By David Pittman
This year’s annual meeting of the American Association of Pharmaceutical Scientists (AAPS) was held virtually for the first time amid the global COVID-19 pandemic. But that did not slow down the programing or diminish the excitement for PharmSci 360, which was headlined by 2020 Nobel Laureate Jennifer Doudna, Ph.D.
This year’s meeting featured 300 sessions across six tracks from October 25 to November 5 plus an additional week of workshops. In all, attendees could view nearly 700 submitted abstracts. PharmSci 360 still hosted live events, including special poster collections with panels of authors. Awards ceremonies were also hosted virtually.
The meeting premiered Connect 360, an artificial intelligence-driven matchmaking tool to pair attendees based on shared interest. The tool helped the thousands of scientists network and connect across the globe while not being able to attend the meeting in-person.
Nobel Prize Winner Headlines
Doudna’s opening plenary was the high point of PharmSci 360. The University of California, Berkley, scientist was awarded the 2020 Nobel Prize in Chemistry with co-recipient Emmanuelle Charpentier, Ph.D., for their pioneering discovery of CRISPR-Cas9, the genome editing technology that has been revolutionary for biomedicine. It is the first time women have not shared the prize with men.
Doudna actually started her career as a biochemist when she began researching the hypothesis that bacteria might have an RNA-guided adaptive immune system. In other words, scientists learned they could adopt bacteria to fight viruses using an RNA-guided mechanism through CRISPR-edited genes. Over time, they have learned to be able to introduce new gene sequences into cells to create new or different functions by introducing breaks in DNA’s famous double helix and leveraging a cell’s natural repair process.
“In the field of gene therapy and genome-editing, scientists have been trying to figure out how to control this repair process by introducing breaks at a precise position where an edit was desired,” Doudna said. “That is exactly where CRISPR comes in.”
The field has exploded in the last eight years, including for clinical applications. One of the many areas CRISPR is being used in is to correct genetic diseases such as sickle cell anemia.
Much of Doudna’s attention today is focused on making gene editing widely accessible and affordable for patients. “That’s a tall order but one I think very worth focusing on,” she added. Early trials suggest that the technology is safe. What lies ahead is how efficient it is and how it can be used more widely.
Discussion continues around how use gene editing in an ethical manner. Recently, the National Academies and UK’s Royal Society recently released a report on how the international scientific and clinical communities can use CRISPR responsibly.
Scientists have quickly pivoted to use CRISPR to help battle the ongoing COVID-19 pandemic. Graduate students in Doudna’s lab are working on a new detection diagnostic for COVID. CRISPR looks for a certain DNA or RNA sequence of the coronavirus and then releases a fluorescent material, allowing the detection of viral load.
“There is a good chance in the next few months we will see technologies coming forward for actual use in laboratories or point-of-care settings, maybe even in an at-home setting, for detection of SARS-CoV-2, which would be a really exciting way to use the technology that has some advantages over current detection methods,” Doudna said.
COVID Updates Prevalent Throughout
In one of the keynotes, Kellie S. Reynolds, Pharm.D., of the Food and Drug Administration (FDA) outlined lessons learned from nearly three decades of handling infectious disease outbreaks at the agency. Reynolds, director of FDA’s division on infectious disease pharmacology in the office of clinical pharmacology in the Center for Drug Evaluation and Research, has been working at the agency since 1994, a pivotal phase of HIV drug development.
The principles of clinical pharmacology—finding the right dose of the right drug at the right time for the right patient—are critical to remember during research, but they must still balance with the need to find treatments quickly.
“During an infectious disease outbreak, decisions about therapeutics must balance the urgent public health need for treatments with the importance of a thorough evaluation of safety and efficacy,” she said.
The three-decade veteran of FDA outlined several considerations drug researchers must understand in the development of COVID-19 drugs, including knowing the pharmacokinetics of a potential treatment, understanding the site and mechanism of action of a drug, knowing the drug’s activity against the drug, and considering the patient population and co-morbidities they may have.
“Viewing the items as a sequence of hurdles may give the impression that they will slow drug development, but having processes and the mindset in place in advance of an emergency can help get closer to the balance between urgency and evidence-based decisions,” Reynolds said.
To better respond to the COVID-19 pandemic and others that may come in the future, Reynolds said the research community needs to examine data and potential solutions from the perspective of different stakeholders. Clinical pharmacology will be necessary to optimize dosing when other information in absent.
During the 2009 H1N1 influenza pandemic, FDA, for example, used its Emergency Use Authorization to allow multiple unapproved drugs or expanded the indication of drugs to treat H1N1, but that work was allowed because of clinical pharmacology, which derived the appropriate doses in these unstudied populations.
Applying Machine Learning to Drug Development
In a “Hot Topics” roundtable discussion, scientists spoke about the use of artificial intelligence (A.I.) and machine learning as an emerging bioanalytical solution. Machine learning, at its highest level, is the discipline of computer science where algorithms are given data and learn how to classify or categorize it.
As Russ B. Altman M.D., Ph.D., of Stanford University described, machine learning can be applied to help find drug targets, predict drug interactions and toxicity, predict gene function, and isolate groups of patients that are similar and therefore might make a smaller or easier drug trial.
A.I. to date hasn’t been predictive, said Christopher P. Calderon Ph.D., president and founder of Ursa Analytics, which applies machine learning to image analysis and signal processing. Instead, software is good at pattern recognition. “We’re nowhere near where Google is where it is predicting what you’re going to type,” Calderon said.
However, machine learning is good for quality control purposes and seeing if something has gone wrong. If the A.I. tool detects something is off, then the human can dive into the potential problem.
Stephanie A. Pasas-Farmer, Ph.D., of Ariadne Software in Lawrence, Kan., said the biggest pushback she receives is from drug researchers who think there are being pushed out of the development process. Her company uses machine learning for quality control and review of bioanalytical data.
“What we have to show in test case after test case is that we’re not taking the human out of the decision making,” Pasas-Farmer said. Instead, they give the computer data to flag. It is still up to humans to decide if alerts are acted upon or what the impact of issues found.
“It is almost an augmentation of the human intelligence as opposed to completely divorcing them from the process,” Pasas-Farmer said.
While use of so called “software as a medical device” is increasing, the application to date has been mostly applied to analysis of images, for example, by radiologists, said Kenny Cha, Ph.D., an engineer in the Division of Imaging, Diagnostics, and Software Reliability with FDA’s Center for Devices and Radiological Health.
“They are there to help you and take away some of the tedious stuff,” Cha said of the software. “We are hoping these devices can help them perform their jobs faster, not necessarily more accurately.”
Manufacturing goes 3D
Thomas West, M.S., vice president of pharmaceutical development Aprecia Pharmaceuticals in New Jersey, shared his company’s latest work in the field of 3D printing. Aprecia developed Spirtam, the first 3D printed pharmaceutical product to receive FDA approval.
Their proprietary manufacturing technology, ZipDose, can be applied to larger doses. With more traditional techniques, tablets were too large for patients to ingest at high doses. Using “open bed” 3D printing, each layer of the drug product is spread onto the paper as a new layer is spread over the last. West likens the process to how a desktop printer prints on a single piece of paper.
Aprecia’s next challenge is printing drugs in individual blister packaging or what it cells in-cavity printing. “In-cavity printing, really the newest variation, we think offers a lot of opportunities for scaling down, up and out,” West said.
Overall, he explained, 3D printing offers opportunities to scale the manufacturing process in ways that better meet supply and demand and as well as patients’ needs.
But currently, FDA has health hazard and safety concerns for certain point-of-care 3D printing techniques, including at hospitals, compounding pharmacies and patients’ homes, said Akm Khairuzzaman, Ph.D., senior reviewer at FDA’s Office of Pharmaceutical Quality in CDER. These concerns center upon inkjet printing and laser sintering because of the potential for cross contamination in the handling of raw materials and solvents.
Khairuzzaman said those concerns don’t necessarily apply to fused deposition modeling. “The reason is this can actually handle material in a much better way,” he added. “The cross contamination can be very minimal.”
Manufacturers can think of point-of-care 3D printers like miniature devices which can be regulated as a drug-device combination whose regulatory pathway is much more clearly defined.
“Currently, there is no regulatory framework for patients or doctors to print personalized medicine at home using 3D printing technology,” Khairuzzaman said. “However, the existing regulatory space can be stretched at the point of care when we appropriately select the 3D printing platform, as for example the path for combination drug product.”
By contrast, 3D printing used in a traditional manufacturing facility is considered by FDA to be no different from traditional manufacturing, Khairuzzaman said. The same goes for continuous manufacturing sites. However, like most other drug products, additional attributes might be included depending on the design and performance of the 3D printing tool used.
FDA recently published guidance for 3D printing, and although it was meant for medical devices, Khairuzzaman said its principles can be applied to drug manufacturing.
New Disease Detection Tools
One PharmSci 360 symposium, focused on different efforts to diagnose and detect diseases earlier. Specifically, two researchers spoke of their work to detect cancer through blood-based biomarkers and to battle heart disease through the body’s natural immune response.
Current cancer tests are either invasive, which can cause other complications, or expensive and lack patient compliance, such as through imaging. If scientists can develop blood tests for cancers, patients could be better served, explained Seungpyo Hong, Ph.D., chair of pharmaceutical sciences at the University of Wisconsin, Madison. Hong and his colleagues are working on detecting circulating tumor cells in blood. Their challenge is that such tumor cells are roughly one in a billion cells circulating in the blood. Also, such tumor cells are very heterogeneous. Hence, detection devices need to be sensitive and expandable to multiple types of biomarkers.
As a basic immune response, blood cells express a certain enzyme when they are injured or when cancer cells metastasize. Normally, that enzyme activates an immune response, but Hong explained that diagnostics could be created to detect those enzymes, thereby enabling a more effective blood-based diagnostic for cancer.
“We showed a strong correlation between a clinical outcome and our [circulating tumor cells] test,” Hong said.
Vincent Venditto, Ph.D., assistant profess in the College of Pharmacy at the University of Kentucky, described his lab’s work around heart disease. While heart attacks can be caused by the buildup of fatty cells in vessels that block the flow of blood, researchers have discovered that the ApoA1 protein helps clear out the buildup of those fatty cells. It turns out that the release of the ApoA1 protein is part of a person’s natural immune response to the buildup of fat in the arties.
Venditto is researching that immune response to cardiovascular disease. Better understanding it will help drug researchers in the future create ways to elicit an immune response to fight the buildup fatty cells. Also, if the ApoA1 protein can be measured, he said it might be a good predictor of cardiovascular disease.
Early studies have shown a good correlation between the immune response to cardiovascular disease in mice and humans, which will make this process easier to study. Venditto’s work is trying to further characterize the molecular and functional characteristics of immune response to the buildup of fatty calls in the arteries. “Our integrated studies with humans and mice are really critical to understanding the role in disease progression,” Venditto said.
Lessons in Leadership
One popular breakout session at PharmSci 360 involved essential coaching skills for leaders. The breakout was led by executive coach Ebony Smith. While she has been executive coaching for the last six years, she holds a bachelor’s degree in chemistry and used to work in the petrochemical industry.
“Good leaders,” Smith said, “are able to empathize with others, define problems, seek ideas for solutions, think about ways to implement those ideas, and then test them out. If you want to improve your leadership skills so you propel you career forward, you must participate in your own advancement,” Smith said. “And one of those ways is deciding you’re going to set a learning agenda for yourself.”
She recommended devoting 10 to 15 minutes a day to learning a new skill around leadership such as empathizing, solution finding and communication. You can also practice skills on a smaller scale. If you’re uncomfortable doing that in the workplace, try it at home first. You will significantly move forward if you design your own plan for advancement, she said.
In her talk, Smith laid out 10 essential coaching skills for leaders; listening, asking empowering questions, inspiring others to act, encouraging others to stretch their abilities, celebrating others’ success, championing, giving accountability, clarifying tasks problems and solutions, forwarding tasks, pushing buttons in good ways.
An example of an empowering question is “what’s your next step” or “what did you learn from that?” Celebrating people’s work is different from acknowledging, which is just recognizing. Celebrating is honoring that accomplishment.
She recommended creating an accountability circle. Each member joins the group with a goal that they want to achieve, and the circle agrees to provide support, inspiration, and championing to each other.
“Many work environments are volatile, uncertain, complex and ambiguous. Instead, good leaders are able to shift from volatility to vision and lay out what they are looking for and where they want to go, Smith said. They are able to move from uncertainty to understanding and seek to gain from the people they’re talking to and be able to better lead them. They give clarity to complex issues. They progress from ambiguous problems by showing agility and demonstrating they can show up for a challenge.”
David Pittman is a science and medical writer in Washington, D.C.