"It's all about Aunt Millie"

"It's all about saving Aunt Millie"
Bob Swanson
Co-Founder of Genentech

I just learned today that Jim DeKloe, who wrote this post as a guest author a few years ago is giving a webinar on May 11th on protein purification from industrial enzymes to cancer therapy.

Jim's webinar, offered through Bio-Rad, has two sessions at 3 pm Eastern and 7 pm Eastern. Registration is free and you can register HERE.

Jim is one of the most inspirational educators I know and he's the sort of person that reminds you why educating students about biotechnology careers is important. His moving story is one that always reminds me that there's more to biotechnology than just the science.

One of those is Jim deKloe. A long-time instructor at Solano Community College, Jim is an amazing individual and an accomplished educator. Full of humor and energy, when I first met him, it was shock to see Jim a few years later, when the ordeal (described below) was recent and the pain was fresh.

No one can tell his story like Jim, so with Jim's permission, I invite you to read on.

My Story

By Jim deKloe

I couldn't have written this story as a script for Hollywood. No one would have believed it.

It was the Sunday morning after Thanksgiving, and my 4-year-old son, Jefferson, woke up at 5:30 with a 102-degree fever. He was fine the night before, even a little hyper in his happy-go-lucky way. He was sleeping in our bed and we did notice that he had some fever during the night, but Motrin easily brought it down.

Then morning came, and the fever persisted.

"Should we take him to the emergency room?" my wife, Laura, asked me that Sunday morning.

"I don't know," I answered. "Trust your instincts, what do your instincts say?"

"My instincts say take him in," she said. "He just doesn't look right."

Kids get fevers of 102 degrees often, and you don't want the triage officer at the emergency room to think you're a hypochondriac. But in this case, he didn't look right. His complexion was ashen. He spoke, but didn't make sense.

We decided to take him to the ER. Had we hesitated, he would have been dead within hours.

Staring into the abyss
It was a move that marked the beginning of a walk through darkness for my family, with days spent staring into the abyss. Jeff hung near death, infected with a deadly bacterium until a miracle drug developed by Genentech brought him back to us. A few years earlier I had helped make the drug for Genentech, which helped convince me it might work for Jeff.

NorthBay Medical Center emergency room staff took the fever seriously and administered antibiotics. Jeff went in and out of consciousness. Laura pointed out a small rash on his chest to the doctor on duty, Dr. William Peterson. He immediately ordered a helicopter to airlift Jeff to Oakland Children's' Hospital. Had he not done that, Jeff would have died.

Jeff had meningococcemia, an infection where bacteria enter the bloodstream. It's due to the same bacterium that's responsible for meningitis, but in this disease the bacterium jumps into the blood rather than into the fluid surrounding the spine. Textbooks report that it has a mortality rate of somewhere between 50 and 80 percent (with death often occurring within hours of outset).

Jeff's grandfather, a pediatrician in practice for 40 years, had not heard of any kids surviving this. When he got the call with the diagnosis that afternoon, he drove from Orange County to Oakland. He assumed he was driving to his grandson's funeral.

The bloodstream is one of the only places on the planet that is bacteria-free. There are live bacteria atop the highest mountains, in the deepest part of the ocean, in volcanic hot springs, and in Antarctic snow banks. If there are bacteria in the blood, a condition called septicemia, it is always life threatening. And these particular bacteria are bad news.

Antibiotics kill them easily, but that's when the real trouble begins.
When you treat them with antibiotics, you go from the frying pan into the fire. You've got to do it; you can't stay in the frying pan. As the bacteria die, they throw a component of their outer membrane into the bloodstream. This is called endotoxin, and it has a couple of dramatic and awful effects.

It isn't that the molecule itself is toxic, but it triggers the immune system to go wild. It induces shock and blood pressure crashes. Science writer Lewis Thomas describes the immune system as containing munitions and this condition as an explosion in the munitions factory.

'Your son is very sick - prepare yourself'
As Jeff was airlifted, his blood pressure crashed. The helicopter paramedic team from REACH, and the Intensive Care Unit at Oakland, set up an IV, began fluids and started epinephrine (adrenaline) that props up blood pressure. The intravenous fluids also boost the blood pressure as fluids leak out of the blood vessels into the surrounding tissues.

Jeff had a net gain of 5 liters of liquid on that first day - more than 10 pounds. And this in a boy who doesn't even weigh 40 pounds - a 25 percent gain in weight. Jeff had the fulminate form of this disease, which means that his blood began to clot.

The rash that Dr. Peterson saw was the beginning of the clotting process. The broken down pieces of bacteria trigger clotting. And they clot everywhere. The condition is called DIC, diffuse intracapillary coagulation. The clotting spread to Jeff's head, and down his body. By the time he reached the hospital's intensive care unit, his body looked like it had been taken to the top of Everest and rolled down to sea level. By the time we reached Oakland, a social worker met us. He said, "Your son is very sick - prepare yourself."

Dr. Vivian Newman and her colleagues were in a flurry of activity over Jeff's purple body on the table.

"First we'll try to save his life, then we'll worry about saving limbs," she told us. And then she said, "We would like to try something experimental. We've tried it once before. It has some risks and we would need informed consent. I would like our hematologist to discuss it with you."

By the time I saw Jeff, the clotting DIC had already spread everywhere. He was purple with bruises from head to tail, except for the ends of his fingers and toes which were beginning to look like they where black with dying flesh. We were in big trouble.

'Yes, I know the risks," I said. "Do it."

Dr. Singer, the hematologist, poked her head in and told me, "we would like to try a thrombolytic agent."

"tPA?" I asked.

"Yes," she said. "You know it?"

"It's a Genentech product. I spent my sabbatical in the department where it is made."

Tissue Plasminogen Activator is an enzyme that dissolves blood clots.
For the past three years I have been working with Genentech to develop a program to train technicians to manufacture this drug and others. In this program, we use tPA, or Activase, as a case study to represent how a typical biotech product comes to market. We discuss tPA's discovery, research and development, economics of production, marketing, effectiveness in treating the diseases for which it was approved, and the risks of using it.

I had never heard about anyone using tPA to treat meningococcemia or DIC. No one at Genentech had either. It seemed at the time to be logical - that an enzyme that digests blood clots would be a good treatment for a boy who had blood clots choking all of his blood vessels, but the staff at Children's were pioneering this new application.

The law on a new use for a drug is well-defined. The law wisely gives physicians wide discretion to use a drug in a way that isn't formally approved by the Food and Drug Administration, as long as they receive informed consent. In this case, tPA is approved to treat heart attack and stroke, where it digests the blood clots that block the coronary artery in the heart or the blood vessels in the brain. It made intellectual sense that an enzyme that digests blood clots could help Jeff, whose entire body was filled with blood clots. But would it work?

"Should we go ahead?" Dr. Singer asked. "There are risks."

"Yes, I know the risks," I said. "Do it."

I calculated that they would be the same as the risks in administering tPA to stroke victims. If there are any small holes in the blood vessels in the brain, the patient dies from bleeding. With the tPA digesting blood clots, there are no clots to seal any hole. It was a bit worse in this case since all of the clotting in Jeff's body had used up all of the clotting factors. I calculated that the blood vessels in the brain of 4-year-old would be intact.

A Medical Miracle
They gave him some platelets and blood, and then started the tPA infusion which would drip in over a 4-hour period. In a little while, the purple visibly had started to clear. The clearing wasn't instantaneous; it was more like clockwork. You couldn't see it clear, but if you looked away from his body, by the time you looked back, the color seemed lighter. A second four-hour treatment improved the condition even more. His brain blood vessels held, and there seemed to be no complications.

Amputations are a big problem with this disease, since the clots that it produces cut off blood flow to the limbs. Several of the workers in Oakland's rehabilitation unit told me "I've had five or six kids who survived this, but I've never seen one who didn't have at least one limb amputated.

Many children lose all of their limbs.
Dr. Newman was watching Jeff's right leg. On day two she said, "This limb is compromised." It was turning purple and cold. She ordered one last round of tPA. Although this third treatment didn't produce results quite as dramatic as the first two, it began to work immediately. The border of the purple area on the foot began to recede, and a star of white pushed into the area.

The cold areas began to feel warmer. His leg was saved. I had prepared myself mentally that he would lose the fingers on his right hand and his right leg, at least below the knee. A medical miracle saved them.

With life and limbs restored, the next question arose: "Is there any brain damage?" We would have to wait until they stopped the intravenous drugs and brought him around. A week on his back had caused fluid to pool in his lungs. They stopped the drugs, pulled out the respirator tubes, and began to suction out the fluids. In the middle of a suction treatment, Jeff opened his eyes, looked at the nurse, and said "Stop it" and "do this to my brother." Since I believe that sibling rivalry represents higher brain function, I then knew that he would be all right.

Jeff remains hospitalized, recuperating from some skin damage on his leg that the temporary loss of blood produced. These areas of skin damage will need grafting, and he has some muscle and neurological damage to his legs.

Mentally he's as sharp as ever; sharp enough to correct me on my Pokemon misidentifications. It will take a bit of time and physical therapy to know how well he can heal - but I haven't forgotten where we were two months ago.

A series of fortunate events all broke our way. We took him in. The bacterium wasn't an antibiotic resistant strain. The NorthBay emergency room staff recognized that the disease was serious enough to order an airlift. The staff at Oakland was familiar with tPA and willing to pioneer a new technique. That particular staff happened to be on duty.

The drug they chose turned out to be the drug that I knew the most about, so I could give a quick approval. The helicopter pad had been closed and only recently reopened. And it all worked.

No one knows how children get this killer bacterium. A significant number of people carry it in the back of their throats with no ill effect. For a reason that isn't clear, in a few it jumps into the bloodstream to cause this deadly disease.

Until recently, the shock produced by this disease killed most of the children who contracted it. The blood clots of the DIC condition make it even worse.

In his four decades of medical practice, my father-in-law had never seen a child with this condition survive. New developments in critical care techniques allow physicians to give the kids a fighting chance.

The pioneering use of tPA by Oakland Children's' Hospital prevented disaster in this case. It isn't hyperbole to call this event a medical miracle.

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