Q: Could you briefly comment on what sorts of work in hemostasis research or platelet research that you're building upon in doing this work? Or do you see it as completely new?
Tullis: Well, the systems of hemostasis and coagulation appear to be far more important than just an intrinsic mechanism for keeping blood in the vascular bed, which is what nature apparently designed it for in the first place. Many of the biochemical and physiologic changes of your other organs and systems of the body draw on the enzymes that are activated at the moment clotting is activated, or when platelets are functionally altered so that they release some of their internal substances. There are many other tissues of the body, and my area right now is to see if one of these is neoplasia. We know, for instance, that clotting is necessary for repair. Otherwise, every time you severed your skin, you would never heal with normal skin again. You have to have, first, a clot, then you have to have fibrin formation, as a matrix, and then you have to have fibroblasts and other new cells laid down on top of the matrix. So all of the enzymatic systems of coagulation are activated for even minor things such as that. Similarly, any mechanism that causes an end product, like a clot, has to have a system of building inhibitors to keep the whole system from turning solid the first time you activate your clotting. So you have to have an anticoagulant system that's even stronger than your coagulant system. And these have to be kinetically balanced, so that you constantly are both making clot, when it's needed, and lysing clot, when it's no longer needed. Otherwise, you would not be able to restore vascular integrity after you have had a thrombosis someplace. So that these systems apparently play a very fundamental role in resistance to infection, because of the mediators, and so on. So I think coagulation and hemostasis create a fairly fundamental, basic--going back to Claude Bernard--milieu interieure, necessary for normal cell function.
Q: This research has, in the main, been research that's been, that you're building upon is work that's been in the main completed since the 1950s, or does it have a history that precedes that?
Tullis: No, this is work that's been since the 1950s. Yes. Very definitely. I'm not building at the present on historical scientific knowledge that antedated this century, no. This is current.
Q: It's current. Now, I was speaking in terms of developments, for example, in research--just the idea of clot retraction, just the idea of coagulation itself or--
Tullis: Well, pick one other than clot retraction, because I'm not sure clot retraction has any role whatsoever physiologically in the human. I think it may have a very fundamental role in very primitive animal forms, but there's no data that clot retraction per se exerts, if you will, a plastic effect on blood vessels to keep blood from leaking out. That remains to be shown. I think it's sort of a phlyogenetic holdover from earlier stages of biologic life.
Q: That's how it--
Tullis: Pick out some other area other than clot retraction!
Q: Because I thought it was in the work, just on clot retraction, that some of the work around the role of fibrin strands was done.
Tullis: Well, yes, now, the interrelationship between fibrin and platelet plug formation is, of course, very fundamental, but the subsequent retraction, which is a function, if you will, of platelets and their need for ADP and energy hasn't shown that the retraction itself has a role, either in strengthening the clot or in doing anything else to restore the potency of the vessel.
Q: Perhaps if I just get out some names on some of the points. On the point, the role of ADP, there's an interesting story there, isn't there?
Tullis: Very--you mean with regard to platelet aggregation.
Q: Aggregation and the use of column chromatography.
Tullis: That's right. I think we have tended to become too pure with respect to working with single cells from the body. For example, everybody attributes to the platelet all of these functions when I think there is some evidence to suggest that platelets and red cells have to interact under the normal circulatory dynamics to have proper balance exist. For example, if you look at the platelet itself, you have an energy need which is apparently supplied, in part, from the red cell, for the right amount of ATP degrading to ADP to AMP and then reverse. Because, if you look at platelet aggregation in the absence of red cells, you'd get totally different findings, from which you get in the presence of the red cells, which was first found out in Scandinavia many, many years ago. Contrary wise, people look at red blood cells and say, “Well, this is what we call a schistocyte, a red cell that's been damaged. Therefore, that means that there is activation of clotting, and the red cells are being pushed through a clot someplace, and they're being physically damaged by this pushing through a clot." Well, that's totally fallacious reasoning, because you can take a red cell and hit it with a hammer, and it just deforms, but comes right back to its normal shape because of its elasticity. You don't damage a red cell unless there has been activation of platelets in the area of the red cell, because it may be one of the prostoglandin byproducts that then changes the red cell from a deformable cell to a rigid cell, so that then, if you push it through a clot in circulation, you have damage to the envelope of the red cell. But it takes the interaction of these processes.
I don't know whether you've ever looked at a living preparation--maybe you have--of the circulation through a microscope, or through an everted hamster cheek-pouch. If you have a big enough vessel, you see something that is really quite distinct. There's the central core of red cells, which are quite dark, and then the light yellowish plasma around the periphery, with a Newtonian kind of flow. Meantime, the platelets are bumping along the endothelial layer, and the white cells, too. So that they're coaxial, they're separated during flow, but then, the moment you damage the vessel and have turbulence there, I think the turbulence creates the interaction between the platelet and the red cell which is necessary to set off the whole process of hemostasis.
Q: I was wondering if you could comment about the series of meetings that, perhaps, date from the early post-World War II period that deal with the question of blood coagulation.
Tullis: Well, there were many meetings in support of the field that unquestionably had a good effect on increasing the flow of information and speeding up the dissemination information from individual laboratories, so that everyone could work simultaneously on it. There were so many it's almost redundant to go through the whole list, but I'll mention just a few: the Macy Foundations, the Josiah Macy Foundation conferences were important. Walter Seegers had a conference every year in Detroit that was very well attended and quite high quality. The Henry Ford Foundation sponsored a series of the same type. We had the meetings of Protein Foundation and later the Center for Blood Research here.
Then, at about this time, the committee on thrombosis and hemostasis, the international committee on thrombosis and hemostasis changed from a committee to a society. This has had a very good effect on the whole field as a subspecialty within hematology. I just returned from meetings last week out in San Diego of the International Society of Thrombosis and Hemostasis, and these are very good meetings, attended by, perhaps, a thousand people, all in the subdivision of what we're talking about. The Committee on Thrombosis and Hemostasis had another good thing to its credit. When it started, it was started purely from a need to standardize the nomenclature after one of the Princeton meetings on coagulation. This was in the late 1950s, I believe. At that time, everybody who had identified a missing coagulation protein, usually named it after a family, or a person, or a drug, or he named it after his patient, or himself, or his town or university, or something else. There was no system. The International Committee got together with the principal investigators, and they all agreed that henceforth they would use a nomenclature system of numbers, Roman numerals, starting with the first protein identified, which was fibrinogen, as number I, prothrombin as number II, which converts, of course, to thrombin; number III was left blank because it, in essence, was the thrombin activated one. Then there was IV, which was assigned to calcium, because that was historically the next thing that was known in the coagulation field. Then the accelerators, beginning with proacclerin which became Factor V, and so on. There was only one that they made a mistake on. That was VI. There is no VI because the one originally assigned to number VI proved to be an artifact, and not real. But VII, VIII, IX, X, XI, XII and XIII were then accepted as bona fide. And each man agreed, and the editors of the principal journals agreed, they no longer would accept for publication any article dealing with these coagulation proteins without using the Roman numeral first, then they could call it anything they wanted afterwards, in brackets. Within a matter of just a very few years, standard nomenclature came in, which clarified the field, so at least students could understand what one was talking about. Unfortunately they have not done anything about new proteins like Protein C and Protein S that have been described and well characterized, I'm sure that they should get numbers, too, but that'll be on down the road, somewhere.
Q: You refer to this number III. Was that the Platelet Factor III?
Tullis: Platelet Factor III, probably, but Platelet Factor III then ended up being called PF-3, rather than Roman numeral three, so it's an artifact too, in that sense.
Q: And that turned out to be an actual artifact?
Tullis: Well, I shouldn't say, "artifact," but the way they used the Roman numeral was incorrect.
Q: Was there more of a story behind that, where there was thought to be an actual--?
Tullis: No.
Q: No. Now, the reason why I was asking was, it seems that this lipid extract, that was talking about in 1936, which predates these meetings on clotting, might be identified with this platelet.
Tullis: Oh, I think it was. I think it probably was, yes.
Q: And this was a case where there was a ten year lag before it was--
Tullis: Precisely, because in those days when he published his original paper, we didn't have the rapid means of dissemination of knowledge that we have now.
Q: Would he have taught people who became his colleagues in the future--would they have been combing the journals, such as the Journal of Biologic Chemistry, which is where this was published?
Tullis: Yes, sure. That's the only way they would get it, because there was no hematology journal, there was no coagulation journal, there was no hemostasis journal, all of which there are now. So they would have to comb all of the biochemical journals.
Q: So, that would be a common feature, that there could be a ten year lag between identification and dissemination.
Tullis: Not uncommon at all. It's just like the "World News Tonight" you hear on the television--everything that's happened in the whole world, today! And believe me, in 1934, you didn't know what was going on in the world or in blood cells!
Q: Are there any other persons whom you would like to comment on who were forerunners of the work that you're engaged in right now?
Tullis: Well, they're not forerunners, but there are many people working in the field who are certainly very credible people--more, I think, in Europe than in this country.
Q: Are there any other areas that you would like to cover, as far as platelet research?
Tullis: I don't think so.
Q: Okay. If we could, I'd like to ask some more personal types of questions at the end of this, which deal with a number of awards that you have received--not to embarrass you. If you could just comment on the work that was recognized; maybe different ones, for the record.
Tullis: Well, let's see.
Q: Should I go through? I have a list, if you want to do it like that.
Tullis: Yes, if you'll just give me the name, I'll tell you what it was for.
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