Sarah Schlesinger - Ralph Was Right

 

Hi. So, 37 years ago, when I was 16, I came through the gates of The Rockefeller University for the very first time. I had never heard of the place, even though it had been on 66th Street, New York Avenue, and I'd probably walked by it more times than I could have counted, but I never knew what was behind those gates. 

 

My high school biology teacher had given me tickets to what were called at that time the Christmas lectures. They're now called the holiday lectures, which are these amazing lectures by world-class scientists, many of whom were Nobel laureates for high school students. And I had the great privilege of hearing Dr. Christian de Duve, who had just been awarded the Nobel Prize for discovering the microanatomy of the cell. This was the hottest science going. He took a room full of high school students on what he called a tour of the inside of the cell for two days. I was completely amazed. I had thought before that I wanted to be a scientist, but this completely nailed it for me.

 

But I was 16 and I was expected to get a summer job, and I thought, well, this would be a really cool place to get a summer job. So, I came home, I told my parents. My parents nicely nodded at me and they said, "Fine, knock yourself out, get a summer job there." So, this would have been the day after Christmas was the lecture, and my mother went to a New Year's party. And just by a series of coincidences, she was talking to a friend of hers who said, “This friend had a friend whose husband--” He was a scientist. And just by coincidence, he worked at The Rockefeller University. So, my mother came home and told me this odd coincidence here. We'd never heard of this place. In a week's time, we'd heard of it twice.

 

So, I said, "Can you get me his phone number, so I can call him and see if he'll hire me for the summer?" I don't think ever again in my life would I have had the nerve to just pick up the phone and call some stranger and ask them to hire me. But I was committed to getting a summer job there, and this seemed like my best opportunity. So, I called Ralph Steinman, who I'd never met before, nor had I ever heard of, and he was extremely nice to me. He said to me, "Well, you know, we can't pay you, but we can give you meal tickets for the cafeteria, and we'll pay for your train ticket to come to work." What he didn't know was I would have paid him for the opportunity. 

 

So, I started to work beside him at the bench. And this was 1977. He had just discovered the dendritic cell. So, this is a cell in the immune system that orchestrates all the other cells. It's called an antigen-presenting cell. Ralph liked to refer to it as the conductor of the immune orchestra. It teaches all of the other cells in the body how to respond to viruses, bacteria, pollen, or even your own cells. 

 

So, I kept working for him in the lab every summer and every January through high school and college and then medical school. In the mid-1990s, I had the opportunity to have my own lab working on these cells with regard to HIV vaccines. And I took the opportunity, and thus began my grown-up collaboration with Ralph. I was in Washington at the Walter Reed Army Institute of Research. And there, even though all I did was work in the lab, because I am an MD, I was required to learn all about clinical development and how to do clinical trials and how to deal with the FDA.

 

Ralph's discoveries had reached the point, where it was beginning to be thought that they could be moved from the laboratory into the clinic, and they could be used for several things, including vaccines and cancer immune therapy. Because remember, these are the cells that make the immune system either get activated or get quiet down. And so, Ralph wanted to start to do this kind of work and I had learned the skills necessary to do it. So, I came back to help him do this. We got a big grant from the Gates Foundation and started working on the first vaccine to prevent HIV that directly targets dendritic cells. And so, this was my project, and it was an amazing time. Everything was going along swimmingly. We had money, things were going well in the lab.

 

Ralph went to a meeting in Colorado, and he came back, and he was yellow. Well, being yellow, bright yellow, is a very bad sign. It's what's called jaundice. And it's a sign that the liver is failing, and that that means that all of the bile salts are backing up into the skin and the eyes. I knew immediately when I saw him that something dreadful was going on. It turned out that I was right. And Ralph, in fact, had pancreatic cancer. He had a grapefruit-sized mass at the head of his pancreas. And as many of you know and probably most of you know, pancreatic cancer is a dismal diagnosis. 97% of people who have what he had would expect to be dead within a year.

 

So, all of a sudden, everything changed. And in addition to having such a grim prognosis, there's very little good standard therapy, hence the grim prognosis. So, after Ralph was diagnosed, he assembled the group of us that were closest to him in his office, and he basically explained that he understood better than probably anybody, he is also a physician, that this was a grim diagnosis. And though he was willing to engage in all of the standard therapy, it was very unlikely to really make a big difference. And so, he saw this as an opportunity to be his grand experiment. He wanted immunotherapy of his own design based on his dendritic cells.

 

So, we all got to work. And the way it works to do a clinical trial or clinical experiment takes a very long time. So, we had to piggyback on things that were already started by our colleagues. And because Ralph, though, I don't think I mentioned it, was a wonderful and warm and caring human being. People came forth literally from the four corners of the earth, offering whatever clinical resources they had, protocols that were open, ideas, vaccines to help him.

 

And so, we started to have these meetings in his office. I'm trained as a pathologist, which is a kind of doctor who deals with making diagnoses in tissue. So, my responsibility was to understand what we needed to do with the tissue when it was removed at the time of surgery, how it needed to be divided up to maximize the various opportunities that existed. And so, when it got close to the operation, everybody else had left and I assembled my pile of papers. I'm clumsy and I was nervous as it was, and I said to Ralph, I said, "I know we're going to do this, we're going to do this, and we're going to do this." I said, "Who's actually going to treat you? Who's going to administer the vaccines to you?" And he looked at me and he said, "I'd like you to do it." 

 

I was overwhelmed, because first, I was honored that he wanted me to do it, and then I was a little sick at the thought [chuckles] of doing it. But he said to me, "Look, you don't have to do it if you don't want to. Think about it overnight." And I said, "No, no, I want to do it." At this point, I didn't really think it was going to make any difference, but I knew that he thought it was going to make a difference. And so, I wanted to give my teacher the comfort of knowing that he had done everything that he could, and I wanted to give myself that same comfort. So, I did think about it overnight, and I came back and I said, "Of course, I'll do it."

 

I reminded him that I wasn't an oncologist. And he said, of course, he knew that. He was always irritated at me when I pointed out the obvious. He reminded me that he trusted me. And frankly, he knew that I would do what he said, that I would follow his scientific direction and not try to substitute my own. And that, frankly, led to our first argument. [audience chuckles] Because he was the consummate scientist and an absolute purist. And he had trusted in his cells when nobody else had. He wanted to do an experiment that was going to be reportable. So, he wanted to do a treatment and then wait four weeks and do the next one. 

 

I and my colleagues realized that if you waited four weeks and something didn't work and the tumor came back, that would be it. We were going to be lucky if we were going to be able to keep the tumor from growing back, let alone, you know, address it if it came back. So, despite all of my arguments about his health and his life, a smarter colleague said to him, "Look Ralph, you're an N-of-1. It's only a case report, no matter how good the data is, [chuckles] so it's not going to have statistical significance." So, only with that argument was he willing to concede that we could do each treatment one right after another. And we did. But before we could start, we had to have all of the appropriate regulatory permissions.

 

And so, I went to see Emil Gotschlich, who is the head of our IRB, our institutional review board, who was responsible for all of this. And he said to me, "Well, that's all fine, but I have to be sure that you want to be doing this and you're not being pushed into it. Do you want to be doing this?" And I said, "Well, I don't want to be doing this, but if anybody has to be doing it, I want it to be me." And then, he said to me the hardest words that I heard during this period. He said, "You know, no matter how good a job you do, no matter how hard you work, this is likely not going to end well." I assured him I understood, though at that time, I really didn't.

 

So, we then proceeded on our journey of eight clinical trials, three different vaccines, two that were made of Ralph's own dendritic cells that he had discovered, and one that targeted his dendritic cells. Ralph lived four and a half years. He saw a daughter married, he saw two grandchildren born, and he was awarded the Lasker Award, which is sometimes known as the American Nobel. But anybody who has a Nobel Prize will tell you there is no equivalent to the Nobel. [audience chuckles] 

 

And so, four and a half years after his diagnosis, he started to get sicker and sicker. All of us who had thought that maybe Ralph was right and maybe this was really going to work were profoundly disappointed. And over the summer of 2011, he got weaker and weaker, and he started to make arrangements for what would happen to the lab and what would happen to the rest of us when he was no longer with us. In the end of September, it was just too much for him. He had fought valiantly, and he decided that there was no winning. And in his own inimitable way, he became impatient for the whole thing to be over. 

 

And so, he retired with his family and was surrounded by his loving family. He passed away very peacefully at the end of September. Now, he died on a Friday night to Saturday morning. I got a call from his daughter on Saturday morning saying her father had passed away peacefully with his family and asking me not to tell anybody. They told me and one or two other people, but they wanted to be private just for that weekend. The community in which we work, because we work so hard in so many hours, where all of our colleagues, or many of our colleagues are our close friends, not all of our colleagues, [audience laughter] but they're close friends amongst our colleagues. And so, to tell one person would alert the community. 

 

They just wanted to be by themselves. They had been through hell and not back. So, I said, "Well, can I come and see you?" And they said, "Please, just let us be." I said, "Can I send food?" And they said, "Yeah, that you can do." So, I sent food. I spent the good part of the weekend planning with my closest colleagues how we were going to tell the lab, and how we were going to break the news to the various people we had to tell, and then what we would do. And I was dreading going to work Monday and telling everybody.

 

So, I didn't sleep well Sunday night. And about 05:45 on that Monday morning, my cell phone rang. I had gotten in the habit of leaving it on and by my bed in case they needed me for something, I never knew what. My phone rang. It was Ralph's daughter. I picked up the phone. I was in that like half sleep, are you asleep, are you awake, are you dreaming, is this real? I still hadn't processed that he had passed away.

 

So, I pick up the phone, I hear her voice, and she said, "Dad won." I'm like, "Honey, didn't your dad die?" And she said, "Yeah, yeah, yeah, he died, but he won. The Nobel committee is calling us and emailing us, and we don't know what to do." Now, you have to remember, in addition to being the ultimate prize, there's a strict rule that the Nobel Prize cannot be awarded posthumously. It can only be awarded to a living scientist. So, the Nobel committee, like everybody else in the world except the three of us, assumed he was still alive. So, I said, "Alexis, I don't know what to do. I'll call the university and we'll find out." 

 

So, I called the people at the university. They got in touch with the president, and then it got taken out of my hands blessedly. There was a bit of a controversy for that morning as to whether he would be able to keep the prize. And the Nobel committee convened, and I've subsequently learned from the people on the committee, they consulted with their lawyers and they decided that it had been given in good faith, assuming he was alive. The rules allow it to be awarded to a live person, even if they don't live to see the ceremonies, which are in December. So, they used that construct to allow him to keep the prize.

 

So, we'll never know the dendritic cells that Ralph received prolonged his life. Clearly, he lived way beyond what one would have expected, even under the best of circumstances. He believed fervently that they did. I'm not sure whether they did or not, and I'll probably never be sure. But his technology, dendritic cells have been approved for treatment for prostate cancer, which you can see advertised on television if you watch golf or the 6 o' clock news. [audience laughter] Really you can. And I sometimes see it and I get so excited. 

 

So, they have moved forward from the lab to a clinical treatment for prostate cancer. Our vaccine trial that we started back thinking of in 2001 is now fully enrolled, and we have the results. 45 people received the vaccine. That was an idea in Ralph's head. They've made good responses to HIV. Good, strong protective responses. It's just the first phase of a trial, so we won't know if they're protected, but that would have been what he would have wanted more than anything. So, though Ralph never saw that and he didn't even ever know he won the Nobel Prize, I had the great pleasure of watching his beautiful wife, Claudia, accept the prize on his behalf in Stockholm in December of 2011. And more than anything, Ralph was right. Thank you.