From The University of Toronto (CA): “University of Toronto scientists use AI to fast-track drug formulation development”
From The University of Toronto (CA)
1.11.23
Kate Richards | Leslie Dan Faculty of Pharmacy
Researchers Christine Allen and Alán Aspuru-Guzik used machine learning to predict experimental drug release from long-acting injectables (photo by Steve Southon)
In a bid to reduce the time and cost associated with developing promising new medicines, University of Toronto scientists have successfully tested the use of artificial intelligence to guide the design of long-acting injectable drug formulations.
The study, published this week in Nature Communication [below], was led by Professor Christine Allen in the Leslie Dan Faculty of Pharmacy and Alán Aspuru-Guzik in the departments of chemistry and computer science in the Faculty of Arts & Science.
Fig. 1: Schematic demonstrating traditional and data-driven formulation development approaches for long-acting injectables (LAIs).
[a] Selected routes of administration for FDA-approved LAI formulations. [b] Typical trial-and-error loop commonly employed during the development of LAIs termed “traditional LAI formulation development”. [c] Workflow employed in this study to train and analyze machine learning (ML) models to accelerate the design of new LAI systems, termed “Data-driven LAI formulation development”.
Their multidisciplinary research shows that machine-learning algorithms can be used to predict experimental drug release from long-acting injectables (LAI) and can also help guide the design of new LAIs.
“This study takes a critical step towards data-driven drug formulation development with an emphasis on long-acting injectables,” said Allen, who is a member of U of T’s Acceleration Consortium, a global initiative that uses artificial intelligence and automation to accelerate the discovery of materials and molecules needed for a sustainable future.
“We’ve seen how machine learning has enabled incredible leap-step advances in the discovery of new molecules that have the potential to become medicines. We are now working to apply the same techniques to help us design better drug formulations and, ultimately, better medicines.”
Considered one of the most promising therapeutic strategies for the treatment of chronic diseases, long-acting injectables are a class of advanced drug delivery systems that are designed to release their cargo over extended periods of time to achieve a prolonged therapeutic effect. This approach can help patients better adhere to their medication regimen, reduce side effects and increase efficacy when injected close to the site of action in the body.
However, achieving the optimal amount of drug release over the desired period of time requires the development of a wide array of formulation candidates through extensive and time-consuming experiments. This trial-and-error approach has created a significant bottleneck in LAI development compared to more conventional types of drug formulation.
“AI is transforming the way we do science. It helps accelerate discovery and optimization. This is a perfect example of a ‘before AI’ and an ‘after AI’ moment and shows how drug delivery can be impacted by this multidisciplinary research,” said Aspuru-Guzik, who is director of the Acceleration Consortium and holds the CIFAR Artificial Intelligence Research Chair at the Vector Institute in Toronto and the Canada 150 Research Chair in Theoretical and Quantum Chemistry.
From left: Zeqing Bao, PhD trainee in pharmaceutical sciences, and Riley Hickman, PhD trainee in chemistry, are co-authors on the study published in Nature Communication (photo by Steve Southon)
Reducing ‘trial and error’ for new drug development
To investigate whether machine-learning tools could accurately predict the rate of drug release, the research team trained and evaluated a series of 11 different models, including multiple linear regression (MLR), random forest (RF), light gradient boosting machine (lightGBM) and neural networks (NN). The data set used to train the selected panel of machine learning models was constructed from previously published studies by the authors and other research groups.
“Once we had the data set, we split it into two subsets: one used for training the models and one for testing,” said Pauric Bannigan, research associate with the Allen research group at the Leslie Dan Faculty of Pharmacy. “We then asked the models to predict the results of the test set and directly compared with previous experimental data. We found that the tree-based models, and specifically lightGBM, delivered the most accurate predictions.”
As a next step, the team worked to apply these predictions and illustrate how machine learning models might be used to inform the design of new LAIs by using advanced analytical techniques to extract design criteria from the lightGBM model. This allowed the design of a new LAI formulation for a drug currently used to treat ovarian cancer.
Expectations around the speed with which new drug formulations are developed have heightened drastically since the onset of the COVID-19 pandemic.
“We’ve seen in the pandemic that there was a need to design a new formulation in weeks, to catch up with evolving variants. Allowing for new formulations to be developed in a short period of time, relative to what has been done in the past using conventional methods, is crucially important so that patients can benefit from new therapies,” Allen said, explaining that the research team is also investigating using machine learning to support the development of novel mRNA and lipid nanoparticle formulations.
More robust databases needed for future advances
The results of the current study signal the potential for machine learning to reduce reliance on trial-and-error testing. However, Allen and the research team identify that the lack of available open-source data sets in pharmaceutical sciences represents a significant challenge to future progress.
“When we began this project, we were surprised by the lack of data reported across numerous studies using polymeric microparticles,” Allen said. “This meant the studies and the work that went into them couldn’t be leveraged to develop the machine learning models we need to propel advances in this space. There is a real need to create robust databases in pharmaceutical sciences that are open access and available for all so that we can work together to advance the field.”
To that end, Allen and the research team have published their datasets and code on the open-source platform Zenodo.
“For this study our goal was to lower the barrier of entry to applying machine learning in pharmaceutical sciences,” Bannigan said. “We’ve made our data sets fully available so others can hopefully build on this work. We want this to be the start of something and not the end of the story for machine learning in drug formulation.”
The study was supported by the Natural Sciences and Engineering Research Council of Canada, the Defense Advance Research Projects Agency and the Vector Institute.
Science paper:
Nature Communication
See the full article here .
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The The University of Toronto (CA) is a public research university in Toronto, Ontario, Canada, located on the grounds that surround Queen’s Park. It was founded by royal charter in 1827 as King’s College, the oldest university in the province of Ontario.
Originally controlled by the Church of England, the university assumed its present name in 1850 upon becoming a secular institution.
As a collegiate university, it comprises eleven colleges each with substantial autonomy on financial and institutional affairs and significant differences in character and history. The university also operates two satellite campuses located in Scarborough and Mississauga.
University of Toronto has evolved into Canada’s leading institution of learning, discovery and knowledge creation. We are proud to be one of the world’s top research-intensive universities, driven to invent and innovate.
Our students have the opportunity to learn from and work with preeminent thought leaders through our multidisciplinary network of teaching and research faculty, alumni and partners.
The ideas, innovations and actions of more than 560,000 graduates continue to have a positive impact on the world.
Academically, the University of Toronto is noted for movements and curricula in literary criticism and communication theory, known collectively as the Toronto School.
The university was the birthplace of insulin and stem cell research, and was the site of the first electron microscope in North America; the identification of the first black hole Cygnus X-1; multi-touch technology, and the development of the theory of NP-completeness.
The university was one of several universities involved in early research of deep learning. It receives the most annual scientific research funding of any Canadian university and is one of two members of the Association of American Universities outside the United States, the other being McGill(CA).
The Varsity Blues are the athletic teams that represent the university in intercollegiate league matches, with ties to gridiron football, rowing and ice hockey. The earliest recorded instance of gridiron football occurred at University of Toronto’s University College in November 1861.
The university’s Hart House is an early example of the North American student centre, simultaneously serving cultural, intellectual, and recreational interests within its large Gothic-revival complex.
The University of Toronto has educated three Governors General of Canada, four Prime Ministers of Canada, three foreign leaders, and fourteen Justices of the Supreme Court. As of March 2019, ten Nobel laureates, five Turing Award winners, 94 Rhodes Scholars, and one Fields Medalist have been affiliated with the university.
Early history
The founding of a colonial college had long been the desire of John Graves Simcoe, the first Lieutenant-Governor of Upper Canada and founder of York, the colonial capital. As an University of Oxford (UK)-educated military commander who had fought in the American Revolutionary War, Simcoe believed a college was needed to counter the spread of republicanism from the United States. The Upper Canada Executive Committee recommended in 1798 that a college be established in York.
On March 15, 1827, a royal charter was formally issued by King George IV, proclaiming “from this time one College, with the style and privileges of a University … for the education of youth in the principles of the Christian Religion, and for their instruction in the various branches of Science and Literature … to continue for ever, to be called King’s College.” The granting of the charter was largely the result of intense lobbying by John Strachan, the influential Anglican Bishop of Toronto who took office as the college’s first president. The original three-storey Greek Revival school building was built on the present site of Queen’s Park.
Under Strachan’s stewardship, King’s College was a religious institution closely aligned with the Church of England and the British colonial elite, known as the Family Compact. Reformist politicians opposed the clergy’s control over colonial institutions and fought to have the college secularized. In 1849, after a lengthy and heated debate, the newly elected responsible government of the Province of Canada voted to rename King’s College as the University of Toronto and severed the school’s ties with the church. Having anticipated this decision, the enraged Strachan had resigned a year earlier to open Trinity College as a private Anglican seminary. University College was created as the nondenominational teaching branch of the University of Toronto. During the American Civil War the threat of Union blockade on British North America prompted the creation of the University Rifle Corps which saw battle in resisting the Fenian raids on the Niagara border in 1866. The Corps was part of the Reserve Militia lead by Professor Henry Croft.
Established in 1878, the School of Practical Science was the precursor to the Faculty of Applied Science and Engineering which has been nicknamed Skule since its earliest days. While the Faculty of Medicine opened in 1843 medical teaching was conducted by proprietary schools from 1853 until 1887 when the faculty absorbed the Toronto School of Medicine. Meanwhile the university continued to set examinations and confer medical degrees. The university opened the Faculty of Law in 1887, followed by the Faculty of Dentistry in 1888 when the Royal College of Dental Surgeons became an affiliate. Women were first admitted to the university in 1884.
A devastating fire in 1890 gutted the interior of University College and destroyed 33,000 volumes from the library but the university restored the building and replenished its library within two years. Over the next two decades a collegiate system took shape as the university arranged federation with several ecclesiastical colleges including Strachan’s Trinity College in 1904. The university operated the Royal Conservatory of Music from 1896 to 1991 and the Royal Ontario Museum from 1912 to 1968; both still retain close ties with the university as independent institutions. The University of Toronto Press was founded in 1901 as Canada’s first academic publishing house. The Faculty of Forestry founded in 1907 with Bernhard Fernow as dean was Canada’s first university faculty devoted to forest science. In 1910, the Faculty of Education opened its laboratory school, the University of Toronto Schools.
World wars and post-war years
The First and Second World Wars curtailed some university activities as undergraduate and graduate men eagerly enlisted. Intercollegiate athletic competitions and the Hart House Debates were suspended although exhibition and interfaculty games were still held. The David Dunlap Observatory in Richmond Hill opened in 1935 followed by the University of Toronto Institute for Aerospace Studies in 1949. The university opened satellite campuses in Scarborough in 1964 and in Mississauga in 1967. The university’s former affiliated schools at the Ontario Agricultural College and Glendon Hall became fully independent of the University of Toronto and became part of University of Guelph (CA) in 1964 and York University (CA) in 1965 respectively. Beginning in the 1980s reductions in government funding prompted more rigorous fundraising efforts.
Since 2000
In 2000 Kin-Yip Chun was reinstated as a professor of the university after he launched an unsuccessful lawsuit against the university alleging racial discrimination. In 2017 a human rights application was filed against the University by one of its students for allegedly delaying the investigation of sexual assault and being dismissive of their concerns. In 2018 the university cleared one of its professors of allegations of discrimination and antisemitism in an internal investigation after a complaint was filed by one of its students.
The University of Toronto was the first Canadian university to amass a financial endowment greater than c. $1 billion in 2007. On September 24, 2020 the university announced a $250 million gift to the Faculty of Medicine from businessman and philanthropist James C. Temerty- the largest single philanthropic donation in Canadian history. This broke the previous record for the school set in 2019 when Gerry Schwartz and Heather Reisman jointly donated $100 million for the creation of a 750,000-square foot innovation and artificial intelligence centre.
Research
Since 1926 the University of Toronto has been a member of the Association of American Universities a consortium of the leading North American research universities. The university manages by far the largest annual research budget of any university in Canada with sponsored direct-cost expenditures of $878 million in 2010. In 2018 the University of Toronto was named the top research university in Canada by Research Infosource with a sponsored research income (external sources of funding) of $1,147.584 million in 2017. In the same year the university’s faculty averaged a sponsored research income of $428,200 while graduate students averaged a sponsored research income of $63,700. The federal government was the largest source of funding with grants from the Canadian Institutes of Health Research; the Natural Sciences and Engineering Research Council; and the Social Sciences and Humanities Research Council amounting to about one-third of the research budget. About eight percent of research funding came from corporations- mostly in the healthcare industry.
The first practical electron microscope was built by the physics department in 1938. During World War II the university developed the G-suit- a life-saving garment worn by Allied fighter plane pilots later adopted for use by astronauts.Development of the infrared chemiluminescence technique improved analyses of energy behaviours in chemical reactions. In 1963 the asteroid 2104 Toronto was discovered in the David Dunlap Observatory (CA) in Richmond Hill and is named after the university. In 1972 studies on Cygnus X-1 led to the publication of the first observational evidence proving the existence of black holes. Toronto astronomers have also discovered the Uranian moons of Caliban and Sycorax; the dwarf galaxies of Andromeda I, II and III; and the supernova SN 1987A. A pioneer in computing technology the university designed and built UTEC- one of the world’s first operational computers- and later purchased Ferut- the second commercial computer after UNIVAC I. Multi-touch technology was developed at Toronto with applications ranging from handheld devices to collaboration walls. The AeroVelo Atlas which won the Igor I. Sikorsky Human Powered Helicopter Competition in 2013 was developed by the university’s team of students and graduates and was tested in Vaughan.
The discovery of insulin at the University of Toronto in 1921 is considered among the most significant events in the history of medicine. The stem cell was discovered at the university in 1963 forming the basis for bone marrow transplantation and all subsequent research on adult and embryonic stem cells. This was the first of many findings at Toronto relating to stem cells including the identification of pancreatic and retinal stem cells. The cancer stem cell was first identified in 1997 by Toronto researchers who have since found stem cell associations in leukemia; brain tumors; and colorectal cancer. Medical inventions developed at Toronto include the glycaemic index; the infant cereal Pablum; the use of protective hypothermia in open heart surgery; and the first artificial cardiac pacemaker. The first successful single-lung transplant was performed at Toronto in 1981 followed by the first nerve transplant in 1988; and the first double-lung transplant in 1989. Researchers identified the maturation promoting factor that regulates cell division and discovered the T-cell receptor which triggers responses of the immune system. The university is credited with isolating the genes that cause Fanconi anemia; cystic fibrosis; and early-onset Alzheimer’s disease among numerous other diseases. Between 1914 and 1972 the university operated the Connaught Medical Research Laboratories- now part of the pharmaceutical corporation Sanofi-Aventis. Among the research conducted at the laboratory was the development of gel electrophoresis.
The University of Toronto is the primary research presence that supports one of the world’s largest concentrations of biotechnology firms. More than 5,000 principal investigators reside within 2 kilometres (1.2 mi) from the university grounds in Toronto’s Discovery District conducting $1 billion of medical research annually. MaRS Discovery District is a research park that serves commercial enterprises and the university’s technology transfer ventures. In 2008, the university disclosed 159 inventions and had 114 active start-up companies. Its SciNet Consortium operates the most powerful supercomputer in Canada.
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