David's First Book Review: The Immortal Life of Henrietta Lacks

I've discovered reading again.  Or maybe what I've done is made a conscious decision to set aside time to read.  Some books I've recently read have nothing to do with cancer, like Cloud Atlas.  Then there's The Immortal Life of Henrietta Lacks.

Rebecca Skloot did a marvelous job telling the story of Henrietta Lacks, a woman from Baltimore whose cervical cancer cells became the very first immortalized cell line.  I think this book is a "must read" for anyone engaged in cancer research, if for no other reason than it reminds us that every cell line we work with was once a tumor growing in an individual... a person who had a family and friends, a person who suffered and probably died of cancer.  Each of these people has a story, and knowing that story can inspire us to work harder to find better treatments with fewer side effects.

But aside from the human interest angle, the book is an interesting study in the evolution of medical ethics.  When Mrs. Lacks was treated, in 1951, there was nothing "unethical" about taking some of the cells that were removed from her during the course of her treatment and trying to grow them in the lab.  She did not give informed consent for her cells to be cultured, but the very concept was not a part of medical research at the time.

Times have changed.  Just last week I was getting informed consent from a woman one of whose children was going to donate bone marrow to another.  Our cancer center has a "leukemia bank," a freezer full of bone marrow removed from patients with leukemia, frozen away for future research.  As I explained to her, it can be hard to tell what is abnormal about the leukemia cells if we don't have normal cells to compare them to.  So we ask each normal bone marrow donor to allow us to freeze a teaspoon or so of marrow for comparison studies.  In order to do this, we have to get approval from an Institutional Review Board and the donor (or the donor's guardian, in the case of a minor) has to sign a statement asserting that he or she consents to having this normal marrow stored away.

And that is just to STORE the marrow.  If we want to use the marrow for research, we have to get approval from the Institutional Review Board for the research project and use the marrow anonymously.  If we need clinical information about the marrow donor (or the leukemia donor), we need to either track that person down and get informed consent for the specific experiment or we have to convince the Institutional Review Board that doing so would be an undue burden (if, for example, the patient has subsequently died or has left no contact information or the study will involved hundreds of samples and the data will be used anonymously).

None of these safeguards were in place in the 1950's.

Another fascinating question raised by Ms. Skloot is the question of intellectual property and a patient's rights to his or her own tumor.  Ms. Skloot contrasts Mrs. Lacks, whose family received nothing in exchange for her cells (although, to be fair, neither Johns Hopkins nor Dr. Gey, the man who cultured her cells, received any money for her cells, either.... they were distributed freely to any interested lab anywhere in the world), with Ted Slavin and John Moore.  Mr. Slavin was a man with hemophilia who sold his serum because it had extremely high levels of antibody against Hepatitis B and then supplied serum to Baruch Blumberg, a virologist who discovered the link between Hepatitis B and liver cancer and created the first vaccine against Hepatitis B.  Mr. Moore's spleen was removed as treatment for Hairy Cell Leukemia, and his physician grew a cell line from the spleen, which he then patented and licensed to biotechnology companies to "commercially develop."  In each of these cases, something of value was taken from a patient, sometimes with their knowledge and consent, sometimes not.  In each case, the material contributed to the development of the nascent biotechnology industry, eventually being used to generate profit.

I would love to hear my readers' thoughts on the ethics of these situations.  After all, it seems wrong for someone to profit from cells taken from my body, but the cells are not inherently valuable... it's how they are used that is valuable.  Without intellectual input from a scientist, they are just cells.  But does this mean that, as the California Supreme Court ruled, I don't have any right to profits generated from tissues removed from my body?

One final note:  Ms. Skloot speaks eloquently about how Mrs. Lacks was treated by Johns Hopkins (and subsequently seemingly forgotten).  Just recently, the Johns Hopkins Urban Health Institute announced the Henrietta Lacks Award for Community-University Collaboration, a prize of $15,000 to a community entity that collaborates with Hopkins to work to improve the health and well-being of the residents of the City of Baltimore.

Thanks to Ms. Skloot, Van Smith, and Mike Rogers (all of whom have written about her), Henrietta Lacks will achieve some level of immortality beyond the HeLa cell.

Photo Credit

What is Life?

Life is hard to define.  Perhaps former Supreme Court Justice Potter Stewart summed it up best (though he was referring to hard-core pornography, not living organisms) when he said, "I shall not today attempt further to define [it]... and perhaps I could never succeed in intelligibly doing so. But I know it when I see it."  

Erwin Schrodinger gave a series of lectures in 1943 that were published under the title "What is Life?" 

NASA has an Astrobiology group that is charged with searching for evidence that there is life on other planets.  Key to that mission is understanding what life is.  How else would they know what to look for?

Up until today, living organisms were thought to require four elements:  oxygen, carbon, hydrogen, nitrogen, sulfur, and phosphorus.  A paper published today by the NASA Astrobiology group has challenged that belief.  NASA scientists discovered a bacterium that can live without phosphorus, using arsenic instead.

The bacterium, designated GFAJ-1, can build the molecules of life, including DNA, proteins, and the energy molecule ATP, with either phosphorus or arsenic.  This is very handy, considering the organism was found in a lake with an extraordinarily high concentration of arsenic in its water.

Up until this discovery, life forms were the stuff of science fiction novels.  I've read novels about silicon-based life forms, based on the idea that silicon, being just below carbon on the periodic table, could take the place of carbon in the building blocks of life.  This is actually the basis for how GFAJ-1 uses arsenic.  Arsenic is just below phosphorus on the periodic table of the elements.  So the bacterium just substitutes arsenic for phosphorus.

This finding has important implications for the search for life away from earth.  Clearly phosphorus is not a requirement for life.  Perhaps neither is carbon.  Maybe not even oxygen is needed.  Life can take many forms, so finding it is going to require knowing it when we see it.

Question to ponder:  if ATP is the main energy molecule in a cell, and the P stands for phosphate, does GFAJ-1 have ATA instead?

You're Kidding, Right?

(Another of David's rants about insurance companies)

I've written many times about the absurdities I've encountered dealing with insurance companies.  I've had another experience that I'd like to share.

The patient came into clinic for chemotherapy.  The PA examined him and heard an irregular heartbeat.  Neither of us know the patient well, so we looked through his chart to see if anyone has ever noticed an irregular heartbeat before.  No one had.  We ordered an EKG, and it showed an abnormal rhythm.  The patient has had several EKGs in the past, and this rhythm was a new finding.  One possible explanation for the new abnormal rhythm would be if the patient's central line had moved a bit and was irritating the right ventricle of his heart.  The best way to figure out if that could be happening is to get a chest x-ray to see where the catheter tip is.

We ordered a chest x-ray, only to learn that the patient's insurance company doesn't cover radiology procedures at Johns Hopkins.  Since an abnormal heart rhythm can cause sudden death, diagnosing a cause is an emergency, so we called the insurance company for "permission" to order the x-ray.

You may think this is a "no brainer."  After all, a chest x-ray is cheap, and we could discover the cause of the patient's abnormal heart rhythm and fix it relatively easily.  The insurance company, however, needed to authorize the x-ray.  So I was told the nurse would review the case and get back to us.


Once again, I find my judgment about a case under review by someone with a financial stake in the decision.  In this case, a nurse, sitting in an office in another state, not able to see my patient, was going to decide if my decision to order a chest x-ray was justified.

No.  I'm not kidding.

But if you ask, insurance companies don't make medical decisions, they make coverage decisions.

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Rare But Serious

The patient and her parents were hardly focused on what we were saying.  Not surprising, since she was still recovering from the news that the pain in her leg was not from a sports injury, but from osteosarcoma.

Kameron was a high school athlete, and now, instead of anticipating a college scholarship to play hockey, she was anticipating a year's worth of chemotherapy and a major leg surgery.  She and her parents were in the office, listening (but probably not hearing) to the side effects she should expect from her upcoming chemotherapy.  At the end of the conference we discussed some of the "rare but serious" side effects, like fertility loss and heart failure.

Fertility loss is something that catches people's attention.  To some extent, so does heart failure.  But for adolescent patients, somehow infertility feels more "real."  So we talked about her possible future fertility problems much more than we talked about her heart.

Throughout her therapy, we monitored heart function with regular testing.  All of the tests were reassuring.  But one day, soon after her treatment was done, Kameron developed chest pain.  When treatment for reflux and then for infections didn't make things better, she came to the emergency room, and that is when we discovered she was in heart failure.

These side effects, the "rare but serious" ones, are some of the hardest for us to deal with.  Kameron's cancer prognosis is excellent.  I am optimistic she will become a survivor.  Unfortunately, she paid a huge cost to survive her cancer.  When she leaves the hospital, she will be on heart medicine for the foreseeable future.  She may even end up needing a heart transplant.  This is not a problem that is just going to go away, and for the rest of her life, Kameron will not only be a cancer survivor, but also a heart patient.

This is what drives us to work hard in the lab for treatments that won't come at such a high price to our patients. 

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How Much Time Do I Have?

I think that is the hardest question I have ever been asked. The emotional weight that goes along with asking how many days are left in a child’s life is staggering. I have been asked this question many times during my career, and I still don’t know how to answer it.


Some doctors answer this question based on disease-specific statistics. For example, since most patients diagnosed with a brainstem glioma die within a year of diagnosis, some will tell the family of a patient who receives this diagnosis that the child has less than a year to live.

Photo Credit

Some doctors answer this question based on personal experience. It is personal experience that has led me to dread this question the most. I would like to share two of these experiences to illustrate why.

It was a Monday night. I was home having dinner with my family when I was paged by the resident covering our inpatient unit. My patient had just completed an MRI, ordered to help us determine why he had lapsed into a coma. The MRI had just been read, and the radiologist had called the resident with the result: not only had my patient’s tumor grown substantially, but it was causing an “uncal herniation” (this is when a part of the brain is compressed, often by blood or a tumor, cutting off the blood supply to vital structures and often rapidly leading to death). Since the family had already decided not to pursue further treatment of their child’s cancer, the progression was not a surprise, but I went back the hospital immediately to talk to them about the herniation, since that was a sign that their child could die as soon as that very night. The previous week, when asked how long they had left, I had estimated several weeks, so this change would come as quite a shock.

Picture Posted By Permission

When I got to the child’s room, we spoke at length about his prognosis. His parents asked me how long they would have with him. I answered honestly that I thought he would die within days, and that he could possibly die within hours. The next morning, when he was still alive, we started to arrange a discharge with hospice care. It was Friday when he was finally able to go home.

That was 52 days ago, as I type this. Since discharge, my patient has regained consciousness, resumed eating, and is considering an exercise program to regain some strength. He is on his second hospice company. My estimates of his lifespan were both way off base.

Picture Posted By Permission

Two weeks after my Monday night conversation, another patient of mine was admitted to the hospital for end of life care. After a couple of days in the hospital, his mother asked me how long he had left. I told her that I had no idea, and shared with her the story of the patient with the herniation, who I thought would die within days and who was still alive almost 3 weeks later (at that point). I told this mother that, based on my experience, the best I could do was to guess how long she had with her son. She really wanted an answer, though, so I guessed for her. I told her that her son’s lifespan could be measured in weeks. Probably not days, certainly not months or years, but weeks. He died three weeks later.

I suppose sometimes I do guess correctly.

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Yoga – Not Just for Skinny, Pretty Women Anymore?

This post is dedicated to a close friend of mine, a budding scientist with an aversion to yoga.

The benefits of yoga for cancer patients were plastered throughout the popular press recently, in anticipation of a presentation by Dr. Karen Mustian from the University of Rochester Medical Center at this year’s meeting of the American Society for Clinical Oncology in Chicago. This study enrolled 410 cancer survivors (96% female, 75% had breast cancer) suffering from moderate or worse sleep disturbance. The participants were randomized to standard monitoring versus a 4 week yoga intervention. Participants in the yoga program had improvements in sleep quality, fatigue, and various measures of Quality of Life compared with the control arm (no intervention). The benefit was significant enough to be covered by mainstream media outlets like CNN as well as web-based media like Breastcancer.org. ASCO president Douglas Blayney, MD, stated that the results are “readily applicable” for a huge patient population.

But wait. As we scientists often ask, do the results support the conclusions?

I think the answer is a resounding “Maybe.”

There is mounting evidence that cancer survivors benefit from participating in yoga programs. Although this study is the largest thus far reported, it is certainly not the first to show a benefit to yoga. Back in 2003 a study presented at the ASCO meeting showed that participation in a yoga intervention improved the Quality of Life of women newly diagnosed with breast cancer.

But is it yoga, per se, that helps? So far none of the studies have compared participation in yoga with any other exercise program. This study, for example, published in 2001, demonstrated that a home-based walking exercise program improved fatigue and other Quality of Life measures in women being treated for breast cancer. The studies cited on this page of the American Cancer Society’s website demonstrate a benefit to using a treadmill or an outpatient wellness program involving aerobic exercise, strength training, flexibility and relaxation. So maybe it’s exercise in general, and not specifically yoga, that helps cancer survivors live better.

Are the results of the yoga study “readily applicable” to a huge patient population, as suggested by Dr. Blayney? Again, I think the answer is “Maybe.” It depends on how you define “a huge patient population.” Dr. Mustian’s study is certainly applicable to the very large number of women diagnosed with breast cancer every year, but her study involved essentially only women with breast cancer. Given the variety of ways various cancers are treated, it may be premature to conclude that because yoga helped these women, that it would make a difference for young adults being treated with intensive chemotherapy for leukemia.

So what can we conclude? I think it is safe to conclude that some degree of exercise is beneficial for cancer patients, probably regardless of where they are in the course of their therapy. But before we can state that yoga is the best form of exercise, the right study has to be performed: patients need to be randomized to various forms of exercise, and research participants need to include men as well. Perhaps for a relatively inflexible man like me, the frustration of not being able to do “downward dog” will make yoga a poor choice, while the feeling of accomplishment associated with being able to last 5 more minutes on the treadmill will make that form of exercise a much better choice. Only a well-designed experiment can tell us for sure.

 
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Genomic Medicine – The Hope and the Hype

Ten years ago this month, President Clinton, along with Drs. Craig Venter and Francis Collins, announced the completion of the Human Genome Project – the complete DNA sequence of the human genome. As is typical of such announcements, there was much pomp and circumstance, as the President declared it a “day for the ages.”

Why the excitement? It was fully expected by participants in the struggle to sequence our genome that achieving this goal would rapidly lead to a new understanding of the genetics of common disease, and would yield new genomic treatments that would revolutionize the practice of medicine. In fact, Dr. Collins predicted that the genetic diagnosis of disease would be accomplished within 10 years, and treatments would begin to appear 5 years later.

This, sadly, has not happened.

So does that mean the Human Genome Project was a bust? Hardly. While medicine has not been revolutionized, basic biology has been. The complete sequence of the human genome has shed tremendous new light on a variety of ways that genes are regulated, especially by RNA, which would never have been understood without sequence information.

So why has the sequence of the human genome not revolutionized medicine? As discussed in an article from The New York Times, there are several reasons. One reason cited by The Times is that many of the sequence variations associated with common diseases are not found within genes. This raises the possibility that these sequence variations are a statistical fluke, not really associated with the disease at all… or by anything other than chance. More disconcerting, if your goal is to develop a new treatment, is that common diseases may be caused by a large number of very rare sequence variations, so that individuals with a particular disease may have very little in common with each other, and nothing amenable to a drug.

Is this result entirely a surprise? To any serious student of human genetics, the answer has to be, “Not really.”

The First Genetic Disease

After reading any article in the popular press about genomic medicine, one would get the impression that the genetics of human disease is a new field, and that before the human genome was sequenced, there was nothing known about how gene mutations cause disease. This, however, is not true. In a paper published in Science in 1949, Linus Pauling and his colleagues demonstrated that sickle cell anemia is caused by a mutant form of hemoglobin, the protein that carries oxygen in red blood cells. In 1956, Vernon Ingram and his colleagues proved that this mutation was at the 6th amino acid of the protein. This change was soon shown to be the result of a single DNA base pair change.

For more than 50 years now, physicians and scientists have understood Sickle Cell Disease in molecular detail. Nevertheless, we are still unable to explain how this molecular defect causes any of the symptoms of the disease, and we are unable to do anything about it. To this day, despite how long we have understood the molecular biology of the disease, treatment remains supportive (meaning prophylactic antibiotics, pain medicine, and transfusions) or aimed at changing the way the hemoglobin genes are controlled (using a medicine called hydroxyurea). There is no treatment available that is directly related to the genetic cause of the disease, the mutation at amino acid 6.

I think this should be a warning to those who think that the path from the molecular understanding of a disease to a treatment will be straightforward. The era of genomic medicine may be upon us, but it is probably going to be a very slow change, not an overnight revolution.

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Another Ethical Dilemma

The ethics of modern medicine has always fascinated me, and Pediatric Oncology has provided me with more than my fair share of ethical issues to contemplate. I want to share today’s, and see what people think about this particular, emotionally charged, situation.


I received an email today from a colleague in another state. He trained under me, and I guess he thinks I did a good job, since he emails me for advice from time to time. He met a new patient today – a 23 year old woman with a new diagnosis of osteosarcoma. Unfortunately, she is 20 weeks pregnant.

One of the mainstays of osteosarcoma treatment is high dose methotrexate. Methotrexate is a very effective drug for terminating pregnancies, and this is where the ethical dilemma begins. The patient has a choice to continue her pregnancy or not. Except that the state in which she lives does not allow medical assistance funds to be used to terminate a pregnancy, and she has Medicaid as her sole source of health insurance. She cannot afford to pay for an abortion herself. If she chooses to continue the pregnancy, either out of necessity or out of desire to do so, giving her methotrexate will be fatal to the baby inside of her.

If the patient chooses to remain pregnant, my friend has some very difficult decisions to make: should he wait to treat her until the baby is born? This would give the tumor as much as 4 months to spread before treatment, a huge risk to the patient. Should he begin therapy early, maybe once the third trimester begins, and just not use methotrexate? This would allow the baby to develop to full term prior to delivery, and only delay beginning chemotherapy a few weeks, but would provide less than optimal care to his patient. Could an obstetrician ethically deliver the baby early, say at 30 weeks, a time when the child’s development is likely to be normal (but, of course, may not be) despite being premature? This would allow him to use methotrexate almost 3 months earlier than if the baby is delivered at full term.

I told him what I think I would do, but I’m glad that for me this is just an ethical puzzle, instead of a real situation where I have to make real decisions.

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How Small a Chance Is Too Small?

I’ve written about difficult cases before, but this case is really eating at me. It touches on issues of patient autonomy and how much influence we, as physicians, have over our patients. But the real issue is one of futility. How small a chance at survival is too small to offer a very toxic treatment?

The patient is a young boy with leukemia. We have been treating him for over a year, and his leukemia just won’t go into remission. For the past 3 months he has been in the hospital, first to receive chemotherapy and then to manage the side effects we caused. His bone marrow is nearly empty, but almost 80% of what few cells are present are leukemia cells. His only potential curative therapy is a bone marrow transplant.

Therein lies the problem. Not only does he have refractory leukemia, but his lungs are significantly injured from his previous chemotherapy, functioning at just about 55% of their predicted ability. For my patient, this is a major problem, because sick lungs make a bone marrow transplant very risky. Also, he doesn’t have a matched donor, so we would have to do a highly experimental type of transplant called a “reduced intensity haploidentical transplant.” This means we would give less than the usual amount of chemotherapy (to try to decrease the toxicity), and would use a donor that is only half matched.

I presented this case to the adult BMT group last week. Not one of them thought going through with the transplant was a good idea. They are convinced the patient will do badly, that he will end up dying in the ICU on a ventilator, and would never be cured with this approach anyway. Better to send him home on hospice care.

I polled a number of pediatric colleagues by email. They all said the same thing – better to do hospice care than a transplant that will most likely make the patient sicker before he dies anyway.

Our group has discussed the case extensively. We all agree that the chance of cure for this child is less than 5%. There is a 95% chance he will die faster and in more pain if we go ahead with the transplant than if we send him home on hospice care. So is the more humane choice to not offer the family a transplant, knowing the odds are overwhelmingly against success, knowing that the transplant will most likely make an already tragic situation worse?

Who gets to decide if the 5% chance of a cure is worth the risk? Is this chance of success so small as to qualify as futile?

If I know the father the way I think I do, if I hold out ANY chance of cure, he’ll take it, no matter the cost. That means, if I offer the family the transplant, he will go for it. But is that fair of me? He doesn’t know what it’s like to watch a child die in the ICU. I don’t think I can fully explain to him how awful a death his son may have, especially compared with what it would be like for him to die peacefully at home. Given that, can he truly give informed consent?

On the other hand, if I don’t offer the transplant, I take away even that slim chance of survival. Can I ethically do that? Or is that a decision the parents get to make?

 Photo Credit

The Irony of Patient Autonomy

One of the cornerstones of medical ethics is the concept of patient autonomy. MedicineNet.com provides a succinct definition: “The right of patients to make decisions about their medical care without their health care provider trying to influence the decision. Patient autonomy does allow for health care providers to educate the patient but does not allow the health care provider to make the decision for the patient.”

At lunch the other day, I was talking about a particularly challenging case when this concept came up. After thinking for a few minutes, I was struck by a sense of irony that I wanted to share in case others have thoughts about this.

The patient is a teenager with leukemia. When she was diagnosed with leukemia, we didn’t really give her parents any choices about treatment. We told them their daughter has leukemia, she needs chemotherapy, and we think she should get this particular regimen. Sure we received informed consent to treat the patient (whether this is truly informed consent is a topic for a future post), but it’s not like we gave the parents a choice of regimens or the option to forego chemotherapy. And because leukemia in children is curable, even if the parents had refused chemotherapy, we would have gone to court to force her to be treated.

Did we respect the patient’s autonomy here? Based on the definition above, I would say we did not. We certainly influenced the decision – by not giving the parents any choices.

Fast forward to last week, when a bone marrow examination revealed residual leukemia. The next course of action at this point is not clear: should she go straight to a bone marrow transplant? If so, should it be a standard transplant, or a more experimental approach? How about more chemotherapy? Is so, which regimen? The right choice is not clear. My “lunch date” is not a physician. So he asked me, “How will the family decide?” Full of respect for the patient’s autonomy, I answered, “Well, I will lay out the options, list some pros and cons, and the family will make a decision.”

This is when Marco asked the question that sparked this posting: “How will they make that decision? They don’t have the expertise to make that call, do they? Isn’t that what you are trained for?”

And that’s when it struck me. This family has had two key decision points: the day the girl was diagnosed, and the day her marrow showed persistent leukemia. At the first point, my expertise was unimportant… any oncologist would have said the same thing (that she needed chemotherapy), and the patient’s autonomy was only a secondary consideration. At the second point, when the optimal choice is NOT clear, when the decision should be MOST informed by someone experienced, that’s when I was explicit about my desire to lay out choices and let the family decide.

I still don’t think I should tell the family what decision to make… I just think it’s ironic that when the decisions are more complex, and my expertise matters more, the patient’s autonomy is even more important.

Maybe that’s how it should be. What do you think?