Scientist Mario Capecchi has a message for all those conspiracy theorists who see something sinister in genetics research. Genetics isn't about cloning celebrities, or engineering an entire race of superhumans, or providing insurance companies with handy excuses to deny health coverage.
If indeed there is a conspiracy involving genetics research, he sees it as a plot against disease.
"The end goal what it's all going to come down to is it's going to change medicine enormously," the University of Utah professor says. "Ultimately, we're talking about the elimination or control of cancer, of heart disease, of all the other diseases out there."
Capecchi believes wholeheartedly in this dream. He believes genetics is gradually taking the guesswork out of medicine. Despite all our advances over the centuries, the practice of medicine is still largely trial-and-error, although radical changes in diagnostic medicine are anticipated with projected sequencing of the entire human genome by the year 2005.
"You just try something," Capecchi says. "Often, you actually have no idea what's happening."
This is particularly true with psychiatric problems, he maintains. We don't really understand the root of the problems, but we've found medications that seem to alleviate many of the symptoms. "So we say, 'Pop a pill,'" Capecchi says. "And for some patients it will work, while for others it doesn't."
But, offers the soft-spoken Capecchi, once we really begin to understand the biological problem, then we can begin to envision solutions. "Medicine will then be based on knowledge. And that's where the payoff is going to be," he says.
That payoff may not be too distant. Capecchi believes we'll begin to see the control of most major diseases "just on the edge of our lifetimes" within the next 20 to 50 years.
The 60-year-old Capecchi, a distinguished professor of human genetics in the School of Medicine and an investigator at the Howard Hughes Medical Institute, is best known for his work in the area of homologous recombination. Capecchi and his colleagues have received international attention for a technique called "gene-targeting," which has enhanced the study of genetics in developing mammals. The method allows scientists to target specific modifications in genes, enabling them to create genetic defects in mice that model human genetic diseases. Since humans and mice are nearly identical in their genetic makeup, and since many diseases or predispositions to disease are inherited as the result of alteration in single or multiple genes, the technology allows researchers to use mice to study the mechanisms of genetic diseases. It also may be used to correct genetic defects by targeting the mutated gene and replacing it with a corrected gene. This may one day lead to advances in combatting diseases such as cystic fibrosis, muscular dystrophy, heart disease, and cancer.
"In my view, this is probably the most important discovery in mouse genetics today," says Steve Hughes, a former student of Capecchi's who now works for the Frederick Cancer Research and Development Center in Frederick, Maryland. "His technique teaches researchers how to put their finger on a particular gene."
Capecchi was born in Verona, Italy, in 1937, and spent his first four years of life with his mother in a chalet in the Italian Alps. When World War II broke out, she was sent to a German concentration camp as a political prisoner and Mario lived with family friends for a short time, but then became a homeless wanderer.
Capecchi spent the next four years alternately living in orphanages, alone on the streets, and with gangs of other homeless children. After the war, Capecchi's mother found him in an Italian hospital suffering from malnutrition and within weeks the pair left Italy and joined relatives in the United States.
Capecchi received his bachelor of science degree in chemistry and physics from Antioch College in 1961, then went on to earn his doctorate in biophysics from Harvard University in 1967.
At Harvard, Capecchi studied under James D. Watson, the genetics giant who shared a Nobel Prize with Francis Crick for discovering the structure of DNA. Watson was impressed by the young graduate student.
"James Watson said Mario had accomplished as much in his graduate career as most people would accomplish in their entire scientific careers," says Geoff Wahl, a professor at the Salk Institute in La Jolla, California. "And Mario went on from there."
Went on, indeed. Capecchi's gene-targeting discovery in the early 1980s was made without support from the National Institutes of Health, which initially refused to fund his research and labeled the idea "not worthy of pursuit." Unfazed, Capecchi persisted, and eventually convinced the NIH and others of its merit.
Wahl, who was a graduate student of Capecchi's in the early 1970s, said Capecchi taught him the importance of this dogged persistence, of never giving up. Capecchi also taught him to "think the hard thoughts" and not simply follow what everyone else is doing. And Capecchi taught his student to think big.
"'Don't think in incremental changes, make the big change,'" Wahl recalls the advice. Or, as Capecchi explains it, "You can ask trivial questions and you'll get answers, but they'll be trivial answers."
While Capecchi lives by this "Think Big" credo, he also knows there is a fine line between cutting-edge science and over-the-edge science fiction. Scientists must ask the right questions, and ask them in the right way.
"I can ask a lot of questions that are not approachable, and that doesn't do any good," he says. The key is asking significant questions in such a way that one gains the tools with which to approach them, and yet they'll provide significant answers.
Hughes also worked under Capecchi's tutelage in the early 1970s. He considers Capecchi to be not only a gifted scientist, but a wonderful teacher and mentor.
"It's fair to say I learned how to do science from Mario," Hughes says. "He stressed science as a process, not as a collection of facts. He taught me the art of doing experiments."
One of Capecchi's greatest strengths, says Hughes, is his preparation.
"He thought about problems very hard before he sat down to pick up a pipette," Hughes says. "He did not rush blindly into a problem. Before the first experiment was done, he had thought intently about it."
And then, when Capecchi finally performed the actual experiment, it was with singleness of purpose. Hughes, who has worked with some of the top scientists in the country, calls Capecchi the hardest working person he's ever seen in a laboratory.
"The man was a maniac in the lab," Hughes says. "He'd lock himself in the micro-injection room for eight, ten hours at a time and only come out to answer the call of nature."
That hard work has not gone unnoticed. Capecchi has been at the University of Utah for 25 years, and during that time he has won his share of awards. Some of his more recent accolades include being a co-recipient of the $100,000 Alfred P. Sloan Jr. Prize for Outstanding Basic Science Contributions to Cancer Research in 1994, and, in 1996, receiving Japan's highest award, the Kyoto Prize, for lifetime achievement in the betterment of humanity.
This past June, Capecchi won the U's top award, the 1998 Rosenblatt Prize, a $40,000 award presented annually to one faculty or staff member who displays excellence in his or her work. In announcing the award, U President Bernie Machen praised Capecchi's "years of selfless service, both to the University and the world community" and said that "his work not just as a researcher, but an educator as well epitomizes what the Rosenblatt Prize has come to represent."
So where does this renowned researcher come down on the age-old question of nature versus nurture? Is it our genes or our environment that shapes us? Capecchi says it's a combination of both although, being a good geneticist, he particularly stresses the genetic side. While it's easy to see the genetic component in our physical characteristics, like eye or hair color, Capecchi says it's important to note that many of our behaviors are genetic as well our fears, our reactions, our likes and dislikes. All these are embedded in our genes.
"The end goal what it's all going to come down to is it's going to change medicine enormously."
"It comes up over and over again, in all sorts of traits," he says. "Even attributes that we think are very complex, such as political preferences, those kinds of things have a strong genetic component."
The strength of that component, however, is difficult to quantify. With laboratory mice, which offer uniform genetic and environmental backgrounds, the task of identifying genetic biases is fairly simple. With humans, whose varied life experiences are rarely conducive to tightly controlled experiments, it's more difficult.
Still, data is trickling in. Capecchi notes that some of the more interesting human genetic studies come from comparison of identical twins separated since birth. One study followed such a pair of 30-year-old twins, who were living on opposite coasts. Capecchi says the similarities between the two were uncanny. Both lived near the ocean. Both wore identical swimming suits. Both, upon wading into the ocean, would turn their backs into the waves, rather than face forward.
Such studies are beginning to hint at the vast similarities among humans caused primarily by genetics. Many of us have assumed we entered this life on a fairly even genetic playing field.
"No, not at all," Capecchi says with a smile. "Particularly when you get into very complex traits, like intelligence. There are many, many genes involved here. We have to take what we're given; unfortunately, we can't choose our parents."
One of the reasons Capecchi is drawn to genetics is the sheer randomness of the science. In biology, he explains, "things just happen. And if a biological solution works, nature will take advantage of it."
That's not to say biology is completely unpredictable. While it is very random, Capecchi says some underlying rules do exist. He likens genetics to an extremely complicated, fascinating game. At this point in the genetic game, Capecchi says scientists can manipulate the playing pieces, but they still don't know all the rules.
"We can change the DNA in any way that we want; there's no problem with that," he says. "But the problem is knowing how to change it. And the only way to do that is to slowly keep changing things and then ask, 'What happened?'"
It's like trying to open a safe without knowing the combination; the safecracker just starts trying numbers. Only in the case of genetics, you're dealing with about 100,000 numbers, which is roughly the number of human genes scientists are trying to catalog.
As daunting as this task sounds, the combination to the safe is actually beginning to materialize, thanks to programs like the U.S. Human Genome Project. Researchers worldwide are in the process of cataloging the full complement of human genes, creating a library of genetic information that can be used by scientists to speed up their own research.
Ultimately, the goal in genetics research is to be able to control the three major aspects of human genes: space, time, and amplitude. Scientists are just now gaining control of genetic space; that is, understanding which genes affect which functions in the body. Much of the current research is devoted to inactivating various genes, and then asking what the consequences are.
"So, for example, if we remove a gene and the little finger disappears, we know we're in the area of genes that is important for making that little finger," Capecchi says. "It doesn't tell us how the gene makes the little finger, but we know that at least we're in the right area for telling us those kinds of questions."
Then scientists can begin to modulate the genes to change the results in a predictable way.
"'Can we make the finger shorter or longer?' 'Can we add digits to the hand?' and so forth," he says. "And if we can do it in a predictable way, then we can start thinking that we understand the process."
The next step for genetics researchers, one they're beginning to study, is the timing in genes. For example, Capecchi and his colleagues would like to be able to inactivate a gene at a particular time during development, even in the adult mouse, to see what the consequences are. The idea, he says, is to gain temporal control of our genes.
And the final area of research, Capecchi says, is amplitude. It's like a volume control. Rather than simply turning a gene on or off, scientists want to see if they can turn it up or down just a bit, and then observe the results.
Capecchi heads a group of researchers who have been with him for years, plus, at any one time, five or six graduate students and 10 to 12 postdoctoral fellows. The graduate students come from all over the country, the fellows from all over the world. Capecchi says he likes his research group to be as diverse as possible representing many different backgrounds, geographical areas, scientific and technological disciplines because the mix makes for better research.
"This way, people come into the group having different perspectives; they bring in with them different ideas and technologies," he says.
Carol Lenz, who hails from Ireland, has been a research technician in Capecchi's lab for 11 years. She testifies to the diversity in the Capecchi research group. "One time I remember looking around at a lab meeting and seeing seven nationalities represented," Lenz recalls. She describes Capecchi as a quiet, humble man who "thinks the big thoughts." She says her boss is particularly adept at managing his diverse group of researchers.
"He hires people who are good at their jobs, and then trusts us to get the job done," she notes. "We hardly ever see him. But at the same time he's very approachable."
Capecchi's one regret over the past few years is that his increasing administrative responsibilities have taken him further from the actual game of genetic discovery. He's hoping to get back into direct experimentation in the coming months.
"I'm trying to be on fewer committees and get back into the lab," he says. "That's really the fun part."
If all goes according to his plan, Mario Capecchi will return to the lab to advance the science of genetics. He knows that conspiracy-mongers will continue to fear the work that he and his colleagues do. And he challenges research scientists to communicate their goals more effectively. Capecchi says, "It's not that there's something scary going on here" with genetics research; scientists simply need to do a better job of articulating their purpose. In addition, Capecchi would like to see more people involved in the decision-making processes surrounding new research and technology.
He's confident the concerns with genetics can be resolved. "Nobody's going to do something evil because they're truly doing something evil," he says. "They may do something bad because they are ignorant, or possibly greedy."
Yet despite that possibility, Capecchi sees an "enormous amount of benefit" from his and others' genetic research.
"I always feel that through knowledge, by increasing our information base, that in itself should be a good thing," Capecchi says. "But then, we also have to gain the wisdom to use it effectively. And this should be a collective wisdom involving scientists and non-scientists alike."
It is through this collective wisdom that Capecchi believes society will advance its understanding of the value of genetic research. And when that comes to pass, we'll take our place beside Capecchi and his colleagues, co-conspirators in the plot against human disease.
Mark Saal BA'84, science and technology writer in the University News Service, returned to the U after 13 years reporting for the Standard-Examiner.
Copyright 1999 by The University of Utah Alumni Association