After years of working in other scientists’ laboratories, Alison Twelvetrees and Daniel Bose have finally landed positions as principal investigators and have grand plans to carve their own paths in science.
They didn’t bank on a global pandemic – or another chance event that would turn their lives upside down.
Nature followed Ali and Dan’s journey over 3 years as they try to launch their careers.
1. The pitch
On the morning of 7 June 2018, neuroscientist Alison Twelvetrees arrives at a slick five-storey building on the traffic-choked Euston Road in London. She has made sure she is wearing her lucky charm — a locket that belonged to her grandmother. Her bag is stuffed with crumpled neuroscience papers and notes that she’s been carrying around like a comfort blanket for the past two weeks. She is here to make a pitch to win a £1.14-million ($1.6-million) fellowship — money that she needs to sustain the fledgling research group she started the previous year in Sheffield, UK.
Outside the interview room, she watches the previous applicant emerge and tries to get a handle on her adrenaline. She has rehearsed for this moment intensively, fielding awkward questions in three practice interviews. The worst moment: when one panel member asked why she’d been so unproductive as a postdoc — a query so aggressive that it took Ali a while to gather herself sufficiently to reel off her scientific accomplishments and point out that she’d also had a baby.
Ali’s now-three-year-old daughter, Ada, is back home in Sheffield with her husband, Daniel Bose. Dan knows what’s at stake for his wife. Both of them are new principal investigators (PIs) — independent scientists building up their own laboratories at the University of Sheffield. A year earlier, Dan had tried and failed to win a £1-million fellowship from the same scheme, funded by the UK charity Wellcome and the Royal Society. It is one of the most prestigious and lucrative grants available to PIs in the United Kingdom.
When Ali walks into the room at Wellcome headquarters, she finds a panel of 20 judges. The chairperson is so far away that she seems to exist in a different dimension. Ali has five minutes to take the panel through just two PowerPoint slides about her research into how cellular cargo is shuttled up and down neurons, and how these mechanisms break down in disease. She then has 25 minutes to answer the panel’s questions. It will take the panel a few weeks to decide whether to award her the money she needs to get her lab off the ground.
The interview is simultaneously painfully slow and over too quickly. At a nearby pub afterwards, Ali sips a half-pint of beer, downcast. “I’m not crying, so there’s that,” she says. “The next three weeks is going to be stuff popping into my head: ‘Why did I answer that? Why did he pull that face when I said that?’”
Firth Court at the University of Sheffield.
Firth Court at the University of Sheffield.
Every year, a few hundred scientists in the United Kingdom try to establish new labs from scratch; globally, thousands of researchers become heads of their own labs. From the outset, it’s a chase for money and a time of intense pressure as scientists try to build research programmes while juggling teaching, fundraising, publishing and family life. Ali began her lab with just £15,000 in grants to cover equipment and experiments; Dan had £20,000. Both need to recruit PhD students, and Dan must also devise and deliver a programme of lectures.
They arrived at Sheffield in 2017 with three years in which to prove themselves, by attracting bigger, lab-sustaining grants and, they hope, publishing papers. If they can do that, they will pass their probation and their positions will become more stable, although the United Kingdom doesn’t have a tenure system like that of the United States. If they fail, the university can terminate their contracts and they’ll be out of a job. Dan and Ali agreed to allow a team of reporters from Nature to chronicle their lives as they struggled to establish themselves in science (see endnote, ’How we found Ali and Dan’).
2. “Okay, where do I start?”
When Dan first opened the door to his new lab in spring 2017, he was surprised to find that it was stuffed with someone else’s junk. Half-full boxes of pipette tips and nitrile lab gloves littered the dusty shelves. In one corner sat a trolley with peeling, dirty white paint. On it stood an ancient computer monitor, a spaghetti tangle of defunct cables and several tired-looking machines.
Dan had one bench and one microcentrifuge. The rest of the space was assigned to people from another lab. He sprayed down his benchtop space, wiped off the dust and walked out again.
For the next two weeks, Dan’s mind would race when he walked into the lab. “Okay, where do I start? What do I do? What do I need to get going? How on earth do I afford what I need to get going?” he thought. Then he would retreat to the safety of his office down the hall to think about something else.
Gradually, things came together. Reagents he’d developed as a postdoc arrived from his former lab at the University of Pennsylvania in Philadelphia. And he learnt to scavenge. In corridors, meeting rooms and the backs of cupboards as well as on his new lab’s shelves, he found an embarrassment of riches: barely used cartons of 96-well plates used to carry out reactions in small volumes, micropipette tips, forgotten tubes of enzymes.
Dan ordered bright orange tape to mark his territory in the shared space, a fridge freezer, a few test-tube racks and a partial set of micropipettes — his first purchases as a PI. But fiscal realities quickly set in. Dan wanted to study enhancer RNAs, which can control when and where genes are turned on. After years as a postdoc, dreaming of the experiments and projects he’d launch in his own lab, Dan realized he would have to rein in his ambitions. He didn’t have the time or the money to race to the bench and get started. He needed to write grants, plan budgets, negotiate rates with vendors and recruit students.
When he did make it to the bench, Dan would sometimes begin an experiment, only to realize that a key reagent was missing. Once a postdoc in an established and well-funded lab, Dan now found himself trying to stretch his scant resources. He borrowed basic molecular-biology staples such as agarose, a compound used to separate molecules on the basis of size, from people in neighbouring labs until he felt their patience wearing thin. When he did place an order, the price tag on some reagents made him shudder.
But at least he had space to play with. For a few weeks after her job started, Ali didn’t have a bench — nowhere to actually do any lab work. “I turned up. And I sat in my office for a few weeks, and then at a meeting, I sort of raised … ‘Can I have a bench, maybe?’”
Her new home, the Sheffield Institute for Translational Neuroscience (SITraN), had been established seven years earlier by drawing together existing scientists from Sheffield. Ali was the first member of staff to join from outside the university, and most lab space was already allocated. Once she prodded, she got a small spot in a shared space.
Feeling that she needed more support from her peers, Ali set up a group on the messaging app Slack for new PIs in the United Kingdom, together with immunologist Sophie Acton, who had also just started her first lab at University College London. Slack groups are a popular way for PIs to share experiences: one set up in 2016 by cell biologist Prachee Avasthi now has more than 3,000 members.
Despite the slow start, Ali began to make plans for her science and to collect some preliminary data. She started collaborating with a scientist from another department who had built a microscope she could use in her research.For a while, Dan and Ali had a game going to see how much they could stretch free samples from vendors. It was a far cry from his postdoc lab, Dan recalls, where all he had to do was wander over to tell the lab manager that he needed a reagent. “Suddenly, you’re hit with having a budget and learning purchasing,” he says. “I was spectacularly unprepared for that.”
Dan was also unprepared for teaching. Unlike Ali, Dan’s position came with teaching responsibilities and, in the autumn of his first year at Sheffield, Dan walked into the first of four lectures he was slated to give for a class on RNA biology. He’d had almost no experience or training, and he was a little nervous, as he often is before public speaking events.
The lecture started well as Dan ran through the basics of the CRISPR–Cas9 gene-editing technique. But when he delved into the enzyme mechanism underlying how this editing system works, 75 faces went blank. “You hear comedians talk about how you can tell when you lose an audience,” he says. “I didn’t expect to see this happening myself.”
Dan felt a whiff of panic but ploughed on with his material, rather than going back over the topic — a choice he later regretted. Looking back on that day, he describes it as “a little bit soul destroying”, but he knows he’s not the only scientist who has had a rough first lecture: “It’s a rite of passage.”
3. “I finally decided I had nothing to lose”
Ali and Dan in 2005.
Ali and Dan met as undergraduates at Imperial College London. They both studied biochemistry, but Dan sat at the back of the lecture theatres; Ali at the front. “I didn’t speak to Ali for three years,” says Dan. “I was kind of shy. She was kind of dating somebody.”
But at a summer ball towards the end of their third year in 2004, Ali persuaded a friend to ask Dan out for her. “I finally decided I had nothing to lose: ‘Well, I won’t see him again, so it doesn’t really matter,’” she says. “But I still wasn’t brave enough to ask him out in person.”
“You were braver than me,” says Dan.
A little over a year into the relationship, the two began what would become a long struggle with the ‘two-body problem’ — a difficulty encountered by many academic couples as they manoeuvre themselves through a tight job market in search of two jobs in the same location. They both got into graduate school in London, with Dan lingering there as a postdoc while Ali finished her PhD. Then Ali got a fellowship that allowed her to split her time between London and the University of Pennsylvania, where Dan found a second postdoc.
Dan in Philadelphia, Pennsylvania, in 2012.
They uprooted and moved to Pennsylvania in December 2011, just three weeks after getting married. A little more than three years later, their daughter Ada was born.
At the end of Ali’s one-year maternity leave, the two-body problem loomed large. Ali had to return to London to finish her fellowship, but Dan was preparing to submit a paper — a crucial step in any young scientist’s career — and he couldn’t leave Pennsylvania just then.
In December 2015, the family packed up its belongings and the cat, and rushed to the airport to fly back to the United Kingdom for the holidays. At the start of the new year, Dan returned to the United States alone.
“It was a really tough time for everybody,” he says.
Ultimately, Dan stayed in Philadelphia for another 11 months, while Ali juggled work and Ada alone in London. Dan did his best to parent by FaceTime. “Ada got very used to talking to an iPad,” he says. “She would do things like carry the iPad around and tuck it up with her toys at bedtime.”
Years later, Dan and Ali still carry the weight of that time apart. The separation seemed a necessary sacrifice to ensure that they both had a solid chance of long-term employment, says Ali. But it also felt like a risk to their family.
Ali and Ada in Philadelphia in 2015.
“It was a big gamble, or at least it felt that way,” she says. “It’s difficult. The ideal, perfect image of a mother … what kind of mother would separate their child from a loving father who wanted to be there for her?”
“Similarly, what kind of a father would leave his wife and daughter in another country and go and take a flight back to do science?” Dan says.
Dan has given talks to new postdocs about his academic career path, and likens the two-body problem to running a three-legged race. “You’re both trying to go in the same direction,” he says, “running with two legs tied together.”
After Dan’s offer from Sheffield had arrived, Ali faced a protracted wait to see whether her application was also successful. When it finally came through, Ali and Dan counted themselves lucky that they were able to find jobs at the same university. When they first moved to Sheffield in 2017, it was the first time that they’d all lived together as two working parents raising a child. “There was a lot of intense discussion about how it was all going to work because we hadn’t had to do it before,” says Ali. “It took a long time.”
Dan with Ada on a family hike in the Peak District, near Sheffield.
But through trial and error, the family settled into a routine that worked. Ali and Dan alternated Ada’s day-care pickup — one week on, one week off — to allow them to work late and tend to experiments.
“The fact that we managed to get here at all is somewhat surprising,” says Dan. “There’s definitely an element — when you’re in the middle of paper reviews and neither of you have jobs sorted out — when you think maybe it’s not going to happen for us.”
Now they’re in the same place, the challenge is to sustain their good fortune and use their stability to break new ground in science.
4. Nanometre steps
When Ali talks about the brain, her eyes widen and sparkle with child-like glee. “All cells are special, but I love neurons the most,” she says. “And they have to function your whole life. It’s crazy. It kind of gives you vertigo, thinking about all this stuff going on in your own cells.”
In every one of these vertigo-inducing neurons, a fleet of motor proteins ensures the safe passage of cargo from the cell’s main body down its axon, or nerve fibre, and back again. That cellular shuttle system is crucial because it supplies materials to the ends of the axon, where electrical signals jump from one neuron to another.
Inside neurons, the motor proteins travel along tracks called microtubules. For some long neurons in the spinal cord, the journey from end to end could take two weeks. When motor proteins fail to do their work, as they do in motor neuron disease, the effects on the network can be devastating.
Ali wants to know how these proteins load and lug their precious cargo. They can carry freight many times their size — large organelles such as mitochondria, or proteins contained in bubbles called vesicles. One class of motor protein called kinesins look like upside-down Ys, and their two ‘legs’ plod along the microtubules in eight-nanometre steps, shuttling newly made components to the ends of the axon.
Ali knows that different cargos can travel to the ends of axons at very different rates. But the kinesin that does the hauling moves forwards at an almost constant speed. Ali wants to understand how kinesin activates — or loads its cargo — and how that sets the pace of the journey. If she can do that, she can take a stab at working out how the process breaks down in disease.
She can just about see these proteins at work in single neurons in a dish, but it’s hard to observe them properly. Ali’s dream microscope, which would allow her to track motor proteins as they carry cargo in live neurons, is a big part of her grant application and costs a quarter of a million pounds. “£250k is a lot of money, but it’s a lot of microscope,” she says. “I always think of the money as science tokens — ‘I can buy this much science’.”
For now, she is having to settle for putting the proteins under a shared microscope and watching them float freely in fluid, spying on them as they open and close like the legs of synchronized swimmers.
Ali describes all of this to the judges in her pitch for the Sir Henry Dale Fellowship at Wellcome in June 2018, outlining how she plans to study kinesin and what she needs to make it happen. Afterwards, Ali recalls, there wasn’t much time to take stock of how it had gone because Dan had a deadline a few days later. “I had to finish my interview, and then sort of drop everything to make sure that I was covering everything at home while Dan was finishing his grant application,” she says.
A few weeks after her interview, Ali checks her phone after a lab meeting: “And literally the first thing I saw was this e-mail in my inbox. And I just knew, even though I hadn’t seen the content of it, that it was negative.”
She forces herself to read the e-mail, which is brief and confirms her fear: she hasn’t got the fellowship. Then she calls Dan. “And then I ran away and had some lunch. And a big piece of chocolate brownie and a small cry and got back to work again.”
Ali is immediately pragmatic about what to do next. She knows she can apply to other funding bodies, and probably to the same fellowship programme, which she is most familiar with. She knows her weak spots. “Even though I can do all this stuff, I don’t necessarily project impermeable confidence. When you’re trying to essentially give a pitch and get people on board with your vision … you kind of have to be bullet-proof in the confidence department.”
But it’s hard to project that confidence when you know your job is at stake. Ali joined SITraN on a three-year, fixed-term contract and must pass her probation to convert it to an open-ended job. The main way to pass is to win a grant that can support the lab, and she fears she’ll be let go if she doesn’t get a cash infusion.
At lunch, Dan had suggested cocktails, but they’d decided to hold off until the evening. “He’s probably more upset than I am,” Ali says. “His phrase is that we win together and we lose together, and I think we get so tied up with wanting each other to succeed.”
The couple had lost together before, in 2017, when Dan applied for a Sir Henry Dale Fellowship in a previous round and didn’t get it. Dan is reworking his presentation for a second application this year, hoping that he can convince the judges to fund his work on a molecular mystery.
The enhancers that he studies reside in poorly understood regions of the genome that do not serve as templates for proteins, but instead encode snippets of RNA called enhancer RNAs.
These are molecular switchboard operators, controlling whether genes are turned on or off at just the right time and place. When the switchboard goes awry, disease can follow. Errant enhancers have been linked to conditions such as cancer and neurodegenerative diseases. This means that these RNAs could provide an attractive drug target — but to design such drugs, researchers need to know how enhancer RNAs do their job.
During his postdoc, Dan showed that some enhancer RNAs bind to a protein called CBP that turns genes on by loosening tightly packaged regions of DNA.
Now, he wants to use that as a jumping-off point to pick apart how those enhancer RNAs work. A key experiment will be to use Dan’s favourite technique — cryo-electron microscopy (cryo-EM) — to see how one particular enhancer RNA changes the structure of CBP when it binds to it. He has been hooked on cryo-EM since graduate school. “I was incredibly taken with the fact that you could look down the microscope and see individual molecules of RNA polymerase in front of you,” he says. “It’s stuff like that that really stirs your excitement in science.”
But to get to that point, there is a slew of molecular biology to be done. Dan and his team must first purify the CBP protein away from all other proteins and cellular gunk, then find the right conditions to coax it to bind to its enhancer RNAs outside the cell. All of that has to happen before Dan even touches the electron microscope and starts collecting data.
These are the crucial steps that molecular biologists sweat over — each represents an opportunity for a project to get hung up for months. The painstaking work to optimize lab conditions and troubleshoot failed experiments rarely makes it into a scientific publication, but it underlies every discovery.
It is also not captivating conversation for a three-year-old.
“Ada shouts at us now,” says Ali. “If she’s bored by the conversation, like if it’s too much work-based, she’s like, ‘What are you talking about? Stop talking.’”
“Which is a very important perspective,” says Dan.
“So we have an extra person to ensure that the work–life balance is enforced at the other end,” adds Ali.
It’s not just for Ada’s benefit that Ali and Dan avoid talking shop. “Scientifically, we’re pretty distant,” says Dan. “We’ve tried quite hard to maintain that distance so we don’t end up talking about science all the time at home.”
Both rely on high-resolution microscopy to peer into the molecular world. But that is where the similarity of their work ends. They both claim to lack the deep background to fully grasp what the other is doing.“The funny thing is, although I’m very familiar with Dan’s work, I have no context for it,” says Ali. “I keep having to ask what enhancers are.”
“Yeah, which probably means I’m not giving you a very good answer,” Dan says.
“What are enhancers again?” Ali laughs, half-serious.
“Outside the realm of the basic techniques, there’s a lot of stuff I really don’t understand about what she does,” says Dan.
They might not sell their science well to each other, but both must think hard about how best to market their work to the grant panel. Around 200 new PIs around the country submit a full application to the Sir Henry Dale scheme each year, and only about 40 will be offered a fellowship. For Dan and Ali, their best shot at keeping their fledgling labs open is to win two of those places.
Next: Good news and bad news
Read part 2 of Starting up in science.
Nature 597, 608-613 (2021)
How we found Ali and Dan: Nature journalists asked staff members across the journal for examples of scientists who were going through big changes, such as starting up new labs or institutions, moving a lab to another country or retiring. We wanted to know — in real time — what these experiences are like. We contacted several scientists to get a sense of their stories and, crucially, whether they would be open to multiple visits over years from our reporting team, based in London. This profile of Ali and Dan does not represent the journey of every new principal investigator, but many researchers will recognize aspects in their own path to independence — including moves to other countries to improve skills, having to attract funding to retain jobs, and the ‘two-body problem’, in which scientist couples seek jobs in the same location.
This article is also available as a pdf version.
Authors: Kerri Smith, Heidi Ledford, Richard Van Noorden
Additional Reporting: Benjamin Thompson
Design: Lizzy Brown, Wesley Fernandes, Kelly Krause
Original photography: Chris Maddaloni for Nature
Subeditors: Anne Haggart, Anna Callender
Podcast editors: Benjamin Thompson, Kerri Smith
Editor: Richard Monastersky
Project leader: Kerri Smith
Personal photos provided by Alison Twelvetrees and Daniel Bose.