When a Career in Pain Research Is Also a Serious Hobby: A Conversation with Allan Basbaum

Editor’s note: The third North American Pain School (NAPS) took place June 24-28, 2018, in Montebello, Quebec, Canada. An educational initiative of the International Association for the Study of Pain (IASP) and Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION), and presented by the Quebec Pain Research Network (QPRN), NAPS brings together leading experts in pain research and management to provide 30 trainees with scientific education, professional development, and networking experiences. This year’s theme was “To Boldly Go… : The Future of Pain Treatment.” Six of the trainees were also selected to serve as PRF-NAPS Correspondents, who provided firsthand reporting from the event, including interviews with NAPS’ six visiting faculty members and summaries of scientific sessions, along with coverage on social media. This is the second installment of interviews from the Correspondents, whose work is featured on PRF and RELIEF, PRF’s companion site for the public.

Allan Basbaum, PhD, FRS, is professor and chair of the Department of Anatomy at the University of California, San Francisco, US. From 2003-2012 he served as the editor-in-chief of PAIN, the journal of the International Association for the Study of Pain. He is a member of the American Academy of Arts and Sciences, the National Academy of Medicine (US; formerly called the Institute of Medicine), and the Academy of Medical Sciences (UK). He is also a fellow of the Royal Society in the UK.

Basbaum’s research examines the mechanisms through which tissue and nerve injury produce changes in the peripheral and central nervous system, resulting in persistent pain. In parallel studies, his lab is examining the circuits through which pruritogens generate itch. At the 2018 North American Pain School, he sat down with PRF-NAPS Correspondent Chulmin Cho, a postdoctoral fellow at the University of Toronto Mississauga, Canada, to discuss cell transplantation as a possible pain treatment, the projects he is working on now, and much more. Below is an edited transcript of their conversation.

At NAPS you discussed transplantation of embryonic cortical GABAergic precursor neurons as a possible treatment option for chronic pain. What hurdles remain before this approach can be implemented in humans?

Neurona Therapeutics, a biotechnology company in South San Francisco, is developing the technology for the treatment of various clinical conditions. The founders of the company included several scientists who introduced the approach in preclinical models. I am a member of the company’s scientific advisory board. They are trying to determine the optimal approach for implementing human transplantation, not only technically, but also with respect to the disorders to target. They have an interest in epilepsy as well as chronic pain, including trigeminal neuralgia, radicular pain and pain from injury to the spinal cord.

You can never anticipate or address all the technical hurdles because many of these are discovered as the work progresses. Having said that, the first hurdle was to develop human embryonic stem cells that will acquire a GABAergic, inhibitory phenotype. This has been accomplished. A subsequent hurdle is to develop these cells for good manufacturing practice so that they can be transplanted.

Additionally, the transplanted cells must not become tumorigenic. In this regard, the results are encouraging, as the cells do not transform into tumors when transplanted into animals. This is potentially a revolutionary approach to treating chronic pain, so the U.S. Food and Drug Administration will be concerned with safety and require a comprehensive list of additional studies.

What research projects in your laboratory are you excited about?

I am excited about every project going on in my lab! I spent a majority of my career studying primary afferents, the spinal cord and brainstem. The focus, therefore, was the transmission of injury messages, that is, nociception. But nociception is not equivalent to pain; pain is a product of the processes that occur in the brain. So in order to better understand pain, it is necessary to decipher what is going on inside the cerebral cortex.

One of the questions I am interested in is how the brain distinguishes and interprets multiple modalities of pain or itch stimuli that are transmitted by projection neurons in the spinal cord and trigeminal nucleus caudalis. To address this question, we are using calcium imaging in awake, head-fixed mice. This technique allows us to monitor the activity of a large, defined population of neurons, in response to different pain modalities, in the cortex, thalamus or amygdala. For example, we are investigating changes in the activity of different subtypes of GABAergic interneurons in response to injury, and subsequent changes in response to opioids, such as morphine.

In other work, a new postdoc in the lab, Jarret Weinrich, is investigating the underlying mechanisms of anesthesia. To date, the majority of anesthesia studies have used either electroencephalography or functional magnetic resonance imaging in humans and animals to look at global changes in the brain. We are interested in subpopulations of cells and their response to various doses of an anesthetic. Furthermore, we are investigating the tipping point at which the anesthetic induces pain relief.

What else are you working on?

We are also conducting a number of transcriptome studies. In light of the possibility that a projection neuron is sending either a labeled line-specific or convergent message, we are in the process of determining whether there are molecularly distinct subpopulations of projection neurons. The majority of projection neurons express NK1 [neurokinin 1] receptors, but there remains a possibility that there are different subsets of these neurons. Racheli Wercberger, a graduate student in the lab, is performing ribosomal profiling of projection neurons, and we believe has identified different subsets of these cells. The next step will be to assess whether specific pain modalities engage these different subsets.

It is worth emphasizing that the questions that we are asking have not changed in the past hundred years; the new techniques that come along simply allow you to focus in on them. So we are still having fun learning and adapting the techniques to answer these questions. I always say that science is my hobby, in the sense that I look forward to coming into the lab to learn new things. But please understand that I take this hobby seriously. I had a student in the lab recently who asked me, ‘Allan, when am I going to see science as my hobby?’ I said, ‘Soon, I hope.’

What key questions in pain research need to be addressed?

As noted above the questions are not new questions. One of the most important unanswered questions is the search for a biomarker for pain. Although we would love to have one, I am not overly optimistic about the discovery of a simple blood biomarker. Pain is unique in that it cannot be seen. Pain is also highly complex. It is not a sole product of the magnitude of an injury but is influenced by affective-motivational and cognitive-evaluative aspects as well. So an absolute indicator of the magnitude of the pain experience will be challenging to find.

Another question is what underlies the transition from acute to chronic pain. We tend to think that pain is acute when it first appears, but the basis for chronic pain may be present in some patients from the get-go. On the other hand, chronic pain may be caused by deficits in the resolution of acute pain. And, disparities in socioeconomic factors, age, sex and other factors also influence the experience of pain.

Of course, the opioid epidemic has put opioids in the limelight. One of the biggest questions is whether and how well or for how long opioids work for chronic non-cancer pain—I don’t believe we know the answer. Although some argue that there is no evidence that opioids do work, there are a few studies to support this. But, those are mostly short-term studies of 12 weeks in length. Development of an alternative treatment better than an opioid would be great. Another option would be to optimize the use of opioids in ways that minimize their side effects, including tolerance and dependence.

It is also worth mentioning the importance of understanding how pain evolves over time, rather than looking only at a given time. In this regard, longitudinal imaging studies, particularly those by Vania Apkarian, are important. There are many other questions, but these will keep us busy for a while.

What are some of the major problems in pain research?

One of the biggest concerns, or at least one receiving significant attention, is the reliability of preclinical models of pain, in large part because we don’t have biomarkers. So the pharmaceutical companies are likely to blame the models when a drug fails in clinical trials. But, I would argue that the recent development of antibodies for various pain conditions illustrate where preclinical studies have had significant translational relevance. An anti-calcitonin gene-related peptide [CGRP] receptor antibody was recently approved for migraine and anti-nerve growth factor [NGF] antibodies are on the horizon as a therapeutic option.

Another problem is that there is the large placebo response in clinical trials. This poses a great hindrance to drug development; a novel drug has to perform better than the placebo, especially in a small trial. Importantly, there are data suggesting that the more pain a person experiences, the more likely it is to observe a placebo response. That fact will only make attributing pain relief to a novel drug that much more difficult.

What other problems are there?

Another issue is that we cannot pinpoint pain inside the brain. With some exceptions, imaging studies to date have concluded that there is no single brain region that is exclusive for pain. What’s important is how the brain interprets incoming inputs—this is a complicated task. In comparison, in more traditional disease entities, such as cancer and Parkinson’s disease, a specific population of cells is affected and, of course, there are biomarkers.

We also need to change our approach and consider neuropathic pain as a disease rather than as a symptom, and attempt to fix the underlying cause—I advocate strongly for this. We are relatively well informed of the changes that occur in the brain in response to neuropathic pain. Whether neuropathic pain is centrally or peripherally driven, the sole manifestation this disease is pain.

An analogy I draw is to epilepsy. Epilepsy derives from hyperexcitability of neurons in the brain that lead to seizures. We can change the language and state that pain is derived from hyperexcitability in the brain or spinal cord. So why isn’t neuropathic pain considered a disease, but epilepsy is? This is one of the reasons why there is a lack of pain foundations that fund research to anywhere near the extent that other disease foundations do. When we change our way of thinking, it might spur government or philanthropic organizations to support pain research on a larger scale.

What do you think about criticism against the use of animals in biomedical research?

If I thought that animal studies were not informative, I would not do them. Animal studies are important not only to study disease conditions but also to understand the normal organization and physiology of the brain.

Here is an analogy. When your car makes a funny noise, you take it to a mechanic who you may not even know and leave it overnight, or for days. Some time later, you get a call that your car is fixed. How is it that the mechanic was able to make the necessary repairs and fix the problem? It is because the mechanic has an understanding of and a manual that describes the process through which the car was built in the first place. The mechanic knows the normal organization of the car that allows him or her to understand the “diseased car.”

This search for the biological manual is the essence of basic science. A better understanding of brain mechanisms that lead to the generation of normal behavior will help us to understand the diseased state. I believe that, despite obvious limitations, enough conservation and similarities exist between species, including humans and rodents. Once there is a computer that can mimic the complexity of the human brain, I will be happy to use it. But I am not holding my breath.

How should the field handle so-called ‘negative’ findings?

That is a very difficult question. You must, first and foremost, ensure that you design an experiment based on a rational hypothesis. But even for negative findings based on a rational hypothesis, there is still a concern in regard to publishing those results. Negative results, once published, might deter others from studying the particular problem. There are journals such as PLOS ONE that publish negative findings, provided that the study was carried out properly. However, positive results are going to move the field forward faster.

It is increasingly difficult for graduate students and postdocs to find academic positions. What advice do you have for them?

This certainly is a problem. There are too many applicants seeking the same job. At UCSF, we receive approximately 300 applications for one faculty position. Meanwhile, there are places in the country where applicants do not consider going, which is another issue.

On the other hand, I am never disappointed when my trainees decide to work outside academia; they may go into industry, writing, or teaching. People in the old days may have said those options are a waste of a PhD. To the contrary, I think those are terrific options if you do not want to dive into the grant-fighting world.

Are we training too many people? I would never take that approach, because you cannot predict ahead of time who might shine and be a great success. Also, the cost to train scientists is relatively inexpensive.

Trainees need to understand that they may not obtain the academic position of their first choice. They need to spread their wings and consider other options; there are other positions outside their first-choice university. I would also advise trainees to choose their postdoc very carefully. The job you eventually get will mostly be based on the work you perform as a postdoc.

It’s been said that, in many ways, managing a lab is very similar to managing a small business. How do you manage your lab?

I attended a one-day seminar at the university years ago where they talked about this specific question. Economically you can say it’s a bit like a business. You have a budget and you’ve got to stick to it.

In terms of personnel, I tend to have people work independently on projects of their own, but also collaborate on different studies. I meet regularly with every trainee in the lab; my office door is always open. I also circulate throughout the lab often to talk to the trainees and have discussions. We hold a weekly journal club to review a paper or a lab meeting for trainees to present their research.

I also believe strongly in mentoring. Trainees need guidance in terms of addressing questions and how to write. I have been fortunate, over the years, to not have much divisiveness amongst trainees. Conflicts may occur, as the trainees are smart and ambitious. As a mentor, you need to be aware of these conflicts and resolve them by sitting down with the trainees and going over the issues with them. And trainees need to know that you are accessible and will resolve a problem, rather than ignore it. Now that I am older, I am more sensitive to these issues.

Another important attribute to have is a sense of humor. Science is a serious business. I tell people that science is amazing in that when you make a new discovery, however small, you are the only person in the world who knows that fact. That’s pretty impressive. I have often told the story of a colleague who came into the lab one day, clearly feeling pretty down. He said that if his research were any less relevant, it would subtract from the body of knowledge. Fortunately, none of my students or fellows have moved the pain research field backwards.

How do you keep up-to-date with all the new research publications that continue to flood in?

I don’t—the literature is vast so it is very difficult to keep up with it. Also, the field of pain cuts across numerous disciplines and our lab tends to take a rather eclectic approach to address a question. So I depend on my trainees to have a breadth of knowledge that extends beyond their specific research area. Then they will inform me of research that might have slipped through the cracks.

I am interested in reading about mechanisms. There are papers that I call the ‘Effect of ‘fill-in-the-blank’ papers that describe the effectiveness of a particular drug or compound. For these types of papers, I usually wait until more studies are carried out that reveal the mechanisms.

Which scientists have significantly impacted your career?

There is no question that the person who had the most impact is Patrick Wall, with whom I did my first postdoctoral research. I was an undergraduate student of Ronald Melzack, who introduced me to the problem of pain, but as an undergraduate my interactions with him were limited. Pat was very untraditional and somewhat of a phenomenologist. What made him special was not the way he performed experiments, but his keen ability to pinpoint interesting phenomena in the midst of an experiment. Then he would ponder the mechanisms, form a hypothesis, and design an experiment to test it.

The other person is Peter Nathan. Pat Wall was interested in patients, so while I was a postdoc in his lab, he referred me to Peter, who was a neurologist at the National Hospital at Queen Square, London. I observed Peter’s interaction with patients once a week for three years. For approximately six months, I just watched and listened. It was not easy for me to not ask questions. But after six months, I would engage and interact with the patients. Peter also thought like a scientist, which allowed us to have discussions about pain. I encourage my students and postdocs to join the pain physicians, some of whom perform research in my lab, when they treat patients. Basic science pain researchers need to learn that a mouse is not a human.

Howard Fields and David Julius also had a significant impact, in terms of collaborations. Working with them on diverse pain research topics and most importantly writing papers together has always been a highlight of my career. And they are also close friends; it doesn’t get better than that.

You said science is your hobby, but how do you spend your time outside of science?

You do need things to do outside of science. Thirty years ago, I started to play jazz piano and I still have a lesson once every couple of weeks. I can’t think about science when I am playing the piano. I don’t read as much as I would like to, but I do read novels on airplanes. I also highly recommend Bill Browder’s recent book, ‘Red Notice.’

I also like to spend time with my family—with my wife, children, and grandchildren. I also play golf about twice a month, but not enough, and not particularly well. As soon as science fails to excite me—I don’t envision that soon—perhaps I will move to the golf course permanently.