Sense and Antisense in Biotech: The First Antisense DNA Company

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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