23 Jun 2020

Part 1 of 2
Three months after it shuddered to a halt to contain coronavirus, Alzheimer’s research is powering up again. How did it weather the shutdown? Some three dozen researchers around the world told Alzforum how the pandemic has cost them time and momentum, and complicated the interpretation of clinical studies. But it has not dealt a fatal blow. Crucial cell lines and animal models have been maintained. Some grants and trials will be extended to make up for lost time. A new guidance from the Food and Drug Administration addresses how to deal with missing data and adjust statistical analyses. Overall, researchers are adapting to the new reality.

AD research looks different than before. Laboratories allow fewer people at a time, with researchers working in shifts. Clinic visits unfold with temperature checks and protective equipment. A greater reliance on remote assessments may become a permanent change. In many places, observational studies and trial enrollment remain paused but are slated to start back up in July (see Part 2 of this story). Across the globe, the timing and details of reopening vary greatly, depending on when and how hard each region was hit by the pandemic. A few places are still on complete lockdown. This staggered reopening itself creates additional problems for multisite trials and collaborations. Nonetheless, most researchers appear confident the field will bounce back.

“I feel strongly that AD research will eventually return to normal once the COVID-19 crisis ends, even if the coming year poses considerable challenges,” Joel Watts at the University of Toronto wrote to Alzforum.

Labs Open Up, With Physical Distancing
Most laboratories shuttered in mid-March (Mar 2020 news). In some parts of the world, where infections were low, labs resumed operations in May. Other places are only now doing so. But everywhere, researchers have changed the way they work to keep the virus at bay. Most laboratories have embraced shift work to aid in physical distancing, and prohibited in-person gatherings. Lab meetings continue to take place online via video conferencing. Many institutions have mandated that people wear masks and other protective equipment, that partitions between work areas be installed, and that shared areas be cleaned more frequently. An article in the June 18 New England Journal of Medicine offers general guidelines for maintaining safety in an office environment (Barnes and Sax, 2020). 

How much the pandemic has damaged research depends on where you live. In Australia, the outbreak was small and laboratories reopened weeks ago, albeit at 25 percent occupancy and shift work. “The impact on our research programs will continue to be significant,” wrote Lars Ittner at Macquarie University, Sydney. The same is true of Japan, where a limited outbreak allowed researchers to return to the lab this month with the same safety measures, according to Taisuke Tomita at the University of Tokyo. His colleagues had to cull mouse colonies by 25 to 40 percent, but were able to keep aged animals and iPS cell lines. “We can recover experiments faster than we imagined in April, although some animal experiments will be delayed,” Tomita said.

Sweden did not lock down due to coronavirus. Martin Ingelsson at Uppsala University noted that his facility never closed, although about half the staff worked from home in April at the height of the pandemic there. Researchers still maintain distance from each other inside the buildings, and hold meetings online.

Other countries were worse off. Marc Aurel Busche and Samuel Harris at University College London said that most laboratories in the U.K. dwindled to a skeleton crew and are only now starting back piecemeal (see comment below). Bart de Strooper, who directs the U.K. Dementia Research Institute based at UCL, said it will take time to rebuild mouse colonies that were extensively culled. “Many projects will suffer from serious delays, but overall I have the impression we will catch up again,” he wrote. He estimates the DRI will be back to full operations by July 15. Facilities in Scotland are taking a more cautious path, with labs still on lockdown as of last week. “We have lost a lot of time on current projects,” Tara Spires-Jones at the University of Edinburgh wrote.

The east coast of the U.S. was hit hard. At the height of the pandemic, laboratories at Brigham and Women’s Hospital in Boston slimmed down to 10 percent of the workforce. They went back to 50 percent capacity at the end of May. Cynthia Lemere at BWH said she has divided the work week in half, with some lab members working Monday through Wednesday and the rest Thursday through Saturday. Researchers work two additional days at home. Lemere’s projects, too, will be delayed by four to six months because she must rebuild mouse colonies.

New safety protocols are slowing research. For example, Lemere noted the challenges of teaching techniques such as tissue sectioning and confocal microscopy while remaining six feet apart. “It requires creativity and patience,” she wrote.

At Washington University in St. Louis, shifts are staggered by time of day, with the early bird shift leaving at noon. Laboratories went to 30 percent occupancy in late May and will ramp up to 60 percent in late June, David Holtzman at WashU told Alzforum.

Marc Diamond at the University of Texas Southwestern Medical Center, Dallas, said his group was able to maintain all their animal colonies and long-term experiments. “I don’t think there will be a big effect in the long term on our AD research, since we didn’t lose experiments, and just sort of went into hibernation for a few months,” he wrote to Alzforum.

Some areas handled the pandemic well, but still suffered setbacks because of shutdowns elsewhere. Nancy Ip at the Hong Kong University of Science and Technology said the lack of international flights has caused problems. Crucial reagents cannot be ordered, samples cannot be shipped, and some research personnel are stuck in other countries. “The pandemic has impeded the progress of our research and delayed completion of studies,” Ip wrote.

Suppliers were struggling to maintain their productivity. For example, Jackson Laboratory in Bar Harbor, Maine, continued filling mouse orders during the shutdown, and was able to keep all of its aging cohorts for the MODEL-AD program, director Michael Sasner wrote to Alzforum. However, the lab had to pause generation of new cohorts, and was unable to analyze samples. The institute is now scaling back up.

Watts said it remains hard to plan for future studies, since fresh outbreaks might force a return to lockdown. “We don’t want to waste time and/or money initiating studies that may ultimately have to be put on hold again,” he wrote. Christian Haass at Ludwig-Maximilians University in Munich said the pandemic has lowered morale in his group. “We did not lose mouse or cell lines, but we lost a lot of time and spirit,” he told Alzforum.

Young Investigators Hit Hardest
Many researchers worry about what the slowdown will do to their careers. Some funding sources, particularly from nongovernmental sources, have temporarily dried up, and young investigators in particular anticipate fierce competition as they seek resources to extend their experiments. Spires-Jones noted that the two main Alzheimer’s charities in the U.K., Alzheimer’s Research UK and the Alzheimer’s Society, have cancelled at least one grant round.

When Alzforum first reported on this back in March, many young investigators, including Chaitra Sathyaprakash, a postdoc with Spires-Jones, fretted about how this would ding their careers. That is still so, Sathyaprakash told Alzforum. She was furloughed at the start of the pandemic to extend her one-year contract. Nonetheless, she lost months of work differentiating iPS lines before the lockdown. “It is not clear whether I will be able to complete my goals for this project or if a potential extension will be possible,” she wrote (full comment below).

Other early career researchers are in the same fix. “[Some] graduate students and junior staff … have found their research prematurely and permanently curtailed, thus harming their future career prospects,” Busche and Harris wrote.

In the June 12 Cell, researchers led by Erin Gibson at Stanford University in Palo Alto, California, argue that the pandemic is an opportunity to rethink how careers are launched. They suggest easing funding requirements for young investigators, extending timelines for grants and tenure, lifting hiring freezes, and providing childcare. These measures could help increase diversity in the academic workforce, they believe. In an article in the June 12 Current Biology, researchers led by Kayla King at the University of Oxford make similar points, advocating for increased support and relaxed deadlines for working parents and others disproportionately affected by the shutdown.

Despite the difficulties, researchers have coaxed some good from a bad situation. Lemere said that besides analyzing data and writing manuscripts, they filled their time at home with extra reading, webinars, and online courses. “It was an opportunity to expand our breadth of knowledge in the field. Hopefully, that will culminate in some novel mechanisms, promising drug targets and inspiring collaborations,” Lemere wrote.

As might be expected, journals are seeing a glut of papers. Elena Becker-Barroso, editor at Lancet Neurology in London, noted that submissions have shot up 70 percent. Alas, the editorial process has slowed, because clinical reviewers are working primarily to contain coronavirus. Some authors have asked for extensions to revision deadlines, because they could not yet return to the lab to run additional analyses requested. Meanwhile, Lancet editorial staff continue to work from home. At EMBO Press in Germany, Céline Carret said some staff have started to return to the office. Submissions there have spiked 130 percent. Carret noted that reviewers only ask for extra experiments if they are absolutely necessary, and the journals extend the revision timeline to allow researchers to complete them.

Joseph Caputo at Cell Press said their journals are continuing to review and accept papers in much the same way as always. Their reviewers are mostly academics, not clinicians, and have remained available, allowing Cell Press to maintain a normal schedule. Like Becker-Barroso, Caputo said that submissions are growing and staff remain at home. “Our working approaches were already well set up for remote operation, so we have been able to maintain our service to the scientific community through this difficult time,” he wrote.

For a status update on clinical studies, see Part 2 of this story.—Madolyn Bowman Rogers

Comments

1. • Samuel Harris
     University College London
   • Marc Aurel Busche
     University College London
   • Posted: 23 Jun 2020

   It is an understatement to say that the COVID-19 pandemic has caused significant disruption to basic research at U.K. universities. Most laboratories remain unable to conduct experimental work or are running severely reduced essential operations only, although there have been recent positive signs of a staggered physical reopening of labs over the coming weeks. Nevertheless, it is clear that the subsequent ramping up of operations will be a prolonged and arduous process. It may be quite some time before labs are able to reach the operational levels seen before the outbreak, given the changes in working patterns and conditions which will be implemented and which may remain in place to mitigate against possible future pandemics.

   In the interim, resources, such as cell lines and animal colonies, have been constrained to those deemed strictly essential, and are being maintained by key staff who, at least in London, often have to use busy public transportation to arrive on-site. Digital platforms have enabled lab members to remain in virtual contact with each other, and many researchers have remained productive where possible by analyzing existing data and preparing manuscripts for publication, as well as attending talks, seminars, and conferences that have become, thankfully, widely available online. Others, however, particularly students and junior staff, have been less fortunate, and found their research prematurely and permanently curtailed, thus harming their future career prospects. We are also saddened by the news of university staff being furloughed and wish them a swift return to their posts. 

   The outlook for basic research following the COVID-19 pandemic remains uncertain. As with so many tragedies, it has rightly stimulated a widespread re-evaluation of a number of economic, social, and environmental issues, and much will depend on the recovery measures introduced by governments and institutions. It seems likely that funding dedicated to pandemic and infectious disease research will increase, and only time will tell whether this will be in addition to, or at the expense of, funding into other disciplines. We feel confident that current levels of research support for dementia, itself a growing pandemic, will continue, given its enduring impact on wider society as well as the increased COVID-related risk in older individuals and those with dementia.

   Amongst the adversity, we have also witnessed touching acts of compassion and solidarity here in the U.K., including the outpouring of public support for the National Health Service, the massive mobilization of volunteers to deliver food and medical prescriptions to vulnerable groups, and the secondment of university staff and facilities to undertake COVID related research. Our hope is that recent events will have emphasized the crucial role of science and open collaboration in improving public welfare, notions sadly eroded of late, and that the hiatus we have experienced as a research community will have broadened our horizons and taught us valuable lessons for the future.  

   View all comments by Samuel Harris View all comments by Marc Aurel Busche
2. • Chaitra Sathyaprakash
     University of Edinburgh
   • Posted: 24 Jun 2020

   My months in furlough: A scientist without a lab

   As an early career researcher, I am interested in the early molecular changes in cellular pathways that lead to the manifestation of neurodegenerative diseases, and study these changes using iPSC-derived cortical neurons. I have a yearlong contract for my first postdoc, while I think about a future in academia.

   At the beginning of the lockdown nearly three months ago, I was placed on furlough, six months into my postdoc. This was the right decision for me as I am unable to produce new data while our lab remains shut. I also don’t have large amounts of data to analyse, students to supervise, or collaborators to interact with. While on furlough I cannot contribute to work being done in my group, so I have been focusing on completing a paper from my Ph.D., keeping up to date with the literature and listening to virtual seminars. However, as someone used to spending my days actively working with my hands, discussing experiments and scientific questions with colleagues, this lockdown has been frustrating.

   While we expect labs to begin opening in the next month, the momentum I gained on the cusp of the lockdown has largely faded, and I imagine it will take time to build again. I will gain back the months lost during lockdown because of the furlough scheme, but I have lost the months from the beginning of 2020 spent differentiating the cultures, which were discarded when my university announced an overnight closure of labs. This was several experiments worth of work, which could have provided vital data for my project. It is not clear whether I will be able to complete my goals for this project or if an extension will be possible.

   I am painfully aware of the numerous ECRs in the same boat, so the future looks a little uncertain. I am also waiting for the decision of a grant proposal submitted in March. Whether further submissions in the immediate future will be possible is unclear due to a high demand for funding that will emerge as we all surface from the lockdown.

   View all comments by Chaitra Sathyaprakash

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References

News Citations

1. In the Wake of COVID-19: Trials Interrupted, Delayed, Cancelled 23 Jun 2020
2. Social Distancing Shutters Alzheimer’s Research 27 Mar 2020

Paper Citations

1. Barnes M, Sax PE. Challenges of "Return to Work" in an Ongoing Pandemic. N Engl J Med. 2020 Jun 18; PubMed.

Further Reading

No Available Further Reading