As a teenager at Del Campo High School, Michael Shepard said, he loved biology but hadn’t an inkling then that he would one day make discoveries and inventions that would save the lives of millions of women diagnosed with breast cancer.
“I didn’t know I was going to do that kind of stuff until after high school. I really liked biology, and I did really well in it,” Shepard told about a dozen Del Campo students. “My favorite things when I was here were the swimming team, and then cross-country running.”
But that was before biotech company Genentech entered the picture – and Shepard wound up as a leader on a scientific team that figured out a strategy to directly target malignant tumors and developed a groundbreaking drug therapy known as Herceptin to quash the tumors’ runaway growth.
Earlier this month, Shepard claimed one of the world’s highest honors in medical research, the Lasker-DeBakey Clinical Medical Research Award. Often called America’s Nobels, Lasker awards have gone to almost 90 scientists who later received Nobel Prizes.
Less than two weeks after rubbing elbows with other luminaries in the science world, Shepard arrived in Sacramento for his Friday evening induction into the San Juan Education Foundation’s Hall of Fame. The day before this ceremony, he walked onto the Fair Oaks high school campus with a backpack slung over his shoulder and talked with students about how he pioneered a drug therapy that some very smart people told him was impossible.
“Genentech had issued me a ticket to do research, so I thought, ‘OK, I’m going to figure out a way to kill cancer without poisoning the patient,’” Shepard said. “Nobody could tell me how to go from where I was at to where I was going to go because nobody had ever done it before. So, we started looking at what made tumor cells resistant to the immune system. We discovered that there was a kind of an enzyme that does it.”
That enzyme was attached to a cancer-causing gene discovered by Axel Ullrich, one of the other two scientists who shared the Lasker-DeBakey with Shepard. Ullrich and another Genentech scientist, Arthur Levinson, identified the so-called HER2 gene in 1985.
Ullrich later connected with UCLA oncologist, Dr. Dennis Slamon, who had a library of human tumors. Slamon and Ullrich analyzed the breast cancer samples from the library and discovered roughly 30 percent of 189 breast cancer samples contained more than one copy of the HER2 gene. More importantly, medical records for women who had tumors with multiple copies of the HER2 gene were more likely to relapse quicker and die sooner than women whose tumors had only one copy of the gene. Slamon also shared in this year’s Lasker-DeBakey honor.
But could these scientists prove that an overabundance of the HER2 gene actually caused breast cancer?
Ullrich was able to engineer some cells from mice into producing extra HER2 protein, and once inside the cells, it kept dividing and producing more of the protein, even in conditions where it should have stopped. This was a sign of cancer. They took the next step, injecting the cells with HER2 into mice, and malignant tumors formed in their lab subjects.
Around the same time, Ullrich and Shepard came together on their separate findings: HER2 responsible not only for rampant tumor growth but also for the tumors’ incredible resistance to the body’s immune response. The two men began to look for ways to get HER2 to turn on itself. What if they could develop a compound to bind to HER2, something that would make the protein vulnerable?
“All we did was make an antibody that would turn off the HER2 gene, just as if it was a bacteria,” Shepard said.
In reality, it was a bit more complicated than that, Shepard quickly added: They had been working with mice, whose antibodies were not ideal for humans.
Scientists weren’t developing drugs in this way at that time, Shepard told the Del Campo students. A decade later, in 1998, when Genentech finally received approval to produce Herceptin, the U.S. Food and Drug Administration had to figure out how to control the manufacturing process.
Sometimes, Shepard said, you’re going to know where you want to go, but you’re not going to know how to make something work. You will spend a day at a time, a week at a time, a month at a time, figuring it out, he said.
“There were people who definitely didn’t think it would work, or they thought I’d done this experiment wrong or I didn’t spend enough time working on some other aspect of it,” Shepard said. “They were probably all right, but … once you know in your heart that something is going to work, you can’t go working on all kinds of other things. You have to go find out if it’s going to work. So we were pretty focused.”
When faced with challenges and second-guessing, Shepard said, people need cheering sections. He learned that at the end of his freshman year at the University of California, Davis – a college so good, he said, he was surprised he had managed to land a spot there. As his first year ended, he headed to a meeting with his academic adviser.
“I go into his office, and he’s looking at this folder, which I assume has something to do with me,” Shepard said. “Then he looks at me and says, ‘I don’t know why they let you in here. You didn’t have the grades. I don’t know if you belong here.’”
A defeated Shepard fled the room, heading back to his dormitory.
“Thank God I was living in a dormitory,” Shepard said. “I told the people there what just had happened, my friends in the dorm, and they just said, ‘Aww, don’t listen to that guy. Don’t listen to him.’ I did listen to him, but after talking to my friends, I got mad instead of being crushed. … And, my GPA really went up. It went up a huge amount.”
Shepard said he learned to be a cheerleader for others and to gather cheerleaders around himself. He also found grit and tenacity and aptitude inside him, he said – all qualities that would come in handy as some of the brightest minds in the nation and at Genentech questioned the course he was taking.
“There was a professor at MIT (Massachusetts Institute of Technology) who had done a lot of work making mathematical models of why tumors are resistant to cancers, why drugs don’t work in cancer, stuff like that,” Shepard recalled, “and he had convinced my senior colleagues at Genentech that there was really no way that an antibody, which is a fairly large molecule, could ever get into a tumor, and he had good reason for that.”
Fortunately, though, one person in senior management at Genentech was a believer, and he had $3 million in his budget for research. That would have to be enough for them to overcome this question, he told Shepard.
“We made an FDA-approved mouse antibody,” Shepard said. “We had this on hand before we engineered it into a human antibody. We spent that $3 million making it, and then we took it down from Genentech to UCLA. We went down into the basement of UCLA and labeled it with radioactivity, and then we injected it into patients. Dr. Slamon at UCLA injected it into patients who had tumors that made a lot of these HER2 protein that the antibodies would stick to.”
Then they X-rayed the patients, Shepard said, and they could see that the antibodies had localized only where there was a tumor with multiple copies of the HER2 protein. The only one way that could happen, he said, would be if the antibody had gotten inside the tumor.
Shepard didn’t recall the year this happened, but he did recall that the month was November. The Genentech management committee would convene in January to determine which drug therapies held enough promise for investment in research, he said, and Shepard and his team knew that only a few concepts would be approved. He and his colleagues felt certain that if they went to the committee with a mouse antibody, it would not be enough, he said.
“After we got the results of that study, from our colleague Dennis Slamon at UCLA, we all went and we worked from Thanksgiving all the way past the first of the year,” Shepard said, “and we were able to clone the mouse antibody and turn it into a human antibody and show that the human antibody worked.”
Shepard said his project team wanted to make it impossible for management to say no.
“We’d done things nobody had ever done before,” Shepard said. “This localization experiment, and then we cloned the mouse antibody, made it into a humanized antibody and showed that it worked, and we did it all in about four weeks. So they said ‘OK, we’ll go ahead and do it.’ But it’s important to remember that was just the beginning. There was still another $500 million that went into the project before it came out the other side.”
People are forever telling Shepard how good he should feel that he made Herceptin, that it’s been used to treat more than 2 million women, he said.
“If you go back and you think about it the way a scientist does, you’re really only helping less than 25 percent of breast cancer patients, Shepard said. “So, for me, that glass has never been half-full. There are 75 percent of breast cancer patients that we can still do something for, if we can figure out how, and then there’s all the other sorts of cancer.”
Shepard, now 70, has continued to work on finding cures for cancer. He said he’s been particularly focused on kidney and ovarian cancers because, by the time people experience symptoms, it often is too late to successfully treat those tumors.
He said he also visits high schools and colleges to convey a message to potential scientists of tomorrow: “The only reason this happened, the good part of it happened, is because there were people that I worked with at Genentech, for the most part, but they were also at UCLA, who were willing to go beyond what anybody had ever tried before. … It’s a good idea to think like that. Nobody can do it unless there’s at least one person who’s there to say, ‘Look, I’ve got this idea.’”