Leading Edge

Obituary

Riley, Kansas. He was always, at heart,

Alfred G. Knudson (1922–2016) a physician and defined himself as a
‘‘pediatrician in an Army uniform’’; in two
An iconic, visionary giant in medical sci- he had established the famous ‘‘Fly years, he cared for 1,500 newborn chil-
ence, Alfred G. Knudson, Jr., M.D., Ph.D. Room.’’ Harbingers of Al’s bright future dren and young adults on the base. Since
died July 10, 2016, one month short of in medicine, Caltech professors Morgan, ‘‘science was passing him by,’’ he re-
his 94th birthday. Often referred to as the Linus Pauling, and Carl Anderson (discov- turned to Caltech to earn a Ph.D. in
‘‘Mendel of cancer genetics’’—Al was erer of the positron) wrote recommenda- biochemistry and genetics in 1956.
widely known for his groundbreaking tion letters for Al. Knudson’s first academic position was
‘‘two-hit’’ hypothesis of cancer develop- Al was in medical school at the time at the City of Hope Medical Center,
ment and his prediction of recessive- DNA was being discovered as the genetic Duarte, where he led a pediatric cancer
acting tumor suppressor genes. His revo- material by Oswald Avery and colleagues, unit and biology department. During
lutionary two-hit hypothesis envisaged across town at the Rockefeller Institute, 1966–1969, he was Associate Dean for
that cancer occurs when both copies of but students never learned of this; later, Basic Sciences at the State University of
such a gene sustain mutations. The first Al emphasized that medical students New York, Stony Brook. He moved to
hit may be hereditary, and the second should be up on basic science, as one M.D. Anderson Cancer Center in Hous-
occurs somatically. This theory, originally never knows where the next medical ton, where, using the detailed records of
based on studies of hereditary and nonhe- breakthrough will come from. He decided children treated for retinoblastoma, he
reditary forms of retinoblastoma, was later to do a residency in pediatrics at New developed his two-hit theory and became
shown to be applicable to many cancers. York Hospital because pediatrics would Dean of the Graduate School of Biomed-
His elegant mathematical models, bor- allow him to combine genetics and devel- ical Sciences. In 1976, he joined Fox
rowed from physics and probability opmental biology. During his residency, a Chase Cancer Center in Philadelphia,
theory, served as the foundation for month spent at Memorial Sloan Kettering where he held positions of Director of
understanding the relationship between Cancer Center provided a life-changing the Institute for Cancer Research and
hereditary and sporadic cancers. Proof experience working in a small unit of President, although his greatest aca-
of his prescient ideas took more than a about 20 children with cancer, most of demic pleasure was that of senior investi-
decade, with the emergence of recombi- whom would not survive to leave the gator working with younger colleagues. At
nant DNA technologies that permitted hospital. Fox Chase, he established the Molecular
validation of the model by Webster During the Korean War, Al was in the Oncology Program, later defined by David
Cavenee and colleagues and subsequent Army as a ‘‘payback’’ for the support he Livingston as the ‘‘left ventricle of the
cloning of the first tumor-suppressor had received by the Navy to attend med- Center,’’ to which he recruited many new
gene, RB1, by Stephen Friend and ical school and was stationed at Fort colleagues, including the authors.
colleagues. In 1976, Al married his sec-
Born in Los Angeles, Knud- ond wife, Anna Meadows, a
son entered Caltech—very petite, energetic, and driven
near the Glendale section pediatric oncologist at Chil-
where he lived—in 1940. He dren’s Hospital of Phila-
first intended to study physics delphia. Anna, who was
but soon thought that much interested in eye-sparing treat-
was already known in that ment for retinoblastoma, told
field and turned to biology, him that she fell in love with
especially genetics, due to his two-hit paper before she
its foundation in mathe- fell in love with him. In return,
matics, a discipline for which Al defined Anna as a ‘‘worthy
he had a keen interest. His opponent’’ with whom he
passion for genetics was discussed ideas and revised
fueled by training with the talks and papers prior to
legendary Thomas Hunt Mor- publication. Together, they
gan and Alfred Sturtevant. published articles on retino-
Al wanted to obtain a Ph.D., blastoma and neuroblastoma
but because of WWII, de- and formed a sort of dialectic
cided to join the Navy as it but loving ‘‘good cop-bad
could support his training as cop’’ couple that animated
a physician. Morgan thought the scientific, medical, and
that there were no good med- social life of Philadelphia.
ical schools in California at Al never officially retired, re-
that time and suggested Drs. Meadows and Knudson at a fundraising gala in Philadelphia in taining titles of Distinguished
Columbia University, where 2005. Image courtesy of Children’s Hospital of Philadelphia. Scientist and Senior Advisor

Cell 166, August 11, 2016 785

to the President. He and his colleagues at
Fox Chase identified a germline mutation
of the tuberous sclerosis 2 tumor sup-
pressor gene, Tsc2, as the genetic deter-
minant of renal carcinoma in the Eker rat.
His continued love of physics and mathe-
matics was reflected in collaborations
with Michael Vilenchik on mutagenesis
by ionizing radiation, rates of induction
of single- and double-strand DNA breaks,
and implications for tumorigenesis.
Finally, over the last decade, his team
worked closely to characterize gene
expression changes in one-hit cells from
genetically susceptible persons, for can-
cer prevention.
Among his numerous awards, Al
received the Charles Mott Prize from the
General Motors Cancer Research Foun-
dation (1988), the Medal of Honor from
the American Cancer Society (1989), the
Gairdner International Award (1997), the
Albert Lasker Award for Clinical Medical
Research (with Janet Rowley and Peter
Nowell; 1998), the Distinguished Career
Award from the American Society of Pedi-
atric Hematology/Oncology (1999), the
Kyoto Prize (2004), and the AACR Lifetime
Achievement Award (2005). He was elec-
ted member of the National Academy of
Sciences, the American Academy of Arts
and Sciences, and the American Philo-
sophical Society and was an inaugural
Fellow of the AACR Academy (2013). He
also served as President of the American
Society of Human Genetics (1978).
On a personal level, Al was a charming
and caring person. Despite his larger-
than-life, charismatic scientific stature,
he remained humble, open, and
approachable. He had a profound influ-
ence on the welfare of Fox Chase. His
career at this institution was marked
by his boundless intellectual curiosity,
generous mentorship, gentle collegiality,
and selfless dedication to scientific prog-
ress, as well as being an inspirational role
model for younger scientists privileged to
work with him. He conveyed an unwaver-
ing passion and excitement for science.
He was, quite simply, the perfect mentor.
Al’s talent extended beyond his own
work. In 1979, in his role as Scientific
Director, he was approached by his Fox
Chase colleague Ernie Rose regarding
the possibility of providing institutional
786 Cell 166, August 11, 2016
support for two young Israeli scientists—
Avram Hershko and Aaron Cie-
chanover—on the mechanism of ubi-
quitin-mediated protein degradation. Al
immediately recognized this project as
having enormous implications, and as an
opportunity for a team with unique drive
and skillset to solve it. Support was duly
provided and the rest, as they say, is his-
tory, culminating in the Nobel Prize being
awarded to this team in 2004.
In 2002, Fox Chase celebrated Al’s
80th birthday. A poster signed by staff in
honor of the occasion repeatedly cited
his inspirational leadership, insightful and
magnanimous mentorship, ability to focus
on the true essence of a scientific prob-
lem, as well as his scientific curiosity
balanced not only by a desire to help col-
leagues with their research, but also by a
genuine interest in their personal welfare.
In 2003, a special issue of Genes, Chro-
mosomes & Cancer celebrated Al’s legacy
with a collection of historical perspectives
and reviews. Included in the collection
was a memoir written by Al, ‘‘Cancer Ge-
netics Through a Personal Retrospectro-
scope,’’ in which he humbly credited the
help of colleagues and trainees, including
Ed Lewis, Jim Neel, Louise Strong, Anna
Meadows, George Klein, Harry Harris,
and David Commings. Reciprocally, es-
says by others highlighted life-changing,
pivotal moments when Al helped shape
the research direction of oncology and ge-
netics fellows, such as Anna Meadows,
who defined Al as ‘‘my best friend and
colleague and the love of my life’’ and Ste-
phen Friend, who called Al ‘‘a visionary
who enables scientists.’’
Al was always generous with his time
and extraordinarily supportive of young
people. He advised them to give more
consideration to important things over ur-
gent things and to be strategic and selec-
tive in the laboratory, stating that ‘‘the
best scientists are the ones knowing
which experiments not to do.’’
Al balanced his research life with
passionate interests in art, music, and
travel. Anna Meadows noted that she
‘‘learned much from Al about astronomy,
geology, history, art and music, and al-
ways with humor.’’ Together, they had a
strong appreciation of both figurative
and abstract art, and their home was filled
with an eclectic and colorful collection of
paintings and sculptures. Al knew the
‘‘K’’ number of every Mozart piece, and
his travel diaries were written with the
precision of a scientific paper: in a pre-
tracking devices era, he plotted by hand
changes in distance and elevation of
every excursion, adding historical notes
and interesting bits of information about
various locales.
He was fascinated by discovery and
was content with the trajectory of his life:
‘‘I have a great life, because I’m interested
in things that aren’t known yet.’’ Looking
back at the amazing, unimaginable ac-
complishments in science over his life-
time, Al noted: ‘‘We had some good years
together at Fox Chase. They were the
best years for me, in terms of liking the
people I worked with, the things we got
done, and the response to our work.’’
Al aged gracefully and with great dig-
nity. In the last year, he told us, with his
gentle chuckle, that his mind was failing
but accepted that realization with wis-
dom, expressing it with his characteristic
clarity: ‘‘It’s sad to be losing your mind,
but I tried to think back about my life
and what I would do differently, and it
turns out I probably wouldn’t change
anything, because I wound up doing
something that was useful, important in
some circles, and I enjoyed doing it, so
what more can you ask for?’’
To those of us fortunate enough to have
had the opportunity to know Al personally,
the passing of this mentor and friend is a
great loss. Up to his final days, he
continued to work on his scientific manu-
scripts and care greatly for the welfare of
scientists at Fox Chase and everywhere.
His visionary work and the generation of
scientists worldwide who continue the
pursuit of his passion for cancer genetics
are a lasting legacy.
Alfonso Bellacosa,1,2,*
Jonathan Chernoff,2
and Joseph R. Testa2,*
1Cancer Epigenetics Program
2Cancer Biology Program
Fox Chase Cancer Center, Philadelphia,
PA 19111, USA
*Correspondence: Alfonso.Bellacosa@fccc.
edu (A.B.), Joseph.Testa@fccc.edu (J.R.T.)
http://dx.doi.org/10.1016/j.cell.2016.07.052