We open the December issue of the Civic Science Series with the launch of the Civic Science Funders Collaborative Advisory Series, which features conversations between philanthropists and exemplars working on the ethical and societal implications of emerging science and technology. Highlighting a variety of perspectives, these dialogues seek to inform and inspire philanthropists, as well as others who want to contribute to building a robust and engaged future of transformative science, with expanded benefits for all.  

At a Glance

– Paola Arlotta, Golub Family Professor of Stem Cell and Regenerative Biology at Harvard University, is an example of a leading research scientist who integrates ethical and societal considerations throughout her work. Engagement with bioethicists has helped shape her work to develop and study “brain organoids”—which allow unprecedented access to understanding human brains and how different people might react to treatments for neurodevelopmental conditions like autism and schizophrenia.

– Dr. Arlotta champions the importance of engaging with ethicists and community members for all scientists working on discovery research with potential societal implications. As Chair of the Department of Stem Cell and Regenerative Biology at Harvard, she ensures that ethics and engagement are part of students’ experience in the lab and beyond.

– “We need to have this conversation to walk into an area of science that can be transformative for society and human health with eyes wide open, with some consideration already made,” she says. And she notes: “The ultimate outcome could be that the science moves faster, not slower, faster if we implement these opportunities.”

– Dr. Arlotta’s recommendations for funders include: prioritizing funding science at the edge of fields; funding ongoing discussions between scientists, bioethicists, and community members as part of funding pioneering research; supporting training for scientists in ethics and communication; and exploring opportunities to better connect scientists, ethicists, social scientists, and scholars from other disciplines across silos.

– See the end of the article for a full summary of recommendations and further resources.

Dear Civic Science Community, 

Paola Arlotta’s research is uncovering how the human brain develops—a process she compares to a symphony. As cells in the brain multiply and diversify, they communicate across regions and react to their environment in ways that are distinctive to humans. That’s what makes Dr. Arlotta’s advances so important. Her lab has developed techniques to study brain tissue as it forms from stem cells over the course of years—the most advanced model yet for studying the early stages of the human brain and how it is affected by different genetic starting points. Through these “brain organoids,” Dr. Arlotta and her team have created an invaluable window into neurodevelopmental conditions like autism and schizophrenia, and how individual people might react to different treatments. Earlier this year, the National Academy of Sciences awarded her the 2024 Pradel Research Award for her contributions to understanding the nervous system. 

Like much emerging research in neuroscience, Dr. Arlotta’s research also raises questions related to ethics and society. As brain organoids continue to develop and improve as model systems, could they experience pain, or develop aspects of consciousness? What information do patients need in order to give consent for their cells to be used to create neural organoids? Do any ethical considerations outweigh the potential of this research to relieve human suffering and save lives? Dr. Arlotta served on a committee convened by the National Academies of Sciences, Engineering, and Medicine to examine these questions with a variety of experts and community members, resulting in a consensus study report that has guided further development of the field. 

Dr. Arlotta has also spoken about her work with podcasts, journalists, and the Science Philanthropy Alliance, and she is working with the Museum of Science in Boston to spread these conversations further. As the Chair of the Department of Stem Cell and Regenerative Biology and Golub Family Professor of Stem Cell and Regenerative Biology at Harvard University, Dr. Arlotta also ensures that engaging with ethics is part of conversations for students and scientists in the lab and outside of it, through lecture series, courses, and student participation in the International Society for Stem Cell Research, which shapes guidance for working with stem cell–derived models. 

“If we want to educate the next generation of scientists,” she says, “we cannot just do science disconnected from everything else when the science is potentially ethically challenging.” 

We recently spoke to Dr. Arlotta about promising directions in neurobiology, the importance of engaging with bioethics from the beginning of research, and priorities for funders who want to support the growth of scientific discovery in partnership with the growth of ethical and societal engagement around the practice and applications of science. It is our pleasure to share an edited and condensed version of our conversation as the first in a new series designed to explore the possibilities and urgency of civic science philanthropy. 

—Elizabeth Christopherson and Caroline Montojo 

Elizabeth Good Christopherson is President and Chief Executive Officer of the Rita Allen Foundation. Caroline Montojo is President and Chief Executive Officer of the Dana Foundation. Both foundations are Civic Science Fellows funding partners and members of the Civic Science Funders Collaborative.

Caroline Montojo: How has the neuroscience field has changed over the past ten years? What’s been most exciting to you about these advances?

Paola Arlotta: The field has changed a lot, and the speed of change has been dictated by the advent of many, many technologies that we could only dream about that are revolutionizing not only neurobiology but other fields as well.

I’m thinking about technology that allows us to read the genes that are expressed in every cell of the body and every cell of the brain. The high-throughput single-cell genomics revolution has really changed what we can do to the brain. In fact, finally, it gave us a picture of what is the brain even made of. How many cell types are present in the brain? How many cell states are present in the brain, and where do they come from? How are they made? We couldn’t even dream about answering those questions before this technology.

There has really been a revolution in terms of assessing and beginning to understand not just the brain, but the human brain. 

Most of what we know about our own brain comes from studying the brain and the nervous system of other species. It is a beautiful idea, except there is so much specialization in our brain. There is some human specialization in our liver compared to the liver of a mouse, but it’s really the brain, especially certain parts of the brain like the prefrontal cortex, that are really different and specialized. There is only so much you can learn about us by studying other species. Neurobiology has begun to extend in this arena of understanding the human brain.

This is not just because of these wonderful and ever-changing technologies that give us access to molecular mechanisms of cells, but also because 20 years ago, [Shinya] Yamanaka was able to reprogram stem cells, induced pluripotent stem cells, from a sample of skin. Today you can do it routinely from a sample of blood. The revolution recently has been also to be able to turn that embryonic stem cell–like cell into a mimic model of the human brain. We’re talking about human brain organoids. Now, in addition to being able to look at the actual human brain that may come from a biopsy or a postmortem tissue, you actually can make a tiny replica of the human brain from the very cell of a person who is living. This has been a revolution for neurobiology, because as we know, you can access blood, but you don’t access people’s brains. So I see that area as a very exciting one.

Finally, in the era of machine learning and AI, this idea of understanding what human neural networks can do, what are the properties of human cells, how much computation can a human network sustain relative to perhaps one day—this is what people are beginning to think about. One day, perhaps there would be a biological substrate, so human or mammalian circuits could run AI calculations. 

It sounds like science fiction. But given that we can take a sample of blood and make human brain organoids and these human brain organs have become very complex, perhaps it’s not as science fiction as it used to be.

That’s a direction that I’m not sure the field will take, but it’s a field that is being discussed and is ethically very, very charged. It’s not quite there science-wise, but not too far. 

Caroline Montojo: How many years do you think it would take to get to that stage of being able to have a biological tissue basis for implementation of machine learning algorithms?

Paola Arlotta: It’s so unpredictable. I think it’s a big question mark, but I don’t think it’s too early to talk about it. We talk about things way before science makes them a reality. In a way we have an opportunity to have this discussion ahead of when the key experiments may be done, and certainly ahead of any success in a certain field. It takes time. So this would be the time to talk about these human models, to talk about what the human brain organoids can do, to talk about human brain organoid–machine interfaces, for example, another area that’s becoming quite current.

Caroline Montojo: Can you tell us more about your work and its significance to understanding brain function in both health and disease?

Paola Arlotta: I’ve been fascinated with understanding how the human brain works, especially how it develops, for a very long time. This fascination led me over many years to try to understand how our own brain develops, but by studying the brain of another species—the brain of a mouse in particular. We have learned a lot from it, but at some point that work hits a wall, and it requires human systems in order to understand human tissues. 

About 2016, maybe a little earlier, my lab decided to take advantage of this revolution in stem cell biology and the ability to drive stem cells to make cells of the nervous system. We asked the question of whether one could take stem cells that carry the genome of an individual and coach them to undergo a process of brain development, and how far could we go with it? Since those early days this work has evolved dramatically. 

Fast forward to today. We are routinely able to take pluripotent stem cells and coach them through specific protocols of culture in the dish, in the lab, into becoming brain tissue. We call them human brain organoids, or neural organoids. We’re very interested in the cerebral cortex, so these are mostly cerebral cortex organoids, but there are also organoids now of other parts of the nervous system.

This is very exciting, because all of the sudden you connect a patient or a person to his own brain that also is an experimental system—something that you can test things on, that you can study, that you can make and destroy, to study it—all things that of course we cannot do with the actual brain of a person.

We’re going to gain as a field enormous understanding of how the human brain is made, and what is unique about the cells of our brain or the way they’re made or the way they interact with each other. I think that these models will be very impactful for that kind of knowledge. 

Then, of course, this also opens the door to begin to understand what happens in the context of diseases. This is very much now an interest of my lab. We moved from just studying development to build on that knowledge to begin to understand what happens in the context of a neurodevelopmental disease. A neurodevelopmental disease can be even something that manifests much later than birth. If you talk about autism spectrum disorder or other developmental diseases, they’re clearly developmental because the disease manifests very early on in life, when the brain is still being formed. And as you know, it’s not only formed when we’re embryos; it is also formed for something like 20 years after we are born. Schizophrenia, for example, many times manifests during the teenage years. But it’s clear that there is something that happened differently to the formation and maturation of that brain earlier on.

With these organoids we’re excited to begin to explore this relationship between genetic states associated with disease and what those genetic states produce in the context of the genome of that person. What do they do to the brain to potentially cause what you see in the clinics? 

The final area is the idea that not only are we different from mice, but we’re also different from each other. We all react to our own brain in different ways to the same stimulus. And by stimulus, I mean a drug, or a gene that normally would cause disease, or it could be anything—but our brain responds differently. This is very much a problem in the context of drug development because a drug for the central nervous system that may be working in a mouse oftentimes doesn’t work in humans as you bring it to the clinic. So we need to study it in humans too. And even a drug that works may work on you and may not work on me.

Nobody really knows why that is. Despite the fact that roughly we have the same brain, the same tissue, we’re all humans, we’re going to respond differently. My work is going now into this development of organoid models, we call them chimeroids (we just published a paper on this), which are generated from the cells of many people, instead of the cells of one person. They allow us to decode in a single organoid, treated for example with a drug, the response of the cells of the brains of different people to the same perturbation. Individual differences are very interesting, so that’s what we’re doing these days. It’s exciting.

Elizabeth Christopherson: What advice do you have for young investigators about how they can better be prepared to consider the ethical, legal, and societal implications of their work?

Paola Arlotta: I know that this is difficult. It is more difficult for junior faculty who might have just started their lab. They have to think about a lot of things, and they may not be as well-funded or as connected to bioethicists and other individuals. But if the intent is to study the human brain—and the brain is unique, it defines us—it’s very important that we have the ethical responsibility, the moral responsibility as scientists to consider the ethical implications of our work. 

“If the intent is to study the human brain—and the brain is unique, it defines us—it’s very important that we have the ethical responsibility, the moral responsibility as scientists to consider the ethical implications of our work.”

I’m a firm believer that science needs to progress and we need to move forward, but there are different ways of moving forward that don’t necessarily mean stopping science. I’m against regulations that may be imposed from above that don’t reflect the science on the ground. That’s why I think that the power should be in the hands of the scientists and their colleagues, bioethicists, in discussing ahead of when major potentially ethically challenging experiments are designed and put in place, even if there are no regulations that from a legal viewpoint would preclude them. As scientists, we have the moral responsibility to think about it, so that we decide whether the science should continue on or not based on actual scientific data and not based on assumptions about what scientists are doing in in their labs.

So my advice would be find a bioethicist. In a variety of different institutions, these colleagues exist, so sometimes it’s not really that difficult. From my experience, there’s actually a lot of interest from bioethicists to discuss this type of science with scientists. I think there is huge value in having colleagues like that on grants. NIH [the National Institutes of Health] really appreciates this. Other funders really appreciate it, even if there is no requirement.

Caroline Montojo: What is the role of the public and different communities within the public, for example patient groups, in thinking about the directions of this type of research?

Paola Arlotta: It’s tricky. I’ll admit it.

We as scientists have not, and I put myself into this bunch, we have not done a particularly good job in effectively communicating the science that we do in the lab to the general population.

Why does that happen? First of all, because it’s not easy to talk science to an audience that may not even have some of the necessary foundation of knowledge. But I could explain the human brain organoid to my son who’s 15, and he would get it, right? So I think that that’s not an excuse.

Out of that failure comes the birth of a lot of assumptions about the work that we do, simply because it’s not really understood what we do.

If you think about the work that I do, if I say, oh, we take a sample of blood from a person, we make stem cells, and then we make a small replica of the human brain and we can study autism. What somebody normally would think of is a big jar with a brain in it. And it couldn’t be farther from that. Until I explain that these are just very small, tiny particles, like an apple seed. They are far from being a whole brain, but they have enough of it to begin to understand what may be going on as the brain of an autistic child develops.

There should be more effective communication between scientists and society, and that requires training. We need to be trained to be able to talk to society. For some particularly hot topics, we also need to be media-trained to be able to talk to journalists or in a podcast or on TV. I would love to see scientists being able to do that rather than other figures that may not know the science as well, so that collaboration could be expanded.

This training could be implemented. I did get media training when I started to work on organoids, because I found myself wondering, can I say this? Can I not say this? How is it going to be received? Is it going to be problematic for the entire field? If we don’t do this well, and if we don’t include society in an informed dialogue, what we risk is that our science will be slowed down by regulations and policies that don’t reflect what is actually happening in labs. The science is delayed, slowed down, the funding is not used. We don’t progress.

Society should be involved, but that requires scientists being better at what they do in communicating the science, and that may require training. If you’re thinking about activities that would be quite useful, one would be to provide scientists with this kind of training from early days.

Caroline Montojo: I thought that it was also really interesting in the National Academies report [on issues associated with neural organoids, transplants, and chimeras] when the Committee interacted with faith leaders as well.

Paola Arlotta: That was amazing because honestly, we as scientists learned so much, and I hope that they learned from the conversation with us.

We talked with leaders from a variety of different religions. We talked with lawyers, with patients, advocates. We talked with scientists, and we dug deeper in the kinds of science happening. 

I myself had assumptions about how, for example, in the context of a certain religion brain organoids would be considered, and I was completely wrong about it. So these conversations are absolutely needed. Otherwise we assume that certain groups in society may have an opposition to it, when they may not. In fact, what emerged from that discussion was there was no concern whatsoever, ethically or religiously or legally, for the use of human brain organoids. However, there was very clear agreement among everybody that this type of conversation needs to happen very often, because the science evolves really quickly.

Elizabeth Christopherson: What elements would you recommend philanthropists consider if we want to support ethical and societal considerations in neuroscience?

Paola Arlotta: There is a huge role for philanthropy, which is giving a lot of money for research at the edges of fields. Science that is very new. Science that is provocative. 

We can have this ethical conversation. We can be well prepared to recognize the risks and limitations of science that might be considered controversial. The science has to progress, but it can do so within the correct ethical framework. So it’s not that we stop the science because we are unsure. We just have to get to the bottom of that conversation and do the best we can to progress in the safest possible way. I don’t want this conversation to be something that stops science. We need to have this conversation to walk into an area of science that can be transformative for society and human health with eyes wide open, with some consideration already made. And we should fund it. 

“We need to have this conversation to walk into an area of science that can be transformative for society and human health with eyes wide open”

Elizabeth Christopherson: If you were speaking to a new philanthropist, how would you prioritize different potential approaches?

Training of scientists is important. There is not a very clear path that will get you to it. Not only PIs [principal investigators] but also postdocs should be exposed to this, so that they can think more about the implications of their work in addition to how to design that perfect experiment. Among the younger generations, because you’re younger and because you really need to design the experiment and get the stuff published and so on, sometimes they don’t think as much about the ethics of their work.

Unless you have a PI that keeps on talking. I tend to do it in my lab. I say, okay, how does it make you feel? Is there something here? Should we talk to somebody? Is there another way? Try to project the science five years from now. What could happen? What if somebody came in and used this for this other purpose? What if you make the perfect human brain organoid–computer interface, and you use it to develop the perfect therapy for autism, but then somebody uses it for really not-so-noble purposes. How would you feel? I don’t think you get out of these discussions by yourself.

Opportunity for connections between scientists and bioethicists would be important because not everybody will have access to these resources. If these connections could be made, if a little bit of funding could add the neuroethical discussion to a grant, I think that would be useful. And then training. Training on how to present your science to society, training on how to present really challenging science.

Some scientists are also a little scared, and I think that’s fair. Not everybody out there likes the fact that you can make a sample of a human brain and you have thousands of samples spinning in an incubator. Sometimes scientists don’t like to interact with the public because of that, and because there is no complete trust that we are able to communicate to journalists the things that we want to say effectively, or that journalists will actually publish what we really say and not an exaggeration of it. 

So I would say to answer your question: training and then a bit of funding, not at the expense of the science. The exciting science at the edge of fields that can really make the field leap forward should always be funded as the number-one priority, but you can also have a bit of funding to allow these ethical discussions and maybe a network of individuals from the ethics side—experts that are willing to engage.

Funding activities in collaboration with the academies also would be a good way to go. For me it would be the International Society for Stem Cell Research or the Society for Neuroscience. It would be possible to work with the societies to figure out courses and training opportunities, even in conjunction with their annual meetings.

Caroline Montojo: Could you point to an example of how the field can effectively tackle the intersection of ethics and science?

Paola Arlotta: I’m in touch with the Museum of Science here in Boston, and we’ve been talking for a long time in the context of communicating to the public. So we’re going to bring the organoids to the museum, using their incredible ability to build stories and walk people through understanding of complex material. There will be of course an ethical component as well. Those are venues that allow you to reach society quite effectively, and they’re already very well set up to communicate effectively.

I can suggest what people should know about the science. I can triple check the information to make sure it’s correct. From a scientific viewpoint, I can give you the images, the videos of how we do this science, and why, most importantly, we do this science for the future. And then they, they turn it into something that is understandable by others in society. 

Elizabeth Christopherson: We also work with social scientists who research how best to communicate and evaluate risky topics—that might be one more element if you’re building a dream team for the museum.  

Paola Arlotta: I would love to connect with something like that. There are experts that know how to do this, right?

Elizabeth Christopherson: But they’re in silos.

Paola Arlotta: We are in silos. Absolutely. Maybe the best would be if philanthropists could help us break some holes into those walls that separate these different disciplines so that we can really have some interactions.

There is a lot that can be done, and it’s very exciting. I think we could really change the way science is seen by society. The ultimate outcome could be that the science moves faster, not slower, faster if we implement these opportunities.

_____

Learn More:

– Homepage of the Arlotta Lab

– National Academies consensus report, The Emerging Field of Human Neural Organoids, Transplants, and Chimeras: Science, Ethics, and Governance

– Resources for civic science funders 

Paola Arlotta’s recommendations for funders:

– Prioritize funding science at the edge of fields poised to make leaps forward.

– Fund ongoing discussions between scientists, bioethicists, and community members as part of funding pioneering research.

– Support training for scientists at every stage of their career to consider the ethical implications of their work, to communicate about their work to society, and to talk to the media—especially about ethically challenging topics.

– Consider funding ethics and engagement training and workshops in conjunction with scientific associations relevant to the area of research you are supporting.

– Explore forming networks of people willing to engage around ethical topics, as well as other opportunities to connect scientists, ethicists, social scientists, and scholars from other disciplines across silos to allow them to interact and accelerate one another’s work.

“There is a lot that can be done, and it’s very exciting. I think we could really change the way science is seen by society. The ultimate outcome could be that the science moves faster, not slower, faster if we implement these opportunities.”