Science begins at home
Overcome with nausea from chemotherapy, Mary Davis distracted herself by studying each leaf on the trees swaying outside her hospital window.
She turned them over in her mind, mentally tracing their edges and veins. The trick worked for a while. But the wrenching sickness always returned, making her feel powerless against her breast cancer and the drugs that were supposed to cure her.
Adriamycin, known to patients as the “red death” because of its color and toxicity, had brought days of vomiting and weakness. Her hair fell out in bunches. Now, cisplatin was destroying her immune system and leaving her with a constant ringing in her ears.
Her husband, Mark, a professor of chemical engineering at Caltech, could not get used to her suffering, or that he could do nothing about it. He kept vigil at her side, rotating the recordings of classical music that helped soothe her.
As Mary struggled with the side effects of chemotherapy, she blurted one winter day in frustration: Wasn’t there someone at Caltech capable of designing a less ravaging drug?
It was less a question than a plea.
Mark didn’t have an answer. Cancer wasn’t his field, and he knew nothing of the science involved -- but he soon would.
Mary Davis was home in Pasadena, dressing for work. It was 1995, and she was starting a job as a business manager at Caltech, her first since giving birth to twins, Andrew and Christopher, 3 1/2 years earlier.
A lump under her armpit stopped her.
Cancer seemed unimaginable. She was 36 and fit, a former swimming instructor who still worked out. Besides, people in her family didn’t get the disease.
Her doctors acted quickly, removing her right breast. Her adjacent lymph nodes, eight of which were cancerous, had to be cut out as well.
That was just the start. Concerned that her lymphatic system might have carried cancer to another part of her body, her doctor recommended aggressive chemotherapy to prevent her disease from returning.
Although chemotherapy has been a mainstay of cancer treatment for decades, it is still a crude weapon, akin to using a bulldozer to pluck a dandelion.
The drugs throw wrenches in the molecular machinery that causes cells to divide. Because cancer cells are continually dividing, they are susceptible to the medicines.
But the drugs also attack normal cells that frequently replicate -- those found in blood, hair, finger nails, reproductive organs, the immune system and the digestive tract’s lining.
The side effects are so severe that doctors must strike a balance between destroying the cancer and killing the patient.
Mary and Mark saw no other choice. “You don’t get a second chance with cancer,” he said.
Her fatigue from the drugs lasted weeks, worse than she had imagined. She told Mark that on some days it took all her energy to lie on the couch and watch their sons play with Lego blocks on the floor.
Her final treatment of high-dose cisplatin was followed by a bone marrow transplant to restore damaged tissue. Mark spent every day at her bedside at City of Hope in Duarte, wearing a surgical mask to protect her from infection. Their daughter, Erica, and the twins had to speak to Mary from the hallway using walkie-talkies, a glass pane separating them.
Mary confided that sometimes she wanted to die, until she thought of them.
--
Mary’s question that winter day had unsettled Mark.
He had never thought about cancer research but felt he couldn’t let Mary down. He started collecting stacks of scientific papers from the hospital’s medical library to read in her room.
He wasn’t sure what he was looking for, and logic told him he was not likely to think of something that had not been considered by scientists who had devoted their careers to cancer. Sometimes he would get an idea, only to discover that it had been knocked down decades before.
But he kept at it. He thought of himself as a problem solver. Like many scientists who had risen to the top, he was brilliant, driven and, some might say, obsessive.
Growing up in the early 1970s in northwestern Pennsylvania, Mark was the sort of mediocre high school student Caltech rejects in droves.
His passion was running. On winter mornings, he would run in the paths left by snowplows, becoming one of the top high school sprinters in the country and earning a track scholarship to the University of Kentucky.
There, Mark discovered chemical engineering and quit the track team, figuring academia offered a better future. After earning his doctorate at Kentucky in 1981, he left to assume a teaching post at Virginia Tech, among the country’s top engineering schools.
One of Mark’s first seminars was on his hobby of underwater photography. A college senior, Mary was in the audience and loved his slides of coral reefs and fluorescent blue-and-yellow fish.
Here is a professor with a life, she thought.
The two of them kept bumping into each other at chemical engineering parties. A week after Mary graduated, Mark asked her for a date. When she went to visit family in Houston, he made up an excuse to go see her. A year later, they were married.
On weekends, the couple hiked in the Blue Ridge Mountains near campus. The outings always ended by early afternoon so Mark could spend the rest of the day in his lab.
As a young professor at Virginia Tech, Mark had begun to rise in the field of catalysis, the process of speeding chemical reactions.
In the early 1980s, the industry was looking for a specific tool -- a molecular sieve that could separate large molecules into smaller components.
It was thought such a tool would make it easier for petroleum refiners to “crack” heavy crude molecules into lighter gasoline. To work, the sieve needed pores of about 10 angstroms. (A human hair is about 1 million angstroms in diameter.)
Before tackling the problem, Mark gathered up every paper on the subject and spread them on the floor of their home, creating a maze that stretched from room to room.
Working with scientists from Virginia Tech and Dow Chemical Co., Mark in 1987 discovered a sieve with pores of 12 to 13 angstroms. The find energized the field and helped him win a National Science Foundation Award, which goes each year to the top U.S. scientist younger than 35.
He joined Caltech in 1991. Supported in part by deep-pocketed oil companies, Mark’s laboratory became one of the largest on campus and a world leader in catalysis research.
In the fall of 1996, Mark told the graduate researchers who had come to Caltech to work on solving big industrial problems that he had an entirely different project for them to consider.
--
His idea was simple.
Chemotherapy drugs, like most medicines, reach cells by slipping through narrow spaces in the walls of blood vessels that crisscross the body.
But all blood vessels are not alike.
The abnormal, leaky vessels that supply cancer cells have openings up to 100 times larger than those found in healthy vessels -- it’s like comparing a soccer ball with a Goodyear blimp.
In a way, this biological quirk was the reverse of the problem he faced in seeking a molecular petroleum sieve.
Instead of creating a mesh, he wanted to bulk medicines up so their molecules wouldn’t pass through the wall of normal blood vessels. At the same time, they needed to remain small enough to fit through pores of vessels feeding cancerous cells.
His idea was to link starch molecules to form a polymer that would flow through normal vessels -- and bypass healthy cells -- as it carried a drug to a tumor.
A harmless starch called cyclodextrin seemed to fit the bill.
Mark soon learned that the big starch molecule was notoriously hard to work with. It became slippery when mixed with solvents, and controlling chemical reactions using them was difficult. Mark recalled Robert Grubbs, a Caltech colleague and a Nobel laureate in chemistry, once asking him: Do you really want to work on this compound?
The cancer project was a bootstrap operation at first. Mark’s chemical engineering lab had none of the equipment needed for biology experiments. Suzie Hwang Pun recalled spending her first summer as one of Mark’s graduate students pushing a cart that served as her portable work space to biology labs on campus.
At one point, Mark asked Pun -- now an assistant professor at the University of Washington -- which immunology text she used in graduate school. He purchased it and devoured its contents.
To turn his invention into a commercial drug, Mark formed Insert Therapeutics Inc. in 2000 with $3 million from local investors. He became the company’s scientific advisor.
The couple stored boxes of scientific equipment in their garage until they found commercial lab space for the company near Caltech. Soon, a small staff of chemists was hard at work.
--
The big question for the researchers was what to put on the bulky polymer.
They worked for years trying to attach a gene that could stop cancer cells from dividing.
But money was draining from the company, and investors soured on the approach. Chances of getting added funds for the project were slim.
Just before Christmas 2001, Mark summoned company scientists into a conference room. The company was down to its last experiment before the money ran out, he told them.
They would prepare a small amount of drug and use it to treat cancer in mice, Mark said. If the mice’s conditions improved, they could take the results to investors.
“We’re going for the home run,” he recalls saying.
Instead of a gene, the polymer would deliver camptothecin, an old chemotherapy drug never approved for human use.
Camptothecin’s cancer-fighting properties were discovered in the 1950s, when federal scientists searching for new drugs mixed it with cancer cells in a laboratory dish.
The chemical created so much excitement that the government turned over federal land in Chico, Calif., to cultivate Camptotheca acuminata, the Chinese shrub from which camptothecin was derived.
When researchers tested camptothecin in cancer patients in the 1970s, however, the poorly soluble drug formed damaging crystals in patients’ kidneys.
Mark thought the easily soluble starch could fix that.
Mark worked all the time, arriving in his office at Caltech before dawn and working well into the night, breaking only for dinner at home. His students often found e-mails sent from Mark at 3 a.m.
Theresa Reineke, now an assistant professor at the University of Cincinnati, recalled feeling so overwhelmed by the workload that she asked Mark to help her set priorities. Which of her many assignments should she do first?
Everything, he shot back. If she wanted to be successful, she would have to learn to do everything at the same time.
He didn’t tell her the pace was wearing him down. Insert’s president had quit, leaving Mark to deal with the company’s troubles in addition to his scientific work. Mary thought he was becoming stressed and edgy, and she started having mixed feelings about setting the drug project in motion.
“There were so many balls in the air,” he said.
The task of getting the drug ready fell to chemist Jianjun Cheng, who was in touch with Mark five times a day.
“There was tremendous pressure to get it right,” said Cheng, now an assistant professor at the University of Illinois at Urbana-Champaign.
Cheng used a chemical linker to attach the camptothecins to the polymer. The result was a dry powder that, when mixed with water, assembled into particles that were just the right size.
The drug was delivered to an animal research facility, and within weeks, tumors in the mice started to shrink.
By the fall of 2002, they had the final results. Through the 140 days of the experiment, the tumors in the mice remained small. The result was better than seen in tests with irinotecan, an approved chemotherapy drug derived from camptothecin.
It was the home run they had all been hoping for.
--
Last summer, the company started testing its drug, IT-101, in people with terminal cancer.
Mark, having carried a mental picture of the moment for years, watched as the first patient, a man with pancreatic cancer, received his drug infusion.
In the trenches of science, however, discovery is rarely flawless.
The first five patients in the tests have seen mixed results. None of them had the severe side effects Mary experienced with her drugs, but two patients failed to benefit from the medicine, researchers reported in June. Cancer remained stable and did not progress in the remaining patients.
The trial is continuing, and Mark is working on other drugs at Caltech, having established a biology lab there.
Mary has been cancer-free since 1998, when she found a lump on her mastectomy scar and underwent six weeks of radiation therapy.
She worries about a recurrence and the chance that breast cancer might one day strike her daughter, Erica, now 18.
After her fight with cancer, Mary reorganized her life around car pools, Scout meetings and kids’ soccer games -- allowing Mark to focus on his cancer drug research, which she considers a joint effort.
“If you go through a life change and remember what you have been through, you want to make things better,” she said.
She wears a hearing aid now because of damage to her ears from chemotherapy. Recently, she developed osteoporosis, another side effect of the drugs.
--
