By Paul Nicolaus
May 30, 2018 | Poverty-stricken, war-torn, and largely rural, the African country of Sudan is not exactly a likely setting for high tech work, so at first glance, proposing a high-flying, next-generation sequencing study in a place like this seems bizarre at best. And yet, there is good reason to pursue research in this corner of the world despite the laundry list of challenges.
After all, the genetic origins of the human species can be traced back to Africa. Those who migrated out of the continent and populated the rest of the planet all stem from the small group that once left, noted Stephan Züchner, a neurologist and molecular geneticist with the University of Miami. As a function of its smaller size, this group carried only a limited amount of genetic variability.
On the other hand, the genomes of people now living in Africa are more varied than those of humans living anywhere else worldwide. In fact, some tribes from Africa are genetically more different from each other than any other non-African people are from one another because they have had the longest uninterrupted stretch of time to accumulate variation.
Studying the make-up of Africans, then, can offer up fresh insight, and Züchner sees the potential. At the moment, he is pursuing a collaborative effort that involves researchers from Sudan who were trained at the French National Institute of Health and Medical Research (INSERM) in Paris and want to carry out genetic projects in their home country. In March, he met with Giovanni Stevanin, the French mentor of this group, to renew their resolve and determine how to best move forward.
The other key collaborator involved is Liena Elbaghir Omer Elsayed, a Sudanese-born scientist who worked with Stevanin while pursuing her PhD in France, and has since managed to build up a team of about 30 researchers in Sudan. Now an assistant professor in the Department of Biochemistry at the University of Khartoum—the largest and oldest university in Sudan—Elsayed unearthed some intriguing findings while working toward her PhD and carrying out a research project centered on Sudanese genetics.
Because the Sudanese people often live in conserved communities, villages, and towns where related marriages are favored for various reasons, consanguinity leads to an enrichment of certain genetic variants over time. As a result, it is more common to come across rare genetic disorders—especially recessive disorders.
Collaborative Challenges
Carrying out population genomics in Sudan is challenging, though. Elsayed’s team at the University of Khartoum is able to gather DNA samples using test kits that can be used in the field without the need for high-tech storage. In a lab without sequencers, though, that portion of the work is outsourced—typically through a PhD student working with a collaborator outside of Sudan.
And international collaboration comes with its share of challenges. The United States has imposed sanctions on Sudan for many years, recently lifting some, but not all, restrictions. Elsayed says that scientific collaboration with researchers in the U.S. is not possible. “If I would like to send samples or send somebody there [to the U.S.], it’s very difficult,” she said. This dynamic has also led to funding disappointments. Last year, for example, Elsayed applied to the International Centre for Genetic Engineering and Biotechnology (ICGEB) for funding. “Scientifically, we earned it,” she said. But she and colleagues later learned that sanctions would prevent a transfer of money to Sudan, and that award was ultimately lost.
Despite setbacks along the way, recent discussions between Züchner, Stevanin, and Elsayed have rekindled interest in an international partnership that would connect Miami, Paris, and Khartoum and begin with a small pilot study focused on Ataxia—a degenerative disease of the nervous system.
Elsayed has a student who is currently in France working with Stevanin, she explained, so samples would be sent to him where they could be screened for known genes related to Ataxia. Samples that test negative for known genes will be forwarded from France to Miami to undergo whole exome sequencing. The research team in Sudan, meanwhile, plans to analyze the whole exome sequencing data to search for new genes linked to the disease.
If the Ataxia project goes well, there could be opportunities to expand that pilot study or look at additional diseases. “But we are going to start at Ataxia and see what happens,” Elsayed said.
Ending Diagnostic Odysseys
Elsayed and her Sudanese research team can’t afford an expensive commercial software product for genomic data analysis. Instead, Züchner said, they will benefit from The Genesis Project (TGP) foundation, a not-for-profit foundation he co-founded as he recognized the need to build a data information system for real-time sharing and analysis of genomic information.
In a nutshell, TGP’s mission is to provide a platform and a place that can support high-quality science in the realm of human genetics, Züchner said. The focus is supporting a global network of scientists working together to better understand the human genome, especially in the context of finding solutions for rare diseases.
At the heart of the foundation is a software platform, originally called GEM.app. In 2015, three years of GEM.app results were published (doi: 10.1002/humu.22836) while introducing GENESIS—its next iteration. GENESIS was designed by ViaGenetics, a company Züchner co-founded about five years ago. (In 2017, ViaGenetics and the TGP foundation parted ways and Züchner completely divested from the company in order to focus on the foundation.)
Today, TGP runs as an all-volunteer, academic, community-managed non-profit organization that brings together a network of academic institutions, scientists, and non-profits to enable big data management and genetic discoveries using the GENESIS platform. With the ups and downs of NIH funding, it can be difficult to pursue long-term projects, Züchner said. He hopes TGP can help sustain research efforts over the long haul.
In addition, it became clear that creating a not-for-profit foundation run by academics is a useful way to provide an independent setting for genomic research. “We sort of play Switzerland,” he said, “in a field that can sometimes be very competitive.” TGP does not own any data that is deposited into GENESIS aside from data that was produced with foundation funding. Either way, the data is made available for research purposes.
TGP holds a perpetual license of the GENESIS software platform and continues to develop and adjust it for the needs of the academic community as well as foundations focused on rare genetic disease research. While he did not divulge pricing specifics, Züchner said the cost to use the platform “is kept at a minimum as GENESIS only supports research projects.” And on an individual basis, the foundation does not charge for projects from developing countries, like Elsayed’s work in Sudan, in order to enable scientific projects in those parts of the world.
“We really care about the patients,” and that is the purpose behind the science, said board member Rosario Isasi, who serves as the ethics and policy director of TGP and works with Züchner as a research assistant professor at the University of Miami.
When families are dealing with diseases that have not yet been diagnosed, that can be an enormous burden to bear, and the foundation is able to help patients and families bring an end to their “diagnostic odysseys.”
As the mother of a child who died at an early age from a rare disease, Isasi said she values the way TGP moves science forward so that “one day some patient, some parent, some family could discover what was the cause of the disease, and if not have a treatment, at least have a diagnosis.”
Advantage of Genetic Diversity
For Elsayed’s team in Sudan, TGP’s GENESIS data analysis platform will let them dig into the genomic data generated from Sudanese samples. In a country that lacks sophisticated genetic labs, it is now possible to log into this web-based platform, feed anonymized data from patients into the system, and perform first-world genetic analysis right in Sudan. “All you need is Internet access and a computer,” Züchner said.
Ultimately, he sees this work in Sudan as an indication that it is possible to reach into parts of the world that have been largely neglected by genetic research to date. And Sudan is far from the only example. Samples have also been gathered in places like Thailand, Taiwan, Korea, and South America, he pointed out, “so it really spans the entire globe.” Currently, GENESIS has about 800 registered users from 44 countries.
“In genetics, I think really the community has understood by now that exploring and supporting diversity in our research is so essential,” he said. There is a need within the scientific community to gather genomic information from all sorts of places. It’s not only the right thing to do to spread the knowledge—include the world, and help develop places that are underdeveloped—but, he added, it’s also essential for quality genetic studies.
To understand the Swedish genetic background, for example, it’s not enough to just study people from Sweden. “You have to study people from all places around the world and compare them to the Swedish genomes,” he said. “That gives you the most power from a pure scientific point of view.”
And yet, there’s still plenty of work to be done. In 2018, if someone has a rare disease in the United States, a physician may turn to a gene testing panel. Depending on the disease and the patient, the panel would test a variety of genes that are known to potentially relate to the disease. When many genes are tested, though, “you almost invariably receive one or two or three genes on that panel that contain a variant that has never been reported before in any database anywhere,” he said.
It isn’t clear whether these variants are benign or pathogenic. “This is true for nearly every patient that’s being tested for a large number of genes,” he said, and these variants of unknown significance (VUS) are “a big problem.” But when scientists conduct their genetic research in places like Sudan, a different spectrum of these variants are found.
“We sort of complement each other’s genomes by comparing them,” he said. The human species has developed over thousands of years and diverged over time, and when the genomes gathered to enrich databases are more diverse, they become more valuable. “And this has a direct impact on a patient from the United States,” he added. “Absolutely.”
Paul Nicolaus is a freelance writer specializing in science, technology, and health. Learn more at www.nicolauswriting.com