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Phil Gutis, an Alzheimer's patient who participated in a failed clinical trial, poses with his dog Abe.

(Courtesy Gutis)


Phil Gutis never had a stellar memory, but when he reached his early 50s, it became a problem he could no longer ignore. He had trouble calculating how much to tip after a meal, finding things he had just put on his desk, and understanding simple driving directions.

From 1998-2017, industry sources reported 146 failed attempts at developing Alzheimer's drugs.

So three years ago, at age 54, he answered an ad for a drug trial seeking people experiencing memory issues. He scored so low in the memory testing he was told something was wrong. M.R.I.s and PET scans confirmed that he had early-onset Alzheimer's disease.

Gutis, who is a former New York Times reporter and American Civil Liberties Union spokesman, felt fortunate to get into an advanced clinical trial of a new treatment for Alzheimer's disease. The drug, called aducanumab, had shown promising results in earlier studies.

Four years of data had found that the drug effectively reduced the burden of protein fragments called beta-amyloids, which destroy connections between nerve cells. Amyloid plaques are found in the brains of patients with Alzheimer's disease and are associated with impairments in thinking and memory.

Gutis eagerly participated in the clinical trial and received 35 monthly infusions. "For the first 20 infusions, I did not know whether I was receiving the drug or the placebo," he says. "During the last 15 months, I received aducanumab. But it really didn't matter if I was receiving the drug or the placebo because on March 21, the trial was stopped because [the drug company] Biogen found that the treatments were ineffective."

The news was devastating to the trial participants, but also to the Alzheimer's research community. Earlier this year, another pharmaceutical company, Roche, announced it was discontinuing two of its Alzheimer's clinical trials. From 1998-2017, industry sources reported 146 failed attempts at developing Alzheimer's drugs. There are five prescription drugs approved to treat its symptoms, but a cure remains elusive. The latest failures have left researchers scratching their heads about how to approach attacking the disease.

The failure of aducanumab was also another setback for the estimated 5.8 million people who have Alzheimer's in the United States. Of these, around 5.6 million are older than 65 and 200,000 suffer from the younger-onset form, including Gutis.

Gutis is understandably distraught about the cancellation of the trial. "I really had hopes it would work. So did all the patients."

While drug companies have failed so far, another group is stepping up to expedite the development of a cure: venture philanthropists.

For now, he is exercising every day to keep his blood flowing, which is supposed to delay the progression of the disease, and trying to eat a low-fat diet. "But I know that none of it will make a difference. Alzheimer's is a progressive disease. There are no treatments to delay it, let alone cure it."

But while drug companies have failed so far, another group is stepping up to expedite the development of a cure: venture philanthropists. These are successful titans of industry and dedicated foundations who are donating large sums of money to fill a much-needed void – funding research to look for new biomarkers.

Biomarkers are neurochemical indicators that can be used to detect the presence of a disease and objectively measure its progression. There are currently no validated biomarkers for Alzheimer's, but researchers are actively studying promising candidates. The hope is that they will find a reliable way to identify the disease even before the symptoms of mental decline show up, so that treatments can be directed at a very early stage.

Howard Fillit, Founding Executive Director and Chief Science Officer of the Alzheimer's Drug Discovery Foundation, says, "We need novel biomarkers to diagnose Alzheimer's disease and related dementias. But pharmaceutical companies don't put money into biomarkers research."

One of the venture philanthropists who has recently stepped up to the task is Bill Gates. In January 2018, he announced his father had Alzheimer's disease in an interview on the Today Show with Maria Shriver, whose father Sargent Shriver, died of Alzheimer's disease in 2011. Gates told Ms. Shriver that he had invested $100 million into Alzheimer's research, with $50 million of his donation going to Dementia Discovery Fund, which looks for new cures and treatments.

That August, Gates joined other investors in a new fund called Diagnostics Accelerator. The project aims to supports researchers looking to speed up new ideas for earlier and better diagnosis of the disease.

Gates and other donors committed more than $35 million to help launch it, and this April, Jeff and Mackenzie Bezos joined the coalition, bringing the current program funding to nearly $50 million.

"It makes sense that a challenge this significant would draw the attention of some of the world's leading thinkers."

None of these funders stand to make a profit on their donation, unlike traditional research investments by drug companies. The standard alternatives to such funding have upsides -- and downsides.

As Bill Gates wrote on his blog, "Investments from governments or charitable organizations are fantastic at generating new ideas and cutting-edge research -- but they're not always great at creating usable products, since no one stands to make a profit at the end of the day.

"Venture capital, on the other end of the spectrum, is more likely to develop a test that will reach patients, but its financial model favors projects that will earn big returns for investors. Venture philanthropy splits the difference. It incentivizes a bold, risk-taking approach to research with an end goal of a real product for real patients. If any of the projects backed by Diagnostics Accelerator succeed, our share of the financial windfall goes right back into the fund."

Gutis said he is thankful for any attention given to finding a cure for Alzheimer's.

"Most doctors and scientists will tell you that we're still in the dark ages when it comes to fully understanding how the brain works, let alone figuring out the cause or treatment for Alzheimer's.

"It makes sense that a challenge this significant would draw the attention of some of the world's leading thinkers. I only hope they can be more successful with their entrepreneurial approach to finding a cure than the drug companies have been with their more traditional paths."

David Levine
David Levine is co-chairman of Science Writers in New York (SWINY) and is a member of the National Association of Science Writers (NASW) and the Association of Healthcare Journalists. He was director of media relations for the American Cancer Society and senior director of communications at the NYC Health and Hospitals Corp. He has written for Scientific American, the Los Angeles Times, The New York Times, Nature Medicine, the Smithsonian, More and Good Housekeeping, and was a contributing editor at Physician's Weekly for 10 years. He has a BA and MA from Johns Hopkins University.

Deep brain stimulation: This neurosurgical treatment involves the implantation of electrodes in the cerebral lobes of the brain, linked through the scalp (top) to wires (down right) leading to a battery implanted below the skin. This sends electrical impulses to specific areas of the brain. DBS was developed for the treatment of Parkinson's disease, but is being investigated for use in other conditions.

(© PASIEKA/Getty Images)


Imagine that you are one of the hundreds of millions of people who suffer from depression. Medication hasn't helped you, so you're looking for another treatment option. Something powerful enough to change your mood as soon as you need a lift.

"If a participant experiences a personality change, does this change who they are or dehumanize them by altering their nature?"

Enter deep brain stimulation: a type of therapy in which one or more electrodes are inserted into your brain and connected to a surgically implanted, battery-operated medical device in your chest. This device, which is approximately the size of a stopwatch, sends electric pulses to a targeted region of your brain. The idea is to control a variety of neurological symptoms that can't be adequately managed by drugs.

Over the last twenty years, deep brain stimulation, known as DBS, has become an efficient and safe alternative for the treatment of chronic neurological diseases such as epilepsy, Parkinson's disease and neuropathic pain. According to the International Neuromodulation Society, there have been more than 80,000 deep brain stimulation implants performed around the world.

The Food and Drug Administration approved DBS as a treatment for essential tremor and Parkinson's in 1997, dystonia in 2003 and obsessive compulsive disorder in 2009. Since doctors can use drugs and treatments "off-label" (not approved by the FDA) to treat patients with any disease, DBS is now also being investigated as a treatment for chronic pain, PTSD and major depression.

And these new applications are raising profound ethical questions about individuality, personality, and even what it means to be human.

"These patients are essentially having a computer that can modify and influence emotional processing, mood and motor outputs inserted into the brain," said Gabriel Lazaro-Munoz, an assistant professor at The Center for Medical Ethics and Health Policy at Baylor College of Medicine. "These responses define us as human beings and dictate our autonomy. If a participant experiences a personality change, does this change who they are or dehumanize them by altering their nature? These are some of the questions we have to consider."

"When we are not in control of ourselves, are we ourselves?"

The U.S. government has similar concerns about DBS. The National Institutes of Health recently awarded grants to study the neuroethical issues surrounding the use of DBS in neuropsychiatric and movement disorders and appropriate consent for brain research. The grants are part of the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative. Walter Koroshetz, director of NIH's National Institute of Neurological Disorders and Stroke said, "Neuroscience is rapidly moving toward a new frontier of research on human brains that may have long-lasting and unforeseen effects. These new awards signal our commitment to research conducted in a responsible way as to anticipate all potential consequences, and to ensure that research subjects have a clear understanding of the potential benefits and risks of participating in studies."

Dr. Lazaro-Munoz's Center was awarded one of the grants to identify and evaluate the ethical, legal and social concerns with adaptive deep brain stimulation (aDBS) technologies. Adaptive DBS is a relatively new version of the technology that enables recording of brain cell activity that is then used to regulate the brain in real time. He and his team will closely observe researchers conducting aDBS studies and administering in-depth interviews to trial participants, their caregivers, and researchers, as well as individuals who declined to participate in such studies. The goal is to gain a better understanding of the ethical concerns at stake in order to guide responsible research.

Dr. Lazaro-Munoz said one of the concerns is dehumanization. "By using this technology are we compromising what makes us human? When we are not in control of ourselves, are we ourselves?" He notes that similar concerns were raised about pharmaceutical treatments for illnesses. "Both change behaviors and emotional processing. However, there is a difference. Culturally we are more used to using drugs, not implanting devices into brain and computer interfaces. Many people think of it as science fiction."

The changes in behavior due to DBS can be dramatic, perhaps none more so than with Parkinson's disease; patients may see their chronic tremors suddenly vanish.

Pills for OCD and depression take longer than DBS to see significant improvement, sometimes months. "A DBS device is either on or off. And patients and families see changes immediately," Dr. Lazaro-Munoz said. "Family members are often startled by these changes, as are the patients." He's observed that patients feel more in control with pills because they can alter and "play" with the dose or even skip a dose.

The changes in behavior due to DBS can be dramatic, perhaps none more so than with Parkinson's disease; patients may see their chronic tremors suddenly vanish, like in this must-see video.

But surgical procedures to treat motor symptoms are also increasingly being implicated as a cause of behavioral changes, both positive and negative, in patients with Parkinson's. The personality changes reported in patients who undergo DBS include hypermania, pathological gambling, hypersexuality, impulsivity and aggressiveness. One patient who suffered from OCD fell in love with the music of Johnny Cash when his brain was stimulated. On the positive side, patients report memory enhancement.

One patient who is pleased with DBS is Greg Barstead, who was diagnosed with Parkinson's in 2003, when he was the president of Colonial Penn Life Insurance Company. He also has dystonia, which affects his neck and shoulders. Barstead said that DBS has been helpful for a range of symptoms: "My shoulder is a lot less stiff and my neck hurts less. And my tremors are under control. It is not perfect, as it doesn't relieve all the Parkinson's symptoms, but it does enough of a good job that both my wife and I are very happy I had DBS."

"We are not exactly sure what part of the brain causes depression. Doctors have not identified where to implant the device."

He said he hasn't noticed any personality changes, but noted that the disease itself can cause such changes. In fact, studies have shown that it can cause many psychiatric problems including depression and hallucinations. And, approximately a third of Parkinson's patients develop dementia.

Arthur L. Caplan, founding head of the Division of Medical Ethics at NYU School of Medicine, notes that unlike psychosurgery, DBS can be turned on and off and the device can be removed. "There are less ethical concerns around treating patients with Parkinson's disease than other illnesses because surgeons know exactly where to implant the device and have many years of experience with it," he said, adding that he is concerned about using DBS for other illnesses, such as depression. "We are not exactly sure what part of the brain causes depression. Doctors have not identified where to implant the device. And I would certainly not advocate its use in patients with mild depression."

Dr. Lazaro-Munoz said of the personality changes possible with DBS, physicians need to consider how the patients were functioning without it. "Patients who are candidates for DBS typically used many medications as well as psychotherapy before opting for DBS," he explained. "To me, the question is what is the net result of using this technology? Does the patient have regrets? Are the changes in personality significant or not? Although most DBS patients report being happy they underwent the procedure, some say they don't feel like themselves after DBS. Others feel they are more like themselves, especially if there are dramatic improvements in movement problems or relief of OCD symptoms."

And then there is the question of money. The costs of DBS are covered by most insurance companies and Medicare only for FDA-approved targets like Parkinson's. Off-label uses are not covered, at least for now.

Caplan reminds people that DBS devices are manufactured by companies that are interested in making money and the average cost per treatment is around $50,000. "I am interested in seeing DBS move forward," he said. "But we must be careful and not allow industry to make it go too fast, or be used on too many people, before we know it is effective."

David Levine
David Levine is co-chairman of Science Writers in New York (SWINY) and is a member of the National Association of Science Writers (NASW) and the Association of Healthcare Journalists. He was director of media relations for the American Cancer Society and senior director of communications at the NYC Health and Hospitals Corp. He has written for Scientific American, the Los Angeles Times, The New York Times, Nature Medicine, the Smithsonian, More and Good Housekeeping, and was a contributing editor at Physician's Weekly for 10 years. He has a BA and MA from Johns Hopkins University.