Sense and Antisense in Biotech: The First Antisense DNA Company

The FASEB Journal Milestone
Sense and Antisense in Biotech: The First Antisense
DNA Company
Thoru Pederson 1
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical
School, Worcester, Massachusetts, USA
“There is a balm in Gilead
To make the wounded whole”
—(Opening lines of an African-American folk song)
AUTOBIOGRAPHY OF A START-UP
No two biotech start-ups have quite the same story
to tell or the same journey thereafter, whether long- or
short-lived. They cannot, because although business
schools present standard models and even instructive
anomalies, there are always probabilistic elements, and
the art is in nimbleness. (We can recall by analogy that
Darwin did not equate evolution with intrinsic superiority
of type but a species’ capacity for adapting to
change.) All sorts of issues loom in the prestart-up
phase. Did one of the potential investors come across as
uninformed? Did the first CEO candidate interviewed—prelaunch—strike
some of the investors as,
well, to use a term sometimes uttered at the University
of Cambridge in the 1930s by C. P. Snow and his
colleagues at High Table, “unsound”? Did something
new and never discussed suddenly appear on the termsheet
24 h before closing? Did the appointed CEO
install a palatial oriental rug in the front office?
Here, I recount my personal experiences in one
start-up venture with perspectives on the often-determinative
degree to which personalities can influence the
formative stages. This case study concerns antisense
DNA as a potential therapeutic advance and has two key
players—one, a scientist of considerable stature, and
the other, a gutsy business strategist more than 40 years
younger. One theater of the story began around 1975
in a venerable lab at Massachusetts General Hospital,
and then in 1979, transited 40 miles west to the
Worcester Foundation for Biomedical Research (where
I came upon it). The other axis of the story began a
decade later at Menlo Ventures in Foster City, CA. Once
all the due diligence by the latter had been completed, a
brave start-up was launched. The company had an initial
run with antisense but subsequently turned its corporate
strategy to an entirely different platform than its foundational
science and went on to achieve tremendous success.
Both the antisense DNA pioneer and the Menlo Ventureslaunched
company subsequently reaped due accolades in
their respective guilds—science and industry. Here, I
convey some less well-known features of the story, which I
believe have much to teach us.
Paul Zamecnik as a resident at the Mass General Outpatient
Clinic, 1943. He was, at this time, approximately the
same age (31) as was Michael Riordan (29) when the latter
started his company. Reproduced from Zamecnik, P.,
(2005) From protein synthesis to genetic insertion. Annu.
Rev. Biochem. 74, 1–28, by permission of Annual Reviews,
Palo Alto, CA, USA.
ACADEMIC PURSUITS
Paul Zamecnik started out as a physician but became a
biochemist—almost entirely self-trained (1). He spent
most of his career at the Massachusetts General Hospital.
In 1978, he and his postdoctoral associate Mary
Stephenson demonstrated that a short (13 nucleotides)
piece of ssDNA could inhibit cell-free mRNA translation
(2). But, even more provocative was their companion
paper, demonstrating that this oligonucleotide,
1 Correspondence: Dept. of Biochemistry and Molecular Pharmacology,
University of Massachusetts Medical School, Worcester,
MA 01605, USA. E-mail: thoru.pederson@umassmed.edu
doi: 10.1096/fj.12-0902ufm
3594 0892-6638/12/0026-3594 © FASEB

added to the cell culture medium, also inhibited the
replication of Rous sarcoma virus (RSV) in intact
cells (3). Zamecnik tried to convince Mass General to
seek patent protection, but the institution deferred.
Presumably, the rights then went to him, but he did
not pursue them with the U.S. Patent and Trademark
Office as far as we know. Meanwhile, 1 year before—in
1977—another key event had occurred.
Zamecnik turned 65 and thus, came up against the
Harvard Medical School’s strict retirement policy. In
an impassioned letter to the dean, Zamecnik made a
case for side-stepping the retirement rule, but the
administration held to the policy. In one of the most
ironic and fascinating twists in this story, Zamecnik
actually had the final satisfaction, 20 years later, as we
shall see.
Reaction to the two papers by Zamecnik and Stephenson
was mixed. At this time, I was at the Worcester
Foundation, a research institute in Shrewsbury, MA,
and had in those years gotten to meet Zamecnik on
several occasions, as he was on the foundation’s Board
of Trustees. A few months after his 1978 papers came
out, I went to see him to encourage the use of in vivo
psoralen-mediated DNA-RNA cross-linking to capture
his oligo in its base-pairing to the target RSV RNA. My
lab was using this approach for other purposes at the
time (4), and I was reasonably optimistic that the
method could detect the base-pairing of his oligo with
its RNA target, and this would thus be an in vivo
confirmation of the envisioned event. I thought this
experiment could overcome the legions of skeptics at
the time. So, on the morning of our scheduled meeting,
I wandered into Mass General thinking of all the
great medicine and medical science that had been
done under its roof and began to think, “What am I
doing here?” (My angst was mainly because I had never
studied medicine, and I felt an imposter in such
hallowed halls.) I found Zamecnik’s location, and we
sat down at a battleship gray desk in a dusky hallway,
leaving me to ponder if this was in fact the office of the
Collis P. Huntington professor of Harvard Medical
School? (It may not have been his real office but simply
a convenient place for us to sit down, yet it may have
been a prescient setting, for I later learned that he
never sought adornments or embellishments in his
office.) He clearly understood the psoralen cross-linking
idea, but he cordially deferred doing the experiment,
saying that his group had too many other things
underway at the time. As I left for the elevator, I had a
sudden realization: he wasn’t worried that he was
wrong! This attribute (extreme confidence but not
arrogance) has often been noted by historians of
science when deciphering the sheer determination of
visionaries. The late Judah Folkman once wrote that
this trait, i.e., being sure (or at least 95% sure) at the
outset, can paint one’s subsequent pursuit of the idea as
either admirable persistence or bulldog obstinacy, depending
on the lens of the observer (5).
SENSE AND ANTISENSE IN BIOTECH
cis/trans AT THE NIH
Zamecnik and his group had played a seminal role in
opening up the entire field of molecular biology by
refining cell-free protein synthesis and discovering
amino acid activation and transfer RNA (1). Now, 20
years later, he had made yet another major discovery—
the first embodiment of antisense DNA—and so, he was
understandably dispirited by the retirement policy of
his institution, one to which he had given so much time
over the years on numerous committees (notably, Mass
General’s Executive Committee, which he once told
consumed one-third of his time) and other substantial
roles beyond his own laboratory. He promptly sought
and received a Fogarty Fellowship to spend 1 year at
NIH, during which he pondered his options. At 65,
Zamecnik was still physically robust and as athletically
inclined as always, so he looked around the NIH
campus for potential tennis partners. He later told me
that he and several NIH scientists had jointly and
amicably “interviewed each other at the net” (a sort of
cis-trans test, to use the genetics metaphor). After a few
games in trans, Zamecnik and one partner became cis.
The mutually chosen partner was Robert Gallo. This
conjunction turned out to be a profound event.
CALLING HOME
As his NIH Fogarty year was drawing to a close, Zamecnik
wrote to his former post doc Mahlon Hoagland,
who had discovered transfer RNA in 1958 when working
in Zamecnik’s group. Hoagland was now president
of the Worcester Foundation for Experimental Biology
and was well along in redirecting the institution from its
original fame in endocrine and reproductive biology—
having played a key role in both the birth control pill
and in vitro fertilization—into molecular biology and
cancer research. In this curious reversal of their previous
roles, Zamecnik was now asking his former post doc
to take him in.
The antisense DNA research program that Zamecnik
wrote up was seen by everyone with whom Hoagland
consulted (including myself) as powerfully promising,
and he was enthusiastically invited to come. (The
write-up Zamecnik had prepared had, at the top, a
phrase in his handwriting that I have always remembered:
“Dear Mahlon, Of course, this reads like a
novel”.) Zamecnik’s pioneering work on protein synthesis
at Mass General had been funded by a longstanding
grant from the Atomic Energy Commission, and on
his arrival at the Worcester Foundation, a very softmoney
institution, the issue arose as to how he and/or
the institution would now fund his promising ideas
about antisense DNA. He soon obtained a grant from
the National Institute of General Medical Sciences, and
his lab was also supported in part by a National Cancer
Institute (NCI) “Core” grant that Hoagland had won in
1971 and that I had successfully renewed as thendirector
of our Cancer Center. Later, after I succeeded
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Hoagland as president of the Worcester Foundation, I
was able to obtain support for Zamecnik’s program
from the Mathers Foundation, and both he and I were
always grateful for the risk that they were willing to take
(very much their ken at the time and still so today).
At the Worcester Foundation, Zamecnik pursued a
number of projects that were all proceeding well, until
his former tennis partner encouraged him to consider
a new target for his antisense DNA approach—a virus
that had just been discovered in isolates from patients
afflicted with a newly recognized immunodeficiency
disease. This was human T cell lymphotropic virus III,
soon to be known as HIV and, shortly thereafter,
established as the etiological agent of AIDS.
HIV AS A TARGET?
Given that Zamecnik’s initial publication (3) had been
with a retrovirus, Gallo’s suggestion didn’t need much
incubation time. Zamecnik immediately turned his lab
full-bore to antisense inhibition of HIV in infected cells.
The synthesis of oligodeoxynucleotides was now far
more facile and less expensive than it had been in 1976
when Zamecnik and Stephenson performed their classic
studies—this due to pioneering advances, notably by
Robert Letsinger and Marvin Caruthers.
In 1986, Zamecnik and colleagues (6) reported the
inhibition of HIV replication in cell culture by an
antisense oligo. Although he enjoyed, as a member of
the National Academy of Sciences, the privilege of
submitting his paper directly, he asked me and I
suspect others, including Gallo, to read the manuscript.
I marked it up more than I probably needed to and
gave him a bit of a hard time here and there. This was
one of the few times when we didn’t agree (there was
another, which is the basis of this story, to come). I felt
that the results were convincing but that the broader
therapeutic potential had been pitched a bit too ambitiously
(or in fairness to Zamecnik, maybe one could
say, “too optimistically”). I also thought the coining of
the term “hybridon” for the envisioned oligo:target
RNA duplex was a reach. The results at the time did
not, at least in my mind, demonstrate a mechanism of
sufficient clarity and cogency as to earn equal stature
with the venerable terms “codon” and “operon”, biblical
concepts in molecular biology to which I felt
Zamecnik’s results should not yet be added by coining
another such sacred-looking term in the nomenclature
of biological information transfer/suppression. To his
credit, Zamecnik and coauthors thoughtfully responded
to most of my points.
Zamecnik often remarked how reprints of the two
1978 papers he had ordered had turned yellow on his
office shelf as few requests arrived (this was of course
many years before the Internet and PubMed). But, the
1986 HIV paper generated much more buzz. This was
the era of still-embryonic but empathically zealous
searches for plausible approaches to antiretroviral therapy
for AIDS patients. For example, at this time Sam
Broder and colleagues at the NCI were racing ahead in
studies that would become the basis of the first effective
anti-HIV therapy, expanding on the Nobel Prize-winning
work on nucleoside analog drugs by Gertrude
Elion and George Hitchings decades earlier. Also at
work at NCI was Jack Cohen, a talented nucleic acid
chemist and structural biologist, who was exploring
oligodeoxynucleotide backbone modifications of various
kinds that might, it was thought then, have superior
pharmacokinetics, bioavailability, and maybe even enhanced
molecular action. (We shall encounter Drs.
Broder and Cohen again in this story.)
REDUCTION TO PRACTICE
By now, Zamecnik’s notion of antisense DNA had been
elevated from skeptical scoldings he had endured from
“experts” to a degree of recognition, in part, as a result
of the widely acclaimed success, already at hand, of the
antisense DNA method for knocking down mRNA
expression in at least cultured cells and certain animal
experiments as well. From the standpoint of epistemology,
note that Zamecnik had no role in the application
of antisense DNA to the knockdown of cellular mRNAs,
an application that brought the antisense DNA concept
more fame than did its therapeutic promise (exactly as
was the case years later for small interfering RNAs as
knockdown agents in cells relative to imagined therapeutic
applications). Zamecnik was never interested in
mRNA knockdown as a lab tool, regarding it as a
sideshow, glad to see this application but not wavering
from his own mission: antisense DNA as medicine. As I
have said elsewhere (1), Paul Zamecnik was unique
among the pioneers of molecular biology in that he
never stopped thinking like a physician.
LEARNING THE BUSINESS
Meanwhile, a surprising thing happened at the Worcester
Foundation. I had come in 1971, recruited by
Mahlon Hoagland. Zamecnik had come in 1979, also
recruited by Hoagland. On Hoagland’s announcement
in 1984 that he would retire 1 year later, a search
committee, led by Harvard microbiologist Bernard
Davis, tapped me to be the next president of the
institution. I asked Alex Rich [Massachusetts Institute
of Technology (MIT)], a member of the search committee,
for advice. He said, “You can do it and your
science too—the Worcester Foundation needs a leader
who can do both”. Thus, in a bizarre scenario, I became
Zamecnik’s “boss” on the retirement of his former post
doc who had preceded me as president of the Worcester
Foundation. Adding to the irony was that with my
expertise also being RNA, Zamecnik and I continued to
be extremely conversant and personally close, with our
employer-employee relationship mutually regarded as
rather absurd, although he was—always the gentleman—dutiful
to the formal requirements of the em-
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PEDERSON

ployer-employee axis, as I have detailed elsewhere in
some amusing vignettes (1). His lab and mine even
collaborated and published together on one occasion,
which was both fun and yet a bit contentious when we
were writing the paper. Our different writing/presentation
styles aside, this project and publication turned
out to have been a good idea (7).
Well before the 1986 paper (6), it had become clear
to both Zamecnik and me that his antisense DNA work,
especially the HIV axis, might warrant a start-up company.
I was worried about the lack of an issued patent,
thinking that Zamecnik’s 1986 paper might be deemed
obvious in light of his (unpatented) 1978 disclosure of
the core idea and art of enablement. Yet, I also felt that
the HIV paper had use “written all over it”, and in at
least U.S. law, this feature can often reign in patent
claim allowances.
The Worcester Foundation did not have a formal
patent income-allocation policy at the time, nor did
we even have a policy that required our scientists to
assign their rights to the institution (although I soon
introduced both). Zamecnik was consistently attentive
to the ways the Worcester Foundation might
benefit if his idea became the basis of licensed
intellectual property. I believe this reflected his prior
association with the Worcester Foundation as a
trustee, as well as his gratitude to Hoagland for
having taken him in. I had also directed some
discretionary funds to his lab after becoming president
and was very much behind his program in all
ways, including with our trustees and donors, and I
think he was grateful for that.
START-UP, OR NOT
Zamecnik’s son is a banker, and they were both connected
to their respective A-lists of Boston Brahmin
grandees, plus his son had some international connections.
Zamecnik also had numerous contacts in pharma
who had been medical students, fellows, or house
officers at Mass General, and he began conversations
with many of them. By 1987–88, we were both aware
that antisense DNA was on the start-up landscape, but
as we later realized, we were not as well connected to
big pharma or the blue-ribbon venture community as
he thought or as I innocently had assumed that we
might be based on his contacts. But R&D representatives
from Merck, Bristol-Myers Squibb, and other large
companies were willing to come and visit us at the
Worcester Foundation, and Zamecnik and I also went
to New York to visit a number of banks and venture
groups, among which I recall Rothschild Ventures as
being the most engaged. We also had a visit from
Hambrecht & Quist, and my recollection is that Zamecnik
didn’t think they understood the science. However,
neither Zamecnik nor I had developed a full-scale
business plan (one of our key mistakes), so all of these
companies, banks, and venture groups saw us as amateurs—a
charming and brilliant scientist with some
SENSE AND ANTISENSE IN BIOTECH
provocative lab results and the cheerful head of his
institution tagging along. Also, the Worcester Foundation
had no analogues of Stanford’s Niels Reimer or
MIT’s John Preston sitting in and advising us. In
retrospect, how I wish we had had such minds at the
table at the time. In October 1988, when Zamecnik and
the Worcester Foundation had reached a zenith in
their dyspepsia over how to commercialize antisense
DNA, I sought a meeting with MIT’s John Preston, who
was good enough to meet with me and offer advice.
This led me into a longstanding relationship with
Preston’s successor, Lita Nelsen, who, like Preston,
shared valuable time with me, even though I was not at
MIT nor was this MIT intellectual property. Nelsen’s
generous willingness to help me think through the
start-up situation and later, licensing issues is something
for which I shall be forever grateful to her.
ALMOST THE FIRST ANTISENSE DNA
COMPANY
The Worcester Foundation, of course, had filed a
patent application prior to Zamecnik’s HIV publication,
and by mid-1988, we had gotten an Allowance of
Claims, leading us to start a different conversation with
potential investors, given that some degree of patent
protection was now a realistic possibility. Thus armed,
Zamecnik and I, together or in other cases on our own,
embarked on another round of discussions with
pharma and banks but still with the same headaches
after every meeting. But then, Zamecnik came upon a
Harvard Medical School-launched venture fund. It was
initially called Ion Corp., but by the time Zamecnik
contacted the company, it was known as Medical Science
Partners. Harvard Medical School’s idea was to have
this entity provide, or help provide, access to seed capital
to nucleate start-ups based on the institution’s inventors
and licensable technology. Zamecnik’s courtship of Medical
Science Partners was technically off-base, as he was no
longer at Harvard, nor did it hold any rights to his
inventions. However, Zamecnik was still an emeritus professor
at Harvard Medical School, and this got him access
(conversationally, at least) to Medical Science Partners.
We had several meetings with its partners, André Lamotte
and Joseph Lovett, and Zamecnik and I both felt
that this was looking like a productive axis of conversation.
Yet, Zamecnik had been bitterly disappointed by
the reaction of pharma, as well as the negativity of the
banks that we had visited in Manhattan. As is often as
the case with an inventor and visionary, he saw his
concept as a perfect Aristotelian-Cartesian reality, but I
viewed it, from my own nucleic acid expertise, as a very
high mountain, not as lab science but in the clinic.
However, I had to put aside my concerns about antisense
as medicine, because as president of the Worcester
Foundation, I had the responsibility to do everything
that I could to turn his work into both an entity to
hopefully, in some possible way, improve the human
condition and also, to potentially return some money to
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an institution that had given the world the birth control
pill with no patent protection and thus, no royalties.
As we continued to keep the conversation with
Medical Science Partners going, one morning, Zamecnik
told me that he had been contacted by someone
named Michael Riordan, who wanted to come and visit.
Riordan had graduated from Washington University in
1979 and from Johns Hopkins School of Medicine in
1984. He had then been a free-lance consultant for 1
year and in 1986, had joined Menlo Ventures, in Menlo
Park, CA. In addition to mentioning these credentials,
Riordan had faxed Zamecnik an article that he had
published, in which he speculated how cell-free protein
synthesis might be scaled up for pharmaceutical production
of therapeutic polypeptides. This article obviously
struck a chord with Zamecnik (it was very well
done), and both of us thought Riordan looked good.
So, we invited him to come to the Worcester Foundation.
The first meeting took place on June 4, 1987, and
led to a second one on June 29th. Zamecnik and I saw
immediately that Riordan was very bright and extremely
well-informed, but there, our reactions diverged.
Zamecnik was unsure of Riordan’s cash position
and also thought in conversations we had after the
visit, that Riordan was too young to know much and
didn’t have credentials in science. I had an entirely
different reaction. I figured we would look into him in
our own due diligence, as well as the quality and cash of
Menlo Ventures at the next step. I also thought that the
fact that someone who actually knew molecular biology
had sought Zamecnik out was noteworthy (a reversal of
all of our previous knocking-on-doors efforts). I also
recognized that Riordan was still surveying the antisense
DNA landscape and was not necessarily to be
viewed as a potential partner. Zamecnik was viewing
Riordan as a possible investor in a company, which
Zamecnik would form, plugging the invested dollars
(from Riordan) into his (Zamecnik’s) start-up scheme
but not Riordan’s, although I sensed from the start that
Riordan had all of the capital to start his own company.
As I reflect back on that time, now 25 years later, I
realize that Zamecnik was, from his goal perspective,
duly wary of both “scientific dilution” and equity dilution,
whereas I thought Riordan was checking out the
entire antisense landscape and figuring out what, if
anything, he might need to license in. Thus, I was
mainly thinking of how the Worcester Foundation’s
pending patent could be licensed. Riordan and his
plans were the best thing I had seen, and in this respect,
I had to separate my roles as Zamecnik’s colleague from
my duty to the Worcester Foundation as president.
AN OLFACTORY VISIT
When Riordan came to visit Zamecnik and me at the
Worcester Foundation, neither of us knew how deeply
he had already dug into the science and promise of
antisense DNA. When he first entered Zamecnik’s lab,
he said, “I smell Beaucage reagent”. At this time in the
antisense DNA field, there was a prevailing idea that
replacing one of the nonbridging oxygens in the phosphodiester
bond with a sulfur atom would attenuate the
metabolic destruction of oligodeoxynucleotides in the
bloodstream. The pioneering work had been done by
Wojciech Stec in Lodz, Poland, and the chemistry
involves a reactant (Fig. 1A), named for the chemist
Serge Beaucage who developed it to introduce sulfur
into the phosphodiester backbone (Fig. 1B). (Although
ever since his name has been attached to this useful
reagent, Beaucage holds far-higher acclaim for his
pioneering role, with Marvin Carruthers, in developing
phosphoramidate-based oligonucleotide synthesis.)
Like many (but not all) sulfur-bearing compounds,
the Beaucage reagent has a distinct odor. Zamecnik’s
and my reactions to Riordan’s astute detection of this
chemical when he walked in (from which he knew
Zamecnik’s people were already making phosphorothioate-backbone
antisense DNA) were, once again,
entirely different. Zamecnik regarded this as an arrogant
affront—some kind of invasion of his lab—
whereas this Sherlock Holmes bravado elevated Riordan
in my mind. I was impressed that Riordan even
knew about phosphorothioates and immediately understood
the deep level in which he was analyzing the
antisense landscape.
However, I did notice something else. Zamecnik,
whereas somewhat discomforted by Riordan (as I was
not), at the same time, seemed to recognize something
in him. Perhaps as the father of a very successful
banker, Zamecnik recognized that talent in business
was what he was seeking for the start-up, and perhaps
A
B
Figure 1. An olfactory part of the story. (A) 3H 1,2-benzodithiol-3-one
1,1 dioxide, also called Beaucage reagent. (B) The
stereoisomeric products in phosphorothioate oligonucleotide
synthesis. These were hopeful in the antisense DNA therapeutic
field but failed.
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PEDERSON

he could overlook Riordan’s nonmembership in the
guild of molecular biology or among Mass General
alumni. In any case, some preliminary communication
between them went back and forth by facsimile (this
was of course before e-mail), and then, one morning,
Zamecnik walked into my lab (upstairs over his) and
said that Riordan had launched his own antisense DNA
company. I was less surprised than Zamecnik, but
nothing I said could cool him down. I told him that
although we had hoped we were being courted, it was
equally possible that Riordan was checking out the
entire landscape in a mission of self-designed due
diligence. What Riordan had promptly understood was
that although Zamecnik was the undisputed “father of
the concept”, not Mass General, the Worcester Foundation,
or Zamecnik himself was holding enabling
patents (the Worcester Foundation’s granted Allowance
of Claims did not reach into the therapeutic
domain). Also, as I suspect, Riordan’s thoughts were
that even if the Worcester Foundation might hold a
patent soon, it could always be licensed in. From his
perspective, why in the world would he want to fold in
an inventor and his institution at the equity allocation
and start-up phase? And, it is to be noted that Zamecnik
had made it clear in the discussions that he wanted the
Worcester Foundation to have an equity stake. I
warmed to this, of course, but I could see Riordan
integrating this into his calculus. Moreover, I had
sensed—just as a zephyr—that Riordan was not totally
keen about Zamecnik’s choice of HIV as the first target.
If so, there is great irony there, given what Riordan’s
company ultimately went on to do in HIV therapeutics.
In his final decision, Riordan chose to give up the
prestige that Zamecnik’s name would have given to his
company relative to the start-up dilution of equity that
would have meant.
Soon, Zamecnik and I became aware of pending
relationships Riordan was negotiating as he sought to
build his company. For example, there was oligodeoxynucleotide
synthesis technology at Northwestern University
(invented by Robert Letsinger) that Riordan was
seeking to license in. He had also, properly, looked into
work by Michael Gait at the Medical Research Council
Laboratory at the University of Cambridge. Zamecnik
was also pursuing both Letsinger and Gait, but Riordan
had already signed them up. Meanwhile and in the
opposite vector of contact and recruitment, another
antisense start-up planner had tried to engage Zamecnik,
but that is an entirely different story, perhaps for
another time.
HYBRIDON
In 1990, 3 years after Riordan launched his company,
Zamecnik and I cofounded Hybridon. I was a cofounder
only by virtue of being president and scientific
director of the Worcester Foundation, and simply represented
the foundation’s equity stake. (I did not take
founder’s stock and never owned stock after Hybridon
SENSE AND ANTISENSE IN BIOTECH
went public, believing that the company was not based
on work from my lab and that I should therefore not
personally gain just because I happened to be president
of the Worcester Foundation. I did receive an honorarium
of $3000/year as a member of the Hybridon
Scientific Advisory Board from 1990 to 1996 and felt
this was acceptable, as my role there was as a RNA
expert, not as the president of the Worcester Foundation.)
Zamecnik immediately focused the company on HIV.
His reasoning was that his “NIH tennis partner”, as he
always described Robert Gallo after that Fogarty year at
NIH, could help get National Institute of Allergy and
Infectious Disease contract funding for the antisense
idea. Meanwhile, I worried that AIDS might be the
wrong choice for an initial proof of principle and
argued for a Hybridon project using antisense DNA in
the arena of hypertension to knock down the messenger
RNA for the angiotensin-renin-converting enzyme
for treatment of essential hypertension. I had a long
conversation with James Wyngaarden, then chairman
of the Hybridon Scientific Advisory Board. Wyngaarden,
formerly a colleague of Zamecnik at Mass
General and later, director of NIH, was open to my
idea, but after further discussion, we agreed that Hybridon’s
cash position could not support a new project at
the time. One thing I learned (I learned so many things
in this biotech experience) is that it is very difficult—at
least in a cash-strangled start-up (almost always so)—to
change the R&D program.
THE ANTISENSE PATENT LANDSCAPE
The intellectual property landscape was murky in the
early days of the antisense field, as it often is in any new
technology. One of the enabling doctrines in U.S.
patent law—nonobviousness—seemed traversable in
the Worcester Foundation patent according to some
experts, but I worried about this going back to denatured
DNA-RNA reannealing studies in the 1950s. And,
in later years, complementary DNAs with base-pairing
recognition to targeted mRNAs were used to demonstrate
the presence and abundance of these mRNAs in
cellular RNA in solution hybridization experiments and
also, to arrest the translation of a particular mRNA in a
cell-free system. However, these publications (which I
knew well from my own field of RNA science) never
advanced or even hinted at the idea of using a short
DNA (or any other oligo) to interrupt gene expression.
Patent drama soon arose, as we all knew it would. The
aforementioned work at the NCI by Sam Broder and
Jack Cohen had resulted in a patent application on the
use of antisense DNA to inhibit HIV, which was being
pondered by the U.S. Patent and Trademark Office.
Later, when Hybridon was deep into its HIV program,
NIH challenged the Worcester Foundation patent application
relative to its own. Hybridon’s executive team
and an attorney from its outside counsel flew to
Bethesda, MD, on August 14, 1996. They asked me to
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come. (I was surprised but did.) We had a cordial
meeting with the NIH tech transfer officer, with whom
I was immediately impressed; she had done her homework
and possessed a deep knowledge of all the issues.
There was the usual give and take as the meeting
proceeded. As it was coming to a close, the NIH tech
transfer officer kindly asked me if I would like to
comment. I was grateful for her courtesy and said, “I am
concerned only for the well being of the Worcester
Foundation and have no other brief to register here”.
This statement stunned everyone in the room. The
entire morning had been devoted to a possible cure for
AIDS, and here was I saying, “I’m only in this for my
institution”.
Why did I make such a seemingly imperious statement,
sounding like all I cared about was my institution?
The answer is that by this time in the meeting, I
had gotten the sense of the NIH tech transfer officer.
She knew the NIH patent might have chinks in its
armor and also knew the Worcester Foundation patent
also had potential weaknesses. The Hybridon representatives
and their counsel were edgy, whereas I was
impressed that the NIH officer had gotten the whole
story. Although the Worcester Foundation and the NIH
had not yet entered into litigation over their patents
(and never did, as it happily turned out), I wanted NIH
to know where I stood, so I decided, in the moment, to
say that the Worcester Foundation would stand on its
patent and was in this only “for ourselves”. This did not
mean that I didn’t want antisense to cure AIDS and
other diseases, but it meant that the Worcester Foundation
would legally challenge NIH on its rights to
antisense DNA. I have always felt that the NIH officer
made a wisely calculated decision. She wanted all of the
intellectual property to find its way in the Patent Office
and not be subject to interference claims, taking years
to adjudicate. Everyone in the room that morning
wanted to help bring forth a new therapy for HIV.
Hybridon invested increasing resources in the HIV
project and eventually, moved a lead compound into a
Phase I trial. However, the efficacy was disappointing,
and the project had to be terminated. Other projects
were rekindled, but it was too late. The Saudi Arabian
investor syndicate that Medical Science Partners had
found as zero-stage investors stood by, and eventually,
Hybridon evolved into Idera, Inc. with the brilliant
Sudhir Agrawal taking up the helm. He had come to
Zamecnik’s Worcester Foundation lab and subsequently
gave Hybridon credentials in nucleic acid
chemistry, as had Zamecnik’s first recruit of nucleic
acid talent, John Goodchild, from the first. Under
Agrawal, Idera today is focusing on nucleic acid therapeutics
in the context of immune modulation and
Toll-like receptor biology.
SUDDENLY, A COMPANY
When Michael Riordan launched his antisense DNA
company, he was one of two partners in a strong
investor group, whereas Zamecnik and the Worcester
Foundation had been trying to align with one. Riordan
had better access to money, whereas much of Zamecnik’s
thinking was, in my opinion, tied to former
Harvard colleagues or other acquaintances who might
not have had the influence he assumed, certainly not in
the venture capital world. As I think back to when we
did our road shows (they really didn’t deserve that
name), at venture firms and banks, he was wary of
anyone who had not been at Harvard Medical School.
In hindsight, I regard this as the single flaw in Zamecnik’s
foray into the biotech world. Of course, hindsight
is 20-20, and I make this assertion with great respect for
all his other talents, which were many indeed. However,
I do think his persistent unwillingness to consider
business or scientific partners who were not personal
acquaintances and/or affiliated with Harvard was an
impediment to him reaching his goal of commercializing
antisense DNA.
Riordan had very good business partners from the
outset, notably, H. DuBose Montgomery, and then got
hyperlucky in getting former Searle CEO, Donald
Rumsfeld to join his company’s board, followed by the
engagement of former U.S. Secretary of State George
Schulz as a subsequent director. Access to ongoing
capital was at-hand, and Riordan’s company ran up an
antisense DNA program. In a reversal of his Worcester
Foundation visits, I had lunch with Riordan, Montgomery,
and others in Foster City, CA, on February 2, 1989.
The dust had settled, and we enjoyed an open exchange;
Riordan and I continued to enjoy a cordial
relationship for some time thereafter.
Riordan’s company pushed ahead on antisense but
eventually moved on opportunistically to other drugdevelopment
programs, selling its antisense DNA patent
estate to ISIS (Carlsbad, CA) in 1998. The antisense
DNA patent portfolio that Zamecnik created at the
Worcester Foundation was also subsequently licensed
to ISIS, which went on to impressively deploy its own
invented antisense technology to reign as today’s leading
antisense company. [For full disclosure, I am a
coinventor on one of the ISIS-licensed Worcester Foundation
patents, arising from the collaborative work
discussed above (7), and share in royalty income distribution
under my institution’s policy.] Meanwhile, I
have enjoyed watching the ascent and creative business
evolution of Riordan’s brave company and marvel at its
successes. One was Tamiflu, and then, shortly after I sat
down to write this piece, the company’s HIV drug mix
Truvada got the nod from a U.S. Food and Drug
Administration advisory panel and won formal approval
just before this article went to press.
In 1997, Paul Zamecnik moved back to Mass General
from the Worcester Foundation, which was then merging
with the University of Massachusetts Medical
School. A dean had held to a rigid retirement policy in
1977, but in 1997, Paul had the last laugh, and as a
friend, I was happy to see him happy. As I have written
elsewhere about his move back to Mass General 20
years later, “At that happy moment, two strands—one a
3600 Vol. 26 September 2012 The FASEB Journal www.fasebj.org
PEDERSON

Paul Zamecnik at the time he moved from the Worcester
Foundation back to Mass General (1997), where he continued
to push forward on antisense DNA therapeutics and
publish actively until just weeks before his death in 2009. His
last publication appeared 1 year before he died, and there
were others in the works. His first publication had been 63
years earlier (1). Reproduced with permission of the University
of Massachusetts Medical School Archives, Lamar Sutter
Library, University of Massachusetts Medical School, Worcester,
MA, USA.
visionary scientist of genetic mechanisms and the other
one of America’s vanguard research-based medical
institutions—had now come back together once again,
a reannealed RNA double helix” (1).
In this article, I have, up to now, referred to Riordan’s
start-up only as “the company”. As biotechnologyoriented
readers recognized early in this article, the
company is of course Gilead (formally Gilead Science).
The biblical line from Jeremiah (8:22), “Is there no
balm in Gilead?” was the posed question to which the
African-American spiritual responded in an affirmative
reply, “There is a balm in Gilead”.
Paul Zamecnik was a pioneer of molecular biology,
and Michael Riordan (now retired) was a pioneer of
bridging molecular biology and business. We should
applaud both phenotypes. This story also teaches that
commercialization of even an idea embodied in foun-
dational and so unassailably correct molecular biology
as antisense DNA was, may nonetheless run into steep
challenges and even cause a company to change direction
and still make contributions to human well being.
So, things do not turn out as the first business plan
asserts, circumstances are almost always more complicated
than first assumed, and “There are more things in
Heaven and Earth ” (as Shakespeare had his character
Hamlet say).
I am grateful to Robert Langer (M.I.T) for encouraging me
to write up this story after an initial conversation, and to John
Goodchild, formerly of the Worcester Foundation and Hybridon,
for confirming certain details and triggering other
important recollections.
The author’s work is supported by National Science Foundation
Grant MCB-1051398 and the Vitold Arnett Professorship
at the University of Massachusetts Medical School.
Note added in proof: While this article was in press the author
learned that there is yet another closure of Paul Zamecnik’s
journey. In 2011 the Massachusetts General Hospital received
a gift to create the Paul Zamecnik Chair in Cancer Research.
The first incumbent will be invested in 2012.
REFERENCES
1 Pederson, T. (2011) Paul C. Zamecnik 1912–2009. Biographical
Memoirs, Washington, DC, National Academy of Sciences
2. Stephenson, M. L., and Zamecnik, P. C. (1978) Inhibition of
Rous sarcoma viral RNA translation by a specific oligodeoxynucleotide.
Proc. Natl. Acad. Sci. USA 75, 285–288
3. Zamecnik, P. C., and Stephenson, M. L. (1978) Inhibition of
Rous sarcoma virus replication and cell transformation by a
specific oligodeoxynucleotide. Proc. Natl. Acad. Sci. USA 75,
280–284
4. Calvet, J. P., and Pederson, T. (1979) Heterogeneous nuclear
RNA double-stranded regions probed in living HeLa cells by
crosslinking with the psoralen derivative aminomethyltrioxsalen.
Proc. Natl. Acad. Sci. USA 76, 755–759
5 Folkman, J. (1990) The fine line between persistence and obstinancy
in research. In Vision and Values for Pharmaceutical Innovation.
ALZA Conference Series, vol. 3, 20th Anniversary Symposium
(Mitchell, ed.), C. Palo Alto, CA, USA, ALZA Corp., 141–149
6. Goodchild, J., Taguchi, Y., Sarin, P., and Zamecnik, P. C. (1986)
Inhibition of replication and expression of T-cell lymphotropic
virus type III in cultured cells by exogenous synthetic oligonucleotides
complementary to viral RNA. Proc. Natl. Acad. Sci. USA 83,
4143–4146
7. Agrawal, S., Mayrand, S. H., Zamecnik, P. C., and Pederson, T.
(1990) Site-specific excision from RNA by RNase H and mixedphosphate-backbone
oligodeoxynucleotides. Proc. Natl. Acad. Sci.
USA 87, 1401–1405
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SENSE AND ANTISENSE IN BIOTECH
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