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Bill Gates
Presidential Symposium, American Society of Human Genetics
Orlando, Florida
October 18, 2017
AS PREPARED

Thanks, Nancy for that introduction. I’m looking forward to the conversation with Francis and to answering questions from the audience after this. Francis and I have known each other for many years, and our foundation and the NIH have a lot of common interests. Although I don’t know most of you, I believe we also share the same aspirations: advancing scientific research to alleviate human suffering.

In fact, I believe there’s an opportunity for us to do some amazing things together. Genetics has the potential to tackle not only rare and inheritable diseases, but also infectious diseases that kill millions of people around the world every year.

Addressing the enormous health disparities between developed and developing countries is at the core of our foundation’s work. During my first trip to Africa in 1993, I saw so many people suffering from diseases that barely exist in wealthy countries, and I started to ask why.

So, when Melinda and I decided to focus on philanthropy several years later, there was no doubt in our minds that eliminating the gross inequities in health would be our focus. One area where we believed we could make a difference was investing in R&D to address the diseases of poverty. In health, as in many other aspects of life, the free market works very well for people who can pay. But for people who can’t, new solutions can take decades or longer.

Even so, the world has made good progress with existing solutions like basic vaccines, TB treatments, and antiretroviral drugs. Over the last 25 years, we’ve nearly eradicated polio. Child mortality has been cut in half. And we’ve significantly reduced deaths from HIV, TB, and malaria. Yet, these three epidemics alone are still killing millions of people a year. And almost 5 million children will die next year – close to half in the first 28 days of life.

To reduce this disease burden, we need new breakthroughs in medicine and science. Many of these will come from this community, which is why I’m excited to be here.

I’ve been an enthusiastic student of genetics for quite a few years. I read The Eighth Day of Creation back in the mid-1980s. And I remember reading the third edition of Watson’s Molecular Biology of the Gene during the Microsoft IPO, in 1986. Then, the fourth edition came out, which was two volumes, and I had to start over.

I had bad biology teachers growing up, so I never saw the potential of genetics the same way I saw the Altair 8800 microcomputer when it appeared on the cover of Popular Electronics in 1975. In that moment, I could imagine what was possible once software and computers were in everyone’s hands.

A decade later – reading Judson, and Watson, and seeing the promise of Boyer and Cohen’s work beginning to take shape in companies like Genentech – I finally grasped the power of understanding the genome and making that information accessible to people everywhere.

As a software guy, I was more acquainted with binary code. But I could see in genetics the hardware-software boundary of a programming language that is quite complex. Evolution wasn’t designed to be simple.

As I learned today, there is still a lot of complexity to the software of life that needs to be worked out. I had a chance this afternoon to meet with a few researchers to learn about the elegant complexity of genetic regulation captured in the architecture of DNA. It’s amazing to see how the 3D structure brings distant control elements into physical proximity with precise timing to control T cell function and development.

In another learning session, I heard about advances in gene therapy that could cure sickle cell disease, which affects 100,000 people here in the U.S. and many more in sub-Saharan Africa.

Studying genetic variation in people from diverse ancestral origins may identify new genetic mechanisms of resistance from many diseases. For example, we know that CCR5 receptor mutations protect some people from HIV infection.

I also learned that genetic variants within a hemoglobin gene can have a beneficial effect; and editing in this variant has recently been used for gene therapy. Developing gene therapy for sickle cell disease would not only have an immediate impact on the lives of sickle-cell patients – it would also allow us to imagine applying gene therapy for a range of diseases that impact millions, including HIV.

In another session this afternoon, I met with researchers to talk about the progress and gaps in producing a truly global understanding of human evolution and disease risk. This is essential to tackling the diseases that disproportionally affect people in the poorest countries.

Frustratingly little is known about why people in poor countries die. One particularly mysterious period is during pregnancy and the first 28 days of a newborn’s life. This year, 300,000 women will die during pregnancy or childbirth – and 2.5 million children will die in the first month of their life.

Pre-term births are an especially big problem. They are the leading cause of death among children under five, and the odds of survival are much worse for pre-term babies in the developing world. The babies who do survive an early birth often face serious and lifelong health problems like chronic lung disease, cerebral palsy, and neurodevelopmental disabilities.

Genome wide association studies may help uncover the biological mechanisms underpinning pre-term birth. Previous research suggested a link between genetic factors and a significant percentage of preterm births. But earlier studies were unsuccessful due to limited sample sizes.

Recently, though, we co-funded a study by the Cincinnati Children’s Hospital and others that tapped into a database of genetic data on more than 50,000 women, provided by 23andme.

Researchers were able to identify three highly significant genetic factors associated with preterm birth. One is a gene involved in placing selenium, an essential dietary mineral, into proteins. This research will allow us to learn if selenium supplementation in pregnancy could have a protective effect.

There are also strong associations between preterm birth and an irregular maternal reproductive biome. Deep gene sequencing and sophisticated bioinformatic analysis can track changes in the microbiome that occur during pregnancy.

By distinguishing abnormal changes in the microbiome during pregnancy, we may be able to give pregnant women probiotic or synbiotic supplements to reduce the risk of pre-term birth.

We also are funding research examining the role of the microbiome in child nutrition. DNA sequencing of microbiomes has shown that malnourished children have a more primitive microbiome than well-nourished children. This insight is pointing researchers toward a combination of probiotics and appropriate local foods that could reverse the effects of malnutrition on children’s physical growth and cognitive development.

And, we are adapting genetic diagnostic approaches to better understand why children in the developing world die. We’re leveraging liquid biopsy approaches to develop liquid autopsies. These minimally invasive tissue samples will provide valuable epidemiological data on what is causing stillbirths and childhood deaths.

We also are funding liquid biopsy research to diagnose infections, track antimicrobial resistance, and record a patient’s history of infection.

The diversity of genetic approaches is staggering. Switching from humans to mosquitos . . . we are investing in the development of gene drives that could accelerate the eradication of malaria by suppressing the mosquito species most responsible for spreading the deadliest type of malaria. And malaria is deadly. It kills one child every two minutes and disables millions more.

Using CRISPR, though, researchers have succeeded in installing gene drives in malaria mosquitos that skew the sex ratio to largely male offspring, or that cause the females to become sterile. Investigators are now exploring whether CRISPR can alter the mosquito’s ability to transmit malaria.

CRISPR has made developing such constructs easy to do, but now we need to prove that we can sustain suppression of the disease-carrying mosquito long enough to clear the malaria parasites out of affected populations.

The first field tests are at least five years away, and we are taking a cautious approach – mapping out next steps for biosafety, bioethics, community engagement, and regulatory guidance. Most importantly, we need to ensure that the communities that would bear the benefits and risk of gene drive are at the heart of decision-making.

Meanwhile, to eliminate the last vestiges of polio, we are using genetic sequencing to track the movement of polio in the few places where it is still endemic or where it occasionally resurfaces.

By tracking strains of the virus, we can understand how long the virus has been circulating and trace its geographic movement. This, in turn, tells us what kind of immunization response is needed to stamp out the virus. Conversely, if we haven’t seen a specific strain in the field for an extended period, that gives us a pretty good idea that it’s gone.

We also are working with a team of genetic researchers on a new polio vaccine – one we hope we never have to use because we have good vaccines today that can get the job done. This new vaccine candidate is kind of an insurance policy in the unlikely event of a future outbreak in communities where coverage using the current oral vaccine is low.

The promise of this new formulation, which is in early-stage testing, is that it will further reduce the small but real risk that the live, weakened virus in the current oral vaccine could mutate and begin to circulate.

I love vaccines. Once you have a good one, they’re an incredibly cost-effective way to save lives and improve health.

We are currently looking at how to develop an HIV or TB vaccine using CMV (cytomegalovirus). To create an effective vaccine, we need to understand how the variability of individuals’ immune responses – governed by their HLA – contribute to the effectiveness of potential vaccines.

We have also been involved in the progress of using gene transfer alone – without a virus – to directly encode antigens in the human body directly. Nucleic acid based vaccines – using DNA or even RNA – are intriguing for a number reasons.

They allow us to experiment with many different antigens quickly. The speed of manufacture, scalability, and the potential to eliminate the need for cold chain storage could be especially useful in the event of an unexpected infectious disease outbreak. And, of course, the reduction in cost could be huge.

We are working with a number of companies to advance their technologies into clinical trials. We realize the importance of solving the problem of gene delivery – something the gene therapy community has been dealing with for several decades. We want to ensure that we are taking every advantage of what the gene therapy community is learning, and apply those tools to vaccinology.

But what if we could bypass the complexity, time, and cost of vaccine development altogether?

Researchers have been working on a malaria vaccine for over 100 years. We still don’t have a safe, effective vaccine for TB. And we’re still searching for an HIV vaccine after almost 40 years. In each of these cases we are still not certain what structures to show the immune system to evolve the protective response—optimal antibodies.

The genetics of the HIV immune response have been extensively studied, perhaps more than that of any other disease. But the HIV-neutralizing antibodies that are most appropriate for protective immunity are not directly elicited by any vaccines that have been designed to date.

However, such antibodies have been found to arise in some persistently HIV-infected people. With today’s genetic technology, it is possible to isolate and read the sequence of these highly-mature HIV antibodies and write the genes required to endogenously express them in uninfected individuals.

The problem is getting a sufficient level of antibody expression and long-term persistence required for immunological protection. This won’t be an easy problem to solve, though I’m optimistic we can get there.

More recently, new tools to edit genomes, developed by your community, are changing medicine. CRISPR technology is being applied to gene therapy, and genome editing of T cells is transforming the field of oncology. But these are expensive therapies – often only used for the person these cells were harvested from.

Imagine if we could edit B cells to make antibodies of our choosing . . . or engineer these cells to be universal donor cells, like O negative red blood cells?

It’s interesting that although so many features of humanity are transferred across generations through inheritance, our immune memory is not. Each generation starts tabula rasa.

What if we could bring together the best opportunities in genomics research to transform the way we approach infectious disease and immunity? Are there better ways to transfer optimal immune memory from the exposed to the immunologically naïve?

There are many technical challenges to overcome, some we can foresee, and others that will only reveal themselves as we get into the work. And of course, we will have to address the ethical considerations as technology advances.

But as fantastical as this may sound today, given the accomplishments of this community, why couldn’t this be achievable? Imagine the suffering that could be eliminated. What a world that would be.

 

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