LUCAS OLENIUK / TORONTO STAR
Documents from the Sanofi Pasteur archives help piece together the role of Dr.
Leone Farrell in finding the polio cure. From the top: a memo from Jonas Salk; a
photo of the bottles and rocking machine Farrell used to produce mass quantities
of the virus; an outline of the responsibilities of the members of the Connaught
team; and a copy of the polio project budget from Connaught labs.
Toronto's unknown polio soldier
A heroine in an unmarked grave
In the 50 years since the world first rejoiced in the success of Jonas Salk's
polio vaccine, the name and famed accomplishments of the renowned American
researcher have grown legendary.
Few, on the other hand, know who Leone Farrell is.
Yet there she was, tucked away in a small Toronto laboratory, a quiet,
50-year-old chemist, who, to Salk's utter delight, figured out how to produce
the virus in the vast quantities he needed for the field trial of his vaccine.
It became the biggest medical experiment of all time, involving close to two
million children, and Farrell was among the teams of American and Canadian
scientists who waited in breathless anticipation for the results to be announced
on April 12, 1955. That triumphant day, Salk's life changed forever.
But although Farrell's contribution was recognized by her contemporaries, she
returned to work in relative obscurity. She continued to publish research papers
well into her 60s and lived to the age of 82. But she died alone. Her gravesite
in the Park Lawn Cemetery just west of High Park reveals nothing of the key role
she played in eradicating polio. Her remains are buried in Lot 707, in an
Throughout the first half of the 20th century, polio swept North America in
epidemic waves, crippling and killing tens of thousands of children. The
poliomyelitis virus entered the body through the mouth, invaded the bloodstream
and could be carried to the central nervous system, causing paralysis and, in
some cases, death.
Epidemics struck in 1931 and again in 1937. In Toronto, children were kept
indoors, swimming pools, parks and churches were closed and the start of school
Stricken families were quarantined. Another epidemic hit in 1946. The worst in
the U.S. came in 1952; Canada's worst year was 1953, when 9,000 children were
News reports appeared daily on the horrors of school-aged children suddenly
unable to walk. Others died days after contracting the virus. Originally thought
to be a children's disease, polio also struck parents, nurses and teachers; many
became permanently imprisoned in iron lungs.
During the 1930s and 1940s, polio researchers throughout the world were on the
hunt for a cure. Small breakthroughs were achieved in understanding the virus,
but they were often countered by frustrating setbacks, cost being one.
In 1949, Harvard researchers discovered a way to grow the poliovirus in a test
tube. Suddenly, the scientific community was in a race to create a vaccine.
Salk made his discovery in 1952, as the worst epidemic yet gripped the United
States. While conducting tests in his University of Pittsburgh laboratory, the
bespectacled scientist came up with an experimental vaccine containing "killed,"
or inactivated virus, which could trigger a person's blood to build immunity.
His team proved it worked with months and months of tests in monkeys, and later
in a small group of volunteers.
Salk now faced another challenge: how to mass-produce the polio virus in order
to treat the millions clamouring for it.
North of the border, Connaught Medical Research Laboratories, owned by the
University of Toronto, had been conducting its own polio research since the late
1930s. Research was briefly interrupted by the Second World War but resumed
before the war ended. According to Canadian medical historian Christopher Rutty,
Connaught's reputation as a true academic research centre put scientists like
Leone Farrell in a unique position to play a major role in what unfolded over
the coming decade.
Unlike the pharmaceutical companies to the south, Connaught's interest lay
squarely in scientific research, vaccine production and public health teaching.
"It didn't have to answer to shareholders, it didn't have that corporate
thinking and it didn't have competitors. It was really the only one of its kind
in Canada," says Rutty, whose doctoral thesis on polio will soon be published in
a book titled The Middle Class Plague.
For that reason, the U.S. National Foundation for Infantile Paralysis, or March
of Dimes founded by then-president Franklin D. Roosevelt, himself crippled by
the disease had been quietly pouring money into Connaught's polio research. By
the late 1940s, the company had set up its own special polio team led by British
virologist Dr. Andrew J. Rhodes.
Farrell was asked to join the team in 1952 the year that Salk made his crucial
Born in Monkland, a rural community south of Ottawa, Farrell was raised in
Toronto. "Very much a lady" is how one of Farrell's colleagues described her,
recalling that she always wore suits and heels and kept her hair short and neat.
Leone Norwood Farrell was no ordinary lady, however. She had, by age 29,
obtained a PhD in biochemistry at the University of Toronto. It was a rare feat
for women in those days; a mere handful of Canadian women each year obtained
PhDs in the 1930s.
Farrell joined the staff at Connaught in 1934, 20 years before the polio field
trials. Her specialty was the study of fungi, and she had spent two years
working as a chemist looking at yeasts in honey for the National Research
Council of Canada. She was hired by Connaught to do studies on staphylococcus
toxoids and conducted significant studies on antibiotics, penicillin and the
prevention of bacterial infections such as diphtheria, cholera and whooping
Farrell lived alone on the second floor of a two-bedroom balcony apartment on
the corner of Avenue Rd. and Oriole Parkway and each day traveled the six
kilometres south to her laboratory at the U of T campus. Not much more is known
of her personal life; her colleagues remember her dedication and skill but
remember little about her interests, her habits, her passions.
In 1943, Connaught by then a world leader in the development and manufacture
of vaccines, insulin and penicillin purchased Knox College and moved its
research and production operations to the towering Gothic revival building on
It was during this period that Farrell came up with a unique method of gently
"rocking" large bottles containing the pertussis bacteria to stimulate its
growth for production of a whooping cough vaccine. This discovery would prove to
be crucial 10 years later in the race against polio.
Connaught's first major polio breakthrough came in 1951. Earlier, its cancer
researchers had developed the first synthetic medium, Medium 199. Other
Connaught scientists tried the medium for growing the polio virus on
kidney tissue and found that the virus rapidly multiplied in the chemically pure
fluid. Suddenly, it was Farrell's job to find a way to produce the virus in bulk
The production race was on.
"Leone was probably the most experienced person in that atmosphere. Her
specialty had been the mass production of bacterial cultures," said 79-year-old
Frank Shimada, a researcher who was part of the testing process and, in his
mid-20s at the time, the youngest member of the polio project.
In the course of regular meetings held at the Spadina lab in 1952, Farrell,
Shimada and others discussed how to grow the virus, what containers to use, how
much medium to use. It was constant trial and error. Farrell was "a good person
and a team player," he recalled. "She knew what she was doing. She was a classic
researcher and disciplined in her work to the extent that she knew you laid out
a plan and followed it carefully for things to get done."
It took months, but research would finally prove the rocking-bottle method used
in Farrell's pertussis studies, later to be called the "Toronto technique," was
the solution they'd been looking for.
Using large, rectangular 5-litre bottles, Farrell adhered a tiny piece of monkey
kidney tissue cells to the inside glass, added the medium and, over the course
of several days, gently rocked the bottles on specially built machines to
agitate the fluid and spur cell production.
The bottles were kept in incubator rooms warmed to a body temperature of 37C. A
few degrees higher and the entire batch could be destroyed. The polio virus was
then added to infect the cells and the rocking continued for several more days.
The gratifying result was an abundance of live polio virus.
With a mass vaccine now in sight, Connaught in 1953 was handed the prestigious
and painstaking task of supplying almost all of the 3,000 litres of virus fluids
needed for Salk's field trials. Farrell remained in charge of what now became a
vast and intricate production involving many more monkeys, medium and bottles,
more buildings and more staff to train. During this period, at least 165 monkeys
a week were required to produce the virus, Rutty said.
"This all had to be done from the ground up," recalled Shimada. "They had to
build labs, incubators, the whole bit. Techniques had to be developed right down
to special washing instructions to clean the bottles."
Farrell was instrumental in the design and implementation of it all an
achievement recognized in the dry, bureaucratic language of an unsigned career
summary placed in her employment file.
"The breadth of these accomplishments bears testimony to the knowledge and
mental fertility enjoyed by Dr. Farrell. Never was she lacking in basic ideas of
how to accomplish her scientific goals," reads the summary, which is now part of
the Connaught archival collection.
"She was a very serious person. She was always doing research. It was always
`try this, try that,'" recalls former colleague Stephanie Schenk. Schenk, now
retired, joined Connaught as a young research assistant in early 1954, by which
time Farrell and others were already working round-the-clock to produce large
volumes of the live virus.
"I didn't know Dr. Farrell all that well, but back then everyone was so wrapped
up in their work. They were so dedicated, it was unbelievable."
In the crucial months leading up to the field trials, bottles of the live virus
were packed in ice, then placed inside dairy cans and loaded onto a station
wagon at the rear doors of the Spadina building. From there the precious cargo
was raced twice weekly to the U.S., crossing the border at Detroit on its way to
two American drug firms where the virus was "killed," or inactivated, for Salk's
Salk, in a signed letter to Connaught director Robert Defries shortly before the
trial results were announced in 1955, thanked the Connaught team for their
"Herculean task" in providing the virus. When the momentous day arrived April
12, 1955 hundreds of scientists gathered in Ann Arbor, Mich., where the
results were being announced. In Toronto, nearly 700 doctors, technicians and
nurses crowded into the Crystal Ballroom at the King Edward Hotel to watch the
report on two dozen TV sets installed specifically for the event.
The late-edition headlines that day said it all the Salk polio vaccine had
proven safe and 80 to 90 per cent effective in tests on children across the
United States and parts of Canada and Finland. With the news, mass immunizations
for millions of Canadian and American schoolchildren and their parents
immediately got under way.
In the days following the announcement, Canadian journalists rushed to the
Toronto lab for interviews and photographs. The faces of the Connaught team,
including Farrell's, were splashed across the front page of the Globe and Mail.
A proud Defries took his team out for dinner at the Royal York Hotel.
"I was totally lost in the limelight," recalled Shimada. "That was the moment
when you thought, `My God, we're making history.' Until then there wasn't any of
that, because that wasn't our purpose."
In the months and years since, some Canadian politicians have felt Connaught
later swallowed up by pharmaceutical giant Sanofi Pasteur did not get the
recognition from Americans that it deserved. Rutty argues, however, that Salk
was in an impossible situation because so many people had been involved in
helping tie all the pieces together, including researchers in his own lab who
also felt slighted. Salk, for instance, appeared alone on the cover of Time
magazine in 1954.
Even so, Farrell has pretty much been written out of history. University of
Victoria women's studies professor Marianne Gosztonyi Ainley, whose book Essays
on Canadian Women and Science reflects on the historical record of women
scientists, hadn't heard of Farrell or her accomplishments. Her case, Ainley
said, raises a lot of questions not just about who she was but about who gets
credit for scientific discoveries and whose name gets perpetuated.
"The public often has trouble understanding that scientific discoveries are team
efforts," she said. "Farrell should be remembered. Her accomplishments should be
Last week, a commemorative piece on Salk published in the Journal of the
American Medical Association recounted the contributions of scientists,
including Salk, to "one of the greatest achievements of the 20th century." Once
again, there is no mention of the role played by Connaught, by Farrell, or
anyone, for that matter, who was part of the polio effort in Toronto names
like Defries, Rhodes, Shimada, Taylor, Macmorine, Wood, Graham, Franklin,
Morgan, Parker or Morton.
Shimada says that if Farrell were alive today, it's doubtful she would care.
"When you're in medicine, what greater accolade can you get than knowing you
helped save thousands of kids from becoming paralyzed? The important thing is
that people know in their own hearts they are contributors. That's what it's all
The former Connaught laboratories building on Spadina Crescent is slated to
undergo a major renovation to house fine arts. The high-ceilinged hallway on the
second floor where Farrell worked is now quiet. The labs are gone; a few
classrooms and offices are in their place.
The only evidence of those exciting days are three heavy wooden doors, behind
which the live virus was kept cold prior to transport.
They remain bolted shut.
Background on Viral Vaccine Development
What is the standard development and manufacturing process for viral
Viral vaccines protect individuals from disease by eliciting an immune
response, which will prevent disease if an individual is subsequently infected
with a disease-causing strain of the virus.
There are three types of licensed viral vaccines: subunit, killed, and
live-attenuated. Subunit vaccines are purified viral proteins. Killed and
live-attenuated viral vaccines are made from virus purified from a medium into
which a viral seed has been introduced. Rotarix and RotaTeq are
live-attenuated viral vaccines.
There are a variety of media used in the manufacture of viral vaccines.
|Whole animal substrates, such as embryonated eggs|
|Primary cells derived from animal tissue, such as chick embryo fibroblasts|
|Cell lines in culture, such as Vero cells, derived from monkey kidneys|
Rotarix was produced in Vero cells.
Live-attenuated viral vaccines are manufactured by purifying whole virus from
infected cells. Because the virus has been attenuated, or weakened, and no
longer is able to cause disease, the purified live virus is used as the vaccine.
The general production process for a live-attenuated viral vaccine can be
divided into four stages:
|Cell culture preparation development of cell lines appropriate for
manufacturing vaccines for human use|
|Virus inoculation and propagation addition of the virus to the cell
culture and allowing it to replicate|
|Virus harvest retrieval of the virus from the medium|
|Purification further processing of the virus for later incorporation
into the finished vaccine|
Vaccine manufacturers are required to have controls in place to ensure the
vaccine products identity, potency, quality, and purity.
What steps do manufacturers and FDA take to assess the quality of
viral vaccines during the production process?
FDA requires vaccine manufacturers to implement certain manufacturing
practices to assure the quality of the viral seed which is used to generate
large amounts of virus needed for vaccine manufacture, the cell culture medium
in which the virus will grow, and any components added in the manufacturing
Vaccine manufacturers must conduct a variety of quality assurance tests
throughout the manufacturing process, including tests for vaccine sterility and
potency. Samples of each finished vaccine are tested by the manufacturer prior
to market release, and FDA may also perform additional testing prior to market
release. The specific types of testing required vary from product to product.
What FDA regulations and guidance apply to the production of
The general standards for assuring the quality of vaccines intended to be
administered to humans can be found in
21 CFR 610
Vaccine manufacturers are required to implement current good manufacturing
practices, as described in the Federal Food, Drug, and Cosmetic Act and in
21 CFR 210 and
21 CFR 211.
On March 2, 2010, FDA issued a Final Guidance for Industry entitled Characterization
and Qualification of Cell Substrates and Other Biological Materials Used in the
Production of Viral Vaccines for Infectious Disease Indications.
Has testing for circoviruses such as PCV1 been required as part of
Circoviruses have not been associated with illnesses in humans, and FDA has
not required the routine testing of vaccines for these viruses. Current FDA
guidance, released in March 2010, recommends that manufacturers consider testing
for these agents. FDA introduced this recommendation as an additional
precaution for vaccines manufactured with animal-based components. The agency
is reviewing the current situation and may update its approach based
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