It was the early 1990s and we were postdoctoral researchers at the University of California at Berkeley, all of us strangely confident that the work we were doing was going to go somewhere, even when nothing was going right. Our optimism wasn’t guaranteed to work in our favor; plenty of other students and postdocs were leaving their time in the lab with little or nothing to show for it. We ignored that evidence and often found that no bad day couldn’t be improved by dinner at the Korean BBQ restaurant in Oakland where they sometimes let Joonsoo, Cynthia’s boyfriend then, do the grilling. Joonsoo had the Trooper and was happy to drive; all of us were living on a small government training stipend, and were fortunate that the only car between us was spacious enough for our group to squeeze into. After commandeering a large enough restaurant table, we’d order beers, indulge in kimchee and debate the day’s results or seminar talks, if there had been one.

In the lab and outside of it, Cynthia’s personality far exceeded her small frame. Even when she was doing solo lab work, silently using a scientific tool called a micropipette to measure and transfer tiny volumes (microliters) of liquid DNA, you knew she was there. When you turned your back and started to talk about an idea, she would chime in to share her own strongly held opinions. Whenever she was nearby, we all knew it—until one day, she suddenly wasn’t there.

Tremendous promise, bottleneck process

Each of us had been drawn to Jim Allison’s immunology lab at UC Berkeley partly due to his unconventional, somewhat brash style. Maybe you would or wouldn’t get something done here but it seemed like it would be fun. He was a good storyteller and a hands-off leader, and in some ways willing to let us try things a bit on our own, to support our work, even when it was a long shot or wasn’t something we already had skills in doing. We loved the freedom he granted us, but we also knew it was eventually conditional; producing good results would eventually be necessary if we intended to stay in science. We wanted to stay—we’d each decided that this was a good path to pursue and had pretty much closed the doors on other professions. Unsurprisingly, we worked long hours, typically weekends, too, and put aside much of the typical twenty-something ideal of ‘getting a job and settling down’. We all innately believed that if we kept at it, we’d figure out something important, maybe something the world had never seen but needed to know. Cynthia was no exception. When she stopped showing up in the lab, we all noticed.

In my experience, some people don’t talk about having cancer because they’d rather not acknowledge what they see as a weakness. For Cynthia, I think that she didn’t want to be a sympathy case. Whatever her reasons for holding back, her sudden absence changed the energy level in the lab, and we all felt it.

Her mysterious absence, we later learned, had consisted of surgery followed by recovery at home. Jim respected her privacy and kept her secret. Months earlier, she’d been diagnosed with cancer—a disease for which our work would eventually provide a new cure, although none of us knew this at the time. She was optimistic about her prognosis after her tumor had been surgically removed. Her cancer was serious, but it seemed to be localized in one area, which made it operable. Perhaps the tumor had not spread into adjacent tissues. With a stoicism that we knew and respected, she didn’t discuss it. Instead, she returned to the lab, ready to get back to work, but soon afterward, she faced a headwind that, for scientists, amounts to a full-body blow.

While she’d been gone, two other labs had successfully “scooped” the project that she’d started. Essentially, they’d independently been testing a similar idea and within a few months of her return, they’d published their results in a scientific journal. They were dramatic results, but they’d found it, and now she would not. Joonsoo had tried to keep some of her work moving forward in his spare time during her absence, but the other labs had already been far ahead by the time she returned. It was a devastating turn of events, especially since her absence had hardly been voluntary. Instead of wallowing in her professional loss, though, she discussed her options with Jim and decided to proceed with the next key experiment and see where it might lead her. Most people would have assumed defeat and given up; we’d watched many who already had.

Cynthia’s perseverance did eventually yield results, producing the next stage of breakthroughs that moved the field of immunology forward. The labs that published before her had received most of the credit, but that didn’t dissuade her. There are scientists among us who are that devoted, who keep going despite steep odds; she was one of them.

Her cancer returned around 2002, by which time she and Joonsoo, by then her husband, had bought a house and settled into their labs and faculty positions at the University of Massachusetts Medical (Worcester). I’d visited them a year previously, in 2001, and she’d seemed gratified by their life and confident the cancer would remain in remission. It did not, reappearing with a vengeance, encircling her spine. She died in 2004.

Ten or so years after she passed away, I met Joonsoo, ever the foodie, at a hip oyster bar in Boston. By this point, the CTLA-4 discovery we’d made at UC Berkeley in the mid-1990s, a cure for certain types of cancer, had finally been approved as a drug protocol. Cancer patients who wouldn’t have survived could now reclaim active, healthy lives, cancer-free. But it was impossible not to think of Cynthia, of how her life might have been spared, if only the clinical trial work to turn our discovery into an accessible cure for patients hadn’t been delayed so many times, for so many years. That process had eventually involved large teams of people across several organizations, but Joonsoo, Cynthia and I hadn’t been part of it. Cynthia had contributed her ideas to the CTLA-4 discovery in our lab, but she hadn’t lived to benefit from its most significant impact—the chance to outlive her cancer.

As I’ve looked back on her story over the years, Cynthia’s tragically early end has affected how I feel about the delays in both clinical trial work and our slow acceptance of a scientific idea. For a long stretch of time, elongated timelines from discovery to patient-accessible cure or treatment were normalized, to countless people’s detriment. Cynthia is a large part of the reason I’ve ventured outside the lab at times in my career to build and develop a small biotech to test new antibodies against a new set of molecules. She’s also a big reason why I started a group adjacent to UCSF that works on making antibodies for human use. Her story, and others like hers, are why I and others are entering cancer vaccine territory right now, an era where risks are low and the evidence of benefits are rapidly accruing and being better understood.

The process of ushering cancer tissue into deep analysis used to take months and even years. Now it can potentially occur in a matter of weeks without sacrificing important harm reduction parameters. Every day we shave off of that process saves lives. Every day we solve a new complex problem, make a discovery and figure out how to use it, we can potentially extend the lives of people like Cynthia, whose own work has since helped others to regain their health and expand their life and health span. She played a very real role in the progress we are now making. All of the current discoveries and the focus on immunity in cancer started with our lab group and multiple other linked groups spread across the globe—riding high in the front seat of a friend’s car like Cynthia did, heading out for a meal in between experiments.

It is near midnight and I am alone in the lab. The stark white of the benchtops—smaller tools and equipment like centrifuges, mixers, incubators that sit on a laboratory countertop—perfectly contrast the blackness outside. The bright fluorescent lights that hang from the ceiling reflect brightly in the mirror-like obsidian of the nighttime window panes. In them, I can see my own image. Despite years of failure and any number of doubts about what I was doing with my life, I am achieving something I am proud of. After years of lackluster results, it is finally real: my PhD research is not a complete waste. Scientifically, what I’m doing may even hold real promise.

Four years prior, in 1989, I’d joined Jim Allison’s lab at UC Berkeley, intrigued by his Texan swagger and laissez-faire leadership style. At the outset, he’d shown me a few projects I could choose from, despite my background, which was steeped more in chemistry than the biology his lab studied. My joining his team was a somewhat risky bet for us both; he was hedging some of his resources on me as a PhD candidate, and I, in pursuing a study of the obscure immune system, which was not considered cool, or even entirely worthwhile, at the time. Most of my fellow students were vying for spots in the larger molecular biology labs pursuing a deeper understanding of DNA, a field that had won the Nobel Prize in the 1960s. But I now realize that I’ve always had a penchant for looking for something different, and Jim Allison’s lab seemed like the perfect spot to do something interesting, maybe even something important.

The project that captured me and brought me into the lab involved a molecule called CTLA-4, which was essentially a ghost at the time. A lab in France had discovered its DNA sequence. During our initial meeting, Jim had had a piece of paper lying on his desk, listing the molecule’s long alphabetical code. We’d discussed it and I’d bought into the idea that it might do something interesting. Really, though, I was gambling a long period of time, and my chance for an early reputation as a budding scientist, on a molecule I couldn’t definitively prove even existed. I trusted Jim that he wouldn’t propose a molecule that had no purpose and the data seemed compatible with that. Months would roll into years before I’d realize just how Sisyphean my choice of research projects really was.

But then suddenly I was standing alone in the lab that night in the summer of 1994, smiling. After a seemingly endless round robin of trial and error, I’d successfully used the CTLA-4 DNA sequence, along with other newer, harder-won knowledge and resources, to create a small molecular tool that specifically bound to CTLA-4. With this in hand, I could finally do some real experiments and see whether CTLA-4 was in any way important as part of the inner workings of the immune system.

During the year that followed, I scoured the literature and tried new experiments and in so doing found all kinds of ways to use my molecular tool to push and pull on CTLA-4. All the results pointed to the idea that it acted as a kind of brake lever, helping to determine the strength of the immune system’s response. CTLA-4 could be manipulated—”pressed,” so to speak, to make the immune system go slower/be less forceful. Or, I could use the molecular tool I’d made to block access to this braking system to enable the immune system to work faster/stronger. Other scientists had already concluded that CTLA-4 wasn’t very important, but my data said otherwise. With molecular tool that bound CTLA-4 in hand, we could “play” the immune system the way a musician plays an instrument.

For months following that night, I’d find myself back in the lab late at night staring at cool new data that showed this in another way, or showed it in another setting where the immune system was thought to be important. I found myself scheming with the lab and Jim to test CTLA-4 on any diseased mouse I could find. Not only could I change the course of a disease, I could make something as simple as a vaccine more effective. It affected a lot of things and I collaborated with almost everyone in the lab and we became bolder together, using it in increasingly odd settings. We built a small quiver of publications we hoped to submit to, and I shared my molecular tool, or reagent, with most of Jim’s lab to collaborate and try increasing numbers of diseases to see what would happen.

Then Jim joined us at the whiteboard one day and mentioned almost off-handedly that we could try it in cancer. Giving mice tumors was simply a case of injecting them with a cancerous cell line that would grow over time. The immune system wasn’t thought to be very important in cancer, but given how quickly we were producing interesting data in all these other mice, why not try? I’d optimized a dosing scheme to give my molecular tool to mice by injection and augment their immune systems. Why not try it?

I set out tubes, some containing my molecular tool, others filled with a control drug, then marked the tubes with letters and numbers that created a code that I then wrote into my lab notebook. This created a double-blind study, the gold standard of scientific research, in which the person watching the mice wouldn’t know which mice had gotten which drug. About twelve days into that experiment, Dana, the lab mate whose job it was to physically handle the mice in this experiment, returned from his latest visit to the mouse house. He looked puzzled. The malignant tumors that had initially been growing in all of the mice had been steadily shrinking in about half of the mice over the past few days. A week later, the trend had continued; the tumors in those same mice had continued to shrink. We ended the study soon afterward, once the mice whose tumors continued to grow were too large to ethically proceed with the experiment. Then we all gathered inside the lab as I read out the code that had “blinded” the study.

That was the first example of what is now called ‘checkpoint blockade’ immunotherapy of cancer: the mice whose tumors had essentially melted had all received my molecular tool, a CTLA-4 treatment, and those whose tumors had grown had been given a placebo. CTLA-4 based drugs and their similar offshoots now cure hundreds of thousands of people each year. Most every patient and absolutely every oncologist on the planet now understands that CTLA-4 is one of a handful of what we call “checkpoint” molecules in the immune system and that these are powerful options that can cure cancer. At the time though, it was just us, investigating how this new CTLA-4 treatment was impacting cancer and other diseases.

Well into the early 2000s, this major breakthrough that we first published in scientific journals in 1995 essentially met a series of brick walls. Initially there was excitement in the popular and scientific press. But soon that died, and few people seemed to care. Just a few months after the discovery, Jim Allison and I pitched the concept to several biotechs, hoping they would invest and transform our CTLA-4 finding into a cancer drug protocol. Although they expressed interest in our lab results, none committed the critical resources needed to complete the clinical trial process. I thought at the time that this might be how science worked—lots of work, lots of excitement, and then you move on. I moved on to new questions, open terrain.

Looking back, I have sometimes been tempted to blame myself for not figuring out the next step on my own. I have stopped short of that, since it was not possible for me as just a graduate student to do so and still build a career as a scientist. I’m still not entirely clear why the process of turning CTLA-4 into a cancer treatment stalled for as long as it did. Maybe the goal of curing cancer had been glorified for so long, people had decided it wasn’t possible. There had been many, many false starts, including a few that came from other immunologists like Jim. Maybe biotech had invested in other bets and their resources were tied up? Maybe investors struggled to wrap their minds around the science, which was unusual at the time? Up until that point, the focus had been on directly removing or attacking cancer cells, typically through surgery and chemotherapy. Checkpoint blockade was different; instead of opting into this more conventional search-and-destroy method, it activated the immune system to eradicate the cancer itself. The results of our approach had been extremely encouraging, but were also new. Perhaps there were too few who believed that the immune system even had the capability to cure a disease like cancer. In such a socially-constructed belief system, maybe it was really an unproven way of conquering disease.

Finally, in 2011, the work we’d done in the lab in 1995 was replicated in patients through the clinical trial process and received FDA approval. In the years since, I’ve had the honor of speaking to a small handful of the many thousands of cancer patients whose lives have been saved by our drug protocol. They’re conversations I’ll never forget, conversations that keep me and my team inspired and committed to moving scientific research forward, no matter the obstacles. I don’t think any of us knew how important this would be when I saw that sequence in Jim’s office, chose to stay there to study it for a PhD project, or kept at it when many years had gone by without success.

By the point it got to patients, the story of the days of its discovery was pretty much forgotten or at least turned into a footnote. No one knew of the dark reflection in the lab windows or the coded tubes that allowed us to first witness the potential of
CTLA-4. By then, I was no longer part of the process—my work and research had expanded well beyond CTLA-4. There are new questions and curiosities and I still sometimes find myself in the darkened lab at the end of a long day excited by the data I’m seeing. Somewhere amongst all the studies we do to understand the basic principles of life, there are more cures waiting to be discovered, to emerge from that darkness. If anyone ever asks, this is why we do science.

As a molecular biologist and immunologist, that question has led me to investigate the body’s ability to heal itself. I first discovered one of its capabilities in the 1990s; when given targeted prompts, the immune system could cure as well as worsen multiple diseases. It was a pretty exciting way to begin a career. Although the cures then took an enormously long time to reach patients in ways that I could not control, that discovery has since saved hundreds of thousands of lives. In that way, it is, to me at least, extraordinary.

Looking around now, it seems entirely possible that we may be entering another interesting period of science history, particularly where the newer roles of the immune system in health and disease are becoming evident. New knowledge and new technology are converging, advancing medical science and potentially changing the future of health. It has occurred to me that others may be interested to explore the untapped potential of the immune system, and how the process of discovery unfolds, inside and outside the lab. During a recent sabbatical, time I split between Paris, Melbourne and San Francisco, that realization brought me here, to launch Immune Beyond as a place to share some of these developments with a broader audience.

I’ve also wanted to talk more about what it’s like, being a scientist. This work, and the life that has formed around it, doesn’t often fit into a typical societal mold. My career in science has led me around the globe and kept me in the lab well past midnight countless times. As the leader of Krummel Lab at the University of California at San Francisco (UCSF), I meet and collaborate with highly motivated deep thinkers across multiple disciplines who are pursuing answers to questions prior generations couldn’t even ask. I also oversee and collaborate with a team of dedicated, intelligent and sometimes quirky group of graduate students and young professionals intent on solving incredibly challenging scientific puzzles. It is intense, engrossing work, and a somewhat eclectic, entertaining life path.

The intention behind Immune Beyond is to explore the work and the life of a research scientist—to provide insights into my world, and the discoveries that continue to transform our health and healthcare.

Hi, I’m Max Krummel.

By the time I found myself alone in a UC Berkeley lab at midnight during the summer of 1994, I’d dedicated years to experiments that had mostly produced only incremental progress. I was a doctoral student at the time. More than once, I’d considered walking away, but the particular questions I’d long hoped to answer and a will to actually discover something kept me engaged. Eventually, I witnessed what I had only dared to hope: a change in the immune system that could be manipulated to accomplish a specific goal.

Within months, my lab mates and I put that capacity to the test. We watched a drug I’d made work do wonders in mice, including inducing rapidly-growing malignant tumors to simply vanish. In 2018, that discovery was awarded the Nobel Prize and given to Jim Allison, my mentor during that portion of my PhD research. That discovery, known as checkpoint blockade, has resulted in a cancer drug therapy that has saved many lives and changed how I define achievement and success.

Scientific discovery is a strange thing. We spend thousands of hours, sometimes in groups, but many times alone, overseeing experiments that we hope will produce results worthy of attention. Science can also be a competitive field; having our names featured in publications, on awards and patents is a mark of achievement that we can be taught to strive for. At the same time, all new science is only made possible by the science that came before it and sometimes by the science that is happening all around and at the same time. All big breakthroughs are enabled by other discoveries, which means by our peers and predecessors.

Life in the lab and the process of discovery work best when the entire hive is involved. We can make big leaps even bigger, and rapid progress faster, when we pull inspiration from the works of our peers and when we collaborate. That belief has anchored me as a leader, and inspired me to found several collaborations: the UCSF ImmunoX Initiative, a radical collaboration platform to accelerate discovery and cures; the Immunoprofiler project, which unites cancer studies to understand individual patient biology; Solving for Science, a group of scientists dedicated to supporting other practicing scientists; and Foundery Biosciences, a biotechnology venture “studio” co-founded to develop transformative immunotherapies for immune-based diseases.

One thing I can say for sure: it’s an interesting time to be a scientist. There’s a lot happening in the world of research science, and plenty to talk about. I hope you’ll join me.