It's All in the Delivery

Wednesday, October 17, 1984

By mid-October 1984, it was already clear that Walter Mondale would not be able to derail President Ronald Reagan’s bid for re-election. Los Angeles, the largest city in Reagan’s home state, was still basking in the glory that had accompanied the games of the XXIII Olympiad – a media spectacle which had boosted patriotism and transformed Carl Lewis and Mary Lou Retton into household names. In New York, Run DMC and the Beastie Boys were popularizing rap music while Bruce Springsteen fans were singing along to his hit single “Born in the USA.” And in Chicago, a promising young basketball star named Michael Jordan was practicing with the Bulls in preparation for his first NBA season. Basketball was also on the minds of the residents of Lawrence, where Jayhawk fans eagerly awaited the debut of All-American Danny Manning.



In this milieu, the arrival of 225 or so “internationally known scientists from Europe, Japan and the U.S.” for a three-day, invitation-only symposium on “Directed Drug Delivery” at the Lawrence Holiday Inn Holidome beginning on October 17 of that year hardly captivated mass attention.



To be sure, most KU students and Lawrence residents could hardly be faulted for lacking interest in the presentation of papers on topics such as monoclonal antibodies. However, the real significance of the conference did not lie in the scope of the papers presented by the pharmaceutical researchers and business executives attending it, but rather in the fact that it honored Takeru Higuchi, one of the most accomplished professors KU has ever had the privilege of claiming as its own.



Born to Japanese immigrants to the United States on New Year’s Day 1918, Higuchi grew up on a small farm in California. After spending three years at San Jose State College, he transferred to the University of California, Berkeley where he earned a degree in chemistry (which was bestowed with honors) in 1939. Later that year he began his graduate studies in physical-organic chemistry at the University of Wisconsin, Madison, which he completed when he received his PhD in 1943.



After spending a year as a post-doctoral research associate in Madison, the promising scientist took a job as a research chemist on a US Rubber synthesis project in Akron, Ohio. In 1947, the University of Wisconsin enticed him back to Madison to take a position in the university’s School of Pharmacy where over the next two decades, “his breadth and depth in basic science and mathematics” combined with his “self confidence, drive, brilliance, cooperativeness, and interpersonal skills” won him international recognition, numerous academic accolades, and acceptance as the leader of what was then the new field of “physical pharmacy.”



Thus, even by 1966, when Higuchi decided to leave his Wisconsin position as the Edward Kremers Professor of Pharmaceutical Chemistry at the end of the 1966-67 academic year to accept a post at KU, his peers in pharmaceutical chemistry already regarded him as something of a legend. His reputation would only grow over the course of the next two decades when he called Lawrence home.



KU had spared little effort to lure Higuchi away from Madison. In addition to naming him a Regents Professor, the highest professorial position at KU, the University also offered Higuchi considerable authority to develop a nationally recognized program in pharmaceutical chemistry, and dangled the promise of new buildings that would facilitate his research and help him draw graduate students. In fact even before Higuchi had made the move to Kansas, KU had initiated plans had to build a Pharmaceutical Chemistry Laboratory Building on West Campus, now known as McCollum Laboratory. Three other buildings that would form a “pharmacy-chemistry complex” would be erected over the next decade.



It did not take long for Higuchi to fulfill KU Chancellor W. Clarke Wescoe’s prognostication that the “father of physical pharmacy” would “make his inspiration felt throughout the University.” His arrival lent immediate credibility to KU’s chemistry department and Pharmacy School, and attracted some of the top graduate students in the nation.



Indeed, he had trained nearly 100 graduate students while he was at Wisconsin and would add another 100 more during his time in Lawrence. By the 1980s, one of his colleagues could reasonably estimate that Higuchi had “trained more people in upper and middle management in the US pharmaceutical industry than anyone else, and that one-third of the nation’s pharmacy school deans and department chairmen [were] former Higuchi students.”



Further, he would more than fulfill the University’s hope that his presence would “have an impact on the economy of the state.” Thanks to his sharp business acumen (which in 1985 would see Kansas Business News honor him as “Executive of the Year”) and a commitment to marrying the “theoretical” research done on university campuses with the “practical” drug production by pharmaceutical companies, he would enable KU to make millions of dollars.



Naturally, Higuchi’s success as a professor and businessman was a function of his capabilities as a scientist. His research centered on improving drug “delivery,” which is to say, making pharmaceuticals more effective and reducing side effects. Because the human body does not differentiate between drugs and anything else introduced into it, drugs “can be destroyed in metabolic processes, which have to be circumvented if the drug is to be effective.” Thus Higuchi and his graduate students focused their energies on devising “biological ‘packages’ for drugs” that would reach the “target tissue” and release their contents in a controlled manner.



Since traditional pills tend to be among the least efficient drug delivery vehicles, releasing all of their medicine as soon as their coatings are dissolved by the stomach’s gastric juices, they frequently work for only a short period of time. As such, pills often require higher concentrations of active chemicals, and may result in varying side effects. (Even aspirin, an example Higuchi liked to use, causes the body to lose one teaspoon of blood per tablet because it erodes the intestinal lining. Many drugs cause far worse side effects.)



Thus he designed a pill that works as a “chemical pump” and uses osmosis to regulate the discharge of the medicine rather than releasing it all at once. Such a pill could limit unwanted side effects. Similarly Higuchi developed an anti-glaucoma agent that “put a chemical wrapper” around a drug molecule, enabling the medicine to penetrate the eye membrane much more efficiently than it otherwise could, and in so doing, making the drug “10,000 percent more effective.” All told, Higuchi published more than 300 articles about his research and acquired more than 50 patents.



During his years in Lawrence, Higuchi also demonstrated a business prowess that rivaled his scientific brilliance. A year after the Japanese-American scientist’s arrival on Mt. Oread in September 1967, Alejandro Zaffaroni solicited Higuchi’s assistance in starting a new California-based drug research firm. As Zaffaroni admitted at the 1984 symposium honoring of the “father of physical pharmacy,” his list of names of people in the pharmaceutical sciences whom he wanted to bring into the company “stopped at one name: Higuchi.” Consequently, he responded to Higuchi’s refusal to accept a position on the West Coast by agreeing to pay for the construction of a building on KU’s West Campus so that Higuchi could head the research for the company.



As part of the deal that Higuchi brokered, the KU Endowment Association received 10,000 shares of stock in Zaffaroni’s Alza Corporation. When Alza erected a research facility in California in 1972, Zaffaroni agreed to sell the building at cost to Higuchi who formed a new corporation, INTERx (which was capitalized by the $500,000 profit that Higuchi and KUEA made in selling their shares of Alza stock). Eight years later, INTERx became a subsidiary of Merck when the pharmaceutical giant purchased it for $9,000,000. Higuchi remained president of INTERx, as well as vice president of Merck’s Research Laboratories. The Endowment Association, for its part, made an estimated $3,000,000.



Having proven capable of putting money into the University coffers, Higuchi had little trouble convincing KUEA to support a new endeavor, Oread Laboratories, following the state’s establishment of KU’s Center for Bioanalytical Research in 1983. The Center was one of three “Centers for Excellence” created by the Kansas Legislature for its Regents Universities with the aim of sparking economic development in the state. Its chief purpose was to develop technology capable of measuring “minute amount of chemical compounds in living systems” and in doing so help to foster a nascent high tech industry in the state. As with the other Centers for Excellence, the state was willing to provide half the funds (which were to come from lottery revenues) to construct the Center, but the other half was to come from corporate donors. Higuchi decided to create such a corporate partner for the Center for Bioanalytical Research and the KU Endowment Association (a non-profit organization) was willing to assist him.



The KUEA thus provided the initial capitalization of $750,000 for Oread Laboratories (a for-profit company, albeit a paper one at the time), which in turn supplied the matching funds. Of course the money granted by the KUEA was not sufficient to make Oread Laboratories a reality, and so Higuchi did some fundraising of his own. By the end of 1985 his efforts had proven so successful that Kansas Business News could estimate that with “the proceeds from the stock sale and a planned industrial revenue bond issue by the City of Lawrence, Higuchi will have raised a total of $7,000,000” to start up the company (which became operational in 1987). In addition to facilitating the development of a “high tech” industry in Kansas (based on the Center’s research), Oread Laboratories was intended to establish a new relationship between industry and the academy – one that would solve an ethical dilemma faced by scientists who sought to accept funding “from profit-minded private industry” while maintaining their academic “purity.” In essence, then, as the scientists working in the Center for Bioanalytical Research made discoveries, Oread Laboratories could patent and commercialize them. Since the Endowment Association would own shares in the company, the profits – “estimated to reach the tens of millions – [would] all flow back to the university.”



The relationship between Oread Laboratories and KU served as a prototype for University “incubators” with ties to particular companies that could market university innovations and has since been much imitated. However, the degree to which the company Higuchi formed actually solved the ethical problems implicit in scientists’ solicitation of funds is debatable. Nonetheless, this approach does reveal that Higuchi, who on occasion drew criticism from those who believed he “used his university position to enrich himself,” was concerned with the ethical implications of his research.



In 1983, he recognized the effect that newer and better drugs had on increasing health care costs, and expressed his concern about whether or not “his work [had] really been in society’s best interests.” Indeed, at the October 1984 conference in his honor, he claimed that health care in the US had “reached the point of disaster.” Worried that the nation’s catering to individuals’ desires to live long lives merely “for the sake of longevity” was already creating exaggerated health care costs (and realizing that newer and more effective treatments were appearing regularly and only increasing the amount of money that might be spent on health care), he asserted that “modern society had not faced basic questions of good and evil implicit in its extravagant approach to health care.” “The irony of it all,” he claimed, “is that we flush down the toilet a perfectly formed fetus and try to keep alive a terminally ill person at a cost that could pay for the child’s education.”



Although he received numerous awards throughout his career, the early 1980s saw his honors reach unprecedented heights. In November 1981, the American Pharmaceutical Association Academy of Pharmaceutical Sciences (for which Higuchi had served as the first president) announced the establishment of the Takeru Higuchi Research Prize that was to be presented for the first time in 1983. The prize would be given to a scientist “who [had] demonstrated effective and persistent efforts in pioneering a new concept in the pharmaceutical sciences” and would entail both a medal and a substantial cash award.



In the year that the first Takeru Higuchi Research Prize was awarded (to Gerhard Levy of the State University of New York at Buffalo), its namesake won the Remington Honor Medal – perhaps the most prestigious honor in the pharmaceutical profession. A year later, when Higuchi reached retirement age, the Lawrence symposium on “Directed Drug Delivery” served as a kind of a career valedictory. As the University Daily Kansan pointed out, the conference was as an opportunity for the “father of pharmaceutical chemistry [to get] a visit … from a lot of his children and grandchildren.”



For some of those at the conference, it would be their last time to see the “father” of their field. Less than three years later, in mid-March 1987, while attending an annual gathering of his former students and a few of his friends and colleagues for informal, “colleague-to colleague” discussions of pharmaceutical matters (at an event that had been dubbed the “Annual Higuchi Research Seminar” nearly 20 years earlier), Higuchi developed serious cardiovascular problems.



Rushed from Lake of the Ozarks in Missouri to the University of Missouri Medical Center in Columbia, he had his second coronary bypass surgery in eight years. (He had long had heart problems and had done what he could to guard against them. Indeed shortly after his arrival in Lawrence, he had developed a reputation as the “jogging professor” because he ran four miles every morning.) At the University of Missouri Medical Center, he appeared to be recovering normally, but on March 24 he died unexpectedly.



More than 1,000 people turned out to pay their respects to Higuchi at a memorial service held in Lawrence three days after his passing. Newspapers ran articles celebrating his accomplishments and his generosity. (With his wife, Aya, he had established eight different scholarship funds through the KUEA.) A few newspapers even attempted to list his awards and honors.



Joseph V. Swintosky, who had known Higuchi since his days as a graduate student in Wisconsin, was one of those who enumerated a good number of Higuchi’s accomplishments. Swintosky wrote a “Personal Remembrance of Takeru Higuchi” for the American Association of Pharmaceutical Scientists in which he included a list of the highlights of Higuchi’s honors that ran 46 lines. Nonetheless, he made no pretense of claiming that the list was complete.



Even the Kansas House of Representatives got in the act, passing a resolution asserting, “Over the past 20 years, it is doubtful if anyone has contributed more than Dr. Takeru Higuchi did to heighten the international respect for and prestige of The University of Kansas.”



His legacy, however, extends beyond all of the praise heaped upon him, awards bestowed to him, and honors that carry his name. While his work in shaping the careers of many who cast large shadows in the field of pharmaceutical chemistry remains evident, it does not encapsulate fully his legacy. His leadership in his field made him more than a great scientist and influential mentor. It made him, as Swintosky pointed out, “a legend and stood him in awe among his peers for almost five decades.”



Few academics prove capable of remaining significant in their field (let alone dominating it), for half a century. Fewer still earn millions of dollars for their universities. And even fewer than that become legends. Takeru Higuchi did all three.



Mark D. Hersey

Department of History

University of Kansas

 

[Source Notes: Takeru Higuchi File, University of Kansas Archives, Spencer Research Library, University of Kansas, Lawrence, Kansas – this contains hundreds of articles, clippings, press releases, curriculum vitae, and correspondences from Higuchi’s two decades at the University. Despite the poor documentation of some of the clippings, the file is a particularly valuable resource; Kansas Business News (December, 1985); Lawrence Journal World: 6 January 1970; 16 September 1966; Explore Magazine (Fall 1983), 8-9; University Daily Kansan: 2 October 1984; 18 October, 1984; 19 October 1984; 25 March 1987; Joseph V. Swintosky, “A personal Remembrance of Takeru Higuchi, American Association of Pharmaceutical Scientists; Journal of Pharmaceutical Sciences 72 (April 1983) – this issue was dedicated to Higuchi; Kansas Alumni (December 1977), 1-2; The author would also like to thank Charles J. Decedue, Executive Director Higuchi Biosciences Center and Howard Mossberg, Vice Chancellor Emeritus, Pharmacology and Toxicology and Dean Emeritus, Pharmacy Practice for their assistance in clarifying certain details of this essay. Any faults that remain belong to the author alone.]