The Pursuit of Global, Sustainable and Cooperative Open Science

“My point and plea today, is to forge a farsighted agenda to develop a more global way of thinking, even a plan for science, to serve our shared future. Not just as individual national communities with narrow interests and viewpoints, and not just for the next few years, but broadly and for the next decades.”

These inspirational words were spoken by Nobel Prize Laureate Elizabeth Blackburn at the beginning of her Keynote presentation during the 68^th Lindau Nobel Laureate Meeting held in Lindau, Germany, in June 2018. It was during this meeting that reverberations of the Lindau Guidelines first began.

The concepts discussed by Blackburn during the meeting resonated with the hundreds of scientists in the audience, and, in partnership with the Lindau Nobel Laureate Meetings, she began to forge a path towards establishing a set of guidelines. These guidelines would aim to help researchers around the world conduct sustainable and cooperative open science.

In a recent interview, I had the pleasure of speaking with Blackburn on her impressive contributions to science and society. She highlights early inspirations that cemented her love of science, elaborates on the research that led to her being co-awarded the 2009 Nobel Prize in Physiology or Medicine, and explains why she is advocating for sustainable, cooperative and open science.

An early appreciation of flora and fauna

Blackburn always knew she would pursue a career in science. She was born in Hobart, Tasmania, on November 26, 1948, to parents Marcia and Harold, who were both doctors. She describes herself as “lucky” because she knew from a very young age, 10 or 12 years old, that science was the path she should follow. Blackburn notes two key inspirations – the environment and reading.

She offers some examples of books that inspired her love of science in the early days: “I read, Ève Curie’s biography of her mother Marie Curie. She paints such a marvelous picture of Marie Curie as a scientist, and it resonated with me.” She also tells me about a book by George Gamow, who “was captivated by the genetic code when it was merely an idea.” She explains that it was the combination of “fun” ideas Gamow had proposed, along with his interactions with scientists such as Crick and Brenner, who were both looking at the genetic code at the time, that had captivated her.

“I was just enchanted by the idea that, if you understood the molecules of biology, that's how you were going to understand living things,” – Elizabeth Blackburn

Elizabeth Blackburn as a schoolgirl, photographed at a chemistry lab balance at her school in Launceston, Tasmania, ca 1963. Credit: Elizabeth Blackburn.

“Launceston, Tasmania was a small enough town that you had some time to think… it was a good place to grow up. And then I always like to say, a good place to leave, eventually, when you want to venture into the wider world,” notes Blackburn.

And following her own advice, she did leave. In 1966 Blackburn moved to mainland Australia with her family and earned a bachelor’s and a master’s degree in biochemistry from the University of Melbourne.

She then enrolled as a graduate student in molecular biology at the University of Cambridge in England, where she worked in the lab of British biochemist Frederick Sanger. She had met Fred through her Master of Science research advisor, Frank Hird, in Melbourne, Australia. Frank had worked on amino acids and nutrition in food with Fred shortly after the second world war.

She reflects on her time working with Sanger: “It was wonderful, Fred was totally hands-on. He himself was developing the first methodologies for sequencing DNA directly. There were other methods being tested in the lab, the method he had assigned me to was to copy DNA into RNA and then use the patching together methods they had developed for RNA sequencing.”

Sanger went on to win the Nobel prize in chemistry – twice. In 1958 he was awarded the prize “for his work on the structure of proteins, especially that of insulin”. And in 1980, the prize was divided between Sanger, Paul Berg and Walter Gilbert. Gilbert and Sanger received a quarter of the prize each "for their contributions concerning the determination of base sequences in nucleic acids”.

“Fred Sanger was very unassuming, but he was excited about the success of sequencing, there's no question about that,” – Elizabeth Blackburn

Blackburn describes Sanger as very ingenious in his science but notes that he was very low key, and her Australian culture welcomed that in some ways. “He wasn't snooty or anything; he just was there, in the lab, doing his research. He also had really a very quiet social conscience. One of his researchers, he'd brought in from high school and he nurtured the career of this researcher, who hadn’t come from a fancy educational background, far from it. Fred was a Quaker, and a pacifist.”

In 1992, Sanger had the honor of a genetics research center being named after him – the Wellcome Sanger Institute, located in Hinxton, just outside of Cambridge. The institute was established by the Wellcome Trust to support work on the Human Genome Project. According to the Institute, while Sanger gave permission for the use of his name, having accepted, he cautioned… “it better be good”.

As we talk about the institute, it’s obvious that Blackburn is amused: “Fred loved it when they started building the center, he was clearly thrilled, but he was always a very hands-on low-tech sort of scientist.” I can tell from her warm smile that the thought of such a technologically advanced facility being named after him was funny.

She shares a story to help explain her reaction, “We got a new centrifuge, and we're walking by the centrifuge, which is out in the hallway. And we're looking at it, and we said to Fred, ‘Look. A nice new centrifuge’. Fred walks by and says ‘ah, too many knobs’. So, I leaned over to take a closer look at the centrifuge. I think there were two buttons – one to adjust speed and one for on/off. So, I always thought he must have been very amused by the Sanger Institute, which was the total opposite in being so very high tech.”

Discovering telomerase

While at the University of Cambridge, Blackburn met her husband John Sedat, who was also a member of Sanger’s Lab. In 1975 she relocated to the United States with him and joined the laboratory of Joseph Gall at Yale University. It’s here that Blackburn began to focus on her telomere research, initially using the ciliated protozoan Tetrahymena. This species was a great model system because it has a particular stage in its development where, for one of its nuclei, it chops its chromosomes into little pieces, and then adds new telomeres.

After getting some early hints about the existence of telomerase  – the enzyme that adds telomeric DNA sequences to the 3' end of telomeres – she decided that it would be a great project for someone in her lab to work on: “I had a very serious postdoc and he said, ‘Well, that's too risky’, but Carol Greider, my PhD student at the time, said she’d take it on.”

Left to right: Joseph Gall (postdoctoral mentor of E Blackburn), Elizabeth Blackburn, Carol Greider (Blackburn’s graduate student). Photo taken in 1999. Credit: Elizabeth Blackburn.

After the team had researched various ways to try to find evidence for such dramatic activity, Greider and Blackburn found one experiment that suddenly tied everything together. “We could see these radioactive products being made in a pattern and it was very hard to say, well, this is nothing. We then spent a year trying to prove that it was something, that it wasn’t just an artifact,” explains Blackburn.

Initially, most people weren’t particularly excited about the findings, because as Blackburn describes, “Tetrahymena is a weird system”. But her molecular biology training had taught her that there are certain principles that biology uses. “I couldn't believe that one organism would do something that other organisms didn't do, there’s evolutionary conservation. When you find things in a specific system, there's usually a general principle, or in this case, an enzyme activity, and that was true for eukaryotes,” says Blackburn.

Fluorescence microscopy image of human cell telomeres (magenta) and chromosomes (blue). Credit: Bradley Stohr.

The connection between science and policy

In the 1990s Blackburn began to consider more closely, the relationship between her research and human health as well as the intertwined nature of science and policy on a broader scale. In her biographical Blackburn notes that she joined the President’s Council on Bioethics in 2002 to share her “knowledge of the relevant fields of science, and long experience in the world of research”, as she felt that her perspectives may help to advise national scientific policy. After serving as a member for two years, she was informed that she would no longer be a part of the council. She notes that during this time, she was “overwhelmed by the great many letters and communications” she received, which were “almost without exception positive and supportive”. This reinforced Blackburn’s view that wherever possible, science should be brought into an argument for deciding what policies should be adopted by society.

“There are so many policies that are related to the health and wellbeing of people. However, you often don't have good measures for them in the population, or at large cohort levels,” Blackburn notes.

She expanded on this point using examples based on her telomere research. What struck Blackburn, was the relationship between people's telomere length and various factors: “Telomeres, on average, were getting shorter with time. In population groups this correlated with, and in fact partly caused, an increased risk of some chronic conditions, for example, cardiovascular disease, mental health conditions, depression, etc.”

Blackburn highlights collaborative studies conducted by Kaiser Permanente – a not-for-profit American healthcare consortium. One such study, based on data collected from ~ 85,000 individuals, demonstrated a connection between the neighborhood an individual lives in, their level of education and the length of their telomeres. The research utilized what is known as a “Neighborhood Deprivation Index”, which is calculated from eight criteria that has been nationally agreed on, for what makes a neighborhood deprived (e.g., income/poverty, education, employment, housing and occupation).

“What makes a neighborhood index better or worse is related to so many economic and policy issues, we can see this quantitative relationship in many different ways,” says Blackburn.

Another key area researched by Blackburn, is the relationship between stress and telomere length.

“We know that stress hormones can affect telomerase activity and can push that downwards, but where I think it gets interesting is you can use this as a measure of the impact of economic policies on health,” she notes. For example, economic policies that are continually exposing individuals to situations that cause chronic, psychological stress.

“Stress has been shown to make telomeres shorter,” she notes. Blackburn is quick to clarify that when she describes “stress” she is referring to long-term chronic psychological stress that can't be well controlled, as opposed to “good stress”, or “challenging stress” which is “perfectly fine”.

“When we look over time, a person’s telomere length can vary,” explains Blackburn. While telomere length trends down with age, it’s a dynamic process and can rise and fall over time because of factors that elongate telomeres – primarily the action of the enzyme telomerase – as well as shorten them.

Blackburn elaborates on the dynamic nature of telomeres: “Telomerase is in stem cells, and actually in a lot of our immune cells too, and it makes telomeres longer. But there are also other influences that can make telomeres shorter. Sometimes it’s just because DNA replication is incomplete, but chemical and oxidative damage can also make them shorter. Even simple kinds of chemical damage can make telomeres shorter. So, when you capture that in length, you must consider the net of the lengthening and shortening.”

In answer to my question, “are there ways we can counteract telomere shortening”, Blackburn responds, “People can make lifestyle choices that will impact their telomere length.” She likened these choices to things your mother would recommend: “Get a good night's sleep, maintain a positive attitude, eat healthily, get some exercise, make sure you have social support.”

“In certain situations where non-medical interventions are introduced, in just a few months, the average telomere length of those in the experimental group actually went up.” The interventions she is describing are intensive actions, such as mindful meditation, or exercise, for example.

“Traditionally medicine had been separated into the mind and the body but, they're actually highly integrated. The mind is doing a lot of physiological controlling and is intimately linked with immune cell function and vice versa,” – Elizabeth Blackburn

Blackburn began exploring the impact of stress and mindful meditation on telomere length back in the early 2000s, with her UCSF psychologist collaborator Elissa Epel. She knew she was collaborating in a field that she knew very little about. So, to gain a better understanding of meditation, she took a meditation course run by a man called B. Alan Wallace. Blackburn reflects on the course, “It was terrific – extremely interesting because you could feel how your brain was changing, even in only a week of totally intensive learning and practicing, which I had never done before. I learned to concentrate on one thing at a time, I became less of a multitasker. There’s nothing like personally experiencing something to appreciate what effect it can have.”

Forging a path towards open, cooperative science

“It's an idea whose time has come; an idea driven in part by young scientists who really would like to have this kind of guidance. They're the ones who are going to be leading the world of science, and they were interested in this idea,” Blackburn says.

The idea of the Lindau guidelines materialized as a result of Blackburn asking two key questions, the first being: “what makes people trust a profession?”. Blackburn wanted to reinforce people’s trust in science, which, of course, unbeknown to her at the time, would be vitally important with the emergence of SARS-CoV-2.

“Physicians take the Hippocratic Oath, which is to do no harm,” notes Blackburn. But there is no real equivalent for scientists, she explains: “as we've seen with the climate crisis, and the COVID-19 pandemic, people don't always trust science, or scientists therefore”. In contrast, “by and large, people do tend to trust their doctors”.

The second consideration for Blackburn was “how can we do science better?”. That led her to consider how, as a community, we conduct scientific research: “Institutions used to reward the more old-fashioned views of science.” Researchers typically worked in a solitary manner, inadvertently creating silos of knowledge. “You had to show that you yourself did it to get a promotion, and so forth. A person’s ability to collaborate effectively wasn’t really valued in that kind of a culture,” Blackburn muses.

“When it became clear that COVID-19 was an international crisis and that no single person or nation was going to solve this alone, it became such an extraordinary kind of momentum in science,” – Elizabeth Blackburn

When looking back over the past two years, it’s fair to say that the COVID-19 pandemic has certainly fuelled collaboration and reshaped the scientific community’s approach to science, globally.

“I've really liked seeing a shift in recent years to a more collaborative approach, it doesn't take away individual creativity and ingenuity and all the marvelous things that are valued in science and leadership, it just demonstrates that you can do so much more,” reflects Blackburn.

Credit: Wolfgang Huang/Lindau Nobel Laureate Meetings.