Q&A with Holden Thorp: Finding Better Ways to Communicate Science
This month, Leaps.org had a chance to speak with Holden Thorp, Editor-in-Chief of the Science family of journals. We talked about the best ways to communicate science to the public, mistakes by public health officials during the pandemic, the lab leak theory, and bipartisanship for funding science research.
Before becoming editor of the Science journals, Thorp spent six years as provost of Washington University in St. Louis, where he is Rita Levi-Montalcini Distinguished University Professor and holds appointments in both chemistry and medicine. He joined Washington University after spending three decades at the University of North Carolina at Chapel Hill, where he served as the UNC's 10th chancellor from 2008 through 2013.
A North Carolina native, Thorp earned a doctorate in chemistry in 1989 at the California Institute of Technology and completed postdoctoral work at Yale University. He is a fellow of the National Academy of Inventors and the American Association for the Advancement of Science.
Read his full bio here.
This conversation was lightly edited by Leaps.org for style and format.
Matt Fuchs: You're a musician. It seems like many scientists are also musicians. Is there a link between the scientist brain and the musician brain?
Holden Thorp: I think [the overlap is] relatively common. I'm still a gigging bass player. I play in the pits for lots of college musicals. I think that it takes a certain discipline and requires you to learn a lot of rules about how music works, and then you try to be creative within that. That's similar to scientific research. So it makes sense. Music is something I've been able to sustain my whole life. I wouldn't be the same person if I let it go. When you're playing, especially for a musical, where the music is challenging, you can't let your mind wander. It’s like meditation.
MF: I bet it helps to do something totally different from your editing responsibilities. Maybe lets the subconscious take care of tough problems at work.
HT: Right.
MF: There's probably never been a greater need for clear and persuasive science communicators. Do we need more cross specialty training? For example, journalism schools prioritizing science training, and science programs that require more time learning how to communicate effectively?
HT: I think we need both. One of the challenges we've had with COVID has been, especially at the beginning, a lot of reporters who didn’t normally cover scientific topics got put on COVID—and ended up creating things that had to be cleaned up later. This isn't the last science-oriented crisis we're going to have. We've already got climate change, and we'll have another health crisis for sure. So it’d be good for journalism to be a little better prepared next time.
"Scientists are human beings who have ego and bravado and every other human weakness."
But on the other side, maybe it's even more important that scientists learn how to communicate and how likely it is that their findings will be politicized, twisted and miscommunicated. Because one thing that surprised me is how shocked a lot of scientists have been. Every scientific issue that reaches into public policy becomes politicized: climate change, evolution, stem cells.
Once one side decided to be cautious about the pandemic, you could be certain the other side was going to decide not to do that. That's not the fault of science. That’s just life in a political world. That, I think, caught people off guard. They weren't prepared to shape and process their messages in a way that accounted for that—and for the way that social media has intensified all of this.
MF: Early in the pandemic, there was a lack of clarity about public health recommendations, as you’d expect with a virus we hadn’t seen before. Should public officials and scientists have more humility in similar situations in the future? Public officials need to be authoritative for their guidance to be followed, so how do they lead a crisis response while displaying humility about what we don't know?
HS: I think scientists are people who like to have the answer. It's very tempting and common for scientists to kind of oversell what we know right now, while not doing as much as we should to remind people that science is a self-correcting process. And when we fail to do that – after we’ve collected more data and need to change how we're interpreting it – the people who want to undermine us have a perfect weapon to use against us. It's challenging. But I agree that scientists are human beings who have ego and bravado and every other human weakness.
For example, we wanted to tell everybody that we thought the vaccines would provide sterilizing immunity against infection. Well, we don't have too many other respiratory viruses where that's the case. And so it was more likely that we were going to have what we ended up with, which is that the vaccines were excellent in preventing severe disease and death. It would have been great if they provided sterilizing immunity and abruptly ended the pandemic a year ago. But it was overly optimistic to think that was going to be the case in retrospect.
MF: Both in terms of how science is communicated and received by the public, do we need to reform institutions or start new ones to instill the truth-seeking values that are so important to appreciating science?
HS: There are a whole bunch of different factors. I think the biggest one is that the social media algorithms reward their owners financially when they figure out how to keep people in their silos. Users are more likely to click on things that they agree with—and that promote conflict with people that they disagree with. That has caused an acceleration in hostilities that attend some of these disagreements.
But I think the other problem is that we haven’t found a way to explain things to people when it’s not a crisis. So, for example, a strong indicator of whether someone who might otherwise be vaccine hesitant decided to get their vaccine is if they understood how vaccines worked before the pandemic started. Because if you're trying to tell somebody that they're wrong if they don't get a vaccine, at the same time you're trying to explain how it works, that's a lot of explaining to do in a short period of time.
Lack of open-mindedness is a problem, but another issue is that we need more understanding of these issues baked into the culture already. That's partly due the fact that there hasn't been more reform in K through 12 and college teaching. And that scientists are very comfortable talking to each other, and not very comfortable talking to people who don't know all of our jargon and have to be persuaded to spend time listening to and thinking about what we're trying to tell them.
"We're almost to the point where clinging to the lab leak idea is close to being a fringe idea that almost doesn't need to be included in stories."
MF: You mentioned silos. There have been some interesting attempts in recent years to do “both sides journalism,” where websites like AllSides put different views on high profile issues side-by-side. Some people believe that's how the news should be reported. Should we let people see and decide for themselves which side is the most convincing?
HS: It depends if we're talking about science. On scientific issues, when they start, there's legitimate disagreement about among scientists. But eventually, things go back and forth, and people compete with each other and work their way to the answer. At some point, we reach more of a consensus.
For example, on climate change, I think it's gotten to the point now where it's irresponsible, if you're writing a story about climate change, to run a quote from somebody somewhere who's still—probably because of their political views—clinging to the idea that anthropogenic global warming is somehow not damaging the planet.
On things that aren't decided yet, that makes sense to run both. It's more a question of judgment of the journalists. I don't think the solution to it is put stark versions of each side, side-by-side and let people choose. The whole point of journalism is to inform people. If there's a consensus on something, that's part of what you're supposed to be informing them about.
MF: What about reporting on perspectives about the lab leak theory at various times during the pandemic?
HS: We’re the outlet that ran the letter that really restarted the whole debate. A bunch of well-known scientists said we should consider the lab leak theory more carefully. And in the aftermath of that, a bunch of those scientists who signed that letter concluded that the lab leak was very, very unlikely. Interestingly, publishing that letter actually drove us to more of a consensus. I would say now, we're almost to the point where clinging to the lab leak idea is close to being a fringe idea that almost doesn't need to be included in stories. But I would say there's been a lot of evolution on that over the last year since we ran that letter.
MF: Let's talk about bipartisanship in Congress. Research funding for the National Institutes of Health was championed for years by influential Republicans who supported science to advance health breakthroughs. Is that changing? Maybe especially with Sen. Roy Blunt retiring? Has bipartisanship on science funding been eroded by political battles during COVID?
HS: I'm optimistic that that won't be the case. Republican Congresses have usually been good for science funding. And that's because (former Sen.) Arlen Specter and Roy Blunt are two of the political figures who have pushed for science funding over the last couple decades. With Blunt retiring, we don't know who's going to step in for him. That's an interesting question. I hope there will be Republican champions for science funding.
MF: Is there too much conservatism baked into how we research new therapies and bring them to people who are sick, bench-to-bedside? I'm thinking of the criticisms that NIH or the FDA are overly bureaucratic. Are you hopeful about ARPA-H, President Biden’s proposed new agency for health innovation?
HS: I think the challenge hasn't been cracked by the federal government. Maybe DARPA has done this outside of health science, but within health science, the federal government has had limited success at funding things that can be applied quickly, while having overwhelming success at funding basic research that eventually becomes important in applications. Can they do it the other way around? They’ll need people running ARPA-H who are application first. It’s ambitious. The way it was done in Operation Warp Speed is all the money was just given to the companies. If the hypothesis on ARPA-H is for the federal government to actually do what Moderna and BioNTech did for the vaccine, themselves, that's a radical idea. It's going to require thinking very differently than the way they think about dispersing grants for basic research.
MF: You’ve written a number of bold op-eds as editor of the Science journals. Are there any op-eds you're especially proud of as voicing a view that was important but not necessarily popular?
HS: I was one of the first people to come out hard against President Trump['s handling of] the pandemic. Lots of my brothers and sisters came along afterwards. To the extent that I was able to catalyze that, I'm proud of doing it. In the last few weeks, I published a paper objecting to the splitting of the OSTP director from the science advisor and, especially, not awarding the top part of the job to Alondra Nelson, who is a distinguished scientist at black female. And instead, giving part of it to Francis Collins. He’s certainly the most important science policy figure of my lifetime, but somebody who’s been doing this now for decades. I just think we have to push as hard as we can to get a cadre of young people leading us in Washington who represent the future of the country. I think the Biden administration leaned on a lot of figures from the past. I’m pushing them hard to try to stop it.
MF: I want to circle back to the erosion of the public’s trust in experts. Most experts are specialists, and specialists operate in silos that don’t capture the complexity of scientific knowledge. Are some pushbacks to experts and concerns about the perils of specialization valid?
HS: You're on the right track there. What we need is more respect for the generalist. We can't help the fact that you have to be very specialized to do a lot of stuff. But what we need is more partnership between specialists and people who can cross fields, especially into communication and social sciences. That handoff is just not really there right now. It's hard to get a hardcore scientist to respect people who are interested in science, education and science communication, and to treat them as equals. The last two years showed that they're at least as important, if not more so.
MF: I’m grateful that you’re leading the way in this area, Holden. Thank you for sharing your thoughts and your work.
Jamie Rettinger was still in his thirties when he first noticed a tiny streak of brown running through the thumbnail of his right hand. It slowly grew wider and the skin underneath began to deteriorate before he went to a local dermatologist in 2013. The doctor thought it was a wart and tried scooping it out, treating the affected area for three years before finally removing the nail bed and sending it off to a pathology lab for analysis.
"I have some bad news for you; what we removed was a five-millimeter melanoma, a cancerous tumor that often spreads," Jamie recalls being told on his return visit. "I'd never heard of cancer coming through a thumbnail," he says. None of his doctors had ever mentioned it either. "I just thought I was being treated for a wart." But nothing was healing and it continued to bleed.
A few months later a surgeon amputated the top half of his thumb. Lymph node biopsy tested negative for spread of the cancer and when the bandages finally came off, Jamie thought his medical issues were resolved.
Melanoma is the deadliest form of skin cancer. About 85,000 people are diagnosed with it each year in the U.S. and more than 8,000 die of the cancer when it spreads to other parts of the body, according to the Centers for Disease Control and Prevention (CDC).
There are two peaks in diagnosis of melanoma; one is in younger women ages 30-40 and often is tied to past use of tanning beds; the second is older men 60+ and is related to outdoor activity from farming to sports. Light-skinned people have a twenty-times greater risk of melanoma than do people with dark skin.
"When I graduated from medical school, in 2005, melanoma was a death sentence" --Diwakar Davar.
Jamie had a follow up PET scan about six months after his surgery. A suspicious spot on his lung led to a biopsy that came back positive for melanoma. The cancer had spread. Treatment with a monoclonal antibody (nivolumab/Opdivo®) didn't prove effective and he was referred to the UPMC Hillman Cancer Center in Pittsburgh, a four-hour drive from his home in western Ohio.
An alternative monoclonal antibody treatment brought on such bad side effects, diarrhea as often as 15 times a day, that it took more than a week of hospitalization to stabilize his condition. The only options left were experimental approaches in clinical trials.
Early research
"When I graduated from medical school, in 2005, melanoma was a death sentence" with a cure rate in the single digits, says Diwakar Davar, 39, an oncologist at UPMC Hillman Cancer Center who specializes in skin cancer. That began to change in 2010 with introduction of the first immunotherapies, monoclonal antibodies, to treat cancer. The antibodies attach to PD-1, a receptor on the surface of T cells of the immune system and on cancer cells. Antibody treatment boosted the melanoma cure rate to about 30 percent. The search was on to understand why some people responded to these drugs and others did not.
At the same time, there was a growing understanding of the role that bacteria in the gut, the gut microbiome, plays in helping to train and maintain the function of the body's various immune cells. Perhaps the bacteria also plays a role in shaping the immune response to cancer therapy.
One clue came from genetically identical mice. Animals ordered from different suppliers sometimes responded differently to the experiments being performed. That difference was traced to different compositions of their gut microbiome; transferring the microbiome from one animal to another in a process known as fecal transplant (FMT) could change their responses to disease or treatment.
When researchers looked at humans, they found that the patients who responded well to immunotherapies had a gut microbiome that looked like healthy normal folks, but patients who didn't respond had missing or reduced strains of bacteria.
Davar and his team knew that FMT had a very successful cure rate in treating the gut dysbiosis of Clostridioides difficile, a persistant intestinal infection, and they wondered if a fecal transplant from a patient who had responded well to cancer immunotherapy treatment might improve the cure rate of patients who did not originally respond to immunotherapies for melanoma.
The ABCDE of melanoma detection
Adobe Stock
Clinical trial
"It was pretty weird, I was totally blasted away. Who had thought of this?" Jamie first thought when the hypothesis was explained to him. But Davar's explanation that the procedure might restore some of the beneficial bacterial his gut was lacking, convinced him to try. He quickly signed on in October 2018 to be the first person in the clinical trial.
Fecal donations go through the same safety procedures of screening for and inactivating diseases that are used in processing blood donations to make them safe for transfusion. The procedure itself uses a standard hollow colonoscope designed to screen for colon cancer and remove polyps. The transplant is inserted through the center of the flexible tube.
Most patients are sedated for procedures that use a colonoscope but Jamie doesn't respond to those drugs: "You can't knock me out. I was watching them on the TV going up my own butt. It was kind of unreal at that point," he says. "There were about twelve people in there watching because no one had seen this done before."
A test two weeks after the procedure showed that the FMT had engrafted and the once-missing bacteria were thriving in his gut. More importantly, his body was responding to another monoclonal antibody (pembrolizumab/Keytruda®) and signs of melanoma began to shrink. Every three months he made the four-hour drive from home to Pittsburgh for six rounds of treatment with the antibody drug.
"We were very, very lucky that the first patient had a great response," says Davar. "It allowed us to believe that even though we failed with the next six, we were on the right track. We just needed to tweak the [fecal] cocktail a little better" and enroll patients in the study who had less aggressive tumor growth and were likely to live long enough to complete the extensive rounds of therapy. Six of 15 patients responded positively in the pilot clinical trial that was published in the journal Science.
Davar believes they are beginning to understand the biological mechanisms of why some patients initially do not respond to immunotherapy but later can with a FMT. It is tied to the background level of inflammation produced by the interaction between the microbiome and the immune system. That paper is not yet published.
Surviving cancer
It has been almost a year since the last in his series of cancer treatments and Jamie has no measurable disease. He is cautiously optimistic that his cancer is not simply in remission but is gone for good. "I'm still scared every time I get my scans, because you don't know whether it is going to come back or not. And to realize that it is something that is totally out of my control."
"It was hard for me to regain trust" after being misdiagnosed and mistreated by several doctors he says. But his experience at Hillman helped to restore that trust "because they were interested in me, not just fixing the problem."
He is grateful for the support provided by family and friends over the last eight years. After a pause and a sigh, the ruggedly built 47-year-old says, "If everyone else was dead in my family, I probably wouldn't have been able to do it."
"I never hesitated to ask a question and I never hesitated to get a second opinion." But Jamie acknowledges the experience has made him more aware of the need for regular preventive medical care and a primary care physician. That person might have caught his melanoma at an earlier stage when it was easier to treat.
Davar continues to work on clinical studies to optimize this treatment approach. Perhaps down the road, screening the microbiome will be standard for melanoma and other cancers prior to using immunotherapies, and the FMT will be as simple as swallowing a handful of freeze-dried capsules off the shelf rather than through a colonoscopy. Earlier this year, the Food and Drug Administration approved the first oral fecal microbiota product for C. difficile, hopefully paving the way for more.
An older version of this hit article was first published on May 18, 2021
All organisms have the capacity to repair or regenerate tissue damage. None can do it better than salamanders or newts, which can regenerate an entire severed limb.
That feat has amazed and delighted man from the dawn of time and led to endless attempts to understand how it happens – and whether we can control it for our own purposes. An exciting new clue toward that understanding has come from a surprising source: research on the decline of cells, called cellular senescence.
Senescence is the last stage in the life of a cell. Whereas some cells simply break up or wither and die off, others transition into a zombie-like state where they can no longer divide. In this liminal phase, the cell still pumps out many different molecules that can affect its neighbors and cause low grade inflammation. Senescence is associated with many of the declining biological functions that characterize aging, such as inflammation and genomic instability.
Oddly enough, newts are one of the few species that do not accumulate senescent cells as they age, according to research over several years by Maximina Yun. A research group leader at the Center for Regenerative Therapies Dresden and the Max Planck Institute of Molecular and Cell Biology and Genetics, in Dresden, Germany, Yun discovered that senescent cells were induced at some stages of regeneration of the salamander limb, “and then, as the regeneration progresses, they disappeared, they were eliminated by the immune system,” she says. “They were present at particular times and then they disappeared.”
Senescent cells added to the edges of the wound helped the healthy muscle cells to “dedifferentiate,” essentially turning back the developmental clock of those cells into more primitive states.
Previous research on senescence in aging had suggested, logically enough, that applying those cells to the stump of a newly severed salamander limb would slow or even stop its regeneration. But Yun stood that idea on its head. She theorized that senescent cells might also play a role in newt limb regeneration, and she tested it by both adding and removing senescent cells from her animals. It turned out she was right, as the newt limbs grew back faster than normal when more senescent cells were included.
Senescent cells added to the edges of the wound helped the healthy muscle cells to “dedifferentiate,” essentially turning back the developmental clock of those cells into more primitive states, which could then be turned into progenitors, a cell type in between stem cells and specialized cells, needed to regrow the muscle tissue of the missing limb. “We think that this ability to dedifferentiate is intrinsically a big part of why salamanders can regenerate all these very complex structures, which other organisms cannot,” she explains.
Yun sees regeneration as a two part problem. First, the cells must be able to sense that their neighbors from the lost limb are not there anymore. Second, they need to be able to produce the intermediary progenitors for regeneration, , to form what is missing. “Molecularly, that must be encoded like a 3D map,” she says, otherwise the new tissue might grow back as a blob, or liver, or fin instead of a limb.
Wound healing
Another recent study, this time at the Mayo Clinic, provides evidence supporting the role of senescent cells in regeneration. Looking closely at molecules that send information between cells in the wound of a mouse, the researchers found that senescent cells appeared near the start of the healing process and then disappeared as healing progressed. In contrast, persistent senescent cells were the hallmark of a chronic wound that did not heal properly. The function and significance of senescence cells depended on both the timing and the context of their environment.
The paper suggests that senescent cells are not all the same. That has become clearer as researchers have been able to identify protein markers on the surface of some senescent cells. The patterns of these proteins differ for some senescent cells compared to others. In biology, such physical differences suggest functional differences, so it is becoming increasingly likely there are subsets of senescent cells with differing functions that have not yet been identified.
There are disagreements within the research community as to whether newts have acquired their regenerative capacity through a unique evolutionary change, or if other animals, including humans, retain this capacity buried somewhere in their genes.
Scientists initially thought that senescent cells couldn’t play a role in regeneration because they could no longer reproduce, says Anthony Atala, a practicing surgeon and bioengineer who leads the Wake Forest Institute for Regenerative Medicine in North Carolina. But Yun’s study points in the other direction. “What this paper shows clearly is that these cells have the potential to be involved in tissue regeneration [in newts]. The question becomes, will these cells be able to do the same in humans.”
As our knowledge of senescent cells increases, Atala thinks we need to embrace a new analogy to help understand them: humans in retirement. They “have acquired a lot of wisdom throughout their whole life and they can help younger people and mentor them to grow to their full potential. We're seeing the same thing with these cells,” he says. They are no longer putting energy into their own reproduction, but the signaling molecules they secrete “can help other cells around them to regenerate.”
There are disagreements within the research community as to whether newts have acquired their regenerative capacity through a unique evolutionary change, or if other animals, including humans, retain this capacity buried somewhere in their genes. If so, it seems that our genes are unable to express this ability, perhaps as part of a tradeoff in acquiring other traits. It is a fertile area of research.
Dedifferentiation is likely to become an important process in the field of regenerative medicine. One extreme example: a lab has been able to turn back the clock and reprogram adult male skin cells into female eggs, a potential milestone in reproductive health. It will be more difficult to control just how far back one wishes to go in the cell's dedifferentiation – part way or all the way back into a stem cell – and then direct it down a different developmental pathway. Yun is optimistic we can learn these tricks from newts.
Senolytics
A growing field of research is using drugs called senolytics to remove senescent cells and slow or even reverse disease of aging.
“Senolytics are great, but senolytics target different types of senescence,” Yun says. “If senescent cells have positive effects in the context of regeneration, of wound healing, then maybe at the beginning of the regeneration process, you may not want to take them out for a little while.”
“If you look at pretty much all biological systems, too little or too much of something can be bad, you have to be in that central zone” and at the proper time, says Atala. “That's true for proteins, sugars, and the drugs that you take. I think the same thing is true for these cells. Why would they be different?”
Our growing understanding that senescence is not a single thing but a variety of things likely means that effective senolytic drugs will not resemble a single sledge hammer but more a carefully manipulated scalpel where some types of senescent cells are removed while others are added. Combinations and timing could be crucial, meaning the difference between regenerating healthy tissue, a scar, or worse.