Posted on by Dr. Francis Collins
At the close of every year, editors and writers at the journal Science review the progress that’s been made in all fields of science—from anthropology to zoology—to select the biggest advance of the past 12 months. In most cases, this Breakthrough of the Year is as tough to predict as the Oscar for Best Picture. Not in 2020. In a year filled with a multitude of challenges posed by the emergence of the deadly coronavirus disease 2019 (COVID-2019), the breakthrough was the development of the first vaccines to protect against this pandemic that’s already claimed the lives of more than 360,000 Americans.
In keeping with its annual tradition, Science also selected nine runner-up breakthroughs. This impressive list includes at least three areas that involved efforts supported by NIH: therapeutic applications of gene editing, basic research understanding HIV, and scientists speaking up for diversity. Here’s a quick rundown of all the pioneering advances in biomedical research, both NIH and non-NIH funded:
Shots of Hope. A lot of things happened in 2020 that were unprecedented. At the top of the list was the rapid development of COVID-19 vaccines. Public and private researchers accomplished in 10 months what normally takes about 8 years to produce two vaccines for public use, with more on the way in 2021. In my more than 25 years at NIH, I’ve never encountered such a willingness among researchers to set aside their other concerns and gather around the same table to get the job done fast, safely, and efficiently for the world.
It’s also pretty amazing that the first two conditionally approved vaccines from Pfizer and Moderna were found to be more than 90 percent effective at protecting people from infection with SARS-CoV-2, the coronavirus that causes COVID-19. Both are innovative messenger RNA (mRNA) vaccines, a new approach to vaccination.
For this type of vaccine, the centerpiece is a small, non-infectious snippet of mRNA that encodes the instructions to make the spike protein that crowns the outer surface of SARS-CoV-2. When the mRNA is injected into a shoulder muscle, cells there will follow the encoded instructions and temporarily make copies of this signature viral protein. As the immune system detects these copies, it spurs the production of antibodies and helps the body remember how to fend off SARS-CoV-2 should the real thing be encountered.
It also can’t be understated that both mRNA vaccines—one developed by Pfizer and the other by Moderna in conjunction with NIH’s National Institute of Allergy and Infectious Diseases—were rigorously evaluated in clinical trials. Detailed data were posted online and discussed in all-day meetings of an FDA Advisory Committee, open to the public. In fact, given the high stakes, the level of review probably was more scientifically rigorous than ever.
First CRISPR Cures: One of the most promising areas of research now underway involves gene editing. These tools, still relatively new, hold the potential to fix gene misspellings—and potentially cure—a wide range of genetic diseases that were once to be out of reach. Much of the research focus has centered on CRISPR/Cas9. This highly precise gene-editing system relies on guide RNA molecules to direct a scissor-like Cas9 enzyme to just the right spot in the genome to cut out or correct a disease-causing misspelling.
In late 2020, a team of researchers in the United States and Europe succeeded for the first time in using CRISPR to treat 10 people with sickle cell disease and transfusion-dependent beta thalassemia. As published in the New England Journal of Medicine, several months after this non-heritable treatment, all patients no longer needed frequent blood transfusions and are living pain free .
The researchers tested a one-time treatment in which they removed bone marrow from each patient, modified the blood-forming hematopoietic stem cells outside the body using CRISPR, and then reinfused them into the body. To prepare for receiving the corrected cells, patients were given toxic bone marrow ablation therapy, in order to make room for the corrected cells. The result: the modified stem cells were reprogrammed to switch back to making ample amounts of a healthy form of hemoglobin that their bodies produced in the womb. While the treatment is still risky, complex, and prohibitively expensive, this work is an impressive start for more breakthroughs to come using gene editing technologies. NIH, including its Somatic Cell Genome Editing program, continues to push the technology to accelerate progress and make gene editing cures for many disorders simpler and less toxic.
Scientists Speak Up for Diversity: The year 2020 will be remembered not only for COVID-19, but also for the very public and inescapable evidence of the persistence of racial discrimination in the United States. Triggered by the killing of George Floyd and other similar events, Americans were forced to come to grips with the fact that our society does not provide equal opportunity and justice for all. And that applies to the scientific community as well.
Science thrives in safe, diverse, and inclusive research environments. It suffers when racism and bigotry find a home to stifle diversity—and community for all—in the sciences. For the nation’s leading science institutions, there is a place and a calling to encourage diversity in the scientific workplace and provide the resources to let it flourish to everyone’s benefit.
For those of us at NIH, last year’s peaceful protests and hashtags were noticed and taken to heart. That’s one of the many reasons why we will continue to strengthen our commitment to building a culturally diverse, inclusive workplace. For example, we have established the NIH Equity Committee. It allows for the systematic tracking and evaluation of diversity and inclusion metrics for the intramural research program for each NIH institute and center. There is also the recently founded Distinguished Scholars Program, which aims to increase the diversity of tenure track investigators at NIH. Recently, NIH also announced that it will provide support to institutions to recruit diverse groups or “cohorts” of early-stage research faculty and prepare them to thrive as NIH-funded researchers.
AI Disentangles Protein Folding: Proteins, which are the workhorses of the cell, are made up of long, interconnected strings of amino acids that fold into a wide variety of 3D shapes. Understanding the precise shape of a protein facilitates efforts to figure out its function, its potential role in a disease, and even how to target it with therapies. To gain such understanding, researchers often try to predict a protein’s precise 3D chemical structure using basic principles of physics—including quantum mechanics. But while nature does this in real time zillions of times a day, computational approaches have not been able to do this—until now.
Of the roughly 170,000 proteins mapped so far, most have had their structures deciphered using powerful imaging techniques such as x-ray crystallography and cryo–electron microscopy (cryo-EM). But researchers estimate that there are at least 200 million proteins in nature, and, as amazing as these imaging techniques are, they are laborious, and it can take many months or years to solve 3D structure of a single protein. So, a breakthrough certainly was needed!
In 2020, researchers with the company Deep Mind, London, developed an artificial intelligence (AI) program that rapidly predicts most protein structures as accurately as x-ray crystallography and cryo-EM can map them . The AI program, called AlphaFold, predicts a protein’s structure by computationally modeling the amino acid interactions that govern its 3D shape.
Getting there wasn’t easy. While a complete de novo calculation of protein structure still seemed out of reach, investigators reasoned that they could kick start the modeling if known structures were provided as a training set to the AI program. Utilizing a computer network built around 128 machine learning processors, the AlphaFold system was created by first focusing on the 170,000 proteins with known structures in a reiterative process called deep learning. The process, which is inspired by the way neural networks in the human brain process information, enables computers to look for patterns in large collections of data. In this case, AlphaFold learned to predict the underlying physical structure of a protein within a matter of days. This breakthrough has the potential to accelerate the fields of structural biology and protein research, fueling progress throughout the sciences.
How Elite Controllers Keep HIV at Bay: The term “elite controller” might make some people think of video game whizzes. But here, it refers to the less than 1 percent of people living with human immunodeficiency virus (HIV) who’ve somehow stayed healthy for years without taking antiretroviral drugs. In 2020, a team of NIH-supported researchers figured out why this is so.
In a study of 64 elite controllers, published in the journal Nature, the team discovered a link between their good health and where the virus has inserted itself in their genomes . When a cell transcribes a gene where HIV has settled, this so-called “provirus,” can produce more virus to infect other cells. But if it settles in a part of a chromosome that rarely gets transcribed, sometimes called a gene desert, the provirus is stuck with no way to replicate. Although this discovery won’t cure HIV/AIDS, it points to a new direction for developing better treatment strategies.
In closing, 2020 presented more than its share of personal and social challenges. Among those challenges was a flood of misinformation about COVID-19 that confused and divided many communities and even families. That’s why the editors and writers at Science singled out “a second pandemic of misinformation” as its Breakdown of the Year. This divisiveness should concern all of us greatly, as COVID-19 cases continue to soar around the country and our healthcare gets stretched to the breaking point. I hope and pray that we will all find a way to come together, both in science and in society, as we move forward in 2021.
 CRISPR-Cas9 gene editing for sickle cell disease and β-thalassemia. Frangoul H et al. N Engl J Med. 2020 Dec 5.
 ‘The game has changed.’ AI triumphs at protein folding. Service RF. Science. 04 Dec 2020.
 Distinct viral reservoirs in individuals with spontaneous control of HIV-1. Jiang C et al. Nature. 2020 Sep;585(7824):261-267.
COVID-19 Research (NIH)
2020 Science Breakthrough of the Year (American Association for the Advancement of Science, Washington, D.C)
Posted on by Dr. Francis Collins
The winter holidays are traditionally a time of gift-giving. As fatiguing as 2020 and the COVID-19 pandemic have been, science has stepped up this year to provide humankind with a pair of truly hopeful gifts: the first two COVID-19 vaccines.
Two weeks ago, the U.S. Food and Drug Administration (FDA) granted emergency use authorization (EUA) to a COVID-19 vaccine from Pfizer/BioNTech, enabling distribution to begin to certain high-risk groups just three days later. More recently, the FDA granted an EUA to a COVID-19 vaccine from the biotechnology company Moderna, Cambridge, MA. This messenger RNA (mRNA) vaccine, which is part of a new approach to vaccination, was co-developed by NIH’s National Institute of Allergy and Infectious Diseases (NIAID). The EUA is based on data showing the vaccine is safe and 94.5 percent effective at protecting people from infection with SARS-CoV-2, the coronavirus that causes COVID-19.
Those data on the Moderna vaccine come from a clinical trial of 30,000 individuals, who generously participated to help others. We can’t thank those trial participants enough for this gift. The distribution of millions of Moderna vaccine doses is expected to begin this week.
It’s hard to put into words just how remarkable these accomplishments are in the history of science. A vaccine development process that used to take many years, often decades, has been condensed to about 11 months. Just last January, researchers started out with a previously unknown virus and we now have not just one, but two, vaccines that will be administered to millions of Americans before year’s end. And the accomplishments don’t end there—several other types of COVID-19 vaccines are also on the way.
It’s important to recognize that this couldn’t have happened without the efforts of many scientists working tirelessly behind the scenes for many years prior to the pandemic. Among those who deserve tremendous credit are Kizzmekia Corbett, Barney Graham, John Mascola, and other members of the amazing team at the Dale and Betty Bumpers Vaccine Research Center at NIH’s National Institute of Allergy and Infectious Diseases (NIAID).
When word of SARS-CoV-2 emerged, Corbett, Graham, and other NIAID researchers had already been studying other coronaviruses for years, including those responsible for earlier outbreaks of respiratory disease. So, when word came that this was a new coronavirus outbreak, they were ready to take action. It helped that they had paid special attention to the spike proteins on the surface of coronaviruses, which have turned out to be the main focus the COVID-19 vaccines now under development.
The two vaccines currently authorized for administration in the United States work in a unique way. Their centerpiece is a small, non-infectious snippet of mRNA. Our cells constantly produce thousands of mRNAs, which provide the instructions needed to make proteins. When someone receives an mRNA vaccine for COVID-19, it tells the person’s own cells to make the SARS-CoV-2 spike protein. The person’s immune system then recognizes the viral spike protein as foreign and produces antibodies to eliminate it.
This vaccine-spurred encounter trains the human immune system to remember the spike protein. So, if an actual SARS-CoV-2 virus tries to infect a vaccinated person weeks or months later, his or her immune system will be ready to fend it off. To produce the most vigorous and durable immunity against the virus, people will need to get two shots of mRNA vaccine, which are spaced several weeks to a month apart, depending on the vaccine.
Some have raised concerns on social media that mRNA vaccines might alter the DNA genome of someone being vaccinated. But that’s not possible, since this mRNA doesn’t enter the nucleus of the cell where DNA is located. Instead, the vaccine mRNAs stay in the outer part of the cell (the cytoplasm). What’s more, after being transcribed into protein just one time, the mRNA quickly degrades. Others have expressed concerns about whether the vaccine could cause COVID-19. That is not a risk because there’s no whole virus involved, just the coding instructions for the non-infectious spike protein.
An important advantage of mRNA is that it’s easy for researchers to synthesize once they know the nucleic acid sequence of a target viral protein. So, the gift of mRNA vaccines is one that will surely keep on giving. This new technology can now be used to speed the development of future vaccines. After the emergence of the disease-causing SARS, MERS, and now SARS-CoV-2 viruses, it would not be surprising if there are other coronavirus health threats in our future. Corbett and her colleagues are hoping to design a universal vaccine that can battle all of them. In addition, mRNA vaccines may prove effective for fighting future pandemics caused by other infectious agents and for preventing many other conditions, such as cancer and HIV.
Though vaccines are unquestionably our best hope for getting past the COVID-19 pandemic, public surveys indicate that some people are uneasy about accepting this disease-preventing gift. Some have even indicated they will refuse to take the vaccine. Healthy skepticism is a good thing, but decisions like this ought to be based on weighing the evidence of benefit versus risk. The results of the Pfizer and Moderna trials, all released for complete public scrutiny, indicate the potential benefits are high and the risks, low. Despite the impressive speed at which the new COVID-19 vaccines were developed, they have undergone and continue to undergo a rigorous process to generate all the data needed by the FDA to determine their long-term safety and effectiveness.
Unfortunately, the gift of COVID-19 vaccines comes too late for the more than 313,000 Americans who have died from complications of COVID-19, and many others who’ve had their lives disrupted and may have to contend with long-term health consequences related to COVID-19. The vaccines did arrive in record time, but all of us wish they could somehow have arrived even sooner to avert such widespread suffering and heartbreak.
It will be many months before all Americans who are willing to get a vaccine can be immunized. We need 75-80 percent of Americans to receive vaccines in order to attain the so-called “herd immunity” needed to drive SARS-CoV-2 away and allow us all to get back to a semblance of normal life.
Meanwhile, we all have a responsibility to do everything possible to block the ongoing transmission of this dangerous virus. Each of us needs to follow the three W’s: Wear a mask, Watch your distance, Wash your hands often.
When your chance for immunization comes, please roll up your sleeve and accept the potentially life-saving gift of a COVID-19 vaccine. In fact, I just got my first shot of the Moderna vaccine today along with NIAID Director Anthony Fauci, HHS Secretary Alex Azar, and some front-line healthcare workers at the NIH Clinical Center. Accepting this gift is our best chance to put this pandemic behind us, as we look forward to a better new year.
Coronavirus (COVID-19) (NIH)
Combat COVID (U.S. Department of Health and Human Services, Washington, D.C.)
Dale and Betty Bumpers Vaccine Research Center (National Institute of Allergy and Infectious Diseases/NIH)
Moderna (Cambridge, MA)
Pfizer (New York, NY)
BioNTech (Mainz, Germany)