“We wish to suggest a structure for the salt of deoxyribose nucleic acid (D.N.A.). This structure has novel features which are of considerable biological interest.”
Those famously understated words introduced a research paper written by James Watson and Francis Crick that appeared in Nature in April 1953. The second sentence set wheels in motion that ultimately revolutionized life science research and provided the foundation for the eventual emergence of the international biotechnology industry.
But as Tim Harris, PhD, points out in his remarkable new book, In Pursuit of Unicorns: A Journey through 50 Years of Biotechnology, modern biotechnology really began with the creation of recombinant DNA plasmids, which could be transferred into bacteria that would manufacture human proteins from the microbes’ coded genes.
Harris should know. An English molecular biologist, he began his career in 1974 and later joined one of the first British biotech companies, Celltech, in 1981 in the U.K. Harris continued to work as both a scientist, executive and entrepreneur, who went on to create several companies. He currently serves as a venture partner at SV Health Investors.
As a bioindustry veteran, Harris provides a broad but richly detailed account of the founding of the pioneer firms in the late 1970s, early 1980s, up to more recent arrivals as new companies continually enter the business. He talks about the key scientists and business professionals involved in this 50-year bioindustrial path along with clear explanations of the science underpinning topics, including monoclonal antibodies, genomics, DNA sequencing, antisense and RNA, gene and cell therapy, and vaccines. Harris supplements the 18 chapters with short sidebars providing additional information about the key technologies.
All the basics that anyone needs to understand on how biotech got started, developed, and where it is headed into the future can be found in Harris’s book. But what also makes the book such a pleasure to read, especially for someone like me who has covered the industry for almost four decades, are Harris’ personal insights and vignettes about the industry he’s been a part of for so long.
For example, I first learned about biotechnology while reading a news story on the famous Asilomar Conference in 1975, which set up the first guidelines concerning the physical and biological containment of recombinant DNA (rDNA) organisms that served as the model for the current guidelines used by the NIH.
However, the groundwork for Asilomar’s exploration of concerns about the potential hazards of rDNA was actually established at the 1973 Nucleic Acids Gordon Conference and in a subsequent meeting at MIT. Yet, despite most scientists giving the Asilomar guidelines their thumbs up, Cambridge, Massachusetts declared a moratorium on genetic engineering experiments in 1976 due to public opposition to the use of rDNA techniques. The moratorium was subsequently lifted in 1977, and today the Boston-Cambridge area is one of the global hotbeds of biotech research and commercialization.
Another major issue discussed by Harris is the reluctance of some academics (in reality, probably more than one would expect based on my experience) to get involved with the business of biotechnology and the jealousy directed at colleagues who do. Regarding the role of Herb Boyer, a professor at UCSF, as a co-founder of Genentech, Harris writes in a footnote:
“Initially there was a certain amount of political sensitivity and jealousy surrounding Herb Boyer and his associations with the company, especially from other UCSF faculty, who subsequently got into their own commercial ventures. Boyer was on the Genentech board of directors but deliberately kept a distance between the work being done in the Genentech labs and his lab at UCSF. Nonetheless, the animosity persisted.”
Mark Ptashne and Tom Maniatis, both molecular biology professors at Harvard University, co-founded Genetics Institute in 1980. But their initial footsteps into the commercial arena traversed a rocky road. The Harvard Management Group (HMG), which oversaw Harvard’s endowment, asked Ptashne if he would be interested in starting a biotech company in which the university would have an equity position. Ptashne called Maniatis, who had moved to Caltech in Pasadena, to meet with the HMG and a number of potential founding scientists, mostly from Ptashne’s lab. Harris recounts what happened afterwards:
“The interactions between the postdocs and the HMG did not go well, and the meeting ended without an agreement to move forward. The duo faced another setback when Derek Bok, the president of Harvard University at that time, introduced the Harvard Faculty Senate to the idea of the University holding equity in a faculty-founded biotech company. The proposal was met with overwhelming opposition from the Harvard faculty.
“Although initially supportive, the negative faculty response persuaded Bok to give up Harvard’s significant stake in a startup, and to denounce all faculty biotech entrepreneurs. Undeterred by the faculty response and Bok’s rejection, Ptashne and Maniatis went forward with blue-chip venture capital support to start Genetics Institute.”
Harris notes that Bok was more than disappointed in the decision because when Genetics Institute went public, Harvard would have had a share in those proceeds.
In my opinion, the petty jealousy and envy along with a good deal of academic revulsion toward the commercialization of pure research findings cannot be underestimated during the early biotech years. In his 2023 book, As Gods: A Moral History of the Genetic Age, Matthew Cobb writes that microbiologist David Martin told Science that “Capitalism sticking its nose into the lab has tainted interpersonal relations.” Nobel Prize winner Paul Berg complained that there was no longer a “free flow of ideas.”
The late angiogenesis researcher Judah Folkman, who often faced ridicule and being called a charlatan, said that he ran into intense “envy, jealousy, or hatred” regarding his work. Both Leroy Hood and MIT’s Bob Langer have written in Genetic Engineering & Biotechnology News (GEN) that they experienced similar resentment among segments of the academic research community.
Sometimes, two very smart people with extremely different personalities and backgrounds working together on a major project can’t help but lead to conflict. Such was the case, as made clear by Harris, with Craig Venter, an NIH scientist working on sequencing express sequence tags (ESTs) and Bill Haseltine, a Harvard professor.
Venter had the reputation of someone who liked to upstage everybody. Time magazine labeled him the “the Gene Maverick” and Science wrote he was a “genome combative entrepreneur.” He was a California beach boy who said, “I was a surfer as a kid” and “a surfer in Vietnam” where he served as a medic.
Haseltine was a wealthy East Coast member of the Ivy League. By all accounts, he and Venter were not fond of each other. Harris recalls his first meeting with Haseltine, an event that does much to highlight why there was a rift between Venter and Haseltine. After being kept waiting for 45 minutes, Harris walked out. He picks up the story:
“This seemed to endear me to him, because that was followed up by an invitation to meet him at his expansive apartment at the Pierre Hotel in New York. I remember this meeting very well too, because the apartment was like something out of an old English country house with a stuffed leopard rug on the floor and other colonial décor.
“I thought Bill would always be most happy wearing a suit. He was reasonably diplomatic but pleased with himself, in the way that a smart and aggressive politician might be.”
Venter was chosen to run The Institute for Genomic Research (TIGR), with Haseltine at the helm of Human Genome Sciences to commercialize TIGR’s findings. Harris neatly describes how the two men clashed to the degree that HGS and TIGR went their separate ways during the fifth year of a ten-year agreement.
What I found especially thought-provoking in Harris’s book were his personal thoughts on several industry topics, such as the following.
Group Think: Harris references the “tulip mania” that gripped Holland from 1634 to 1637. Everyone thought that tulip prices would forever be high but when value eventually exceeded their real worth the bubble burst and tulip sales plummeted. Harris then looks at the group think impact on the bioindustry:
The “group think” that led to these bubbles does still occur, even in the biotech sector. Group think, for example, prevails over the technology where several companies are formed around the same or similar technology when one or two at most would be sufficient to exploit the technology effectively… Sometimes companies should not be formed at all around a technology, owing to the time it takes to get any product launched. There are also times, as we have seen recently, when many companies that should have remained private, manage to go public in a bull market. When the market collapses, as in 2022, these small public companies are left high and dry with no way available to raise additional money. It gets very ugly very quickly under those circumstances, as companies fold up their tents and lay off all their people.
Technology Development: The key driver behind the creation and growth of a biotech business. Harris says:
Most of the small biotech companies that are set up fail in two ways: either quite quickly or painfully slowly. In 2015, there were ∼2700 biotech companies of various shapes and sizes. It is more than double that now. Those numbers translate to many failures and a few successes, the outcome for each largely dependent on the products that the companies make rather than the technology used to make them.
[But] technology takes you only so far. Technology always develops at such a pace that your technology becomes history more quickly than you or your investors anticipate. Look at gene editing: “plain old vanilla” CRISPR-Cas9 is being rapidly superseded by base-editing technologies… I expect a Nobel Prize for base editing in the not too distant future.
Artificial Intelligence (AI): Biofirms love to tout themselves as fully embracing AI in one area or another, but especially in drug discovery. Harris waves a timely warning flag:
I find the hyperbole around the use of AI in discovering drugs stunning. At its most hyperbolic AI “will discover (and develop) the drug for you without you having to do that much of anything experimentally.” In fact, AI is just another tool and technology to help control the uncertain process of drug discovery. The ability to predict the three-dimensional structure of many thousands of proteins, as has been done by AlphaFold and Rosetta, does not mean that new drugs will emerge like Excalibur from a lake of data. People sometimes forget that drug R&D, whether it be in biotech or pharma or even academia, is an experimental science. Although a computer tells you what might work, you still must test it in relevant experimental systems, both in cells and in animals. The results of those tests are often unpredictable, and without predictability you cannot design computer programs to predict, at least not yet. In time, when the data sets of cells, animals, physiology, pathophysiology, etc. are big enough and consistent enough, AI may be able to discover a good target and drug candidate.
There are many books on the market that cover all aspects of biotechnology. But as a writer and editor who has followed the industry for forty years, I cannot think of one packed with so much information and written so engagingly as In Pursuit of Unicorns. The book should appeal to anyone either in or outside the bioindustry and wants to know more about its history and current trends.
This book review was originally published in the August 2024 issue of GEN‘s sister peer review journal, GEN Biotechnology.
