have a significantly increased life span and this provides evidence that the cyanate inhibition of sickling observed in the test tube is retained in the patient.

This strengthens the rationale for further clinical investigations of cyanate. As a result of these studies, we have received the necessary approval from the Food and Drug Administration and the Rockefeller University Hospital Committee to begin a limited investigation of the use of sodium cyanate in the treatment of sickle cell disease. We have initiated this program, and hope to establish within the next 6 months whether cyanate will prove to be a useful therapeutic agent in the treatment of sickle-cell disease.

There are many important questions which must be answered regarding the long-term effectiveness and safety of this treatment. Since the cells that are inhibited from sickling will eventually be replaced by new untreated cells, the patient will have to be on a maintenance program of cyanate treatment for his or her entire life. It is therefore obvious that the question of long-term toxic effects is of paramount importance. In addition, many patients will have to be treated and followed to determine whether the treatment with cyanate is effective in ameliorating the disease process.

One of the significant implications of our work is that abnormal molecules can be caused to function normally by treatment with specific therapeutic agents. This leads us to hope that other genetic disorders may be studied and treated in similar fashion.

We and other scientists have been encouraged to approach further studies optimistically and with the reasonable expectation that our results will produce new hope for patients with sickle cell disease. The continuation of research will depend on the extent to which funds are made available. I urge you to consider the need for continuing research funds as you formulate the legislation to combat sickle-cell disease.

Senator KENNEDY. Very good.

Is there any question in your mind, Doctor, that a great deal of money could be usefully expended in increasing research in the sickle cell disease, the genetic area, for example? We are talking approximately about $5 million a year now. Do you think that could be expended valuably?

Dr. CERAMI. I could give you an estimate that we obtained just to develop cyanate as a drug for possible use in the treatment of sickle cell disease; it will probably cost anywhere in the range of $3 to $10 million in order to do the long-term toxicity programing and in order to do evaluation of patients.

Senator KENNEDY. And this is just one sort of hopeful effort, is it not?

Dr. CERAMI. That is right.

Senator KENNEDY. But as a clinical researcher, do you think this money, at least the $5 million a year, could be very well and carefully spent?

Dr. CERAMI. Yes, I believe it can be, because I think the problem is attackable, there are many reasons why people have not investigated sickle-cell disease, as you have heard witnesses explain their reasons. The other important thing, as a scientist in the devising of new drugs, was that it was very difficult to figure out what to do, and so people were thinking in terms of long-term answers-changing the bone marrow, for example, of a person with the disease so that he would now produce normal cells. Technically, I think this is a problem that we may be able to solve in the future, but not for quite a while.

Senator KENNEDY. Dr. Scott and Dr. Rhodes and Dr. Rabb, do you think in terms of what you know about, one, the facilities that exist generally in the country; and two, the types of manpower which are presently in service in the Nation; and three, with the equipment that we do have against the background and experience of years of work in this field, do you think that $25 million a year for the next 3 years is excessive resources to devote toward this particular problem? Do you think that money could be valuably expended and in worthwhile programs to provide some immediate relief to people?

Dr. RHODES. Well, certainly I feel that $25 million a year is a sum of money that could be valuably spent for sickle-cell disease with an association with some programs which are now in effect and to create other programs which are not in effect. I think that $25 million is certainly not too much money.

I think it is a beginning point in terms of expenditure of funds in this particular area. In supporting the patient-not only in researchI feel research is important, but I also feel it is equally important to do something for the patient now in terms of the things that can be done to help the patient clinically and to develop both the university medical center and also to bring home to the local physician that treats many of the patients and at the small medical centers here the capability of helping people with sickle-cell anemia. This is one of the things that money could certainly be valuable and useful for.

Dr. SCOTT. Senator, I would think that $25 million is certainly not too much. My question would be if it is enough.

I was just looking at some figures we have here at Howard University, in order to set up a center that would provide comprehensive care for patients and to provide the necessary staff and to renovate or put up new laboratories and to provide all of the facilities that one would need in order to have a comprehensive center. We would need $4.4 million the first year to set this center up, and then subsequently, about $2 million a year for ongoing expenses.

If one would extrapolate that to other centers and other activities throughout the country, to say nothing of the screening programs which would be carried out in the neighborhood clinics and so on, I think the $25 million probably is not quite adequate.

Senator KENNEDY. You know, just finally, it seems to me, of course, we come down to, tragically, the questions of dollars and cents, and that does not even begin to measure the heartache and suffering and anxiety that both the victims and the immediate family and friends feel about this; but just to make a hardnosed business judgment, this is really going to be saving the taxpayers millions of dollars, as I understand by the time you extrapolate on the figures of people that have the disease, their various visits-as I understand, approximately five to 10 crises a year up to 6 years of age and three crises after thatthe cost of $1,000 to $2,000-about $10,000 a year for the young people you are talking about, anywhere from 50,000 to 100,000 people in this country that have had that. I mean, what we are talking about is hundreds of millions of dollars spent by people that have the disease, and what we are talking about here is really a very modest kind of an attempt by the Federal Government to support existing kinds of local efforts and research groups which I think you have commented on, and to save the taxpayers money, which is always a factor ultimately in terms of what this Congress does, let alone the enormous saving in suffering and human misery.

Dr. RABB. I would just like to add that from an ophthalmological viewpoint, so far there is no treatment or cure for sickle cell disease. However, those patients with the less severe disease, the SC hemoglobin disease, may not have many symptoms, generally speaking, but may have eye problems that can lead to blindness. Presently, we can treat these patients with argon laser and other photocoagulation instruments, but these instruments cost money; for instance, one instrument could be $30,000 for one center. Also, there are many people in other areas of this country where there are not university centers, and for these patients to also have the opportunity to be treated would bring about a much higher cost.

Therefore, I do not really think that the $25 million is enough for this type instrumentation alone.

Senator KENNEDY. I could not agree with you more. Thank you very much, gentlemen. You have been very helpful. I am sure you have given careful attention to the bill. If there are any other technical comments that you want to make or file with us, we will be happy to consider them when we bring up the bill next Tuesday in executive committee. You might take the bill with you if you have any other particular kinds of questions.

(The prepared statement of Dr. Cerami follows:)

Testimony before the Senate Health Subcommittee on S.2676

Washington, D.C., November 12, 1971

Anthony Cerami, Ph.D.

The Rockefeller University, New York, New York

Hardly more than a year ago there was an atmosphere of dispair and pessimism about the possibility of making a breakthrough in the treatment of sickle cell disease. Recent investigations have provided scientists with a new insight, which has created a more optimistic attitude toward research on this disease.

The purpose of my visit here today is to discuss with you our investigation of the possible use of cyanate in the treatment of sickle cell disease.*

Several months ago, Dr. James M. Manning and I found that cyanate, a very simple molecule consisting of carbon, nitrogen and oxygen, could permanently prevent, in the test tube, the sickling of red blood cells from patients with sickle cell disease (PNAS 68: 1180, 1971). We were able to pinpoint exactly where on the hemoglobin molecule the cyanate reacted. Fortunately this location is such that it reacts with cyanate · much faster than other proteins and this confers a high degree of specificity. We have done many experiments to study the toxicity of cyanate.

For example, in the mouse, approximately 5% of an injected dose of cyanate reacts with the hemoglobin molecule and the remainder is excreted as the harmless waste products, ammonia and carbon dioxide.

We have found that cyanate, in experimental animals, is no more than three

times as toxic as aspirin

a relatively safe compound. We have been

injecting or feeding a sublethal amount of sodium cyanate daily to dogs,

monkeys, mice and rats for several months and have not observed any

abnormalities.

In our

Recently, in collaboration with Dr. Peter N. Gillette of the Rockefeller University Hospital, we have begun an evaluation of the antisickling effect of cyanate in patients with sickle cell disease. initial studies, which will appear in the November issue of the Proceedings of the National Academy of Sciences, we compared the life span of a small sample of cells that had been treated with sodium cyanate, in a test tube, and then returned to the patient.

The life span of untreated red cells, from a patient with sickle cell disease is abnormally short due to sickling and the eventual entrapment of the cells within the tissues. On the other hand, cells that have been treated with cyanate in the test tube and returned to the patient have a significantly increased life span and this provides evidence that the cyanate inhibition of sickling observed in the test tube is retained in the patient. This strengthens the rationale for further clinical investigations of cyanate. As a result of these studies, we have received the necessary approval from the Food and Drug Administration and the Rockefeller University Hospital Committee to begin a limited investigation of the use of sodium cyanate in the treatment of sickle cell disease. We have initiated this program, and hope to establish within the next six months whether cyanate will prove to be a useful therapeutic agent in the treatment of sickle cell disease.

.