When Kelly Chibale recounts how he made the decision to leave the US, forgo a fellowship in the UK, and start his research program in South Africa just after the end of apartheid, it sounds almost providential. “It was like a missionary going to a war zone,” says Chibale. “I was coming here convinced you couldn’t talk me out of it.”
Kelly Chibale is a 2023 AI2050 Senior Fellow and a Professor of Organic Chemistry at the University of Cape Town (UCT) where he holds the Neville Isdell Chair in African-centric Drug Discovery and Development. He is also the Founder and Director of the UCT Holistic Drug Discovery and Development (H3D) Centre, a Johnson and Johnson Centre for Global Health Discovery.
Chibale’s research is in the field of global health and drug discovery for infectious diseases. His AI2050 project uses AI to accelerate drug discovery and development capacity on the African continent. His primary focus is treatments for tuberculosis (TB), and the additional impact of the disease’s causative agent, the pathogen Mycobacterium tuberculosis (Mtb). Mtb mediates the metabolism of drugs used to treat TB and other frequently co-occurring diseases, which in turn, could affect the efficacy of treatments. This work concerns Hard Problem #4, leveraging AI to address humanity’s greatest challenges. Historically, the vast majority of both drug discovery research and drug development for clinical trials has been conducted in the Global North, leading to significant global health inequity.
By developing open-source AI models that simulate the metabolism of potential drug candidates—and crucially, account for African populations’ physiology and genetics, health needs, and social and cultural environment— he hopes to address the dearth of research conducted within and for the most genetically diverse continent in the world.
“I’m very grateful that I made that decision,” says Chibale. “I’m grateful for what Cape Town has given me, and to see that we can build something from scratch, which of course, is inspiring other people to believe that it’s possible to do this.”
The AI2050 initiative gratefully acknowledges Fayth Tan for assistance in producing this community perspective.
Your work focuses on both a scientific as well as a public health and equity component, and you proposed tackling the pathogen that causes tuberculosis. What about this pathogen makes it such a relevant and compelling problem in both aspects?
Outside of the peak of the COVID-19 pandemic, tuberculosis (TB) remains the number one killer amongst other infectious diseases. In the African context, it’s even more significant because of comorbidity with other infectious diseases, especially HIV. If you look at South Africa, TB is most significant because of the impact on HIV and vice versa.
A second reason is that investment in discovering new medicines for TB really lags behind. It took close to 50 years before we saw a new TB drug with a novel mechanism for action, when the drug called Bedaquiline was discovered and developed by Johnson and Johnson, was approved at the end of 2012. There had been no new innovation for TB until the introduction of Bedaquiline to treat multidrug resistant TB. Because of this under investment in new tools, whether it’s diagnostics, or therapeutics—there is no vaccine, for example—it’s a significant unmet medical need, with very low investment in the field. And of course, compounded by co-morbidities in places like Africa. It is arguably the most significant infectious disease agent today.
I should also comment on why it is important to do drug discovery in Africa, regardless of the disease. There is a very strong correlation between the genetics of a population, the social and physical environment in which those patients live, and [the] treatment of disease. Therefore, it makes sense to do the drug discovery and development in close proximity to [the patients’] social and physical environments. Africa is arguably the most genetically diverse continent—everybody’s an African because people came from Africa, and then they went somewhere else. The genetics of this continent are so diverse and so heterogeneous.
Most drug discovery is done in the Global North, and the majority of the world is not represented in this process. Could you speak to the impacts that this has had on populations in the Global South, and on the African continent?
Although Africa makes up roughly 15% of the global population and more than 20% of the disease burden, [only] between 3% and 4% of global clinical trials happen on the African continent. Because of this low volume of clinical trials that happen in Africa, medicines are often optimized in the Global North—which means the dosages, the frequency of dosing—are optimized on the largely Caucasian population that participate in clinical trials. And the African perspective, in terms of intrinsic factors, like our physiology, like our genetics, are not considered.
There are also extrinsic factors, like the way that Africans practice medicine. If you think about where most people live, [and] the way people practice traditional medicine—when they go to a “Western” doctor, at what stage of the disease do they present themselves for treatment? It’s usually much later. So you have to consider the practice of medicine in this community.
I’ll give you one practical example to illustrate this—there’s a HIV/AIDS drug called Efavirenz. Before a drug goes into people, we need to know which enzyme in the human body is going to be responsible for metabolizing it. The enzyme that is responsible for the metabolism of this drug—in people of African descent, there is a genetic variant in this enzyme which renders African patients [with a] slower metabolism [than Caucasian populations]. If you give a person with a slower metabolism the same dose that you give to a so-called normal metabolism, you are going to overdose them—certain people die from drug toxicity, not from the HIV virus.
How would the involvement of AI facilitate this process?
We’ve been using AI to identify genetic variants that are prevalent in Africa and are likely to metabolize drugs of interest. In this particular context, we are working on TB and malaria drugs. There are variants that have been identified and reported—for example, the genetic variants for Efavirenz were identified in the clinic. But there are many, many variants that have not been identified, and we only discover it when drugs don’t work as well as they should.
Once we identify these genetic variants, we use them as inputs in refining mathematical or pharmacometric models that are used to predict the human dose. In phase one [of a clinical trial], we want to see how the human body tolerates the drug, and identify the maximum tolerated dose that the human body will tolerate. Once we establish that, we go into phase two with actual patients, but the safe dose is determined in phase one. If you do the modeling and simulation and predictions, but use data [that] doesn’t factor in genetics, you can get the dose wrong. You can either underdose, which means you don’t see the efficacy and could also encourage resistance, or overdose, [which is] a safety concern. Instead of waiting to genotype every Jim and Jacqueline and African, we are using AI and machine learning to find these variants and applying it to infectious diseases like TB.
You founded H3D, which is the first drug discovery center on the African continent. It’s been over 10 years since it was founded—how has the landscape of drug discovery changed over the last decade? What do you most look forward to?
I founded the center at the end of 2010. At that time, I only had 5 postdoctoral fellows in chemistry. Today, I have 75 people across chemistry, biology, and pharmacology. In 2022, we became one of the three Johnson and Johnson centers for Global Health discovery. It’s a testament to the infrastructure we’ve developed over the years.
Back in 2017, I made a proposal to the Gates Foundation to expand the drug discovery ecosystem and community in Africa. They liked the idea—not capacity building for the sake of it, but expanding the model that we used here at H3D in Cape Town, which was to focus on projects. Executing projects, doing what we can do with what we have, and then relying on our partners for what we didn’t have. Because our partners are also project partners, they want us to succeed—and so we share everything.
In 2018, we put out an open call to people in Africa to propose a drug discovery project which they would do from their home institution. But they would work with H3D to access our infrastructure, our technologies, and everything else that they were lacking. In the first cohort, we had 8 people, and in the second, we had another 8. Last year, we decided with the Gates Foundation to do something with these 16 people. That led to the formation of what is known as the Grand Challenges African drug discovery accelerator. We mobilized another funder, a medical charity based in the UK, LifeArc. LifeArc and the Gates Foundation are co-funding this [program] over the next 3-5 years. That’s $7.2 million to support drug discovery in Africa.
To answer your question, this is where we are: expanding the ecosystem and community in Africa so we can benefit from economies of scale—[such] that many other parts of Africa can be doing this, that we can share data from different parts of Africa, and really build an industry in the future. Maybe not in my lifetime, but in the future.
You have quite an international background. With many international researchers, the belief is you go where the opportunity is. But you chose to return much closer to home. How did you make that decision?
28 years ago, I was at Scripps Research Institute in La Jolla [as a postdoctoral fellow]—beautiful weather, beautiful climate. I was on a long term traveling fellowship from the Wellcome Trust so I was meant to go back to England to do that. But let me put it this way: I just felt a calling. It was a calling that’s not easy for me to explain. When I was in England [for a Ph.D. at Cambridge University], someone in Cape Town initially made me an offer to do a postdoc, but I declined because South Africa was just coming out of apartheid. I thought there was going to be a civil war with the first elections after Nelson Mandela was released. So I opted to go to Scripps.
But I also got the opportunity to consider coming to Cape Town. It felt as if it was coming not from my head, but from my spirit. I flew from San Diego to Cape Town for interviews. When I told my [Ph.D.] adviser at Cambridge that I was considering opportunities [in Cape Town], he said to me, you should really consider this—South Africa is just coming out of a difficult period, and this is an opportunity to really make a difference. If you’re in the US or in England, you’re a small fish in a very big pond, but in a place like that, you could make an impact. So he convinced me to do this.
Then I told the Wellcome Trust that I decided to take a job in Cape Town, so I’m not coming back to England. And they said, on your way to Cape Town, come and see us in London, we’ve just begun a program of funding in South Africa— to cut a long story short, [that] gave me a boost when I began my career.
So there was an opportunity, but I also felt the calling to come here. If everyone just leaves, well, who’s going to do it for the next generation? But you have to feel that you have the opportunity and the calling to do it, because not everybody can.
I think researchers from the US or UK don’t always understand the kinds of decisions international researchers who leave their home countries have to make. What would you tell young researchers who find themselves thinking about the same things you were?
I would say the following 3 things, always in this order. Number one, you need to keep an open mind and look for opportunities wherever you can find them. Go with the opportunity wherever it presents itself, and when you have it, make the most of it. Because before you know it, one thing leads to another, leads to another, and suddenly, [it’s] something big—because you took your chance.
Second: be consistent. You’re the only person that knows what you’re good at. You’re the only person that knows what you want. You can’t live anyone’s life, and no one can live your life. If I believe in something, I will be consistent with that.
And then the final thing I say to people is [that] I believe that God made me unique. I’m a unique person. You have to understand that people who make history don’t conform, and you need to be careful not to allow other people to define what success is for you. Some people achieve things quicker than others, but life is one day at a time, one step at a time, and just keeping an open mind. I think it’s funny, [when] you talk to somebody, and they say I’ve always wanted to be an engineer, I’ve always wanted to be a doctor. Really? In your mother’s womb, you figured it out? How do you know you were meant to be this? How can you imagine it when you haven’t been there? There are no formulas, only principles. It’s just one day at a time, one step at a time, because suddenly, things can change.