Not all research projects start in the lab. As it turns out, some can start on a walk to Whole Foods.
For Alexander Marneros, MD, PhD, a dermatologist and researcher at Massachusetts General Hospital, a decade-long journey of discovery began with a chance encounter on his way to lunch.
As he walked by a father who was pushing his young son in a stroller, Marneros noticed a scar on the back of the boy’s head. He recognized it as aplasia cutis, a curious congenital scalp skin wound which results in scarring on the back of the head, but nowhere else on the body.
Alexander Marneros, MD, PhD
Though he had never studied the disease before, Marneros knew that the gene underlying the condition had not been found.
On impulse, he turned around, introduced himself, and asked the father if anyone else in the family had the same scar.
The father leaned down, parted his hair, and showed Marneros a telltale scar on his scalp. He told him that many other members of his family had it as well.
Marneros, who knew that the inherited form of aplasia cutis was incredibly rare, then made a second spontaneous decision—he would work with this family to find the gene behind the disease.
“I find this disease very interesting because of the very localized skin defect,” he explains. “Why wouldn’t it be everywhere?”
Learning more about this curious condition could lead to new insights into the development and mechanisms of skin formation. Marneros invited the father to have coffee with him and the journey of discovery started from there.
Starting Out Solo
Examples of the scalp scarring that occurs with aplasia cutis.
Marneros received institutional approval for the study, consented the family members, and collected blood and skin samples.
Since he is not a geneticist by trade, his first thought was to find collaborators within the Boston genetics community. However, potential collaborators were reluctant to join him if there was only one family to study.
“For a disease caused by a single gene mutation, you usually want to have several affected families to start out with," Marneros explains. "This increases the chances of finding the causative gene.”
Despite the high risk that this project may not result in success, Marneros decided to do the genetic analysis himself. His work over the next three years resulted in the identification of the first gene for aplasia cutis.
This discovery highlights the power of human genetics, as the mutation was in a gene that had previously not been implicated to have a role in the skin, revealing novel insights into skin formation.
To identify additional genes that can cause aplasia cutis, Marneros then focused then on a rare disorder called Scalp-Ear-Nipple syndrome, in which patients have aplasia cutis and lack nipples or breasts.
Identifying a second aplasia cutis gene by studying this patient population would help him uncover the precise cellular abnormalities that cause this skin condition.
This time, an international collaboration of researchers led to the identification of a new gene, called KCTD1, that causes aplasia cutis in this syndrome. The function of this gene was completely unknown at that time.
“We then had to question what to do with this discovery, because it is a completely novel gene, making it challenging to identify its functions,” Marneros says.
“Maybe it is important for skin development or formation, and could open up a new avenue of research in the lab.”
Investigating a Novel Gene
It took several years of work to generate knockout mice that lacked the KCTD1 gene, and Marneros was not sure what to expect when the mice were born.
He was hoping the newborn mice would have the telltale signs of aplasia cutis and/or absence of nipples. But other than being smaller than normal, the mice had normal skin and no visible scalp marks. While this was disappointing, Marneros wasn’t ready to give up yet.
“It’s important to keep your eyes open, look beyond the skin and be open to studying other organ systems."
Making the Connection to the Kidney
The KCTD1 knockout mice continued to be smaller than normal as they grew into adulthood.
This suggested to Marneros that there could potentially be kidney issue, as there are some kidney diseases that result in reduced postnatal growth.
He put the mice into metabolic cages to see if they would produce more urine than usual—an indication of kidney dysfunction.
When he came back the next morning, the urine collection tubes were overflowing, demonstrating that these mice were unable to concentrate their urine.
A detailed analysis of the kidneys of these KCTD1 knockout mice showed defects in the development of their distal nephron tubules, which play an important role in urinary concentration and salt reabsorption.
These defects also affected the main drug targets of our most common diuretics (medicines that reduce fluid buildup in the body). As the mice grew older, they developed all the symptoms of chronic kidney disease and renal fibrosis. They eventually died of kidney failure.
Marneros then reassessed the patients with Scalp-Ear-Nipple syndrome and found that they too died of kidney failure later in life. This established kidney abnormalities as part of the syndrome.
In experiments where the KCTD1 gene was inactivated in the kidneys of adult mice, the mice also developed kidney disease. This suggested that the gene was not only important in the formation of the kidneys, but in their continued functioning as well.
Suddenly, a project that started by investigating a rare skin disease that affects only a few families had pivoted into an investigation of a key element of kidney function that could impact millions of people with chronic kidney disease and kidney failure.
Following the Science
Further investigation of the function of KCTD1 in different cell types helped to solve some mysteries that Marneros encountered along the way.
His findings showed that the aplasia cutis skin defect is not the result of a lack of KCTD1 in keratinocytes (the starter cells for skin), which was a long-held belief in dermatology.
Instead, aplasia cutis was the consequence of a loss of KCTD1 function in neural crest cells, which play a key role in the proper formation of the midline cranial sutures of the skull.
He could show that these cranial suture cells normally express growth factors that induce the formation of the overlying scalp skin.
Loss of KCTD1 resulted in abnormal midline cranial sutures that impaired proper skin formation at that site. This explains why aplasia cutis only occurs at the site of these cranial sutures on the scalp and not elsewhere on the skin, solving a centuries-long medical enigma.
Marneros and his team also discovered that there is a protein that is very similar to KCTD1, called KCTD15, that can replace its function in the neural crest cells of KCTD1 knockout mice. This complementary protein is not found in the kidney cells that produce KCTD1, however.
This explains why the KCTD1 knockout mice did not have skin defects and aplasia cutis but did develop kidney abnormalities.
In humans with aplasia cutis, the mutation in the KCTD1 gene renders both KCTD1 and KCTD15 ineffective in the neural crest cells, which is why these individuals have scarring on the scalp.
The Journey Continues
While more research needs to be done before the findings can be translated into the clinic, the journey has opened up several new exciting avenues of discovery, both for kidney and skin diseases.
It has also been a confirmation of Marneros’ belief that researchers should follow the science wherever it takes them—even if that means stepping outside of their comfort zones and the fields they are normally working in.
“I think in science it should be encouraged to work between different specialties, although it is associated with a lot of risk career-wise,” he says.
“If you take the career path out of it and say, ‘I want to make a good contribution and I’m really curious about this,’ I think that can be very beneficial for science.”
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