Microvillus inclusion disease is a rare genetic condition that causes severe watery diarrhea starting in newborns or early infancy. People with microvillus inclusion disease often become dehydrated quickly and may have poor weight gain and nutrient loss. The condition is lifelong, and symptoms usually begin within days to weeks after birth. Many living with microvillus inclusion disease need intravenous nutrition, and some are considered for intestinal transplant. The outlook varies with access to specialized care, and early treatment can lower complications from dehydration and infections.
Overview
Microvillus inclusion diseaseSymptoms
Microvillus inclusion disease usually appears soon after birth with relentless watery diarrhea. Early signs of Microvillus inclusion disease include dehydration, poor weight gain, and lethargy. Doctors may also note salt imbalances and metabolic acidosis from severe fluid loss.
Outlook and prognosis
Many living with Microvillus inclusion disease need lifelong nutritional support, often through tube or intravenous feeding, especially in infancy. Outcomes vary: some stabilize with specialized care or intestinal transplant, while severe infections and liver or catheter complications can affect longevity. Regular, expert follow-up improves day-to-day health and long-term outlook.
Causes and risk factors
Microvillus inclusion disease results from changes in both copies of the MYO5B gene, rarely STX3. Risk is highest when both parents are carriers or there's family history. No known environmental or lifestyle risks; variants may affect severity.
Genetic influences
Genetics are central in Microvillus inclusion disease. Most cases arise from inherited mutations—often in the MYO5B gene—that disrupt how intestinal cells move and recycle membrane, causing severe diarrhea from birth. It’s usually autosomal recessive; carrier testing and family counseling matter.
Diagnosis
Microvillus inclusion disease is diagnosed using clinical features with severe diarrhea, plus intestinal biopsy showing typical microscopic changes. Genetic tests for MYO5B variants confirm the genetic diagnosis of Microvillus inclusion disease; stool and blood tests exclude infections and other causes.
Treatment and drugs
Treatment for microvillus inclusion disease focuses on steady hydration and nutrition, often with long‑term intravenous feeding while carefully managing diarrhea and salt losses. Many children use special oral rehydration and limited‑fat formulas; medications may slow stool output. Some centers consider intestinal or combined liver–intestinal transplant when nutrition can’t be maintained safely.
Symptoms
In newborns, feeds can feel constant, diapers are repeatedly soaked with watery stool, and yet weight doesn’t climb. Early on, this might look like diapers soaking through and little weight gain. Early features of microvillus inclusion disease often include persistent watery diarrhea, dehydration, and poor growth. Features vary between babies, and some also develop vomiting, belly swelling, or jaundice.
Large, watery stools start within the first days of life and continue despite changes in formula or feeding. This is a hallmark of microvillus inclusion disease and often happens many times a day.
Dry mouth, fewer tears, and a sunken soft spot can appear as fluids are lost faster than they’re replaced. You may see fast breathing or cool hands and feet when dehydration worsens.
Babies may not gain as expected, or weight can even drop despite frequent feeds. In microvillus inclusion disease, nutrients and fluids pass through too quickly to be absorbed well.
Fewer wet diapers than usual can signal dehydration. Urine may look darker and have a stronger smell.
How people usually first notice Microvillus inclusion disease?
Parents and clinicians often first notice microvillus inclusion disease in the newborn period when severe, watery diarrhea begins within hours to days after birth and doesn’t improve with standard feeding changes. Babies may quickly show signs of dehydration and poor weight gain, leading to urgent hospital care where stool volumes are high and lab tests reveal electrolyte imbalances. In many cases, the “first signs of microvillus inclusion disease” prompt doctors to perform specialized tests—such as stool studies, intestinal biopsy, or genetic testing—to confirm the diagnosis and start intravenous nutrition support.
Types of Microvillus inclusion disease
Microvillus inclusion disease (MVID) has a few well-recognized clinical variants tied to different genes and how early symptoms begin. These variants can look similar—severe watery diarrhea, dehydration risk, and trouble gaining weight—but the timing, severity, and liver involvement can differ. Clinicians often describe them in these categories: classic early-onset forms, a later-onset form, and a related gene variant that may include liver features. Knowing the types of MVID can help families and care teams anticipate needs over time and understand the types of Microvillus inclusion disease they may encounter.
Classic early-onset
Symptoms start in the first days of life with profuse watery diarrhea and rapid dehydration. Feeding intolerance and poor weight gain are common despite specialized formulas. Most infants need early parenteral nutrition.
Congenital SLC9A3
Caused by biallelic SLC9A3 variants with MVID-like diarrhea plus higher chance of cholestasis and liver problems. Diarrhea may still begin in infancy but liver features can be more prominent. Some have milder intestinal findings than classic MVID.
Late-onset variant
Diarrhea begins later in infancy or early childhood rather than right after birth. Symptoms can fluctuate, sometimes worsening during infections or stress. Growth may be better initially but nutritional support is often still required.
MYO5B-related MVID
Due to MYO5B variants, the most common genetic cause, typically with neonatal onset. Severity varies from constant high-volume diarrhea to intermittent episodes. Some develop associated liver dysfunction such as low bile flow.
What genetics can tell you about symptoms
Certain MYO5B gene mutations disrupt how intestinal cells move salt and water, leading to severe watery diarrhea in newborns, poor weight gain, and dehydration. Variants that partly spare the protein’s function can cause milder, later-onset diarrhea with intermittent symptoms and slightly better nutrient absorption.
Causes and risk factors
Microvillus inclusion disease is usually caused by inherited changes in the MYO5B gene, and less often STX3 or STXBP2. Some risks are written in our DNA, passed down through families. It follows an autosomal recessive pattern, so a child is affected when both parents carry the nonworking gene. Risk factors for Microvillus inclusion disease include having two carrier parents, a family history, and parents who are related. Environment and lifestyle do not cause the disease, but infections or dehydration can make symptoms worse.
Environmental and biological risk factors
Microvillus inclusion disease is rare and begins before birth, so most risk comes from biology inside the developing intestine rather than the outside world. While families often first notice early symptoms of Microvillus inclusion disease after birth, the factors that raise risk are set earlier. Doctors often group risks into internal (biological) and external (environmental). For this condition, internal factors dominate and no specific outside exposures have been confirmed.
Risk arises from changes in how the intestinal lining forms before birth. These body-based factors are present from day one and do not depend on events around delivery.
No specific environmental toxins or infections during pregnancy have been shown to raise the likelihood of Microvillus inclusion disease. Research to date has not confirmed air pollution, radiation, or heavy metals as triggers.
Advanced maternal or paternal age has not been linked to higher risk. Reported cases occur across a wide range of parent ages.
Common maternal conditions such as diabetes, high blood pressure, or thyroid disease have not been tied to a higher chance of Microvillus inclusion disease. When the condition appears, it reflects biology within the developing intestine rather than the parent’s health during pregnancy.
Genetic risk factors
Inherited changes in key cell-transport genes are the main cause of Microvillus inclusion disease. Some risk factors are inherited through our genes. Most cases involve MYO5B, with rarer forms linked to STX3. Because these changes are present from birth, early symptoms of Microvillus inclusion disease often begin in the first days of life.
MYO5B variants: Pathogenic changes in the MYO5B gene are the most common genetic cause of Microvillus inclusion disease. They impair how intestinal cells move proteins to the surface, creating the hallmark inclusions and severe diarrhea.
STX3 variants: Rare, biallelic changes in the STX3 gene can also cause Microvillus inclusion disease. They disrupt membrane fusion steps needed to build normal microvilli, leading to a similar clinical picture.
Autosomal recessive: Microvillus inclusion disease occurs when a child inherits two non-working copies of a relevant gene, one from each parent. Each pregnancy for two carriers has a 25% chance of an affected child.
Carrier parents: When both parents silently carry a pathogenic variant, their children face a 25% chance to be affected, 50% to be carriers, and 25% to inherit no variant. Carriers are typically healthy with no symptoms.
Family history: Having a sibling or close relative with Microvillus inclusion disease raises the chance that others in the family carry the same variant. Targeted testing for the known familial change can clarify risks for future pregnancies.
Consanguinity: Parents who are related by blood share more of the same DNA, increasing the chance they carry the same rare variant. This raises the likelihood of Microvillus inclusion disease when both are carriers.
Founder effects: In some communities, a single ancestral variant is more common, increasing local carrier rates. Genetic counseling can explain whether a known founder change affects your family.
Variant type matters: Different kinds of MYO5B or STX3 changes may influence severity and age at onset. Some children develop classic, very early diarrhea, while others have mixed features such as liver involvement.
Compound heterozygosity: Children can inherit two different non-working variants, one from each parent, and still develop Microvillus inclusion disease. The specific combination can shape the clinical picture.
Genetic testing: Gene panel or exome testing can confirm Microvillus inclusion disease by identifying changes in MYO5B or STX3. Confirmation supports accurate carrier testing, prenatal options, and recurrence counseling.
Lifestyle risk factors
Microvillus inclusion disease is a congenital condition; lifestyle habits do not cause it, but daily choices can influence symptoms, hydration, and complications. Below is a practical look at how lifestyle affects Microvillus inclusion disease, focusing on feeding, hydration, medications, and infection prevention. These habits work alongside medical and surgical care to support stability.
Energy-dense, hyperosmolar formulas can worsen diarrhea and stool losses in MVID. Clinician-guided, lower-osmolality feeds or specialized formulas may reduce output and improve tolerance. Avoiding sugary juices can limit osmotic diarrhea.
Large bolus feeds may trigger rapid intestinal transit and dehydration in MVID. Smaller, more frequent feeds can sometimes lessen stool volume. Coordinating feeds with medications may improve absorption.
Plain water alone can worsen sodium losses and hyponatremia in MVID. WHO-style oral rehydration solutions help replace salt and fluid more effectively. Use recipes or products recommended by the care team.
Infrequent monitoring of intake and output can delay detection of dehydration in MVID. Daily weights and stool or ostomy logs support timely adjustments to fluids and electrolytes. Sharing logs guides clinical decisions.
Risk prevention
Microvillus inclusion disease is an inherited condition that starts at birth, so the disease itself cannot be prevented once the genes are passed on. Prevention focuses on spotting problems early and acting fast to avoid dehydration, infections, and liver stress from long-term IV nutrition. For families with a history, genetic counseling and testing can clarify the chance of having an affected child before pregnancy. Knowing your risks can guide which preventive steps matter most.
A genetics visit can explain how the condition runs in families and your personal chances. This helps with planning before pregnancy or newborn testing.
Blood or saliva testing can show if you and your partner carry the gene change. If both partners are carriers, each pregnancy has about a 25% chance of being affected.
Prenatal testing during pregnancy or IVF with embryo testing can identify an affected pregnancy early. These options help families make informed choices.
Newborns who develop severe, watery diarrhea in the first days of life need urgent evaluation. Fast treatment reduces dehydration and lowers the risk of complications.
Transmission
Microvillus inclusion disease is not infectious, so it cannot be caught through contact, air, or food. It is a genetic condition passed down in an autosomal recessive way: parents typically carry one changed copy of the gene without symptoms. When both parents are carriers, each pregnancy has a 25% (1 in 4) chance of a child with microvillus inclusion disease, a 50% (1 in 2) chance of a child who is a carrier, and a 25% chance of a child who inherits neither change. If one parent lives with the disease, all children will be carriers unless the other parent is also a carrier; in that case, the chance of an affected child is 50% (1 in 2). This describes the genetic transmission of microvillus inclusion disease.
When to test your genes
Consider genetic testing if a newborn has severe, persistent watery diarrhea starting soon after birth, especially with dehydration and poor weight gain despite specialized care. Testing is also appropriate when there’s a sibling affected or parents are known carriers, including before pregnancy. Results can confirm the diagnosis, guide nutrition and transplant decisions, and support family planning.
Diagnosis
For many families, the first clues come soon after birth when a baby has continuous watery stools, dehydration, and trouble gaining weight despite frequent feeds. Early and accurate diagnosis can help you plan ahead with confidence. Because this is a rare inherited condition, doctors combine what they see in the clinic with specialized tests to confirm what’s going on. In some cases, the diagnosis of Microvillus inclusion disease is clear quickly; in others, several steps are needed to rule out look-alike causes.
Doctors look for severe, persistent watery diarrhea starting in the first days or weeks of life, dehydration, and poor weight gain. These patterns raise concern for a congenital secretory diarrhea rather than a temporary illness.
Basic stool tests help show if the diarrhea is secretory, meaning it continues even when feeding is paused. Results that point to ongoing fluid loss, without signs of infection, support suspicion for Microvillus inclusion disease.
Blood and stool tests check for common infections and treatable causes. Ruling these out is important before moving to more invasive testing.
A small tissue sample from the small intestine is examined under the microscope. Doctors may see shortened villi and other changes that suggest a structural problem in the lining of the gut.
Stages of Microvillus inclusion disease
Microvillus inclusion disease does not have defined progression stages. It usually begins in the newborn period with early symptoms of microvillus inclusion disease—persistent watery diarrhea, dehydration, and poor weight gain—and its course depends on nutrition support and intercurrent infections rather than a step-by-step decline. Different tests may be suggested to help confirm the cause, such as measuring stool output and body salts, a small-intestine biopsy under the microscope, and genetic testing for changes in the MYO5B gene.
Outlook and prognosis
Looking at the long-term picture can be helpful. Microvillus inclusion disease is lifelong and typically begins in the first days of life with severe watery diarrhea and poor weight gain. Many people ask, “What does this mean for my future?”, and for many families it means ongoing reliance on IV nutrition (parenteral nutrition) to maintain growth and hydration, especially in infancy and early childhood. With careful monitoring, many children with Microvillus inclusion disease reach developmental milestones, attend school, and build routines around medical care, but hospital stays for infections or dehydration can still happen.
Prognosis refers to how a condition tends to change or stabilize over time. Survival has improved over the past two decades thanks to advances in nutrition support, careful line care to prevent bloodstream infections, and better management of liver health. Early care can make a real difference, particularly in preventing complications like liver disease from long-term IV nutrition. Some centers may discuss intestinal transplant when complications become hard to control; outcomes after transplant vary, but for selected candidates this can reduce dependence on IV nutrition and improve day-to-day life.
Everyone’s journey looks a little different. In early childhood, the main risks are severe dehydration and infections; later on, long-term issues can include catheter-related infections, blood clots, and liver problems, which is why early symptoms of Microvillus inclusion disease that signal dehydration or infection should prompt quick care. With ongoing care, many people maintain growth and activity, though full independence from IV nutrition is uncommon without transplant. Talk with your doctor about what your personal outlook might look like, including whether and when to consider referral to an intestinal rehabilitation or transplant center, and how your care team will monitor for and prevent complications.
Long-term effects
Microvillus inclusion disease often has lifelong health consequences shaped by how much the intestine can absorb and how well nutrition can be maintained. Although early symptoms of microvillus inclusion disease appear in the newborn period, the long-term picture centers on growth, liver health, and infection risks. Long-term effects vary widely, and they can shift over time. Survival has improved with specialized care and, for some, transplant, but the course remains very individual.
Many children have slow weight and height gain over years. Catch-up growth can happen when nutrition is stable. Short stature may persist into adulthood in some.
Limited tolerance of oral or tube feeds can continue. People with microvillus inclusion disease may rely on small amounts of enteral feeds alongside intravenous nutrition.
Long-term intravenous nutrition may be needed to meet calorie and fluid needs. This can span years and sometimes continues into adulthood.
Intravenous nutrition can lead to bile build-up and scarring in the liver over time. In severe cases, this can progress to liver failure and the need for transplant.
How is it to live with Microvillus inclusion disease?
Living with microvillus inclusion disease often means navigating life around frequent, severe diarrhea, the risk of dehydration, and dependence on intravenous nutrition (parenteral nutrition) to grow and stay healthy. Daily routines revolve around careful fluid and electrolyte management, central line care to prevent infections, and frequent medical visits, which can be exhausting for families and caregivers. Many find that planning school, work, and travel requires extra coordination, backup supplies, and rapid access to medical support. Even so, with a skilled care team and shared caregiving, families can build stable routines and protect time for connection, play, and milestones beyond the hospital.
Treatment and drugs
Treatment for microvillus inclusion disease focuses on replacing what the gut can’t absorb and preventing complications. Most babies and children need long-term total parenteral nutrition (TPN), which delivers fluids, calories, vitamins, and minerals through a vein to maintain growth and hydration. Doctors sometimes add special formula trials and medicines that reduce diarrhea or stomach acid, but these usually offer limited benefit because the intestine itself cannot absorb well; a doctor may adjust your dose to balance benefits and side effects. The only treatment that can correct the underlying problem is an intestinal transplant (sometimes combined with liver transplant if TPN has caused liver damage), though this is a major procedure with lifelong immune-suppressing medications and careful follow-up. Supportive care can make a real difference in how you feel day to day, including infection prevention for central lines, monitoring electrolytes, and close coordination with a nutrition and transplant center.
Non-drug treatment
Care for microvillus inclusion disease centers on keeping fluids, nutrition, and growth on track while reducing complications. Alongside medicines, non-drug therapies can stabilize day-to-day health, support development, and buy time for longer-term options. Most plans are individualized and led by teams experienced with complex intestinal conditions. Families are key partners in care, especially when managing treatment at home.
IV fluids replace heavy water and salt losses during flare-ups. Care teams adjust electrolytes to prevent problems like low sodium or potassium.
Nutrition given through a central line provides calories, protein, fats, vitamins, and minerals when the gut can’t absorb enough. This supports growth and energy while reducing dehydration risk.
Small, carefully chosen feeds keep the gut working and may protect the intestinal lining. Elemental or amino-acid formulas are often used in tiny amounts.
Meticulous line care lowers the risk of bloodstream infection. Families learn sterile techniques and signs of trouble to act early.
Your genes may have an impact on how drugs work for you
Some medicines used for microvillus inclusion disease work differently depending on genes that affect drug-metabolizing enzymes and transporters, altering how fast a drug is processed or how much reaches target cells. Genetic testing can sometimes guide dosing or choice to improve safety and benefit.
Pharmacological treatments
Drug therapy in Microvillus inclusion disease focuses on reducing stool losses, protecting the gut and liver, and managing complications from long-term nutrition support. Medicines do not reverse the underlying transport problem or the early symptoms of Microvillus inclusion disease, but some can modestly ease day-to-day losses and discomfort. Not everyone responds to the same medication in the same way. Doses and choices are highly individualized and should be guided by a specialist team familiar with congenital diarrheal disorders.
Slows gut movement to help reduce stool volume and frequency under specialist supervision. Drugs that target symptoms directly are called symptomatic treatments.
Lowers fluid secretion in the intestines and may modestly reduce stool output. It is used more often in the EU and can be considered in children with Microvillus inclusion disease.
A somatostatin analogue given by injection that can decrease intestinal secretions. It may help some people with high-output diarrhea but often offers limited benefit and needs monitoring for side effects like gallstones or glucose changes.
Medicines such as omeprazole reduce stomach acid, which can lessen fluid loss into the gut and protect the esophagus. In Microvillus inclusion disease, they may be used to ease reflux symptoms and reduce irritation from frequent stools.
Genetic influences
In most cases, Microvillus inclusion disease stems from inherited changes in a gene that helps intestinal cells move key proteins to their surface, most often a gene called MYO5B. It follows an autosomal recessive pattern: usually both parents carry one silent copy, and a child who inherits two changed copies is affected. When two carrier parents have a child, there’s a 25% (1 in 4) chance in each pregnancy that the child will have Microvillus inclusion disease, a 50% (1 in 2) chance the child will be a carrier, and a 25% chance the child will inherit neither change. A “carrier” means you hold the gene change but may not show symptoms. Because these gene changes disrupt how the gut’s lining cells develop their tiny surface ridges (the brush border), early symptoms of Microvillus inclusion disease often begin in the first days of life. Gene testing can confirm the specific change and help relatives understand their own risks, and doctors may recommend genetic counseling.
Is Microvillus inclusion disease genetic?
Genetics are central in Microvillus inclusion disease. Most cases arise from inherited mutations—often in the MYO5B gene—that disrupt how intestinal cells move and recycle membrane, causing severe diarrhea from birth. It’s usually autosomal recessive; carrier testing and family counseling matter.
Pharmacogenetics—how genetics influence drug effects
In Microvillus inclusion disease, the genetic change that causes the condition mostly shapes the overall care plan rather than pointing to a single “right” medicine. A confirmed genetic diagnosis tells teams that standard anti‑diarrheal drugs rarely help, so care often focuses early on reliable intravenous nutrition and, when needed, planning for intestinal transplant. Pharmacogenetics can matter for medications used in Microvillus inclusion disease care, especially around transplant and line infections, because people vary in how fast they break down certain drugs. Doctors can use your genetic information to guide dosing of anti‑rejection drugs like tacrolimus and to check safety for medicines such as azathioprine, aiming for good control with fewer side effects. This gene–drug matching—often done alongside blood level checks and routine labs—can reduce trial and error before and after transplant. Even so, genes are only part of the picture; age, liver and kidney health, infections, and other medicines also influence how treatments work over time.
Interactions with other conditions
For infants with Microvillus inclusion disease, even a routine stomach bug can sharply worsen diarrhea and dehydration, sometimes leading to urgent hospital care. Doctors call it a “comorbidity” when two conditions occur together. Long-term parenteral nutrition raises the risk of bloodstream infections from central lines and can also contribute to liver problems like cholestasis and scarring; existing liver disease can, in turn, limit nutrition options and raise complications during infections. Because MYO5B-related disease can also reduce bile flow on its own, liver disease may overlap with Microvillus inclusion disease rather than being only a side effect of treatment. Repeated dehydration can strain the kidneys and disturb electrolytes, and any additional illness that causes vomiting or fever may make fluid losses worse. Early symptoms of Microvillus inclusion disease can look a lot like common infections, so coexisting illnesses—especially in premature newborns—may be overlooked at first.
How genes can cause diseases
Humans have more than 20,000 genes, each carrying out one or a few specific functions in the body. One gene instructs the body to digest lactose from milk, another tells the body how to build strong bones and another prevents the body's cells from beginning to multiply uncontrollably and developing into cancer. As all of these genes combined are the building instructions for our body, a defect in one of these genes can have severe health consequences.
Through decades of genetic research, we know the genetic code of any healthy/functional human gene. We have also identified that in certain positions on a gene, some individuals may have a different genetic letter from the one you have. We call these hotspots "Genetic Variations" or "Variants" in short. In many cases, studies have been able to show that having the genetic letter "G" in the position makes you healthy, but having the letter "A" in the same position disrupts the gene function and causes a disease. Genopedia allows you to view these variants in genes and summarizes all that we know from scientific research, which genetic letters (Genotype) have good or bad consequences on your health or on your traits.
History
Throughout history, people have described infants who could not keep weight on despite frequent feeds, with diapers that stayed watery no matter what parents tried. Families and communities once noticed patterns—newborns who became dangerously dehydrated within days of birth, even when breastmilk or formula changed. What we now call microvillus inclusion disease often appeared in these stories as a mysterious, severe diarrhea that started very early in life and resisted standard treatments.
First described in the medical literature as a neonatal form of intractable diarrhea, it was initially recognized by its clinical pattern: onset in the first days of life, rapid fluid losses, and the need for intravenous hydration to survive. Early reports focused on what doctors could see—very frequent stools, poor weight gain, and salt and acid imbalances in the blood. Over time, descriptions became more precise as pediatric pathologists examined small intestine samples under the microscope. They noticed that the tiny, brush-like surface of the intestinal lining, which normally helps absorb nutrients, was altered in a distinctive way. This microscopic signature helped separate microvillus inclusion disease from other causes of severe infant diarrhea.
As medical science evolved, specialized staining and electron microscopy confirmed the hallmark changes inside the cells lining the intestine. That visual evidence moved the condition from a puzzling clinical syndrome to a defined diagnosis. In recent decades, knowledge has built on a long tradition of observation. Researchers linked many cases to inherited changes in a gene that helps the cell transport proteins to the right place, explaining why the intestine’s surface architecture was disrupted from the start of life.
Once considered rare, now recognized as a distinct cause of early-onset, life-threatening diarrhea, microvillus inclusion disease also revealed patterns within families. In some communities, several affected newborns were born to healthy parents, pointing to an autosomal recessive inheritance, where each parent silently carries one changed copy of the gene. This recognition allowed for carrier testing, genetic counseling, and earlier diagnosis in future pregnancies.
Treatment history reflects these scientific steps. Before the condition was defined, care centered on trying different formulas and medications, often without success. With clearer understanding, teams shifted toward prompt intravenous nutrition and careful fluid and electrolyte management to prevent complications. For some, intestinal transplant emerged as a potential option when long-term intravenous nutrition led to serious problems.
Looking back helps explain why early symptoms of microvillus inclusion disease were once misattributed to infections or formula intolerance. Today, combining clinical clues from the first days of life, targeted intestinal biopsies, and genetic testing allows earlier, more confident diagnosis. Not every early description was complete, yet together they built the foundation of today’s knowledge.