Rock star science

Nobel Prize winner Craig Mello is about to step on to a new stage

Craig Mello and UMass Medical School Chancellor Michael Collins, with the
Albert B. Sherman Center in the background.

craig mello is sitting in a chair outside the office of UMass Medical School Chancellor Michael Collins. Mello is dressed casually, his hair stylishly long. I introduce myself and within seconds the famed biologist is talking enthusiastically about two of his greatest passions.

One is kiteboarding, an extreme sport where the participant races across the water riding a board while hanging on to a large kite. Mello is just back from a trip to the Bahamas, where he spent a lot of time on the water. The conditions were fairly calm for most of the trip, he says, but then the wind reversed and the waves picked up. His eyes light up as he recalls the combination of speed and danger he experienced flying across the water. “You should have seen the waves,” he says.

His other passion is his research on the inner workings of the cell. He says he’s never been more excited about his lab results, and that’s saying quite a bit considering he won a Nobel Prize for his work in 2006.

Mello won the Nobel along with his colleague Andrew Fire (then of the Carnegie Institution of Washington) just eight years after their discovery of how genes are controlled within living cells. Their work centered on ribonucleic acid, or RNA, which, along with its cousin DNA, orchestrates many cell activities. Mello and Fire injected a round worm with double-stranded RNA that had the same chemical sequence as the gene they were targeting. The gene responded by switching off, a discovery that suggested genes responsible for a multitude of diseases could also be switched off. A new field of RNA interference, or RNAi, was born.

What made Mello’s Nobel so special for the University of Massachusetts Medical School in Worcester was that he had done all the work there. The prize helped put the school on the map, and transformed Mello into a valuable state resource. How valuable became clear two years later when Gov. Deval Patrick and the Legislature approved legislation steering $1 billion over 10 years into the life sciences. Nearly a tenth of the money, or $90 million, went to the UMass Medical School to help build a new stage for the state’s rock star scientist.

The new $400 million stage, called the Albert B. Sher­man Center, for the former vice chancellor of university relations who retired in 2010, is a nine-floor building with 480,000 square feet of labs and classrooms, a fitness center, and dining hall. The impressive band of scientists moving into this new facility will focus on three areas: RNA biology, stem cell biology, and gene therapy.

The university is paying for the building with $280 million in borrowed funds, $30 million from campus funds, and the $90 million grant from the state’s Life Sciences Center. The campus wants to raise another $50 million to $100 million to fund recruiting efforts.

With the Sherman Center scheduled to open in Oct­ober, Mello and Collins are sending a message to Beacon Hill that the state’s big bet on UMass Medical School will pay off. Collins is promising that the new center will yield $1 billion in economic impact, and both Collins and Mello are saying the research done there will not only unlock the mysteries of the cell but vanquish some of the diseases that plague mankind.

I talked with Mello and Collins inside Collins’s office on the UMass Medical School campus. Here is an edited version of our conversation.

                                                                                                                            —Bruce Mohl

commonwealth: What’s the importance of the Albert Sherman Center?

craig mello: We think of it as a new hub for the campus that’s going to connect researchers on the basic science and clinical side and get them working even more closely together. We already have a very collaborative research environment here. The key to developing new medicines now in the post-genomic era is to move back and forth between the bench and the bedside. It’s not a one-way street either way. We have so much potential now to understand disease at the very basic level of the genes, and yet that understanding doesn’t always translate to therapy. The goal now is to take that knowledge of the human genetics underlying disease and translate that into new discoveries that will lead to new therapies.

cw: How do you go about making those discoveries?

mello: My chair in molecular medicine, Michael Czech, who recruited me here to UMass, has this vision for molecular medicine which I think is kind of a foundation on which we’re building the Sherman Center. Basically, get the best athletes you can get is what Mike always says. Try to bring together a community of people who think about different problems. Get them together in the same room and get the ideas bouncing around. For me, the Sherman Center is the realization of that vision. We’re taking it to another level. Without the Sherman Center we couldn’t do that. We needed this new infrastructure in order to continue the trajectory of growth that we’ve been on. We’ve exhausted all the available space we have.

cw: Is it hard to attract top-notch scientists to Worcester?

mello: When I came here originally in October 1994, I didn’t have a lot of other opportunities. But after 1998, when we were publishing on RNAi, I had people asking me: “Why are you staying in Worcester? Come to Harvard. Come here.” All through 2000 I kept getting that question. When the Lazare Research Building [at UMass Medical School] came online in 2000 and we started recruiting new faculty, then the question stopped being, “Come here,” and changed to, “Can I come there?” I kid you not. We can recruit anybody. We are getting fantastic applicants from all over the country and the world. They’re not coming here because it’s like San Francisco. They’re not expecting that. The reason they’re coming is for the research. I could go anywhere I want, practically, if I wanted to shop myself around, but this is a great place to be.

michael collins: When we recruited Victor Ambros [a professor of molecular medicine], I sat down with him before we did some press. I asked him, “Victor, why are you coming here? What is it about UMass that you want to come to?” And he said: “Very simple, Michael. We owe it to the world.” And I said, “What do you mean?” He said: “We are making these discoveries as scientists. We’re making them in our individual labs. Look at what Craig discovered. Look what I discovered. And look at what Melissa Moore has discovered and Phillip Zamore is doing. [Mello, Ambros, Moore, and Zamore are codirectors of the RNA Therapeutics Institute at UMass Medical.] If we come together as the finest RNA biology community that could exist anywhere in the world, then our discoveries will multiply. We owe it to the world to make these discoveries and make a difference for mankind.”

Here’s another example. Bob Brown was a senior neurologist at the Mass General, and he made a discovery of the SOD 1 gene in ALS [often called Lou Gehrig’s disease]. His life’s commitment is to cure the disease. He wakes up and goes to bed thinking about ALS. So he becomes our chief of neurology. I told him I had been trying to recruit someone like him my whole life. So I asked him why he was leaving Harvard to come here, and he said: “I’m 58 years old. I’ve made this discovery of the gene that’s defective in the familial cases of ALS, and I don’t know if it’s going to be RNA interference or gene therapy or stem cell therapy that I’ll be able to use to cure the disease. But I do know that the finest place in the world I can go to make the discovery is the University of Massachusetts Medical School.” That’s a quote.

cw: Those are powerful testimonials, so why aren’t more people aware of what’s going on at UMass Medical.

collins: Institutions have moments, and I think this is a moment for ours. If you go back to 2006, when Craig won his Nobel, there was a tremendous amount of enthusiasm in the state for that discovery, for a home-grown scientist. Massachusetts is very fortunate in that we have a lot of Nobels, but none captured the imagination of the Com­monwealth like Craig.

cw: How did the state’s investment in the Sherman Center come about?

collins: The governor was conceiving of a life science fund. You have to remember this is in the context of California putting up $3 billion. Maryland, Illinois, and Texas were putting up these major amounts of money around the notion of science and stem cell research. When Craig won the Nobel, he had some conversations with the governor about what could be done to further his science. At that point, we began a conversation about what the campus might need and what the Commonwealth might do. There was this desire to invest in something that could make Craig’s discovery be more exponential in its impact.

cw: Dr. Mello, what did you say to the governor

mello: There was such an obvious need to increase investment, not only here in the state but in the nation and the world in order to develop new therapies. No one was listening. Funding was completely flat during the Bush administration. I wrote a letter to President Bush telling him there is a revolution going on and it was happening during his administration. I told him this was an opportunity for him to get out in front of major discoveries in biomedical science that can have a tremendous impact on the lives of Americans. I got no response. He never even wrote me back. I did get a response from his office, but not a personal response from the president. I wrote the same letter to the governor and I got an unbelievable response from him. Many of the people on Beacon Hill wrote me back as well. We have a tremendous opportunity now to begin to take advantage of these insights into the nature of the basic biology of information flow in the cell.

cw: Do you think there is widespread public support for these types of investments?

mello: In the two years after the Nobel, I spoke to hundreds of audiences, especially lay audiences. They love science. I think there’s a disconnect between the political bodies where decisions are made and the people who I think would vote for more funding. Nobody wants more taxes, but we could be missing an opportunity unless we all step up. So philanthropy is one way, but the heart of the scientific enterprise in this country is the federal government. To our credit, we’ve invested in research in this country, especially since the Sputnik era. That’s what made us great. We’ve done it in a really good way. We’re probably the best in the world at assigning priority to research based on peer review. If you go elsewhere in the world, they just don’t have the infrastructure in place to make those hard decisions.

“Institutions have moments, and I think this is a moment for ours,” says UMass Medical
School Chancellor Michael Collins

cw: Why is this so important to you?

mello: I have a child with Type 1 diabetes who has had it since she was one-and-a-half. She’s now 11. I can tell you, you really appreciate molecular medicine when someone you love depends on it every day for their very survival. She has to have insulin or she would die. There’s so much suffering going on out there. I feel fortunate that the worst in my family is Type 1 diabetes. It’s bad but there’s much worse and we need to do more. I think it’s really possible to lick some of the diseases that have been around with mankind throughout our history.

cw: What is the economic argument for the Sherman Center?

collins: There was money to support Craig and his discovery, but we had to make a different argument to get $90 million for a new building. I can remember the first phone call I had about this idea. The person laughed, absolutely laughed. They said we wouldn’t get $90 million. I don’t know if you know, but less than 4 percent of the money that runs this institution comes from the state, so getting a lot of money from the state for this place is not in the cards. I initially went to the Legislature and said we’re running out of research space, we won the Nobel Prize, and we could have a greater impact if we got more money. But I was getting blank stares. Then I made the case that we have this great scientist, Craig Mello, and we have this opportunity to get other great scientists. They loved Craig and all that, but I still was getting blank stares. Then I had this idea to have the Donahue Institute at UMass look at the economic impact of the Lazare building [which opened in 2000]. They looked at all the bricks and mortar and the fixtures we bought and the impact of having $100 million of science running through that building each year. And it made somewhere between a $400 and $500 million impact. So then we began studying what would happen if we create a new building that would be about $400 million in size, with another $100 million worth of people in it, and then run $130 million of research through that building every year. And the impact was about $1 billion. So I went to the state and told them we could have $1 billion of economic impact, and all of a sudden they came right to the table and said: “Let’s talk.”

mello: There’s a science side to this moment as well. In so many ways, this truly is the life science moment not just in this state but on this planet. For 3.8 billion years, life has been evolving here, right? And now we have entered the information age as a species. We understand super computers and all this stuff. That’s what so cool about the convergence between the genomics revolution and RNAi and the potential for unlocking the secrets of the genome and understanding disease. One of the reasons RNAi was such a big splash scientifically had nothing to do with what Andrew Fire and I did. It was more a realization that RNAi is a search engine, like the type you use on your laptop to search the Internet. It uses short pieces of genetic code to search for information that matches that information. And then we can do stuff to it. We can regulate it or permanently turn it off. We know how to trigger the search engine of the cell. We can use this approach to directly control the information that’s flowing in the cell. Sometimes the information is flowing in the wrong direction because the cell is out of whack and you’ve got a disease state. We could potentially interfere with that adverse flow and maybe in the future we could learn to manipulate the flow in a positive way.

cw: It sounds promising, but it’s a lot of money at a time when state funds are short.

mello: One good analogy is striking oil and how much it’s going to cost you to build the pipeline and everything else to deliver the oil to market. Yeah, it’s going to cost you a lot, but what do you get when you do that? That’s where we’re at right now. We’re at this really incredible moment in the history of biology where we’ve begun to understand living things in a new way. I’m so happy the state has made this investment. It’s good economics, I’m sure of that. We’ll attract a lot of new National Institutes of Health funding for this building, but it’s also really good science to grow our research enterprise at a time when the body of knowledge we’re researching is growing astronomically.

collins: We took a risk expanding when we did because nobody else was doing it. But we’re probably getting much more building because no one was building buildings when we were building ours. And we got it built faster and better because we got people’s attention. We made the decision that it was absolutely prudent to do it now. When the economy gets better and the dollars start to flow, our building will be ready to go.

cw: Should the state be doing more?

“We have a tremendous opportunity now” based on our understanding of “the basic biology
of information flow in the cell,” says Mello.

collins: I think the state’s doing what it can right now. I think our president [Robert Caret]has talked about getting the university back to 50-50 [50 percent funding from the state for the entire UMass general education budget and 50 percent from tuition and fees; currently the split is 45-55] and I certainly would endorse that.

mello: We’re talking very lean funding times right now, which is why a lot of institutions have stopped building. It’s not because there’s not a great opportunity to do science. It’s because funding has not kept pace due to the economy. I think that’s just wrong. It’s a way to stimulate the economy and also generate new knowledge that will lead to new therapies, new drugs, new income, great jobs. Ultimately, what are we here for anyway

cw: Is there anything different about the building itself?

collins: In the past, much of science was individual PhDs. They’d do the work, write their dissertation, and then publish it. Today it’s much more about a team.

The RNA Therapeutics Institute is a perfect example. We have four outstanding investigators here. You have Craig Mello, Victor Ambros, Melissa Moore, and Phillip Zamore. We went looking for a typical lead to that department, but then Craig came down with his colleagues and said they had an idea. They suggested the four of them take on this responsibility rather than have one department chair. So we’ve done that. We now have four co-directors of the RNA Therapeutics Center, any one of whom could be the lead in any of the major universities of the world. Think of that being the pebble in the pond. You have the RNA Therapeutics Center and we’re going to surround those wet lab scientists with the dry lab scientists who are going to support their initiatives. So we designed the building with the wet labs here and then all of the dry lab scientists enveloping them. We worked with each of the scientists to talk about the adjacencies. Who are the people you work most closely with? Let’s put them together. We’ve created these innovative stairways from four to five, five to six, and six to seven, so that actually you have adjacencies this way [he motions horizontally] and that way [he motions vertically].

cw: Dr. Mello, you’re one of the centerpieces of this effort, yet you don’t show up as an employee of UMass. I understand you actually work for the Howard Hughes Institute. Why is that?

mello: Howard Hughes was an interesting guy. When he died, he left a lot of money. I think it’s somewhere in the neighborhood of $15 billion that funds the Howard Hughes Institute. Their mechanism of dispersing the money has been to fund investigators at their home institutions. In order to do that, they essentially take over your salary and they pay rent for your space so they can call it the Howard Hughes Institute at the UMass Medical School. Almost every major medical school has one or two. We have seven Howard Hughes investigators. [Moore and Zamore are also Howard Hughes investigators.] It’s small money compared to the NIH, but it’s an important source of private funding for medical research in this country and it’s helped to keep us as a nation in a position of leadership in this area.

cw: Are you too busy now doing the political work related to science that you don’t have enough time to get your own scientific work done?

mello: I’m definitely torn in a lot of directions. I’ve learned to say no more often. It’s important to stay focused on the research. We have some really exciting stuff going on in the lab right now. Frankly, I’ve never been more excited about our scientific results, and that includes the double-stranded RNA stuff. Not that it’s going to be a Nobel Prize or anything like that. It’s just really, really cool biology. In a way, it’s more cool than the double-stranded RNA discovery because that was more just phenomenalogical. We’re beginning to understand that the cell, at least in this worm, is keeping track of everything that’s being expressed and can tell its own nucleic acids from those that are coming from a transgene, for example, that is experimentally put in. I’ve got a lab of about 20 people and that’s my main job. I have to keep that lab going, keep the research going, keep the papers coming out, keep it funded.

cw: What’s left to do for you, Chancellor Collins?

collins: We have the transformative science. We need the transformative gift. That’s the one thing this medical school needs. It’s something we spend a lot of time thinking about and talking to people about, and hopefully someday we’ll find that person. If there’s an Achilles heel for the medical school, it’s the lack of an endowment that the institutions we want to be like have.

cw: Do you agree, Dr. Mello?

mello: If we were in any other state, we would be the gem of the state. Being in Massachusetts, we’re very underappreciated and we’ve felt that for years, even though we’ve known we’re on track and we’ve got this great trajectory. It’s a little hard sometimes when you see the type of philanthropy that goes to institutions in Boston. I won’t name any names and they deserve it, they’re doing great stuff. But if just a fraction of that philanthropy would come here it would have a bigger impact. It’s hard to get that message out. There’s really, really great stuff going on here. It’s not as much of a secret as it used to be, but it’s still too much of a secret. We really want this story to get out there so we can cure diseases.