Kira Makarova, PhD, could have easily coasted through college and her career.

But she didn’t.

She took advantage of opportunities and overcame setbacks along the way.

As a staff scientist at NLM’s National Center for Biotechnology Information (NCBI), Makarova is making her mark in the scientific world by supporting computational biologists all over the globe.

A Good Fit for the Ever Curious

Makarova would be the first to tell you she had support from her parents, her school, and the system in which she grew up to pursue her scientific passions.

She grew up surrounded by people who encouraged her and in a place where science is revered.

Makarova was raised in Narva, Estonia, when it was part of the Soviet Union. Her parents, especially her mother, encouraged their daughter, but they didn’t push her.

“If I’d had Bs or Cs in school, she would have said, ‘It’s fine. No problem,’” said Makarova. “My mother gave me absolute freedom.”

But her biology teacher, Gertruda Sedova, wasn’t so laid back.

Her teaching style, which involved asking a lot of questions, suited Makarova.

“She gave us biology books and we discussed them,” recalls Makarova. “This was very interesting to me, because in biology you never basically know the answer. You have to make hypotheses. This helped us develop scientific thinking.”

Studying biology—a subject with more questions than answers—was a good fit for the ever-curious Makarova.

In addition, the school system was organized to inspire students like Makarova.

The Olympics

“There was a biology competition throughout the whole country that started in school, then the republic, then the whole country at Moscow State University,” recalls Makarova. “It is called the Biology Olympics or the Biology Olympiad.”

You could say Makarova was destined for gold.

For several years, she competed and was recognized at the national level.

It seemed only natural that after graduating from high school she would continue her studies in the biology department of Moscow State University.

And yet after two years and three unsuccessful attempts at admission, “enough was enough.”

Plan B—and C

She would need a Plan B and eventually a Plan C to continue her education.

Makarova applied to and was accepted by her second choice of colleges, ironically called the Moscow Medical Institute, Number Two—which she describes as a “special place because it was an institute with a medical biology department focused on providing education for people who were not supposed to be doctors but work as scientists within the medical field.” (Moscow Medical Institute is now called the Pirogov Russian National Research Medical University.)

She studied biology and took lots of classes in mathematics, physics, and chemistry, but she also made time for a social life.

And that’s why she couldn’t continue her education in Moscow.

She had married Yuri Wolf, a biology student and her boyfriend of many years, and soon the couple was expecting a child.

“I had an opportunity to continue my education even when I had a small baby,” she explained. She enrolled at Novosibirsk State University (NSU) in Novosibirsk, Siberia, so her in-laws could help with child care.

Not only did her son thrive, Makarova did, too.

“NSU is a very special place. The university itself is inside a small town with a lot of scientific institutes for all disciplines, with different labs and different focuses,” she said. “I was very lucky because NSU was one of the first places in the Soviet Union that started to do computational biology.”

A Dry Idea

Throughout her studies, Makarova had choices about which labs to work in. Her initial decision helped her focus.

“I had some experience with wet labs, and I kind of didn’t like the experience,” she confessed. And there were practical considerations. “There were a lot of issues with organizational workflow.” And there could be a long wait for supplies and equipment.

This was unacceptable.

Working in computational biology made it possible for her to get to work right away.

How did she do it?

After earning an MS in biology from NSU in 1991, Makarova started her postgraduate studies at the Institute of Cytology and Genetics.

The Institute of Cytology and Genetics was the first in the country to establish the “theoretical department” and was the birthplace of Russian bioinformatics.

Makarova worked on the development of a tool for optimal design of oligonucleotides for directed mutagenesis and classification of protein sequences based on their oligopeptide frequencies.

Not only did she simultaneously work on two very different projects, they were both published.

How did she do it?

“I don’t know. It was natural and easy for me,” she said. “For me, it was all very interesting. I try my best to find solutions for any problems I tackle.”

Moving

She could have stayed, but her husband had accepted a position as a staff scientist at NCBI in the Evolutionary Genomics Research Group, headed by Eugene Koonin, PhD. “He knew my husband very well, because my husband was his student at Moscow State University,” she explained.

While her husband was hired, Makarova didn’t have any job prospects. Undeterred, she reached out to Koonin.

NCBI didn’t have any jobs open, but Koonin had other connections.

He introduced her to people at the Uniformed Services University of the Health Sciences, where she became a research fellow. In the late 1990s at USUHS, she studied one of the first sequenced genomes, Deinococcus radiodurans.

“This genome was very interesting because it’s an extremely radiation-resistant organism,” said Makarova. “My task was to study all the proteins in this genome and find out if I can identify something special about them with respect to this particular phenotype.”

She and her colleagues published many papers about Deinococcus radiodurans.

Good news

In 2001, Makarova moved to NCBI to work as a staff scientist in the Evolutionary Genomics Research Group led by Koonin. She was thrilled—not only to have the opportunity to work alongside her husband and with Koonin—but to have the intellectual freedom NCBI offered.

“At NCBI, I started to analyze different genomes and different gene arrangements within genomes,” she said. “At some point, we found a very interesting system, which is now known as CRISPR-Cas—even before it was called that. I felt that there was potential, especially for computational biologists, to figure out what it is. We thought it had something to do with DNA repair, because of the particular features of the system.”

Makarova was fascinated.

“It was interesting to me. I thought that we can do more,” she said. “I wanted to understand the organization of this system and how it works.”

Makarova was in the right place.

As she and other NCBI computational scientists studied more genomes, they were able to match the CRISPR-associated short DNA fragment with viruses known to infect bacteria. This led to the realization that they had discovered a bacterial adaptive immunity.

CRISPR was becoming a name to know in the scientific community—and Makarova was on her way to establishing a name for herself in this growing field.

In 2006, Makarova published a paper with detailed analysis of this system and suggested that this system is a microbial analog of eukaryotic RNAi system. The paper triggered the first experimental analysis of the system.

Global reach

CRISPR-based research advanced quickly. Makarova calls it a “huge explosion.”

The CRISPR-Cas (Cas stands for CRISPR-associated gene system) is now used as a programmable editing tool for creating animal models for human diseases, identifying genes underlying biological processes, modifying plants to increase yield, and, just a few months ago, correcting a genetic mutation in a single-celled human embryo. The NCBI team employs a computational strategy to examine large sets of genomes to locate Cas genes and predict their function.

Dozens of labs use this computational strategy and the NCBI databases to search for new CRISPR-Cas systems as future biotechnological tools for a wide range of applications.

“We have a lot of collaboration, not only inside NIH but around the world,” said Makarova. “We basically have a specific reputation that we can do a lot with sequences. People write and ask us to help, especially people working in microbiology, and specifically on archaea.” Archaea is a single-celled prokaryote that constitutes one of the three distinct domains of life.

Makarova’s work has been vital.

“We have a very specific database which was developed to be a good framework for the comparative analysis of archaeal genomes. This database is the archaeal clusters of orthologous proteins (arCOGs),” said Makarova. “People here and around the world find this very useful. We have a lot of references to our database.”

Gratitude

Like when she was growing up, Makarova enjoys support from her family and her coworkers. She works with her husband, who also works in computational biology, and her son is pursuing a joint master’s degree/PhD in the same field.

As a leading expert in microbial computational biology, Makarova is involved in comparative genomics and evolutionary studies of archaeal genomes and functional predictions for archaeal proteins. She is an author of the database of archaeal clusters of orthologous proteins (arCOGs) which is widely used to compare and annotate archaeal genomes.

She is respected by her colleagues at NIH and around the world.

“Our group, the Conserved Domain Database, collaborated with Dr. Makarova on classification of CRISPR-Cas families. She generously came on several occasions to talk to a full house on this. She lights up a room with her enthusiasm and professionalism, and very clearly explained her needs,” said Myra Derbyshire, PhD, staff scientist at NCBI. “We were grateful of her guidance.”

Koonin, a member of the National Academy of Sciences, added his own string of superlatives. “I have been working with Kira Makarova for 20 years, and during this time, she has grown from a near novice to a veritable guru of computational genomics. These days, there are many skillful bioinformaticians, but there are precious few who have Kira’s unerring intuition and insatiable hunger for new discoveries. And, on top of that, Kira is the best collaborator I have ever known, a unique member of the lab who is always willing to walk the extra two steps for her coworkers. She is, simply, the best.”

By Kathryn McKay, NLM in Focus writer

In Focus on NLM Scientists, we introduce you to some of the scientists at the National Library of Medicine.  If you’d like to read more profiles of NLM scientists, let us know by commenting, liking or sharing.