Does the possibility of having an abnormal gene seem too remote for the reader to consider? If so, it may be noted that, by some estimates in the past, on the average, each seemingly healthy person carries an abnormal "genetic load" of perhaps four deleterious genes. We are all carriers of inborn metabolic diseases.
In preceding chapters, we have seen how an understanding of an inborn metabolic disease evolves through the following sequences: clinical description, pathological description, histochemical clues, chemical identification of the substrate and the corresponding enzyme.
Here, we must apply the "so what?" test. Well, so what? Now that we have this information, what practical value, if any, does it have? Let us consider four examples:
Turning back to MLD, it now appears possible to diagnose MLD in the unborn fetus. Fetal cells show the sulfatase A deficiency. This means that the informed parents can decide, if they wish, to end the pregnancy. If they do, they will be spared the heartache and expense of rasing a child soon to die of a progressive neurological disorder, and can later go on to have normal children if they choose.
Now, one can also identify seemingly normal carriers, who may transmit the disease, even before they have children.' The technique is called genetic screening. If each parent carries the recessive gene, and if they have four children, then one child (on an average) will come down with the disease. Two of the four would be carriers, but like their parents, would be symptom-free. One of the four children would not be a carrier and would be both genetically free and clinically free of the disease. The ultimate hope of eradicating MLD lies in identifying and saving this entirely normal child.
What about the MLD patients whose diagnosis is delayed until after they're born? At present, one effective form of therapy exists: the patient needs to receive a transplant of cells that make normal sulfatase A. This is initiated by infusing normal bone marrow cells from a healthy compatible donor, one proven not to be a carrier.' The approach works best when started very early, before symptoms appear, whether the patient has the form of MLD that appears in late infancy, or during the juvenile or adult period. The same general principle has been applied to treat several other deposition disorders."
One hopes that some day it may also be practical to supplement the biochemical activity of the deficient enzyme. This naive statement of faith hinges on several observations. First we found that the sulfatase A enzyme is not absent in MLD. The enzyme protein is usually present,' but its structure-or that of certain other molecules required for its activity-is chemically altered in ways that interfere with the enzyme's achieving full functional activity in the patient's body."
Second, we found, to our astonishment, a way to increase the activity and stability of the normal enzyme. This increase occurred when we combined sulfatase A with another molecule that reacted intimately with it. (This other molecule happened to be an antibody to the enzyme.) The two important findings above were made by Dave Stumpf and Ed Neuwelt, two outstanding medical students who have done extraordinarily fine research in MLD in our laboratory. Our working theory was that some other appropriate small molecule could be designed, a molecule soluble enough to penetrate the nervous system, there to selectively engage key biochemical pathways in the enzyme's micro-environment, and enhance its net effect at cellular sites where its functional activity was most needed. This is a tall order.
Third, it has been shown that the activity of an abnormal enzyme can be increased by using the kind of approach just described. For example, a biochemist, Dr. Norman Radin, and his colleagues have persisted in pursuing this biochemical approach for the last three decades, with generally intriguing results." I happened to run into Norman at the meeting at which he first presented his work. He and I then collaborated in a studydesigned to see whether his earlier results on enhancing the activity of the normal enzyme, cerebroside galactosidase, could be duplicated using the abnormal enzyme present in diseased tissues obtained from human globoid leukodystrophy patients (GLD). Kuni Suzuki had already shown that this galactosidase was deficient in GLD. It was not necessary to test out all these and related kinds of biochemical approaches in living children with GLD, because there already existed a precise animal model for GLD: the West Highland and Cairn terriers that have the same galactosidase enzyme deficiency found in humans."
Once we know which molecule is increased in a disease, there are several ways to bring its levels down to normal. For example, it isn't necessary to focus only on the enzyme that normally disposes of the molecule. We might be able to inhibit the enzyme system producing the molecule. This would be another way to reduce the elevated levels of sulfatides in MLD. Some years from now we might even try to correct the abnormal DNA itself using appropriate drugs or even viruses. If its DNA were restored to normal, the cell could then go on to produce a normal enzyme. I cite these "science fiction" approaches to indicate how molecular biology has opened up an exciting range of therapeutic possibilities in what seemed to be only yesterday a hopeless field of medicine.
The previous three sentences were written twenty-five years ago, and remain unchanged. Last year, an article appeared from Germany that reflects both the deferred promises and the caveats inherent in the kinds of feasibility tests currently underway worldwide." Matzner and coworkers began with an animal model for MLD: a strain of mice deficient in sulfatase A. What they needed next was both a good so-called "gene delivery system" and some "extra good" DNA. Into normal bone marrow stem cells from a normal donor, they then introduced a special kind of enhanced mutant DNA. They used a retrovirus to carry this augmented DNA into the donor cells. When these mutant DNA cells were injected into the MLD mice, they did produce a little sulfatase A that remained active. The recipient MLD mice did move better, but it wasn't clear why this had occurred, because the microscopic sections still showed abundant sulfatide deposits.
In the interim, what other function do deposition diseases serve? They serve as models-as prototypes. Progress in understanding, or in diagnosis or therapy in any one disease, makes it much easier to advance in other similar diseases. For example, years ago we developed a simple inescapable hypothesis. Given the sulfatase A deficiency in MLD, there ought to exist another disease caused by a deficiency of sulfatase B. We filed away this possibility in the back of our "prepared mind." Nothing came of it for many years. But, once again, while analyzing control tissues (tissues that we had first understood were from patients with Hurler's disease), the unpredictable happened. This time, Dave Stumpf, the same exceptional medical student who worked on MLD, went on to establish that what these "control disease" tissues actually had was a single sulfatase B deficiency, one specific for a completely different form of mucopolysaccharidosis. This separate disease is known as MPS VI (mucopolysaccharidosis VI, or Maroteaux-Lamy disease)." (See figure 7.) The sulfated molecule that piles up behind this sulfatase B enzyme deficiency is dermatan sulfate.
Starting bone marrow transplantation early in life has clearly benefited children who suffer from MPS Vt." It can reverse many of the disabling cosmetic, other soft tissue, and cardiac complications of the disease, improving posture and joint mobility as well. Cats also inherit the feline form of MPS VI, and have recently helped researchers study various newer potential therapies.''
In overview, medical scientists can now visualize many of the storage diseases in their broader biological perspective. We have this greater conceptual understanding because of the pioneering work begun in 1949 by the Belgians, de Duve, Hers, Van Hoof, and their collaborators. These investigators characterized small particles, called lysosomes, in living cells."' Lysosomes contain many enzymes that collectively break down all major constituents inside our cells: lipids, carbohydrates, proteins, and nucleic acids. Such digestive enzymes normally help the cell avoid abnormally high concentrations of these molecules. Sulfatase A, sulfatase B, and cerebroside galactosidase are included among these lysosomal enzymes. In short, lysosomes can be viewed as the digestive apparatus of the cell. If lysosomes lack o
ne digestive enzyme, then the molecule they normally would digest builds up in the cell and stays there. We can visualize MLD as a disease in which lysosomes lacking sulfatase A cannot dispose of sulfatide molecules. In this sense, MLD is a "lysosomal" disease.
In the polyglucosan deposition disorders and the aging disorders at the right in figure 10, researchers now have a better idea of which molecules are increased (and decreased), but still lack a specific mode of therapy to reverse the condition. When the answers do arrive, many will probably reflect the operations of chance events of the kinds described herein. Short of a sea level change in our attitudes toward chance events, few such events (if any) seem likely to be acknowledged in print in the standard research journals.
We have spoken of mutations in the medical sense, as though they were all bad. But as biologists we realize that the genetic accidents we call mutations have been the basic fact responsible for the evolution of mankind up to Cro-Magnon man and beyond. Monod emphasizes this fascinating point about mutations: "Since they constitute the only possible source of modifications in the genetic text, itself the sole repository of the organism's hereditary structures, it necessarily follows that chance alone is at the source of every innovation, of all creation in the biosphere.'"' Anything this important deserves our attention. Let's look next at chance, and then at creativity.
Part II
The Varieties of Chance
What is life but a series of inspired follies? The difficulty is to find them to do. Never lose a chance: it doesn't come every day.
George Bernard Shaw
13
Chance and the Creative Adventure
But if adventure has a final and all-embracing motive, it is surely this: we go out because it is in our nature to go out, to climb the mountains and sail the seas, to fly to the planets and plunge into the depths of the oceans. By doing these things, we make touch with something outside or behind, which strangely seems to approve our doing them. We extend our horizon, we expand our being, we revel in a mastery of ourselves which gives an impression, mainly illusory, that we are masters of our world. In a word, we are men, and when man ceases to do these things, he is no longer man.
Wilfred Noyce
If you are completely candid with yourself, you will soon discover how much your discoveries hinge on contingencies. Every now and then, when you happen to combine both boldness and skill, you may be able to exploit a few of the lucky situations that arise. But skill alone will not be enough, for much of the novelty in creativity is decided only when you are bold enough to thrust at chance.
At this pivotal moment, research is more than all the things we have discussed thus far. In essence, it is an adventure. To be fully creative, you must respond positively to the risk and the challenge of exploring new frontiers. This mobilization of self to seek out and confront a new situation, whatever its primitive origins and subsequent refinements, is a powerful agent of creative discovery. One of my teachers of neurology at Columbia, Professor Houston Merritt, used to say, "Behold the turtle, he makes progress only when he sticks his neck out." Like the lowly turtle, we too will only lurch forward if we first stick our necks out to look around, then chance the consequences. We must take the chance.
We do need a sense of adventure in our lives, and adventurous impulses may appear in some other form if they are not channeled off into our work. Why do I think this is so? Each summer when I stop work and go on vacation, we head up into the mountains for two or three weeks of camping and fishing. Two days after camp is set up, I start becoming very relaxed and "loose." At this time, I develop what I have called for many years "adventure dreams." Vivid and colorful, they involve me either as an awed participant or spectator in some extraordinary situations. The plot involves adventure and exploration almost anywhere on the surface of the earth; the tone is one of excitement without fear. Most locales I have never visited or seen in photographs, nor are the experiences those I have lived or read about before. I became so engrossed in the story that as the dream fades with wakefulness, I try vigorously to steer it back, while still remaining astonished at the range of situations portrayed. Rarely do I have adventure dreams in the city, and then only after two or more days of respite from the usual work-filled routine. Surely one of our deeper needs in life is to find a daytime occupation that satisfies the innate thirst for adventure we find out about in our dreams.
Dreams do tell us who we are and what interests us. If you are a person who does better on open-ended tests requiring imaginativeness and mental fluency, you will also tend to specialize in the liberal arts rather than in the physical sciences. You will probably recall more dreams, they will more frequently involve people and animals,' and your dreams will also involve you in more frequent and more aggressive interactions with other persons. If you area biomedical investigator, hope that your personality contains a generous blending of the elements in both the arts and sciences, for you surely need to meld the attributes of each in your work.
But let us now return to the investigator on the job during the daylight hours. He is in a reflective mood at his laboratory bench. He may still be chasing the elusive possibility of finding something new, yet he knows there is more to research than this-more than simple curiosity, more than the fun of solving problems, more than occupational therapy. As he looks back, he feels a positive thrust of many years' duration in his work, sees it operate on a sweeping scale throughout the course of his lifetime. To him, biomedical research is taking one step after another into pitch darkness-not a fussy rearranging of familiar furniture in a floodlighted room. He senses the depth of his commitment to an entire life of uncertainty, testing, and challenge, to an acceptance of failure far more often than success. Yet he will take the chance.
No ground the researcher really wants to explore is secure under foot. The shaky nature of his footing was summed up well by the American painter, Albert Pinkham Ryder, when he said:
Have you ever seen an inchworm crawl up a leaf or twig and there, clinging to the very end, revolve in the air feeling for something to reach? That's like me. I'm trying to find something out there beyond the place I have a footing.2
The investigator groping away at a major problem knows he is engaged in a trial and error business, and freely accepts its implicit "back to the drawing board" philosophy. Only in his readiness to generate hypotheses is he well-prepared when he begins his search. Thereafter, he must remain ready to change tactics (always), strategy (many times), and policy (less commonly, but whenever the situation warrants). The worm does turn. It must.
At the beginning, the researcher will send up as many trial balloons as he can, having little immediate knowledge of their validity or, indeed, of their final destination. Most will pop; a rare one soars to an unforseen height, drifting in the winds of chance. Surprisingly, he finds himself aboard, aloft, jettisoning old certainties, patching holes in his new craft with the tattered fabric of previous failures. Like as not, he will wind up in some other county, and if he's lucky, in a foreign country, where other unexpected adventures will await him.
In his quest, the investigator is kin to other explorers, pioneers, and mountain climbers. He begins his journey not realizing its full implications. Beginning, he is swept along by an exciting chain of contingencies. Rewards, apart from the stimulation of the search itself, come more as an afterthought. In the risking, he is most alert, most alive; in the seeking, lie has found. He needs to take the chance.
What else does he find, as a by-product? No permanent satisfaction for his innate curiosity, for it is insatiable-instead a way to ensure that it is constantly engaged. No path that reveals the outside world alone, for each new project is also self-revelatory; each adventure involves a voyage of self-discovery. Anyone as consumingly curious as is the investigator about his external world is also curious about how his own internal world came to grow up and function. And, bit by bit, glimpses of this, too, will be revealed to him in one guise or another. If but for this reason alone,
he cannot afford not to take the chance.
14
On the Trail of Serendipity
This discovery indeed is almost of that kind which I call serendipity, a very expressive word.... I once read a silly fairy tale, called The Three Princes of Serendip: as their highnesses traveled, they were always making discoveries, by accidents and sagacity, of things which they were not in quest of.... you must observe that no discovery of a thing you are looking for comes under this description....
Horace Walpole
We use the word often nowadays. But what does serendipity really mean, where did it come from, and who were the three princes exemplifying it? If we dig down through many layers, we find a term deeply rooted in antiquity. The tale of the three princes in Walpole's letter is at least 700 years old! Indeed, parts of the legendary story probably go back more than 1,500 years to old folktales told around the campfires at night when camel caravans were resting (figure 11).
It was in 1557 that Christoforo Armeno' gathered together and published a number of the ancient stories that originated in Persia and India. He focused on the story of three princes, and, possibly to tend a still more exotic note to his tale, he placed their home on the island of Sri Lanka (formerly Ceylon). However, he still preserved the flavor of Persia, where many of the stories originated, for he called the island "Serendippo." In doing so, he was thinking of the medieval Arabian name for Sri Lanka. It was Sarandib, or Serendip in later Persian.'
Chase, Chance, and Creativity Page 8