRE Faculty fellowship in 2012. This meant that Lipi now had a generous research allowance of 7 lakhs per annum for a period of five years. The scheme was launched specifically to attract young scientific talent less than 32 years of age. With a fellowship in hand and two more published papers, Lipi joined IGIB as faculty. Today she is a senior scientist.

At the time she started her career in India, Lipi noticed that some senior, orthodox male scientists reacted peculiarly to her. A fellowship of Rs 80,000 a month is considered sizeable in Indian science and most scientists don’t get that much. As a result, there was some resentment. “The problem is that I am compared sometimes to the wife of a fellow male colleague,” she said, protesting against her income being seen as the secondary salary in a family, as the husband is still considered the primary earner. Many consider Lipi’s fellowship to be too much. “This is the kind of computation everyone does and I find it hilarious. I’m not to be compared with your wife! I’m the one with the PhD!”

“The problem is that I am compared sometimes to the wife of a fellow male colleague.”

Research at her lab today

In her lab, Lipi and her students develop computational tools to study the interaction of proteins with membranes (the cover enclosing cells or parts of cells from the outside environment). Protein-membrane dynamics are a crucial part of many bodily functions and form the basis of many diseases like cancer. To illustrate the significance of this, Lipi used the example of autophagy, the cellular phenomenon for which Yoshinori Ohsumi of Japan has won the 2016 Nobel Prize in Medicine. Autophagy is the process in which debris and unwanted material in a cell get enclosed in a bubble called a vesicle and are transported to the lysozyme (a cell organelle) for degradation. This degradation produces energy. Because of this, when a cell is starving, autophagy is triggered as a way for it to make energy.

Computational modelling enables Lipi to understand this process at a fundamental level. What takes place on the vesicle membrane that tells it how and when to act? This molecular perspective is unimaginably difficult to attain experimentally.

Specifically, Lipi looks at proteins which can be used as ‘markers’ or indicators of autophagy. The knowledge of such marker proteins can make it easy for scientists to detect if autophagy is happening in a cell or not. One such protein is LC3. Lipi used her software tools to predict that LC3 plays a crucial role in vesicle formation. For autophagy to initiate, LC3 needs to be present. Only when LC3 interacts with c-shaped isolation membranes will they elongate and form the enclosed bubble or vesicle. She even predicted the exact amino acids of LC3 protein that were responsible for this function.

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The small green balls represent LC3. This image (Source: Vassilios Will Kotiadis’s ResearchGate) shows how the isolation membrane elongates to form the vesicle.

All of the research required for getting these results was done virtually. Lipi collaborated with experimentalists in the lab, who found out that without LC3, the whole process broke down. This proved her finding.  “If we narrow down the region responsible for a function, we can go on to develop inhibitors of autophagy.” This process of recycling energy in the cell can be switched on and off.

Why is controlling autophagy useful? “LC3 protein has been reported to play a role in cancer. What is unknown is: does it increase cancer or inhibit it?,” said Lipi. A paradox arises because some experiments have shown that autophagy is elevated in cancer cells, whereas other studies have shown that autophagy obstructs tumour formation. “If we study this further, we can have answers.”

To aid her research, Lipi is grateful for the services of CSIR’s supercomputer situated in Bengaluru’s 4th Paradigm Institute. “Computationally, you have to understand – these are multi-million atom systems. The molecular assemblies are really large in number and to tackle them one needs resources. The supercomputer allows this.”

Lipi feels that India has some great things going for it with regard to computational biology research. “In Germany, they struggle to get people with good coding knowledge. But we are an IT hub. We have all these people who are trained in software development. I urge them to explore how they can utilise this knowledge to address biological problems.” So what’s missing?

“We have an excellent pool but we are scared to ask the bigger questions. For example, can I, at an atomistic level, simulate an entire cell?”

Can we? Absolutely, affirmed Lipi. “I can see this happening in my lifetime.”

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