Synapse - The UCSF student newspaper, Volume 36, Number 32, 21 May 1992 — Yuet Wai Kan An Interwiew [ARTICLE+ILLUSTRATION]

Yuet Wai Kan An Interwiew

Dr. Yuet Wai Kan is a world-renowned researcher in the field of prenatal diagnosis of hereditary disorders. He pioneered the first successful prenatal diagnosisfor a hemoglobin disorder. He currently is the Louis K. Diamond Professor of Hematology and Chief of the Division of Molecular Medicine and Diagnostics at the Department of Laboratory Medicine. He also is the director of the Institute of Molecular Biology at the University of Hong Kong. DillonChen.afirst-yearmedicalstudent, interviewed Kan for this issue of Synapse.

Synapse: Can you tell us something about your childhood?

Dr. Kan: I came from a big family, and I am the youngest of 14 children. After graduating from the University of Hong Kong, I spent two years there doing internship and residency, and then I decided to go abroad. Usually people who go abroad from Hong Kong go to England. I decided to come to America for a couple of years and then go to England. That was in 1960. I never left for England. Synapse: How did you become interested in science? Kan: Well, it's really very simple. In those days, we listened to our father. My father said, "You are going to be a doctor." And that was that. But when he said "doctor" he meant the kind that sees patients, so that's why I went to medical school. In those days, when your father told you to do something, you did it. I have five brothers, none of them are in the medical field. He just decided 1 should be the one.

Synapse: Was your father a role model for you?

Kan: Yes. He was a very strong person. He started a bank in Hong Kong, and ran the bank for many years. So he was a role model for me in the sense of character, but not in the sense of his work. It was very tough in those days to go to the university. In the British system, one goes right to medical school without going through college. Medical school class size in those days was about 50, and there was only one medical school in Hong Kong. So the competition was very tough.

Synapse: Was it common for college students to go abroad in those days?

Kan: Things have changed. Now, a lot of people go abroad for medical school. But in those days, most people, if they could, would go to the University of Hong Kong Medical School. After a few years of clinical training, they usually went to England to take the "membership exam," which is like the American "boards." They worked one or two years, doing some specialty training, and then returned to Hong Kong.

Synapse: What was it like moving to a new country?

Kan: Terrible! For the first few months, I absolutely hated everything! One of the natural defenses against new things one can't cope with is to dislike it. But I got over it in a few months. At the Brigham Hospital in Boston, I was beginning to do some research work in hematology, and I realized that I really did not

have a very good background in doing research work. I needed to spend a year in a basic science laboratory. I talked to the people at MIT and was accepted to Vernon Ingram's lab. He was doing some work on hemoglobin structure. Synapse: How did you become interested in hematology? Kan: My professor in Hong Kong was interested in hematology. As a house staff, I was already doing some work in blood diseases under the direction of David Todd. After three years in Boston, I had to leave the country because my visa expired. I went to Canada for two years, continuing my hematology work at the Royal Victoria Hospital. While in Canada, I saw a Chinese infant bom with a condition called "hydrops fetalis." He had severe edema and did not survive. That was about '64. In the early '60s, this condition was first described by an UCSF physician from Indonesia. Not much was known about mis disorder except that the patients cannot make a chain hemoglobin. I decided that this was a very interesting problem. After I returned to Boston, I worked on quantifying hemoglobin synthesis in the fetus, hoping to apply mis method to prenatal diagnosis of sickle cell

anemia and thalassemia. Indeed, just before I left Boston in 1972, we successfully detected the presence of sickle hemoglobin in a sample of fetal blood using an assay mat required only microliters of fetal blood.

In 1972, I moved to San Francisco and assumed the position of Chief of Hematology at the SF General.

Synapse: When did you first succeed in prenatal diagnosis of hemoglobin disorders?

Kan: In 1974, Mitchell Golbus (an obstetrician at UCSF) and I began to set up the procedure in San Francisco. Our first case was a patient who flew in from Peoria, Illinois ~ the heartland of America. She was Italian and already had one child affected by Bthalassemia, which is common among Mediterranean people. She asked me about the possibility of a prenatal test for B-thalassemia for the child she was expecting. At that time no one knew whether or not it was possible to detect the B-thalassemia phenotype in the fetus. I explained the experimental nature of the procedure to the parents, but they were insistent about undergoing the lest. As luck would have it, Mickey obtained fetal blood with the first sample. The results indicated mat the most

The first mother tested named her son after me. Imagine an Italian boy called Ignacio Yuet!

trait, but without any previous experience we could not be sure. I remember sitting up all night worrying about what to say to the parents, because I know how patients often follow the physician's advice, depending on how he expresses his opinion. About 2 o'clock in the morning, I called Hong Kong and had a long chat with David Todd about this, not mat he (nor anyone else in the world at that time) could have given me any scientific answers, but just to make myself feel better. The next morning I told the parents that based on the findings, our most reasonable guess was that the child did not have homozygous B-thalassemia. They decided to continue with the pregnancy and the diagnosis was confirmed at birth. The parents were so happy that they took out an advertisement in a Peoria newspaper to thank everybody. And rightly so, because this was the first successful prenatal diagnosis for a hemoglobin disorder. Synapse: Afteryour success, who wereyour next patients?

Kan: They came from Sardinia, Italy. Sardinia has a very high frequency of thalassemia, about 14% of the people are

carriers. A pediatrician in Sardinia was very interested in the idea of prenatal diagnosis and decided to send someone to my laboratory to learn the techniques. However, before all the logistics had been worked out, some Sardinian couples caught wind of the possibility of prenatal diagnosis and decided tocome to San Francisco for the test. Practically none of the mothers spoke English; indeed many had never before been out of Sardinia. Altogether, about thirty pregnant women flew to San Francisco for the test before the procedure was set up in Sardinia. The first mother tested named her son after me. Imagine an Italian boy called Ignacio Yuet!

Synapse: What was your progress with athalassemia during all this time?

Kan: Alpha-thalassemia had interested me ever since I saw the first hydropic infant in Montreal. We already knew that no a-globin chains are synthesized in fetuses affected by the homozygous form of the disease. We used nucleic acid hybridization todetermine whether the a-globin genes are present or absent in the genome of such infants. The answer came back loud and clear —the a-globin genes are deleted from the chromosome. This was the first time ever that gene deletion had been demonstrated

as the cause of human disease. This also was in 1974.

Synapse: Did anti-abortion advocates'give you problems because of your research?

Kan: I don't mink at mat time they were really mat vocal. There were some problems, but they weren't that serious. The Italian patients who came here all were Catholics. Interestingly, in Italy the law allows abortion for medical reasons and specifies thalassemia since this disorder is so common.

Synapse: What are your current research interests?

Kan: What we are doing now falls mainly into two directions. As I said, thalassemia is a problem very common in Mediterranean, Middle East, Africa, and Asia. In fact, it is probably the most common genetic disorder in the world as a group of diseases. Because these parts of the world include many developing countries, we have been concentrating on adapting the diagnostic test to be cheaper and simpler. Another direction which we are pursuing is the treatment of thalassemia. One ol" the things we still don't understand about the hemoglobin problem is why it is only made in red blood cells and at such high levels. The other question is what signal causes the switch of hemoglobin expression from embryonic to fetal to adult forms. These two problems are not yet understood. They are important problems because if we know precisely the mechanism why globin genes are turned on at such a high level in the red cells, maybe we can encode this signal into a gene as gene therapy. As of now, gene therapy has been tried in the case of adenosine deaminase deficiency which affects T-cell function. But when you deal with enzymes, you don't need very much enzyme in the cell. A little bit of protein will do. But a little bit of protein doesn't help the hemoglobin problem, so you need a lot of hemoglobin. Until we understand why the globin gene is expressed at such a high level in the red cell, we can't even think about gene therapy for thalassemia or sickle cell anemia.

In the last few years there have been some breakthroughs. Now we understand that there are certain sequences way upstream from the globin gene that are important for this high level of expression. So right now we are trying to study exactly what mechanism, what proteins bind to them, how they interact with the globin genes. Hopefully, with this understanding, we will know how to make the globin gene "work harder" and therefore think about gene therapy. Synapse: On the personal side, what hobbies do you have?

Kan: I love tennis and ski ing. I don't have time to do much of either now.

Synapse: And would you care to comment on your favorite Chinese restaurants?

Kan: I have several, all of them Cantonese: Harbor Village, The Mayflower, and The Flower Lounge. And yes, Chinese food is my favorite food.

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