Sickle Cell Anemia

It was a brisk fall day in Boston--the type of day that Dr. William Castle preferred to start with a cup of coffee while he caught up on his correspondence, which often appeared to be an endless task. As a faculty member of Harvard Medical School, he had always received a fair amount of inquiries, but after he had published his data indicating that pernicious anemia was due to a vitamin B12 deficiency, the amount of mail he received was sometimes overwhelming.

Sitting in his reclining chair he sorted through the large pile that had accumulated. He began to meticulously segregate it into smaller piles he would open in a prescribed order. Usually the delegation of a particular envelope was a relatively easy choice. There were a few that caused him to pause for a moment, such as the one he was currently holding. The return address indicated it was from an Irving Sherman at Johns Hopkins University. Since it was from someone he had never heard of, he was inclined to place it in the pile to be opened later. But on this day he decided to take another sip of coffee and see what Mr. Sherman had to say.

"Well, this may have some merit," Dr. Castle mused to himself. He recognized that these results indicated it was likely that there was a difference in one or more molecules found either in the blood or within the red blood cells. Since sickle cell anemia was named due to the change in the shape of the red blood cells, the molecule involved was most likely within the red blood cells. Dr. Castle placed the letter in a conspicuous place on his desk so that he would remember to send a reply to the ambitious student.

A few months later, Dr. Castle found himself taking a train to a conference. As usual, he had brought a manuscript to work on. As he glanced around the car he was surprised to see Linus Pauling sitting a few rows in front of him. Dr. Pauling was a renowned chemist who had been doing some innovative research on elucidating the structure of different proteins. Having met Dr. Pauling at a previous conference, Dr. Castle decided to strike up a conversation.

"Well, Linus, this is a surprise."

"Hello, Bill. Where are you heading?"

"Oh, I've been invited to give the plenary talk at this symposium on the physiology of red blood cells down in Atlanta."

"What a coincidence. I'm heading to the same meeting to present some of my recent data on hemoglobin."

A surprised look crossed Dr. Castle's face. "I had no idea that hemoglobin had caught your attention."

"Yes, I've been working on it for the last year or so. It appears to have a number of interesting structural properties."

Dr. Castle remembered the letter from Irving Sherman. "Linus, have you given any thought to studying hemoglobin from individuals suffering from different forms of anemia?"

"I'm not very familiar with anemia. I had thought that anemia was a condition in which the body simply made fewer red blood cells. Is there any indication that there is a difference in the hemoglobin?"

"Until a few months ago I would have told you no, but a young medical student recently mentioned that he has observed that blood from individuals with sickle cell anemia transmits light differently than normal blood. I was thinking that this may be due to some difference in the structure of their hemoglobin."

"It definitely seems worthwhile looking into. If you could send me some blood samples, I could try a couple things when I get back to the lab and let you know what I find out."

A few weeks later, one of the letters in his stack of mail caught Dr. Castle's eye. "Ah, let's see what Linus has found."

Eagerly Dr. Castle reached for his lab notebook and quickly looked to see which samples came from the individuals with sickle cell anemia. "Jim, come and look at these results Linus Pauling just sent to me," he called to his research assistant. He handed the letter to Jim and said, "The samples labeled 48WC03 and 48WC15 are from some patients who have been diagnosed with sickle cell anemia. The others are the controls."

"This is interesting," exclaimed Jim. "It seems to fit nicely with what I have recently learned. I was at a meeting last week and heard a talk by Vernon Ingram. He used different enzymes to cleave the hemoglobin from sickle celled and normal individuals. He found that all the fragments generated were identical except for one. After analyzing that fragment, he determined that the only difference between normal and sickle-cell hemoglobin is the amount of glutamic acid and valine residues. Hemoglobin from sickle-celled individuals contains more valine."

Questions

1. Why did Dr. Castle not tell Dr. Pauling initially which samples came from the sickle-celled individuals?

2. From these results, what level(s) of protein structure of the hemoglobin is altered in the sickled-cell condition? Explain the basis for your answer.

3. Are Linus Pauling's results supported by Vernon Ingram's results? Hint: compare the molecular composition of the different amino acids implicated.

References

1. Bloom, Miriam. Understanding Sickle Cell Disease. Jackson: University Press of Mississippi, 1995.
2. Todd, James Campbell, and Arthur Hawley Sanford. Clinical Diagnosis by Laboratory Methods, 14th ed. Edited by I. Davidson and J.B. Henry. Philadelphia: W.B. Saunders Company, 1969, 227-237.
3. Edelstein, Stuart J. The Sickled Cell, From Myth to Molecules. Cambridge: Harvard University Press, 1986.
4. Stryer, Lubert. Biochemistry, 2nd ed. San Francisco: W.H. Freeman & Company, 1981, 57-102.

   
   

Go to Section 2: To Sickle or Not to Sickle: What's a Cell to Do?

Disclaimer: This case is a work of fiction that refers to real events and people. All of the discoveries mentioned in Section 1 were made by the individuals they are attributed to, as were the observations made by Dr. Vernon Hahn described in Section 2. The time between discoveries has been dramatically condensed, however. Every effort has been made to present the scientific considerations concisely and accurately. Any errors should be attributed to the author and not the original investigators.
Image Credit: Electron micrograph by Patricia N. Farnsworth, Department of Pharmacology and Physiology, New Jersey Medical School. Used with permission.
Case Posted: 9/14/00 mb