Craig Mello
A Conversation with Craig Mello, 2006 Nobel Prize Recipient -- Medicine
May 11, 2007
Introduction
The University of Massachusetts Uncommon Leadership Series was held on May 11, 2007. The featured guest was Craig Mello, Nobel Laureate for Medicine 2006. Craig was interviewed by Glenn Mangurian, University of Massachusetts “Executive in Residence." The topic was “Road to a Nobel Discovery.” Jack Wilson, President of the University of Massachusetts, hosted the program. The following excerpts are from that conversation.
President Wilson:
It's not often that I start an introduction of a Nobel Prize winner by talking about a governor. But the two really are related, because this week you all heard about Governor Duval Patrick’s announcement of a $1 billion stem-cell and RNAi therapeutics initiative, a life-sciences initiative that’s broader than any such initiatives in other states. We’re all very excited about that initiative, because those kinds of announcements don't happen accidentally. They happen because of a lot of good work that’s been done, including the great planning work that occurred along the way. I can tell you that a significant motivation for that initiative was, in fact, Craig's work and Craig's visibility in the community, his willingness to go out and talk about his work and to tell his own story of how winning the prize even transformed his way of looking at his work as he began to hear from patients and think about how their lives might be changed. The governor was moved by Craig’s story.
I have to say that I've worked with a lot of governors over the years, and throughout our discussions, this is the first time that a governor has come in and asked questions about the science and the therapy. Governor Patrick was at the table; he didn’t just leave it up to his aides to work things out. He was involved throughout the process, and eventually he built the initiative around RNAi therapeutics and stem cells as two technologies. It certainly gives us a competitive advantage over other states. Now you’ve seen what all of Craig’s work has led to. I should also mention that Mark Robinson, from the Mass Biotech Counsel, was a key partner in working with us on the preparations leading up to the $1 million initiative
Beyond his work, though, Craig is a family-oriented guy. If you've seen the TV ad for UMass, you’ve seen the little girl that turns her hat. That young girl is Craig’s daughter, Victoria, who's an inspiration to him. Other family members have inspired him as well—his wife, Edit, who couldn't be here today, and his mother and sister, who are with us today. You know that Craig is a Brown University graduate and a Harvard graduate, but he finally saw the light and came to the University of Massachusetts, and ever since he joined the university, he's been a magnet for other talented individuals. Talented people tend to cluster. They want to be around other bright people, who are also doing great things. That has certainly been the case at the medical school.
I will try to be brief in the scientific portion of my introduction. Let me just add a few words about I, or interference; Craig will explain the concept more extensively. Everyone recognizes that gene silencing, interference, is a potential therapy for diseases, a way of attacking, studying, understanding, doing the research; but also a way of coming up with the therapies that didn't exist before 1997 or ‘98…Wait, I shouldn't say that. As Craig points out, interference probably existed longer than most mechanisms, but we didn't know about it until 1998—and Craig made that happen. So, I'm delighted to introduce to you my friend, a great scientist and the 2006 Nobel Prize winner, Craig Mello.
Glenn M:
Craig, I have to tell you, when I heard the announcement of your winning the Nobel Prize—and I think I speak for everyone here—no matter what campus we went to, we all felt proud to be associated with the University of Massachusetts.
When I read what it was about, RNA interference, it sounded to me like a Bill Belichick offensive football play. You know … you get the RNA, and we'll have a little interference over here. Seriously, from what I gather, there's a natural mechanism that genes can be silenced, am I correct?
Craig Mello:
That's right. You've got it! Basically, none of us would be here if it weren’t for RNAi. Right now, RNAi is working to keep every one of you in this room alive, to keep you functioning, to keep your cells from dividing out of control, from making cancers. It's a very, very fundamental mechanism that we simply did not know about until 1998.
As Glenn pointed out, it's a mechanism that existed in worms. A common ancestor of worms lived about a billion years ago. RNAi existed in the worms—and in humans. It existed in plants and in animals. You can actually use RNAi to modify crops. It's being used in agriculture today. Monsanto has a license to our patent, and they're genetically engineering plants to modify the plants’ properties using this mechanism. A recent report explains how cottonseed can be modified so that the oil is edible, by using RNAi interference to silence some of the genes that make the unpleasant substance—terpenol, I believe—that's in the seed.
Glenn M:
If this mechanism always existed, but we didn't know about it, how did you happen to discover it? You didn't just go out looking for it, right?
Craig Mello:
You're raising a great point, Glenn. That's why university science is so important. You fund research broadly, and you let people investigate what interests them, and sooner or later these discoveries are made. But if you start out by saying, “I'm going to cure cancer,” you're not going to find RNAi. Yet, now we know that RNA interference plays an important role in suppressing cell division, maintaining the normal function of cells so that they don't divide out of control.
Every differentiated cell in your body has these little RNAs that regulate other genes that occur naturally. So experimentally what we learned was that we could design a small RNA that would have a sequence of nucleotides that would match the sequence of a particular gene in your body.
As everyone knows, genes are made up of a DNA polymer, which has a very simple code to it. It has only four letters in its alphabet, so it's actually fairly easy to engineer a sequence that matches any given gene. There are four of them instead of 26 or whatever we have, and you just put them together in the right order, and you can identify any gene in the cell.
Obviously it sounds too good to be true that you could actually turn off a gene by making this 20- or 30-nucleotide segment of RNA that matches that gene. Here we have the genome sequence done, and now we have a technology that allows us to turn off genes one at a time. Well, the reason it's sort of too good to be true is that organisms have been relying on it for billions of years just to survive. They have this huge problem of managing information. They have all of this DNA inside them, and they have to figure out when to express which gene and which cell type. As you know, there are 10 trillion cells in a human, and many of these cells have very specific functions, but they all have the same DNA, so you have to turn on the right genes and the right cell type, or you've got a total mess.
Glenn M:
Now, is the therapeutic value, the potential therapeutic value, from generation to generation … from me to my children, or is the therapeutic value within someone who may have some disease?
Craig Mello:
The therapeutic application would most likely work almost like a traditional drug therapy. If you were sick, you’d get RNAi therapy. You might also get gene therapy.
I don't think we introduced Terry Flotte, our new dean at the medical school. We're really excited to have Terry, who’s. joining us from the University of Florida. He's a world leader in the application of gene therapy to diseases, in particular cystic fibrosis. You can put genes back using a viral vector, for example. That allows you to take a good copy of a gene and put it back into a patient.
RNAi is a way of turning off genes if there's a disease state where a gene is defective or missing and you need to silence it or put it back. By having gene therapy as a tool, you can silence a defective gene or put back a missing one. Interestingly, gene therapy works great with RNAi, because you can express these interfering RNAs as well, the ones that are functioning naturally in our bodies. We call them micro-RNAs, because they're these short, little RNAs. You can put them into a gene therapy vector, and that will silence a gene. With gene therapy, it used to be that you could only put back a gene, but now you can put back a gene or express a silencer of a gene. So you can use RNAi in either way.
Terry and I and some of the people at the medical school have been planning an advanced therapy center or cluster where we'll put the infrastructure together for doing stem-cell biology, gene therapy and RNAi, all in one center. We'll hire new people. We'll probably need to construct a new building to bring together these talented people for research as well as to facilitate clinical translational efforts to bring those new therapies into the clinic.
Glenn M:
You know, the process of getting to this discovery … is there a point at which you walk into the lab and look into the microscope and say, “Look at what we've just found!” Is it like that?
Craig Mello:
Sometimes, if you've heard me talk, I make the analogy to commercials for the Ginsu knife. It's like those commercials. You think, This is incredible! I can't believe this! We actually named the components of the pathway. One enzyme we called Dicer. The other enzyme we called Slicer. It dices, and it slices. But the commercial always says, "But there's more," right? The steak knives … you just want to buy them. It keeps going on and on.
That's what the discovery process has been like. It's been overwhelming, and it's so cool. For example, the micro-RNAs, the developmental regulators, came sort of midway through the discovery process. I'll tell you that that discovery was made really around 2002. So, in 1998 we identified the mechanism. In 1999 Andrew Fire and I, through a collaborative effort—although most of the genetics and so on was done at UMass—identified the first gene involved in RNAi, and that was the moment for me … just incredible excitement. In 1999 it was still fairly new, but it was a phenomenon, something that happens, and gee whiz, we don't know how it works, we don’t know anything about the mechanism, but when we clone a gene that's required for the mechanism to function, then we get the first insight into the genetic mechanism.
This first gene turned out to be very interesting because it had human horologes. Humans have eight copies of this gene, and interestingly, all eight have been knocked out now, in the mouse. They're all essential genes. So there are eight copies of it, and a mouse can't live without even one. Very interesting. So, by following that lead, researchers at UMass, as well as at other institutions, have been investigating the function of the human members of this [gene?] family, We have a great colleague Phil Zaymore, who actually co-founded Alnylam Pharmaceuticals with some others at MIT. Phil's group and others around the world have done work in parallel with our work so we've had one exciting discovery after another, coming on the heels of this work.
Glenn M:
What might some of the lead therapies be? I know that this technique is being used by a lot of people right now.
Craig Mello:
It's not only a therapy in and of itself; it's also an engine that drives discovery. It can be harnessed in the laboratory to silence human genes in culture dishes. As you know, cells from humans can be grown in the laboratory very easily, especially tumor cells, for example, and you can do all kinds of experiments so much more rapidly in the laboratory setting. So right now at UMass, we have an entire set of silencing vectors for essentially every gene in the human, in the mouse … I don't think we have the rat yet, but that's available too.
You can take these laboratory tools and silence genes and then look at whether the cell forms a colony, whether it grows or stops growing. That's one waythe technique is being used. In fact, one example of that use has already led to a new treatment for cancer that remarkably just requires applying aspirin to the tumor growth; the aspirin can suppress the tumor. That discovery was made because RNAi allowed the researchers to place the type of tumor into a genetic pathway—the genetic cause of the tumor was identified, and it was clear from the cause that aspirin would be a potential treatment. So amazingly RNAi is speeding the discovery of therapies in the laboratory setting. That's the main way that RNAi is going to have an impact on biology. It will have an impact potentially even on spinal cord injuries, because the basic research can be done on any type of cell, and it can be done very rapidly.
Merck just bought Sirnna Therapeutics, an RNAi company, for $1 billion. One of the reasons Merck gave for buying the company was that this technology was working so well in the labs at Merck. It was being used to discover new targets against which to design the traditional small molecule drugs. The big pharma and all the biotechs are using this technology. Incidentally, they're not all licensing through UMass; we have only about 50 licensees, but we've estimated that there are more than 500 corporate users.
I want to come back to the therapies, though. The therapies that will be and are now in the clinic involve direct delivery of RNA into a tissue, and there's a reason for that. To deliver it elsewhere, you have to come up with nano-particles or viral vectors or something that's more complicated to get it to go through the bloodstream. RNA is a fairly big molecule. It doesn't go through the bloodstream easily. You can't deliver it easily by ingestion, for example. So the targets that are most amenable at this time are targets where you can directly deliver the RNA. For example, the central nervous system is being studied as a target for ALS.
We have a company that we're starting up at UMass called RXi Our first target will be Lou Gehrig's disease. There's a defective gene that needs to be turned off in certain families with Lou Gehrig's disease. We've shown in laboratories at UMass that we can silence the gene for Lou Gehrig's disease in a laboratory mouse model. By silencing that gene, we can prevent the disease and extend lifespan in that model. That's one example of RNAi application. Another would be macular degeneration. There's already been efficacy shown by direct injection of RNA, silencing blood vessel growth in the eye that causes macular degeneration. There's another trial with Alnylam for respiratory syncytial virus. There's a gene therapy trial that I'm aware of for HIV. These things are coming along. It will be really exciting to see.
Glenn M:
When laypeople hear, “We're going to turn off this gene” and “We silenced that one,” are they likely to engage in the same types of ethical debate evoked by stem cells?
Craig Mello:
I think RNAi is less controversial. Like any technology, some applications probably wouldn't really be ethical. But, you know, for such diseases as ALS, where there simply is no treatment, if there's an intervention that seems reasonable, that doesn't harm anyone, certainly you would want to at least try to intervene in that disease process. To me, it's unethical not to allow that intervention.
A lot of these diseases affect a small group of people. If you rely on big pharma to decide what drug development to do, you’ll have 18 varieties of Viagra, and nothing for cancer. Unfortunately, you can't let the market alone drive research. That's why academic research is so important, and one reason why we’re developing the therapeutic center at UMass. Academics are interested in the biology, the pathology, the disease process itself, and they're going to investigate and study all diseases. There's a great opportunity for UMass to be a leader in the development of therapies, to bring along the development inside the university setting. It can be done very efficiently now with gene therapy, stem-cell work and RNAi. All of this work can be done in an academic setting and brought along almost to the point where the work is applied directly to patients.
Glenn M:
What conditions at UMass facilitated your work? Do you see the investment the governor is planning to make, specifically in RNAi and the stem-cell bank, accelerating those favorable conditions?
Craig Mello:
Jack put his finger on it earlier, when he said you get great people together, and more people want to come. That's why I came to UMass; it was already a great place to work. In 1994 I was looking for a position, and I got an offer from UMass and I came. I thought it was UMass Boston—I like to sail!—but it ended up being in Worcester. After looking on a map, I realized that Worcester is a wonderful location in that it's right in the middle of New England. I could easily get to Narragansett Bay, where I like to sail, and I could actually afford to own a house. On a starting professor's salary, I could live within four miles of work, in a beautiful area with rolling hills and lakes. I fell in love with the spot.
Still, if there aren’t good colleagues, and if there’s nothing interesting happening, then it’s difficult to recruit talented people. I went to UMass in Worcester, and I met Mike Check, Michael Green, Craig Peterson, a whole group of young people … Steven Doxy, …great guys, and since then we've recruited many more. We have a new building on campus that houses 100-some faculty. It's been a lot of fun to see the team grow and to see the energy build.
One thing that's been fun for me in the last few months is getting better acquainted with the other UMass campuses. We really do have a lot of strengths as an institution, and I look forward to building the bridges between our campuses and our groups. Just as the marching band showed what you can accomplish working together, it also showed that you have to practice a bit, you know, so it's going to take some work. Still, we can really build those bridges and get people working together. There are ways of shortening the distances between our campuses and bringing people together. That's something that I look forward to working on with Jack as his science advisor. One of the strengths of UMass is that it reaches out more broadly in Massachusetts than does any other academic institution in the state.
Glenn M:
Those of us from business know the challenges of getting people to work across silos, and certainly those challenges also exist within the academic environment. I'm old enough to remember when UMass didn’t have a medical school, and as you might imagine, when the idea of a medical school was first proposed, it wasn’t received warmly by competitive institutions. Who might have imagined that some 30 years later a Nobel Prize winner would come from that medical school? We're very, very proud that it has grown to be one of the top medical schools in the country, and certainly one in very high demand.
On a more personal level, the Boston Herald hit the nail on the head in its reporting of your accomplishments—you're now a rock star.
Craig Mello:
Is that what they said?
Glenn M:
They called you the “bio-rock star.” I think what they meant is that you've inherited a new job. You’re not only doing research and representing the university, but you’re also a spokesperson for a new realm of science. How does that all feel, and how do you feel about the responsibilities associated with that status?
Craig Mello:
Well, it certainly hasn't sunk in. I certainly am not thinking of myself as the “bio-rock star”! In fact, we recently suffered a setback in my hometown of Shrewsbury, where I tried to use my “rock star” status to get an override passed in the town. Although we had more voters come to the polls than, I’d guess, anyone had seen in the town at any election, even in a national election, for the last 20 years or so, sadly, only 52 percent of those eligible to vote showed up. Even though the turnout was a record-breaking number, barely over 50 percent voted. We fell short by 400 votes. I do feel the responsibility that comes with that status and with the opportunity that I now have.
Glenn M:
Do the people in your lab interact with you differently now? Do they think, This is not the Craig that I used to know?
Craig Mello:
I sure hope that’s not the case. I haven't noticed any difference. They tease me just as much. I'm coming to work in suits now, and they're like, "What's wrong? Why are you wearing a suit?" They're used to the old, torn T-shirt look. But it's important not to let them view me differently, because the dialogue, the discussion with coworkers, is so important. The last thing you want to do is project an aura of total knowledge and over-confidence so that nobody ever questions you, because you should be questioning yourself all the time. I don't care who you are. I don't care if you're George Bush.
I think you can see what happens if you take the stance that you know everything, that you're right about everything. The way real progress is made scientifically is through dialogue, and that's something the United States school system has done well. We teach our kids to think. I'm not quite sure how we do it. It's not by making them cram a bunch of facts into their heads. That's why those textbooks are so useless. Ultimately they're wrong, anyway. What you really need to do is have a discussion with kids about what's interesting to them and then to dig deeper and deeper along a line of investigation.
Glenn M:
As you know, one of the nation’s challenges is that we just don't have people majoring in science and mathematics at the rate we’d like. I was a mathematics major as an undergraduate. Certainly universities in this state are at the forefront in trying to address the issue with the STEM initiative—STEM stands for Science, Technology, Engineering and Mathematics. Do you have any comments on how we can meet this challenge?
Craig Mello:
The numbers of students going into these fields is something that we need to address, and I think UMass can play a role in addressing the issue. We have to tell our kids that challenges are ahead. Our kids have been growing up watching MTV, and they think they're going to have a wonderful, glamorous life that just unfolds for them. In fact, if you look at the way things are going on the planet, I think there's a lot of uncertainty about the future. We have global climate change happening. Whether we like it or not, whether we're causing it or not, it's happening. We have fossil fuels running out; we have all these challenges ahead. The university—and I think the popular culture—has to tell our kids, "You've got some big problems to solve in the future," and the kids will respond to the challenge. We can solve these problems, but we can't go around telling them everything is fine, it's cool, you're going to be rich, you're going to have big sports cars. If they think that's just the way life will be, then they’re probably not going to study science and math and chemistry, because they don't realize the importance of those fields.
You know, sometimes it has to get worse before it gets better. That seems to be the way Washington functions right now. I hope that in academia we can avoid getting distracted, that we can try to look ahead not only at the problems, but at the opportunities those problems present, and I believe that UMass will be at the forefront in solving some of those problems. The university is already doing that. We just need to make known what we're doing—for example, the great work on the fisheries going on at the Dartmouth campus. What a terrible problem we have with over-fishing. Again, that's an example of our impact on the climate.
Glenn M:
For those of you who weren't with us at the Boston Pops last night, Craig was given the presidential medal, which is the highest honor that the university bestows. However, we have something else for Craig that he didn’t get last night.
President Wilson:
Every bio-rock star needs a bio-rock star poster. This is our bio-rock star poster. It’s the advertisement poster that we put together for the Pops. It led, by the way, to the first sellout in a very, very long time. I was making jokes about scalpers on the street, but last night, as you came in, did you notice there were scalpers on the street? It was actually true. The poster is autographed by Keith Lockhart, who is very relieved that Craig is going to continue his work in the medical field and not in conducting.
Craig Mello:
Thanks, Jack.
Glenn M:
We're not done yet. George Parks is the director of the marching band. Now, I heard, Craig, that you said you were a member of the marching band. Is that correct? Do you play an instrument?
Craig Mello:
I play the cowbell.
Glenn M:
Well, if you're a member of the marching band, George has something that he wants to give to you.
George Parks:
Now, poor Dr. Mello. A couple of years ago, he sees the band, and to be polite, he says to President Wilson, "You know, you've got a good band there," and the next thing you know, everywhere he goes, there's the band. He wins the Nobel Prize, they hold an event in Worcester, and there's the band. He comes to Amherst, he sneaks in the back door, and there's the band. So he calls Mom in Virginia and says, "This Nobel Prize is kind of cool, but … well, I think I have a stalker, and it's really scary because it has 300 heads!"
Many of you probably don't know this, but the day before we played in Worcester, my band manager—I think she went overboard on this—ran into a tree skiing, and so the day that we're playing in Worcester, I happened to mention that one person couldn’t be there, our band manager, who very badly broke her hip and ribs. The next day … now, Craig has 24 hours to get out of town after his presentation … I get a phone call from this band manager, and she says, "Mr. Parks, Dr. Mello just came to see me." And I'll tell you, the impact he had …
We're here listening to an explanation of RNA, and every time I hear the explanation, I get a little bit closer to understanding that I don't understand. But really what’s more important is the human being, and the amount of time that he has taken with my band manager and talking to her parents … It’s the warmth and the human side that he showed them. So we've made Craig Mello an honorary member of the band, and from everyone in the band, we are giving him one of our official fleeces. It says, “Dr. Mello, Honorary Member of the Minuteman Marching Band.”
Craig Mello: Thank you, George, thank you.