Ernest McCulloch and James Till: Stem Cell Pioneers

Ernest McCulloch (1926-2011)

• Canadian hematologist Ernest McCulloch hoped to find a cure for leukemia
• McCulloch recognized odd results from a radiation experiment as something entirely new
• McCulloch studied medicine at the University of Toronto, becoming a doctor in 1948
• In 1957, he joined the Ontario Cancer Institute and researched blood formation
• McCulloch collaborated with James Till to research stem cells
• Their work transformed cancer research and led to regenerative medicine
• McCulloch became Head of Hematology at the Ontario Cancer Institute in 1957
• In 1963, McCulloch and Till published stem cell research findings with Andrew Becker in the journal Nature
• In the 1970s, McCulloch focused stem cell research on the mechanisms of human leukemia
• McCulloch, along with Till, was inducted into the Canadian Science and Engineering Hall of Fame in 2010

James Till (1931-)

• Physicist James Till shifted focus to cancer research and radiation treatment
• Till and Ernest McCulloch discovered stem cells
• Till grew up in Lloydminster, Canada, won a scholarship to study physics, and earned a biophysics PhD from Yale in 1957
• In 1958, Till began working with McCulloch at the Ontario Cancer Institute
• James Till's research later included cancer treatment ethics, patient quality of life, and internet advocacy and support
• Till and McCulloch discovered that most bones contain unspecialized adult stem cells in the inner marrow, capable of developing into any blood cell
• In 1957, Till declined an assistant professorship at Yale to work at the University of Toronto
• In 1961, Till and McCulloch published a paper on the "radiation sensitivity of mouse bone marrow cells."
• Till became a Fellow of the Royal Society of Canada in 1969
• Till and McCulloch jointly received the Albert Lasker Award for Basic Medical Research in 2005

Stem Cell Research Breakthrough

• McCulloch and Till combined cellular biology and biophysics to discover stem cells in 1961
• They discovered a unique cell type that can become specialized cells and self-renew
• McCulloch described the discovery as accidental, highlighting serendipity
• McCulloch was interested in radiation's medical potential and its effects on cancer cells
• They measured mouse bone marrow cell radiation sensitivity by irradiating mice and replacing bone marrow with donor cells
• Both donor marrow in transplants, and mice were exposed to radiation doses
• Monitoring the mice's response measured how many donor cells survived radiation doses
• After repeating the experiment, autopsies on the mice after 10 days were carried out
• McCulloch saw small bumps on the dead mice's spleens, proportionate to the number of live marrow cells received
• Till and McCulloch needed to find out if nodules grew from a single cell or many cells
• They irradiated donor cells again with Till's student Andrew Becker, to create an altered chromosome marker
• The team found that each nodule grew from a single cell, making them clones
• Original cells were called “colony-forming units."
• Colonies in each nodule contained all three types of blood cells
• In 1961, Till and McCulloch published their findings in a plainly titled paper
• Till, McCulloch, and Becker further published results in Nature in 1963, gaining attention
• They showed that bone marrow contains cells that can reproduce and develop into other types of cells
• It is now known that adults have stem cells in organs and tissues that heal or regenerate damaged tissue
• Yamanaka introduced 24 specific genes into adult skin cells in mice in 2006 and returned them to an immature stem-cell state
• Yamanaka showed that they could become any type of cell, and jointly received the Nobel Prize in 2012
• After marrow transplants, the mice were examined for 10 to 11 day
• Each mouse spleen nodule corresponded to 10,000 bone marrow cells
• Stem cell research accelerated the development of bone marrow transplants

Tu Youyou (1930-)

• Chinese pharmacologist Tu Youyou researched thousands of compounds for antimalarial properties

• At the end of the 1960s she isolated artemisinin, which became the main malaria treatment worldwide

• Her discovery earned a Nobel Prize in 2015

• Tu contracted tuberculosis as a teenager in 1937, which inspired medicine research

• Tu studied schistosomiasis in 1955 to gain insights into parasite diseases

• At age 39, she built a team in 1969 to find a new antimalarial after many compounds failed screening

• In 1971, she read a 1,600-year-old recipe that helped her find artemisinin extraction solution

• Tu Youyou was born in Ningbo on China's east coast

• She studied pharmacology at Peking University, where herbal medicine was introduced

• In 1955, she researched Lobelia chinensis for schistosomiasis at the Academy of Traditional Chinese Medicine

• Malaria, caused by the Plasmodium parasite, was rising due to resistance to drugs like chloroquine.

• The Chinese government appointed Tu to head the secretive “Project 523" in 1969

• It was on Hainan Island to source new drugs from Chinese medicines

• Tu and her team gathered more than 2,000 herbal, mineral, and animal substances in 3 months with medicinal potential

• They tested 380 extracts from 200 plants for their ability to kill malaria-causing Plasmodium parasites in mice

• An extract of Artemisia annua (sweet wormwood) initially seemed favorable, but the results were inconsistent

• A standard way of preparing many plants in Chinese medicine is to simmer the root in water to make a decoction

• Ge Hong's, "A Handbook for Prescriptions for Emergencies", states to immerse qinghao in two liters of water, wring out the juice and drink it all

• Tu thought that heat from boiling might destroy the active ingredients contained within

• The aerial parts of the plant might have active properties instead of the roots

• She redesigned the experiment and extracted active ingredients from the leaves and stems using a low-temperature method involving water, ethanol, and ethyl ether in 1971

• Her method worked, and Tu isolated the active compound artemisinin, which successfully treated malaria in mice

• Artemisinin kills the malaria parasite by damaging its membranes

• Analyzed chemically, artemisinin proved to be sesquiterpene lactone which is a different compound to any other known antimalarial drug

• Tu's team carried out clinical studies on humans in July 1972

• Tu and two colleagues offered to evaluate artemisinin's toxicity by taking it themselves

• They ran a successful clinical trial in 1973, and the drug was licensed for use in 1986

• Continuing research into artemisinin, Tu developed a second compound, dihydroartemisinin, that was 10 times more potent

• It was licensed by the Chinese Ministry of Health in 1992

• Fast-acting artemisinin-based drugs are now widely given as part of combination therapy for malaria

• In 2011, Tu won the prestigious Lasker Award

• In 2015, she shared the Nobel Prize in Physiology or Medicine with Satoshi Omura and William C. Campbell

• Tu was the first Chinese woman ever to win a Nobel Prize and the first Chinese person to win the Nobel Prize in Medicine

• Tu continues to work as chief scientist at the China Academy of Traditional Chinese Medicine

• Scientists worldwide tested more than 240,000 compounds prior to the discovery of artemisinin

• Tu received the Nobel Prize when she was 85

• Artemisinin combination therapy treats 198 million annually

Jane Goodall (1934-)

• British primatologist Jane Goodall is the world's expert on chimpanzees
• Her 55+ year study of chimpanzee behavior led to discoveries about animal welfare and conservation
• At 26, Jane Goodall traveled to Gombe National Park in Tanzania in 1960 for a 6-month chimpanzee study
• Kenyan paleontologist Louis Leakey funded the trip after sending her to London in 1958 to study primate anatomy and behavior
• Goodall overcame initial rejection and was accepted into the chimpanzee community, which was extended into decades
• Her research revealed the personalities, emotions, and social behaviors demonstrated by chimpanzees for the first time
• Chimpanzees are omnivorous, hunt cooperatively, and wage war with one another, which was previously believed to be human traits
• Noted was their close similarities to humans in terms of emotional behavior, intelligence, social structure, and relationship-building
• In 1977, Goodall founded the Jane Goodall Institute, a global organization that promotes conservation
• Today, she is a world leader for chimpanzee protection and their environments
• A pioneering woman in a male-dominated world, she is an inspirational figure for a new generation of scientists
• Goodall began a 6-month trip to Tanzania in 1960
• She presented her first lecture in 1964 which led to her becoming a public figure
• Despite not having a prior degree, she gained a PhD in ethology from Cambridge University in 1965
• Goodall founded the Jane Goodall Institute in 1977 to promote research, education, and chimpanzee conservation

Valentina Tereshkova (1937-)

• Valentina Tereshkova is a Soviet cosmonaut and engineer
• In 1963 she was the first woman and first civilian to fly in space
• Tereshkova worked in a textile factory at 16 and took up parachute jumping
• In 1961, Tereshkova volunteered for the Soviet space program
• After 16 months of training, Tereshkova became the first woman to fly in space
• On June 16, 1963 she was launched in Vostok 6, and completed 48 Earth orbits during 71 hours of flying
• Gained a doctorate in engineering in 1977, made a Hero of the Soviet Union in 1966, but never flew in space again
• Helped Tereshkova as a cosmonaut to be an amateur parachuter

Patricia Bath (1942-)

• American Patricia Bath is an inventor, laser scientist, and ophthalmologist
• Made huge global advances in the prevention of blindness and was a pioneer for women
• Patricia Bath studied medicine at Howard University and graduated in 1968
• She was the first African American to complete ophthalmology residency at New York University
• In 1974, she became associate professor of surgery and ophthalmology
• A fierce eyesight proponent should be a basic human right
• In 1976, Bath co-founded the American Institute for the Prevention of Blindness
• She launched "community ophthalmology,” bringing primary eye care to poor areas
• In 1986, Bath invented the Laserphaco Probe, a laser that enabled more precise removal of cataracts
• Accepts a position as the first female ophthalmologist at UCLA's Jules Stein Eye Institute in 1975
• Completes the Laserphaco Probe in 1986 and receives patent for her invention 2 years later
• In 1983, is first US woman to set up and direct an ophthalmology residency training program

Stephen Hawking (1942-2018)

• Theoretical physicist Stephen Hawking used mathematics to reveal the nature of "black holes" and the Universe
• He was gifted at science popularizing, who enabled millions to deepen their understanding of space-time, gravity, and humanity's place in the cosmos
• Grew up in St. Albans, north of London
• In 1963, he was diagnosed with ALS, a form of incurable motor neurone disease while studying at Cambridge
• Although his mental faculties were unaffected, Hawking was confined to a wheelchair from 1969
• In 1985, the disease robbed him of the use of his voice, and thereafter he communicated via a computer linked to a speech synthesizer
• Although Karl Schwarzschild hypothesized their existence in the 1910s, the term “black hole” was coined in 1967
• It was thought that as matter is dragged into a black hole, X-rays are created
• In 1964, astronomers were able to detect “X-ray binaries” close to star-forming regions in the Milky Way, indicating a possible black hole
• He studied the work of mathematician Roger Penrose (see p.300), which proved that if Einstein's general theory of relativity is correct
• The death and collapse of a giant star could culminate in a “singularity”—a point in space-time that is infinitely dense and infinitely small
• He wrote in "Properties of expanding universes" that the Universe started from a singularity, written in 1966 for his PhD thesis
• Proved that gravitational singularities may exist while working with Roger Penrose in 1970
• Draws on quantum theory in 1974 to predict that black holes emit heat and eventually evaporate
• Became Cambridge's Lucasian Professor of Mathematics in 1979
• A Brief History of Time sold well and launched him to cultural stardom, and he attempted to use a commercial perspective

Hawking Radiation

• Hawking refined his black hole theories in 1972 to account for the laws of quantum mechanics, following a debate with Israeli physicist Jacob Bekenstein
• Throughout the Universe, pairs of particles and antiparticles meet and annihilate each other
• Hawking calculated that when this occurs near the event horizon the negatively charged particle falls into the black hole and the positively charged half of the pair streams as Hawking radiation
• According to Hawking, black hole loses energy and mass in black hole evaporation
• In 1974, Hawking published his calculation showing both how the Universe began and evaporate black holes
• Penrose collaborated with Stephen Hawking in 1969 to prove that black holes can arise from the gravitational collapse of massive stars
• Known for his work on black holes and the Big Bang theory

Jocelyn Bell Burnell (1943-)

• Postgraduate student Jocelyn Bell Burnell was the first scientist to detect pulsars, opening up astrophysics
• In 1967 she observed a pulsar
• Northern Ireland native Jocelyn Bell Burnell developed a flair for science at boarding school
• In her teenage years, she resolved to work in astronomy
• After graduating from Glasgow University in 1965, Bell Burnell began a PhD thesis at Cambridge University
• Bell helped to design and build an array of radio telescopes
• November 1967, instruments detected unexpected signals: radio waves pulsating every 1.337 seconds, coming from a fixed point in space
• Radio waves came from radiation beam of a rotating neutron star
• In 1974, her supervisor receives the Nobel Prize without her being named in the award
• 2007 made a Dame Commander of the British Empire for her services to astronomy

Tak Wah Mak (1946-)

• Immunologist and molecular biologist Tak Wah Mak discovered how T-cells recognize antigens
• T-cells are part of the body's immune system
• He advanced knowledge of cancer cells
• Mak was born in southern China in 1946, the son of a wealthy silk trader, and spent his childhood in Hong Kong
• Obtained a PhD in biochemistry at the University of Alberta, Canada, in 1968
• Solved a longstanding immunology problem, researched T-cells and antigens
• Genes of T-cell receptors used for antigen recognition have a unique genetic sequence and origin.
• Opened a chapter in treatment and study
• In 1972, he accepted a fellowship at the Ontario Cancer Institute
• He detailed the genetic encoding of human T-cell receptors in journals
• Mak used experiments with mice to isolate genetic function for cancer and immunology
• In 1999, he identifies a chemical to block the fuel supply of Hodgkin's lymphoma

Tim Berners-Lee (1955-)

• British computer scientist Tim Berners-Lee invented the World Wide Web

• Early program

• Multimedia library, workplace, and shopping and social space can be accessed via the internet.

• Berners-Lee interested in computers from an early age: met at UK company Ferranti, where they worked as computer programmers

• Built his first homemade computer using a second-hand television, some logic gates, and a processor

• Joined CERN and consulting in 1980: communication demands of international laboratory,he hit on the idea to transform the way the world communicates

• Tim Berners-Lee wrote ENQUIRE, a program that could store information and track the connections

• From the start, Berners-Lee urged CERN to make the World Wide Web

• Berners-Lee put his inventions in the public domain instead of patenting it

• After 1994, he set up the World Wide Web, continuing to develop the Web's open standards which made it

• In 2004 Queen Elizabeth knighted him

Discover the groundbreaking work of Ernest McCulloch and James Till in stem cell research. Their collaboration transformed cancer research and regenerative medicine. Learn about their key experiments, findings published in Nature, and contributions to understanding human leukemia.