Dr. Francis Collins
Posted on by Dr. Francis Collins
As a kid who was home-schooled on a Virginia farm in the 1950s, I wasn’t around other kids very much, and so didn’t get exposed to measles. And there was no vaccine yet. Later on as a medical resident, I didn’t recognize that I wasn’t immune. So when I was hospitalized with a severe febrile illness at age 29, it took a while to figure out the diagnosis. Yes, it was measles. I have never been that sick before or since. I was lucky not to have long-term consequences, and now I’m learning that there may be even more to consider.
With the big push to get kids vaccinated, you’ve probably heard about some of the very serious complications of measles: hearing-threatening ear infections, bronchitis, laryngitis, and even life-threatening forms of pneumonia and encephalitis. But now comes word of yet another way in which the measles can be devastating—one that may also have long-term consequences for a person’s health.
In a new study in the journal Science, a research team, partly funded by NIH, found that the measles virus not only can make children deathly ill, it can cause their immune systems to forget how to ward off other common infections . The virus does this by wiping out up to nearly three-quarters of the protective antibodies that a child’s body has formed in response to past microbial invaders and vaccinations. This immune “amnesia” can leave a child more vulnerable to re-contracting infections, such as influenza or respiratory syncytial virus (RSV), that they may have been protected against before they came down with measles.
The finding comes as yet another reason to feel immensely grateful that, thanks to our highly effective vaccination programs, most people born in the U.S. from the 1960s onward should never have to experience the measles.
There had been hints that the measles virus might somehow suppress a person’s immune system. Epidemiological evidence also had suggested that measles infections might lead to increased susceptibility to infection for years afterwards . Scientists had even suspected this might be explained by a kind of immune amnesia. The trouble was that there wasn’t any direct proof that such a phenomenon actually existed.
In the new work, the researchers, led by Michael Mina, Tomasz Kula, and Stephen Elledge, Howard Hughes Medical Institute and Brigham and Women’s Hospital, Boston, took advantage of a tool developed a few years ago in the Elledge lab called VirScan . VirScan detects antibodies in blood samples acquired as a result of a person’s past encounters with hundreds of viruses, bacteria, or vaccines, providing a comprehensive snapshot of acquired immunity at a particular moment in time.
To look for evidence of immune amnesia following the measles, the research team needed blood samples gathered from people both before and after infection. These types of samples are currently hard to come by in the U.S. thanks to the success of vaccines. By partnering with Rik de Swart, Erasmus University Medical Center, Rotterdam, Netherlands, they found the samples that they needed.
During a recent measles outbreak in the Netherlands, de Swart had gathered blood samples from children living in communities with low vaccination rates. Elledge’s group used VirScan with 77 unvaccinated kids to measure antibodies in samples collected before and about two months after their measles infections.
That included 34 children who had mild infections and 43 who had severe measles. The researchers also examined blood samples from five children who remained uninfected and 110 kids who hadn’t been exposed to the measles virus.
The VirScan data showed that the infected kids, not surprisingly, produced antibodies to the measles virus. But their other antibodies dropped and seemed to be disappearing. In fact, depending on the severity of measles infection, the kids showed on average a loss of around 40 percent of their antibody memory, with greater losses in children with severe cases of the measles. In at least one case, the loss reached a whopping 73 percent.
This all resonates with me. I do recall that after my bout with the measles, I seemed to be coming down with a lot of respiratory infections. I attributed that to the lifestyle of a medical resident—being around lots of sick patients and not getting much sleep. But maybe it was more than that.
The researchers suggest that the loss of immune memory may stem from the measles virus destroying some of the long-lived cells in bone marrow. These cells remember past infections and, based on that immunological memory, churn out needed antibodies to thwart reinvading viruses.
Interestingly, after a measles infection, the children’s immune systems still responded to new infections and could form new immune memories. But it appears the measles caused long term, possibly permanent, losses of a significant portion of previously acquired immunities. This loss of immune memory put the children at a distinct disadvantage should those old bugs circulate again.
It’s important to note that, unlike measles infection, the MMR (measles, mumps, rubella) vaccine does NOT compromise previously acquired immunity. So, these findings come as yet another reminder of the public value of measles vaccination.
Prior to 1963, when the measles vaccine was developed, 3 to 4 million Americans got the measles each year. As more people were vaccinated, the incidence of measles plummeted. By the year 2000, the disease was declared eliminated from the U.S.
Unfortunately, measles has made a come back, fueled by vaccine refusals. In October, the Centers for Disease Control and Prevention (CDC) reported an estimated 1,250 measles cases in the United States so far in 2019, surpassing the total number of cases reported annually in each of the past 25 years .
Around the world, measles continues to infect 7 million people each year, leading to an estimated 120,000 deaths. Based on the new findings, Elledge’s team now suspects the actual toll of the measles may be five times greater, due to the effects of immune amnesia.
The good news is those numbers can be reduced if more people get the vaccine, which has been shown repeatedly in many large and rigorous studies to be safe and effective. The CDC recommends that children should receive their first dose by 12 to 15 months of age and a second dose between the ages of 4 and 6. Older people who’ve been vaccinated or have had the measles previously should consider being re-vaccinated, especially if they live in places with low vaccination rates or will be traveling to countries where measles are endemic.
 Measles virus infection diminishes preexisting antibodies that offer protection from other pathogens. Mina MJ, Kula T, Leng Y, Li M, de Vries RD, Knip M, Siljander H, Rewers M, Choy DF, Wilson MS, Larman HB, Nelson AN, Griffin DE, de Swart RL, Elledge SJ. et al. Science. 2019 Nov 1; 366 (6465): 599-606.
 Long-term measles-induced immunomodulation increases overall childhood infectious disease mortality. Mina MJ, Metcalf CJE, De Swart RL, Osterhaus ADME, Grenfell BT. Science. 2015 May 8; 348(6235).
 Viral immunology. Comprehensive serological profiling of human populations using a synthetic human virome. Xu GJ, Kula T, Xu Q, Li MZ, Vernon SD, Ndung’u T, Ruxrungtham K, Sanchez J, Brander C, Chung RT, O’Connor KC, Walker B, Larman HB, Elledge SJ. Science. 2015 Jun 5;348(6239):aaa0698.
 Measles cases and outbreaks. Centers for Disease Control and Prevention. Oct. 11, 2019.
Measles (MedlinePlus Medical Encyclopedia/National Library of Medicine/NIH)
Measles History (Centers for Disease Control and Prevention)
Vaccines (National Institute of Allergy and Infectious Diseases/NIAID)
Vaccines Protect Your Community (Vaccines.gov)
Elledge Lab (Harvard Medical School, Boston)
NIH Support: National Institute of Allergy and Infectious Diseases; National Institute of Diabetes and Digestive and Kidney Diseases
Posted on by Dr. Francis Collins
Can you identify a familiar pattern in this image’s square grid? Yes, it’s the outline of the periodic table! But instead of organizing chemical elements, this periodic table sorts 46 different types of neurons present in the visual cortex of a mouse brain.
Scientists, led by Hongkui Zeng at the Allen Institute for Brain Science, Seattle, constructed this periodic table by assigning colors to their neuronal discoveries based upon their main cell functions . Cells in pinks, violets, reds, and oranges have inhibitory electrical activity, while those in greens and blues have excitatory electrical activity.
For any given cell, the darker colors indicate dendrites, which receive signals from other neurons. The lighter colors indicate axons, which transmit signals. Examples of electrical properties—the number and intensity of their “spikes”—appear along the edges of the table near the bottom.
To create this visually arresting image, Zeng’s NIH-supported team injected dye-containing probes into neurons. The probes are engineered to carry genes that make certain types of neurons glow bright colors under the microscope.
This allowed the researchers to examine a tiny slice of brain tissue and view each colored neuron’s shape, as well as measure its electrical response. They followed up with computational tools to combine these two characteristics and classify cell types based on their shape and electrical activity. Zeng’s team could then sort the cells into clusters using a computer algorithm to avoid potential human bias from visually interpreting the data.
Why compile such a detailed atlas of neuronal subtypes? Although scientists have been surveying cells since the invention of the microscope centuries ago, there is still no consensus on what a “cell type” is. Large, rich datasets like this atlas contain massive amounts of information to characterize individual cells well beyond their appearance under a microscope, helping to explain factors that make cells similar or dissimilar. Those differences may not be apparent to the naked eye.
Just last year, Allen Institute researchers conducted similar work by categorizing nearly 24,000 cells from the brain’s visual and motor cortex into different types based upon their gene activity . The latest research lines up well with the cell subclasses and types categorized in the previous gene-activity work. As a result, the scientists have more evidence that each of the 46 cell types is actually distinct from the others and likely drives a particular function within the visual cortex.
Publicly available resources, like this database of cell types, fuel much more discovery. Scientists all over the world can look at this table (and soon, more atlases from other parts of the brain) to see where a cell type fits into a region of interest and how it might behave in a range of brain conditions.
 Classification of electrophysiological and morphological neuron types in the mouse visual cortex. N Gouwens NW, et al. Neurosci. 2019 Jul;22(7):1182-1195.
 Shared and distinct transcriptomic cell types across neocortical areas. Tasic B, et al. Nature. 2018 Nov;563(7729):72-78.
Brain Basics: The Life and Death of a Neuron (National Institute of Neurological Disorders and Stroke/NIH)
Cell Types: Overview of the Data (Allen Brain Atlas/Allen Institute for Brain Science, Seattle)
Hongkui Zeng (Allen Institute)
NIH Support: National Institute of Mental Health; Eunice Kennedy Shriver National Institute of Child Health & Human Development
Posted on by Dr. Francis Collins
There’s been tremendous excitement recently about the potential of CRISPR and related gene-editing technologies for treating or even curing sickle cell disease (SCD), muscular dystrophy, HIV, and a wide range of other devastating conditions. Now comes word of another remarkable advance—called “prime editing”—that may bring us even closer to reaching that goal.
As groundbreaking as CRISPR/Cas9 has been for editing specific genes, the system has its limitations. The initial version is best suited for making a double-stranded break in DNA, followed by error-prone repair. The outcome is generally to knock out the target. That’s great if eliminating the target is the desired goal. But what if the goal is to fix a mutation by editing it back to the normal sequence?
The new prime editing system, which was described recently by NIH-funded researchers in the journal Nature, is revolutionary because it offers much greater control for making a wide range of precisely targeted edits to the DNA code, which consists of the four “letters” (actually chemical bases) A, C, G, and T .
Already, in tests involving human cells grown in the lab, the researchers have used prime editing to correct genetic mutations that cause two inherited diseases: SCD, a painful, life-threatening blood disorder, and Tay-Sachs disease, a fatal neurological disorder. What’s more, they say the versatility of their new gene-editing system means it can, in principle, correct about 89 percent of the more than 75,000 known genetic variants associated with human diseases.
In standard CRISPR, a scissor-like enzyme called Cas9 is used to cut all the way through both strands of the DNA molecule’s double helix. That usually results in the cell’s DNA repair apparatus inserting or deleting DNA letters at the site. As a result, CRISPR is extremely useful for disrupting genes and inserting or removing large DNA segments. However, it is difficult to use this system to make more subtle corrections to DNA, such as swapping a letter T for an A.
To expand the gene-editing toolbox, a research team led by David R. Liu, Broad Institute of MIT and Harvard, Cambridge, MA, previously developed a class of editing agents called base editors [2,3]. Instead of cutting DNA, base editors directly convert one DNA letter to another. However, base editing has limitations, too. It works well for correcting four of the most common single letter mutations in DNA. But at least so far, base editors haven’t been able to make eight other single letter changes, or fix extra or missing DNA letters.
In contrast, the new prime editing system can precisely and efficiently swap any single letter of DNA for any other, and can make both deletions and insertions, at least up to a certain size. The system consists of a modified version of the Cas9 enzyme fused with another enzyme, called reverse transcriptase, and a specially engineered guide RNA, called pegRNA. The latter contains the desired gene edit and steers the needed editing apparatus to a specific site in a cell’s DNA.
Once at the site, the Cas9 nicks one strand of the double helix. Then, reverse transcriptase uses one DNA strand to “prime,” or initiate, the letter-by-letter transfer of new genetic information encoded in the pegRNA into the nicked spot, much like the search-and-replace function of word processing software. The process is then wrapped up when the prime editing system prompts the cell to remake the other DNA strand to match the new genetic information.
So far, in tests involving human cells grown in a lab dish, Liu and his colleagues have used prime editing to correct the most common mutation that causes SCD, converting a T to an A. They were also able to remove four DNA letters to correct the most common mutation underlying Tay-Sachs disease, a devastating condition that typically produces symptoms in children within the first year and leads to death by age four. The researchers also used their new system to insert new DNA segments up to 44 letters long and to remove segments at least 80 letters long.
Prime editing does have certain limitations. For example, 11 percent of known disease-causing variants result from changes in the number of gene copies, and it’s unclear if prime editing can insert or remove DNA that’s the size of full-length genes—which may contain up to 2.4 million letters.
It’s also worth noting that now-standard CRISPR editing and base editors have been tested far more thoroughly than prime editing in many different kinds of cells and animal models. These earlier editing technologies also may be more efficient for some purposes, so they will likely continue to play unique and useful roles in biomedicine.
As for prime editing, additional research is needed before we can consider launching human clinical trials. Among the areas that must be explored are this technology’s safety and efficacy in a wide range of cell types, and its potential for precisely and safely editing genes in targeted tissues within living animals and people.
Meanwhile, building on all these bold advances, efforts are already underway to accelerate the development of affordable, accessible gene-based cures for SCD and HIV on a global scale. Just last month, NIH and the Bill & Melinda Gates Foundation announced a collaboration that will invest at least $200 million over the next four years toward this goal. Last week, I had the chance to present this plan and discuss it with global health experts at the Grand Challenges meeting Addis Ababa, Ethiopia. The project is an unprecedented partnership designed to meet an unprecedented opportunity to address health conditions that once seemed out of reach but—as this new work helps to show—may now be within our grasp.
 Search-and-replace genome editing without double-strand breaks or donor DNA. Anzalone AV, Randolph PB, Davis JR, Sousa AA, Koblan LW, Levy JM, Chen PJ, Wilson C, Newby GA, Raguram A, Liu DR. Nature. Online 2019 October 21. [Epub ahead of print]
 Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Komor AC, Kim YB, Packer MS, Zuris JA, Liu DR. Nature. 2016 May 19;533(7603):420-424.
 Programmable base editing of A•T to G•C in genomic DNA without DNA cleavage. Gaudelli NM, Komor AC, Rees HA, Packer MS, Badran AH, Bryson DI, Liu DR. Nature. 2017 Nov 23;551(7681):464-471.
Tay-Sachs Disease (Genetics Home Reference/National Library of Medicine/NIH)
Sickle Cell Disease (National Heart, Lung, and Blood Institute/NIH)
Cure Sickle Cell Initiative (NHLBI)
What are Genome Editing and CRISPR-Cas9? (National Library of Medicine/NIH)
Somatic Cell Genome Editing Program (Common Fund/NIH)
David R. Liu (Harvard, Cambridge, MA)
NIH Support: National Institute of Allergy and Infectious Diseases; National Human Genome Research Institute; National Institute for General Medical Sciences; National Institute of Biomedical Imaging and Bioengineering; National Center for Advancing Translational Sciences
Posted on by Dr. Francis Collins
When your world has been touched by a life-threatening disease, it’s hard to spend a lot of time dreaming about the future. But that’s exactly what Jenny, an 8-year-old girl with cystic fibrosis (CF), did 30 years ago upon hearing the news that I and my colleagues in Ann Arbor and Toronto had discovered the gene for CF [1,2]. Her upbeat diary entry, which you can read above, is among the many ways in which people with CF have encouraged researchers on the long and difficult road toward achieving our shared dream of effective, molecularly targeted therapies for one of the nation’s most common potentially fatal recessive genetic diseases, affecting more than 30,000 individuals in the United States .
Today, I’m overjoyed to say that this dream finally appears to have come true for about 90 percent of people with CF. In papers in the New England Journal of Medicine and The Lancet [4,5], two international teams, including researchers partly supported by NIH, report impressive results from phase 3 clinical trials of a triple drug therapy for individuals with CF and at least one copy of Phe508del, the most common CF-causing mutation. And Jenny happens to be among those who now stand to benefit from this major advance.
Now happily married and living in Colorado, Jenny is leading an active life, writing a children’s book and trying to keep up with her daughter Pippa Lou, whom you see with her in the photo above. In a recent email to me, her optimistic outlook continues to shine through: “I have ALWAYS known in my heart that CF will be cured during my lifetime and I have made it my goal to be strong and ready for that day when it comes. None of the advancements in care would be what they are without you.”
But there are a great many more people who need to be recognized and thanked. Such advances were made possible by decades of work involving a vast number of other researchers, many funded by NIH, as well as by more than two decades of visionary and collaborative efforts between the Cystic Fibrosis Foundation and Aurora Biosciences (now, Vertex Pharmaceuticals) that built upon that fundamental knowledge of the responsible gene and its protein product. Not only did this innovative approach serve to accelerate the development of therapies for CF, it established a model that may inform efforts to develop therapies for other rare genetic diseases.
To understand how the new triple therapy works, one first needs to understand some things about the protein affected by CF, the cystic fibrosis transmembrane regulator (CFTR). In healthy people, CFTR serves as a gated channel for chloride ions in the cell membrane, regulating the balance of salt and water in the lungs, pancreas, sweat glands, and other organ systems.
People with the most common CF-causing Phe508del mutation produce a CFTR protein with two serious problems: misfolding that often results in the protein becoming trapped in the cell’s factory production line called the endoplasmic reticulum; and deficient activation of any protein that does manage to reach its proper location in the cell membrane. Consequently, an effective therapy for such people needs to include drugs that can correct the CFTR misfolding, along with those than can activate, or potentiate, the function of CFTR when it reaches the cell membrane.
The new triple combination therapy, which was developed by Vertex Pharmaceuticals and recently approved by the Food and Drug Administration (FDA) , is elexacaftor-tezacaftor-ivacaftor (two correctors and one potentiator). This approach builds upon the success of ivacaftor monotherapy, approved by the FDA in 2012 for rare CF-causing mutations; and tezacaftor-ivacaftor dual therapy, approved by the FDA in 2018 for people with two copies of the Phe508del mutation.
Specifically, the final results from two Phase 3 multi-center, randomized clinical trials demonstrated the safety and efficacy of the triple combination therapy for people with either one or two copies of the Phe508del mutation—which represents about 90 percent of people with CF. Patients in both trials experienced striking improvements in a key measure of lung capacity (forced expiratory volume in 1 second) and in sweat chloride levels, which show if the drugs are working throughout the body. In addition, the triple therapy was generally safe and well tolerated, with less than 1 percent of patients discontinuing the treatment due to adverse effects.
This is wonderful news! But let’s be clear—we are not yet at our journey’s end when it comes to realizing the full dream of defeating CF. More work remains to be done to help the approximately 10 percent of CF patients whose mutations result in the production of virtually no CFTR protein, which means there is nothing for current drugs to correct or activate.
Beyond that, wouldn’t it be great if biomedical science could figure out a way to permanently cure CF, perhaps using nonheritable gene editing, so no one needs to take drugs at all? It’s a bold dream, but look how far a little dreaming, plus a lot of hard work, has taken us so far in Jenny’s life.
In closing, I’d like to leave you with the chorus of a song, called “Dare to Dream,” that I wrote shortly after we identified the CF gene. I hope the words inspire not only folks affected by CF, but everyone who is looking to NIH-supported research for healing and hope.
Dare to dream, dare to dream,
All our brothers and sisters breathing free.
Unafraid, our hearts unswayed,
‘Til the story of CF is history.
. Identification of the cystic fibrosis gene: chromosome walking and jumping. Rommens JM, Iannuzzi MC, Kerem B, et al. Science 1989; 245:1059-1065.
. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Riordan JR, Rommens JM, Kerem B, et al. Science 1989; 245:1066-73. Erratum in: Science 1989; 245:1437.
 Realizing the Dream of Molecularly Targeted Therapies for Cystic Fibrosis. Collins, FS. N Engl J Med. 2019 Oct 31. [Epub ahead of print]
. Elexacaftor-Tezacaftor-Ivacaftor for CF with a Single Phe508del Mutation. Middleton P, Mall M, Drevinek P, et al.N Engl J Med. 2019 Oct 31. [Epub ahead of print]
 Efficacy and safety of the elexacaftor/tezacaftor/ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial. Heijerman H, McKone E, Downey D, et al. Lancet. 2019 Oct 31. [Epub ahead of print]
 FDA approves new breakthrough therapy for cystic fibrosis. FDA News Release, Oct. 21, 2019.
Cystic Fibrosis (Genetics Home Reference/National Library of Medicine/NIH)
Research Milestones (Cystic Fibrosis Foundation, Bethesda, MD)
Wheezie Stevens in “Bubbles Can’t Hold Rain,” by Jennifer K. McGlincy
NIH Support: National, Heart, Lung and Blood Institute; National Institute of Diabetes and Digestive and Kidney Diseases; National Center for Advancing Translational Sciences