The Persistence of Pennica

“Sorry, Diane, you don’t have it,” said the sequencer as he put the papers down on Diane Pennica’s desk. She stared down blankly at the sheet in front of her. It had been the same story for months and she’d been working day and night on the project without a break. She was determined to prove her detractors wrong but this was bad. She needed a match. Then she saw it: Part of the sequence she had committed to memory. Shaking with excitement, she jumped up and announced to her team, “We’ve got it!”

Over the next few months, Pennica and her colleagues would succeed in cloning the full length gene of the blood clot-dissolving “tissue plasminogen activator” (tPA) enzyme and, in so doing, fundamentally change the treatment landscape for heart attacks, pulmonary embolisms, and strokes. It was an extraordinary scientific breakthrough, but one that might never have happened had it not been for the early encouragement of a biology professor, the mistake of a Swedish hotel clerk, and the persistence of Diane Pennica.

Drawn to Science

Encouraged by her parents, Pennica had originally set out to become a teacher. She attended the State University of New York in her hometown of Fredonia to major in education but had little enthusiasm for the subject. “I was so bored I couldn’t stand it,” she says. Fortunately, during her second year she took a biology course with Dr. Kevin Fox, and suddenly was hooked – going from a C to an A-grade student overnight. Fox recognized Pennica’s talent, inviting her to study the genetic causes of cystic fibrosis in his lab and persuading her to pursue a Ph.D. “Teaching was not for me,” Pennica says. “But a teacher changed my life.” By 1980, she was a 29-year-old post-doctoral researcher at Hoffmann-La Roche and soon after that was hired by Genentech as employee number 60.

Serendipity in Sweden

Less than a month into her new job in South San Francisco, Pennica was asked to attend a meeting in Sweden on fibrinolysis, the body’s natural process to prevent blood clots from causing problems. She arrived a day early and was told by a hotel clerk that the meeting had already begun. Thinking she had mixed up dates and was late, Pennica ran to a room where 30 scientists were listening to renowned researcher Désiré Collen describe how he’d used a protein purified from melanoma cells to dissolve a blood clot in a patient’s leg. It was a private pre-conference workshop that Pennica, the unknown junior scientist, was not invited to. But as female scientists were scarce back then, the room of men in suits simply assumed that the young woman in jeans and a T-shirt was one of the scientists’ daughters waiting for her dad. They let her stay.

Chris was given Activase after he suffered an acute ischemic stroke. Read more about Chris' experience.

Excited by the discussion and possibilities it presented, Pennica introduced herself at the break and was invited to dinner. That night she spoke with Collen, who in 1979 was the first to isolate and purify a sufficient quantity of tPA to learn about its important function in the body. The enormous clinical potential for the enzyme in dissolving heart attack-inducing blood clots had been well established by Collen and others. But nobody thought it would be possible to clone and express it in large enough quantities for it to be used in patients. According to Collen, at best it would be “overwhelmingly demanding” and at worst “totally impractical.”

In spite of all this, with a tremendous amount of confidence and more than a touch of naiveté, as she had never cloned anything before in her life, Pennica told Collen she believed she could do it. “For some reason the potential for failure never occurred to me,” she reflected later. “I didn’t know if it could be done or how to do it. I just said, ‘sure I can.’”

No protein that complex had been cloned before and many in the room were skeptical. One prominent scientist told Pennica, “If I thought it was worth doing or could be done, I would have cloned it years ago.” Undeterred, Pennica convinced Collen to work with Genentech as a consultant and share some of his reagents with her.

Laboring in the Lab

Pennica came back to Genentech and had to persuade co-founder Bob Swanson that she could take on what amounted to a second full-time job attempting to clone tPA. She worked 15-hour days, seven days a week for nearly two years. Structuring her days around bacteria growth, she would start at eight in the morning so that by 11 at night she could harvest them. “I just couldn’t wait to get to the lab,” she said. “I didn’t want to let anybody down because I told people I was going to do it. You just have to keep going and not give up. You don’t take weekends off. You don’t take nights off and I didn’t have a life, basically. But it was so exciting.”

When she finally saw the tPA sequence on the paper in front of her, she was justifiably elated. “It was such an incredible high,” says Pennica. “Science is 99 percent failure but the successes are so high, you get so excited. I can’t explain it. It’s amazing.” The scientific community shared her enthusiasm: In 1982, she was able to return triumphant to the very same conference in Europe and announce the cloning of the tPA gene where she received a standing ovation.

Diane Pennica in the lab in 1987. Photo courtesy of Terrence McCarthy.

Outside the Lab

In November 1987, Pennica’s breakthrough led to the Food and Drug Administration approval of Activase® (alteplase) Indication and Important Safety Information for the treatment of acute myocardial infarction or heart attacks after it was shown to dissolve blood clots obstructing coronary arteries, improve ventricular function, and reduce the incidence of congestive heart failure. Since then it has also been approved to treat acute ischemic strokes and acute massive pulmonary embolisms. The most frequent adverse reaction associated with Activase in all approved indications is bleeding. More than 2.25 million patients have received Activase since its approval and it remains the only medicine used for the treatment of strokes today.

What it Treats

Acute Ischemic Stroke

Activase (alteplase) is indicated for treating patients with acute ischemic stroke (sudden stroke), which is caused by a blood clot in the brain’s blood vessels. Patients can receive Activase only if they begin treatment within 3 hours after their stroke symptoms start and only after bleeding in the brain has been ruled out.

Acute Myocardial Infarction & Pulmonary Embolism

Activase (alteplase) is approved for treating an acute myocardial infarction, also known as a sudden heart attack. In patients whose heart attack puts them at low risk for death or heart failure, the benefit that comes from the use of Activase may be outweighed by the risk of stroke that Activase presents.

Activase (alteplase) is indicated to break apart an acute massive pulmonary embolism, which is a large blood clot lodged in the blood vessels of the lung. The pulmonary embolism must be severe enough to block blood flow to the lungs and cause an unsafe drop in blood pressure.

Important Safety Information

Important Safety Information – Acute Ischemic Stroke

Who should not take Activase?

Activase should not be used in patients who have: current bleeding in the brain; bleeding in the area between the brain and the thin tissues that cover the brain; active internal bleeding; recent (within 3 months) brain or spinal surgery or trauma; brain tumor, an abnormal connection between veins and arteries in the brain, or an abnormal bulge in the wall of an artery that supplies blood to the brain; problems with blood clotting; or current severe uncontrolled high blood pressure.

What are the possible serious side effects of Activase?

Bleeding: The most common side effect with Activase is bleeding. Some patients may or may not benefit from Activase because of an increased risk of bleeding, including those with the following conditions: recent major surgery; disease of blood vessels in the brain; recent bleeding in the brain; recent internal bleeding; recent trauma; uncontrolled high blood pressure; inflammation of the sac around the heart; infection of the inner lining of the heart and the heart valves; increased bleeding risk associated with liver or kidney problems; liver problems; pregnancy; bleeding in the eyes; swelling and infection associated with blood clots; elderly patients; patients on blood thinning drugs.

Allergic reaction (hypersensitivity): Allergic reactions including hives and severe or life-threatening allergic reactions can occur very quickly. Rare reports of death from severe allergic reactions have been reported. Swelling of the mouth and throat (angioedema) has been observed in patients treated for sudden stroke (acute ischemic stroke) and sudden heart attack (acute myocardial infarction). This occurred during and up to 2 hours after infusion of Activase. In many cases, patients were also taking angiotensin-converting enzyme inhibitors (a type of medication that can make blood vessels expand).

Migrated blood clot (thromboembolism): Drugs used to dissolve blood clots may be administered to patients with a high likelihood of a blood clot in the left chamber of the heart, such as patients with narrowing of a heart valve.

Cholesterol Embolization: A plug of cholesterol that blocks an artery (cholesterol embolism) has been reported rarely in patients treated with all types of clot dissolving agents. This is a serious condition, which can be lethal, and is also associated with invasive medical procedures involving the arteries and veins.

What is the most common side effect with Activase?

The most common side effect with Activase is bleeding.

Patients and their caregivers are encouraged to report side effects to Genentech and the FDA. They may contact Genentech by calling 1-888- 835- 2555. They may contact the FDA by visiting www.fda.gov/medwatch or calling 1-800-FDA-1088.

Please see accompanying full Prescribing Information for Activase for additional important safety information.


Important Safety Information – Acute Myocardial Infarction & Pulmonary Embolism

Who should not take Activase?

Activase should not be used in patients who have: active internal bleeding; history of recent stroke; recent (within 3 months) brain or spinal surgery or trauma; brain tumor, an abnormal connection between veins and arteries in the brain, or an abnormal bulge in the wall of an artery that supplies blood to the brain; problems with blood clotting; or current severe uncontrolled high blood pressure (hypertension).

What are the possible serious side effects of Activase?

Bleeding: The most common side effect with Activase is bleeding. Some patients may or may not benefit from Activase because of an increased risk of bleeding, including those with the following conditions: recent major surgery; disease of blood vessels in the brain; recent bleeding in the brain; recent internal bleeding; recent trauma; uncontrolled high blood pressure; inflammation of the sac around the heart; infection of the inner lining of the heart and the heart valves; tightening of blood vessels associated with liver or kidney problems; liver problems; pregnancy; bleeding in the eyes; blood clots; elderly patients; patients on blood thinning drugs.

Allergic reaction (hypersensitivity): Allergic reactions including hives and severe or life-threatening allergic reactions can occur very quickly. Rare reports of death from severe allergic reactions have been reported. Swelling of the mouth and throat (angioedema) has been observed in patients treated for sudden stroke (acute ischemic stroke) and sudden heart attack (acute myocardial infarction). This occurred during and up to 2 hours after infusion of Activase. In many cases, patients were also taking angiotensin-converting enzyme inhibitors (a type of medication that can make blood vessels expand).

Migrated blood clot (thromboembolism): Drugs used to dissolve blood clots may be administered to patients with a high likelihood of a blood clot in the left chamber of the heart, such as patients with narrowing of a heart valve or types of irregular heartbeat. Activase has not been shown to treat adequately underlying blood clots that form deep inside the body (mainly in the leg) in patients with PE. There is a risk of blood clots dislodging, traveling to the lung, and stopping blood flow to the lungs.

Cholesterol Embolization: A plug of cholesterol that blocks an artery (cholesterol embolism) has been reported rarely in patients treated with all types of clot dissolving agents. This is a serious condition, which can be lethal, and is also associated with invasive medical procedures involving the arteries and veins.

What is the most common side effect with Activase?

The most common side effect with Activase is bleeding.

Patients and their caregivers are encouraged to report side effects to Genentech and the FDA. They may contact Genentech by calling 1-888- 835- 2555. They may contact the FDA by visiting www.fda.gov/medwatch or calling 1-800-FDA-1088.

Please see accompanying full Prescribing Information for Activase for additional important safety information.