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Biomedicine

Riding the DNA Railroad

The Human Genome Project is as good as done, says MIT’s Eric Lander. Now it’s time to start thinking about how the data will be used.

For insiders in genome research, the name Eric Lander evokes a palpable image of the trends sweeping biology-automation, computers, entrepreneurialism, big science and big ideas.

A mathematician turned Harvard Business School professor turned gene scientist, the 42-year-old Lander is director of the Whitehead Institute for Biomedical Research/MIT Center for Genome Research. Lander has built the lab into the world’s most productive academic gene sequencing facility and the flagship of the international Human Genome Project.

Personifying the future of medicine isn’t easy. Lander’s pronouncements on biology’s new age are in demand from the White House to Wall Street, and he’s been a key figure in trying to broker a collaboration between public-sector scientists and Celera Genomics, the Rockville, Md., startup (See “The Gene Factory,” TR March/April 1999) that’s racing to create a private copy of the genome. Although those negotiations collapsed amid angry accusations this spring, the Human Genome Project remains on course to produce a draft of the human genetic makeup within the year. TR Senior Associate Editor Antonio Regalado managed to catch up with Lander by phone early on a recent Sunday morning.

TR: What’s been happening at your center during the last year?
LANDER: Well, it has been tremendously exciting. The international Human Genome Project had a three-year pilot project phase which was devoted to developing the methodology for how to sequence genomes. That phase came to an end in March of 1999, and we went from a pilot operation to a production level in excess of 15 billion nucleotides, or DNA letters, per year. We scaled up 20-fold over the course of about nine months, and we did so by less than doubling the staff involved in that process to about 80 people. And if we had had to go up 100-fold we could have done that too, because the whole thing is really quite automated.

TR: Last spring, the breakdown of negotiations between Celera Genomics and the Human Genome Project was front page news. What’s behind that conflict?
LANDER: I think you put your finger on it. The origin of the conflict is that it has been on the front page of the newspapers from the beginning! What happened in May of 1998 [when Celera was founded] is that this all blew up in The New York Times, which decided to turn this into some kind of race and battle.

I think the public face of this, the journalistic feeding frenzy, has served no one terribly well and I am just not impressed by it. If you look at things from a 20-year perspective, this is about as exciting as the New Hampshire primaries. In the grand scheme of things people aren’t going to care an awful lot who did what three months earlier than anybody else. As scientists we should look past all this, but that’s hard with the media recognizing that this is a cheap and easy way for science writers to get their story on the front page. What can you do? People are very susceptible to that.

TR: Apparently, Celera and the Human Genome Project are still negotiating a joint publication of the genome data. What has your role been in these discussions?
LANDER: Oh, I talk to everybody in the community. This is a public service project and I think it would serve the world well for everyone to be talking. I find the racing and the acrimony to be kind of silly and I don’t see why everyone isn’t managing to work together in mature ways. What is the benefit of a field in which everybody talks to each other? Progress is made much more quickly. That has always been the case in science.

TR: What does it mean for the genome project to be finished?
LANDER: The truth is that the human genome is going to have all kinds of nasty little bits that are hard to fill in at the end: the middles of chromosomes, called the centromeres, the ends of chromosomes, called the telomeres, and so on. This is not like the transcontinental railroad, where at some point someone is going to nail in the golden spike, and then and only then can you go cross-country. There is no golden nucleotide to be nailed into the double helix at the end.

What’s important is that every bit of the DNA railroad is already being used today. As of this month, more than 85 percent of the human genome is freely available on the Web. So the notion that biology will be suddenly transformed when we cross a specific finish line is wrong. The point is that biology has already been transformed. The race is over in the sense that everyone is taking the human genome for granted. That is the achievement right now.

TR: What are the next big opportunities in genomics?
LANDER: Well, let’s start with the basic research question, which is how do you use the information in a genome to figure out how physiology really works. The genome is a very elaborate program, and we don’t know how to read it. It’s as if we have some ancient computer code that was written three billion years ago and now we are trying to figure out what it does. I think what biologists are going to be doing for the next decade is figuring out the circuitry of the genome by monitoring how the 50,000 to 100,000 genes are turned on and off and how all the proteins come on and off in the cell.

A lot of technology is going to be needed to do that, so I also think that detector technology [such as gene chips] is going to be a driving force of genomics in the future. I see a real merger of physics, chemistry, biology and computer science to be able to build these detectors and interpret their results.

TR: How will that affect the creation of new drugs?
LANDER: It was noted about 10 years ago that in order to maintain the valuation of the pharmaceutical industry it would be necessary for the typical pharmaceutical firm to bring to market three new drugs each year. In fact, most companies bring to market one new drug a year, at most. So there is a huge productivity gap. And the reason for that is that making a new drug is not an act of engineering. It’s an act of art mixed with a lot of luck.

When you make a new drug you often have no idea whether the target you have chosen is valid, and no way to know whether your drug will be non-toxic or if it will be absorbed and metabolized by a human in the right way. Right now the only way to find out those answers is to pay hundreds of millions of dollars to test the drug in human clinical trials.

Imagine what would happen if one could reverse that by using technologies that had high predictive capability and could be deployed early in the process. That would mean when you go to do your clinical trial, there would be a very high probability of success, compared to the current low probability. Well, that would have a huge impact on the number of drugs that one can develop. That is what the industry sees as the promise of genomics and of biotechnology. When people look back 30 years from now, they are going to be looking back from a pharmaceutical industry that is an engineering industry. And they are going to marvel that anything at all got done in the 20th century.

TR: Your center works closely with industrial partners, including Bristol-Myers Squibb, Affymetrix and a company you helped start, Millennium Pharmaceuticals, to develop just such predictive technologies. Have the lines between academia and industry been redrawn?
LANDER: Oh absolutely, but industry and academia still have very different jobs. Academia continues to be the place to make the basic discoveries that are not “appropriable” as private intellectual property. So for example, the understanding of cancer and how a cancer cell works are things that no company can lock up and therefore it makes no sense for companies to be investing in. It’s what is called a “public good.”

I think the majority of biology remains a public good, in the sense that it is fundamental knowledge. The minute something becomes appropriable in an economic sense, however, it often makes more sense for industry to take it over. What used to happen is that the gap between the fundamental and applied knowledge was decades in biology. Now the gap is six to 12 months. So it means there is a much tighter coupling and a much greater intellectual interchange between the two.

TR: Your industry partners have commercial rights to improved genomics technologies developed with their money. What kind of restrictions does that put on you as an academic?
LANDER: The conditions of that alliance are very explicit in that regard. We are free to publish or speak about anything as long as we have given 60 days’ notice. The 60 days are there to be able to file any patents that should be filed. We have yet to find this to be a serious limitation, because it’s hard to get anything in a scientific journal faster than 60 days. Also, the benefit of this industrial consortium is not so much specific patents as it is a community of researchers both in academia and industry who are working together to push the edge of the technology.

TR: Is the Human Genome Project racing in order to prevent Celera from patenting human genes?
LANDER: Really, the issue has less to do with patents than with secrecy. The international Human Genome Project is about guaranteeing that the sequence of the human genome will not be a trade secret and will be freely available in everyone’s hands, with no restrictions on its distribution or on its analysis. That is our purpose and that is the race that we have won.

The patenting problem is a decade old, and Celera is a Johnny-come-lately. Most of the patents that are going to matter are held by the five or six genomics companies that preceded Celera, like Human Genome Sciences and Incyte Genomics. While I do agree that there have been very serious problems with patent law, Celera is not going to be the principal beneficiary of any of that.

TR: What is your view of gene-related patents?
LANDER: All patents are a bargain between society and inventors made to incent innovation. The question is, what sort of bargains do we want to strike? For the last three years the Patent Office was saying that naked gene sequence about which you know nothing, or very little, is patentable. When something is trivial and involves no substantial inventive step, like running a gene sequencer, it’s my sense that society shouldn’t be setting the bar so low.

In fact, the difficult step is figuring out what a gene does and what it’s good for. And therefore we ought to have a social policy that sets the bar there. Recently, the Patent Office has begun to move in the right direction, although it still has a ways to go. We don’t want to find that we have given away the monopolies to the people who did the easy steps and have left less to incent the people who have to do the hard steps. Pharmaceutical companies already are worrying about working on a particular gene for fear that some other company has a patent on it. Well, the big losers in this case are patients.

TR: The Hollywood movie GATTACA is about unhappy people living in a world where success and social status are determined by their genes. Is that where we are headed?
LANDER: That’s the idea of genetic determinism, and I am quite opposed to it. Privacy and nondiscrimination are really the two big issues and there are many people, including myself, who are worried that our society has not put in place the proper protections.

I believe in absolute privacy for genetic information. I want this to be information that every patient can have access to on his or her own terms. And I don’t want any insurance company, any employer or any government to have any say over that information or to be able to gain access to it without the explicit consent of the patient.

I would also like to see strong statements in legislation that say that genes are not an allowable basis for discrimination. There are a lot of things that we have decided that it is just flat-out wrong to discriminate on, such as race. Well, I don’t see why we shouldn’t put genes in with that. And if there are any exceptions to be drawn, we can worry about that later.

TR: In the absence of any national legislation, are there a lot of examples of genomic information being misused?
LANDER: Examples of misuses still remain few because, as with many technologies, there is a phase where it is not efficient to use this information and so people don’t gather it. But then there comes a tipping point after which it is very efficient, but by then it’s too late if you don’t have the legislation in place. It’s a mistake to conclude that we have a long time to sort this out, because a decade from now it will probably be too late. We have to get everyone to understand that the human genome should never be used as a tool to divide people.

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